The following module was designed to supplement medical student’s learning in the clinic. Please take the time to read through each module by clicking the headings below. Information on epidemiology, screening & testing, classification, signs & symptoms, diagnosis, radiology, pathology, staging, management and treatment of lung cancer is provided.

By the end of the tutorial, the following objectives should be addressed:

1. Describe the general progression of lung cancer.
2. Know the common risk factors for lung cancer.
3. Understand which risk factors are modifiable.
4. Define cancer screening.
5. Understand the current recommendations for lung cancer screening in Canada.
6. Describe the differences between small cell and non small cell lung cancer.
7. List the variants of non small cell lung cancer.
8. Describe the histological features of small cell lung cancer.
9. Describe the common signs and symptoms of lung cancer.
10. Understand the common areas of metastasis.
11. Define paraneoplastic syndrome.
12. Understand the general approach to lung cancer diagnosis.
13. Understand the imaging techniques used in lung cancer diagnosis.
14. Know the common radiologic tests used for evaluating lung cancer.
15. Know the different biopsy techniques for lung cancer.
16. Understand some of the advantages and disadvantages of the different techniques.
17. Understand the general TNM staging for NSCLC.
18. Know the general classification for SCLC.
19. Understand the two forms of lung cancer treatment.
20. Describe the importance of patient, tumour, and treatment factors in cancer management.
21. Describe the three modalities used in lung cancer treatment.
22. Describe some indications, advantages, and disadvantages of the varying treatment modalities.

Carcinogenesis is generally considered to be a process of three steps: initiation, promotion and progression. Initiation is defined as genetic damage that is irreversible but non-lethal to the cell. Promotion is the clonal expansion of an affected cell resulting in excessive growth. Progression occurs when the tumour has grown to the point of invasion and metastasis.

There are numerous factors that can cause development of lung cancer. Cigarette smoking is the most important risk factor, being associated with causation in up to 90% of cases. Non-modifiable risk factors for lung cancer include gender, age, and race. Lifestyle factors such as occupational exposures, diet, and low physical activity are also associated with lung cancer risk.

Risk Factors for Development of Lung Cancer

Known risk factors [4]:

• Tobacco smoking
• Second hand smoke
• Radon
• Asbestos
• Occupational exposure to certain chemicals
• Outdoor air pollution
• Personal or family history of lung cancer
• Personal history of lung disease:  specific lung diseases that scar the lungs can increase the risk of developing cancer including COPD, tuberculosis and certain infections
• Exposure to radiation
• Arsenic in drinking water
• Pollutants from cooking and heating: burning coal indoors, burning wood or other fuels, frying foods in oil at high temperatures
• Weakened immune system
• Lupus
• Beta carotene supplements in smokers

Possible Risk Factors

• Occupational exposures to certain chemicals
• Genetic mutations: some families have very strong histories of lung cancer which suggests particular genetic mutations may carry an increased risk
• Smoking cannabis: some studies show long term cannabis smoking can increase the risk of lung cancer but the evidence is not yet as robust as for tobacco
• Physical inactivity
• Diet low in fruit and vegetables

Cigarette Smoking

The number one modifiable risk factor for lung cancer is cigarette smoking. There are more than 300 chemicals in one cigarette, 60 of which are known carcinogens. Commonly cited cigarette carcinogens are nitrosamines (eg. NNK) and poly aromatic hydrocarbons (PAH) which cause the formation of DNA adducts (ie. DNA and cancer-causing agents bound together). Such DNA disturbances can cause mutations within tumour suppressor genes, interrupting repair and cell cycle regulation mechanisms.

The duration, intensity and age of onset of smoking influence the risk of lung cancer. For patients with similar pack year histories, longer duration of smoking puts one at greater risk of cancer compared with a higher intensity of smoking. Smoking cessation lowers the risk of lung cancer and should always be recommended. Modern cigarette formulations do not reduce the risk of developing lung cancer but in fact appear to increase the risk of adenocarcinoma.

Genetics

Genetics are believed to play a role in the development of lung cancer. A family history of lung cancer has been associated with a 1.7 fold increase in the risk of lung cancer development. Genome wide association studies have associated multiple chromosomal regions with increased lung cancer risk [5].

Occupational/Environmental Exposure

Some of the identified occupational/environmental carcinogens are asbestos, metals, radon, and organic compounds like PAHs, diesel fumes and air pollution. Patients who have previously received ionizing radiation (e.g. previously treated breast cancer patients) are also at increased risk for developing lung cancer. Typically, there is a dose-response curve in terms of whether or not a person exposed to these hazards will develop lung cancer, with substantial exposure leading to higher risk.

Diet

Data surrounding the role of diet as a factor influencing lung cancer risk is controversial. Several studies have suggested that increased intake of fruit and vegetables may reduce the risk of developing lung cancer [4].

Cannabis Smoking

The effect of smoking cannabis on lung cancer risk is currently unclear [5]. The combustion of organic material while smoking cannabis does produce carcinogens, and the concentration of tar and PAHs is higher in cannabis compared with tobacco. Although epidemiologic studies have failed to show a strong correlation between smoking cannabis and lung cancer several case control studies have shown increased risk [5]. Further research is required to delineate the relationship between smoking cannabis and developing lung cancer.

Summary

Initiation, promotion, and progression are the three main steps involved in the progression of lung cancer. Cigarette smoking is the number one risk factor for lung cancer. Genetics may play a role in lung cancer risk, however, specific mechanisms are not known and are currently being investigated. Occupational and environmental exposures are also risk factors for developing lung cancer.

In Canada, lung cancer causes the most deaths of all types of cancers. Lung cancer is frequently diagnosed in advanced stages which partially contributes to the low five year survival rates. There have been significant efforts to establish an approach to screen for lung cancer in order to diagnose at earlier stages where treatment would be more effective.

The National Lung Screening trial was a study in which participants were screened with either low-dose CT or chest x ray. This trial showed a 20% decrease in mortality from lung cancer in patients screened with low dose CT compared to chest x ray [3]. The Canadian Preventative Task Force guidelines published in 2016 recommend use of low dose CT for lung cancer screening only in patients with at least a 30 pack year history, who are current smokers or quit within the past 15 years and are between 55 and 74 years old [4]. In this population there is a weak recommendation based on low quality evidence for yearly screening for up to three consecutive years. As this screening protocol is likely to result in a significant number of false positives and overdiagnosis, risks and benefits of screening should be discussed with patients to facilitate shared decision making.

There are currently no territorial or provincial screening programs available for lung cancer. In order for lung cancer screening to be effective it requires expertise in interpretation of screening tests, in resources for further testing to make a diagnosis and in availability of treatment and support for patients. Prior to adoption of a screening program at the provincial level infrastructure will need to be developed throughout the province to support this initiative [5].

*FOR MORE INFORMATION SEE: LUNG CANCER SCREENING WITH LDCT

Summary

Screening is used to detect cancer in asymptomatic individuals. The Canadian Preventative Task Force recommends use of low dose CT for lung cancer screening in patients with at least a 30 pack year history, who are current smokers or quit within the past 15 years and are between 55 and 74 years old.

The first consideration in management of lung cancer patients is determining the type and stage of their lung cancer. The main division is between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for the majority of lung cancers (85-90%) and is further divided into sub-categories, including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. SCLC is also called oat cell carcinoma and accounts for the remaining 10-15% of lung cancers.

SCLC and NSCLC categories of cancers typically behave differently, and as a result treatment options and management also differ. NSCLCs can all generally be treated in the same way and so are grouped together. SCLC is generally more aggressive, growing and metastasizing rapidly compared to NSCLC. To differentiate between the various types of lung cancer, a tissue biopsy must be performed and evaluated by a pathologist to identify the type of cancerous cells present.

Occasionally tumours will have features of both SCLC and NSCLC and are referred to as “mixed” tumours.

TABLE 1: COMPARISON OF SMALL CELL AND NON-SMALL CELL LUNG CANCER

It should be kept in mind that tumours in the lung are not necessarily primary tumours that arose originally in lung tissue. Bone, breast, colon, skin, and testicular cancer are the common tumours that metastasize to the lung. However, almost any tumour can metastasize to the lungs through hematogenous spread [1].

Within the NSCLC category, there are three main subtypes of lung cancer: squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma. Bronchoalveolar carcinoma is a variant of adenocarcinoma that behaves differently than other adenocarcinomas.

TABLE 2: COMPARISON OF NON-SMALL CELL LUNG CANCER SUBTYPES

Features of SCLC

Small Cell Carcinoma:

• Accounts for about 10-15% of lung cancers
• Characterized by small, round and blue cells (on histologic staining) that are approximately twice the size of lymphocytes
• Lesions usually centrally located
• Aggressive tumour that spreads quickly to distant sites (often distant metastases present at time of diagnosis)
• More responsive than NSCLC to chemotherapy and radiotherapy BUT prognosis still poor.

Summary

Lung cancer can be divided into small cell (SCLC) and non small cell lung cancer (NSCLC). More than 85% are NSCLC which can be further divided into squamous cell, large cell, adenocarcinoma, and bronchoalveolar carcinoma. SCLC is more aggressive and divided into limited & extensive stage disease while NSCLC is less aggressive and staged using the TNM system.

Early stage lung cancer is generally asymptomatic while at later stages patients may present with signs and symptoms. Many of the signs and symptoms of lung cancer are also seen in other lung conditions or are non specific such as weight loss, anorexia, fatigue and night sweats. The variety of presentations depends on the type of lung cancer, location and size of the tumour, and presence of distant metastases.

Symptoms of lung cancer can vary depending on the extent of disease spread. If the tumour is confined to the thorax, symptoms will arise from local tumour effects, while metastatic disease will result in symptoms arising from other organs of the body. Paraneoplastic effects cause systemic illness secondary to substances released by cancer cells. Lung cancer may also be discovered incidentally on a chest x-ray or CT chest scan.

As a final note, lung cancer is not typically diagnosed in asymptomatic patients, but there are new guidelines suggesting low dose CT scan may serve as an appropriate screening tool in certain high risk populations.

Local Symptoms

Cough

The most common symptom of lung cancer is a new or worsening cough. New onset of cough in a smoker or former smoker should raise the suspicion of lung cancer.

Hemoptysis

Coughing up blood is worrisome for lung cancer.

Dyspnea

Patients often present with shortness of breath. Dyspnea can occur due to mass effects of the tumour pressing on the bronchi or trachea, or it can develop when the tumour induces fluid to flow in around the lungs, heart, or chest cavity.

Wheeze

This symptom may be heard with or without auscultation if the tumour is pressing on the lumen of the airways.

Chest Pain

Pain can develop depending on where the tumour is located. If there is invasion outside of the lung parenchyma (eg. into the pleura, ribs, and/or chest wall), pain may be present. Chest pain can also be present if the tumour or involved lymph nodes are large enough to press on surrounding structures.

Hoarseness of Voice

This symptom arises when the tumour compresses the recurrent laryngeal nerve around the trachea that innervates the vocal cords.

Headache, Swelling of Face, Arms and/or Neck

The great vessels entering/exiting the chest can be compressed by a tumour if it is at the right location or has grown large enough to exert mass effects. Compression of blood vessels carrying venous return to the heart can cause distension and fluid backup resulting in swelling into the regions drained by the superior vena cava.

Arm, Shoulder and/or Neck Pain

If a tumour is located at the apex of the lung, the nerves in this area may be compressed. Pancoast tumours (or superior sulcus tumour) can cause compression of the sympathetic plexus causing ipsilateral Horner’s syndrome characterized by miosis, ptosis, and anhydrosis. Progression of this type of tumour can lead to the involvement of the brachial plexus, causing arm and hand weakness.

Metastatic Cancer

The most common sites of metastasis for lung cancer are the bones, liver, brain, and adrenal glands. The workup for metastases should involve investigations for all of these commonly affected sites.

Bone metastases can present as localized bone pain or as a non-traumatic fracture due to bone weakness. The bones most commonly affected are the spine, ribs, and pelvis. Jaundice, weakness, and weight loss may indicate liver metastases. Brain metastases have a wide-range of presenting features, from confusion, headache, nausea and vomiting to personality changes and seizures.

Paraneoplastic Signs and Symptoms

Paraneoplastic symptoms and signs are caused by the release of substances by the tumour rather than by direct tumour effects [2]. Symptoms are a result of hormonal or electrolyte alterations. Examples of hormonal and electrolyte abnormalities include: hypercalcemia (weakness, fatigue, nausea and vomiting, confusion), syndrome of inappropriate ADH (muscle weakness and cramping, restlessness, confusion, fatigue, nausea and vomiting), Cushing syndrome (hypertension, hyperglycemia, round face, muscle weakness, striae), and Lambert Eaton syndrome (muscle weakness, loss of movement).

Summary of Signs & Symptoms

• Cough
• Shortness of Breath
• Wheeze
• Chest Pain
• Hoarseness of Voice
• Headache
• Swelling of face, arms and/or neck
• Arm, shoulder and/or neck pain
• Fever
• Night sweats
• Weight loss
• Decreased appetite

Summary

Lung cancer can present with numerous respiratory and constitutional symptoms that should be asked about when taking a history. Asymptomatic individuals are not commonly diagnosed as there is currently no screening test widely implemented. The most common sites of metastasis are brain, bone, liver, and adrenal glands. Paraneoplastic syndromes are those that are caused indirectly by the cancer and not based on the localized tumour cells.

History

The following are important aspects of a history for suspected lung cancer:

• history of presenting complaint (onset, duration, alleviating/aggravating factors, associated symptoms, etc.)
• Complete medical history, including discussion of co-morbid illnesses
• Risk factor assessment including family history of lung cancer and potential occupational, environmental and lifestyle exposures.
• To rule out other causes, questions about travel history and contacts who are having similar symptoms may be useful.
• A thorough review of systems should also be conducted to determine if there are any symptoms indicative of metastases or a paraneoplastic syndrome.

Physical Examination

A physical exam should be done to find clinical signs of lung cancer. A focused respiratory exam would be appropriate, with emphasis on palpation of lymph nodes, especially in the supraclavicular and cervical regions. Extra-respiratory physical findings should also be assessed such as weight loss or bony pain secondary to metastases. Absence of clinically significant findings does NOT rule out the diagnosis of lung cancer.

Laboratory Investigations

Lab investigations such as a complete blood count can be used to look for signs of lung cancer including anemia, leukocytosis, thrombocytosis or hypercoagulable disorders. Blood tests can also be indicative of metastasis such as elevated calcium, phosphate and ALP with bone metastasis or elevated liver enzymes with liver involvement.

Imaging

The next step in the workup for a patient with suspected lung cancer is to have a chest x-ray performed. A chest CT is often done at the same time. Depending on the results from these imaging studies, further investigations can be done. The diagnosis of lung cancer can only be definitively confirmed by a tissue biopsy. Possible techniques used to obtain such a sample are described in the pathology section.

If there is a mass seen on the CT, the family doctor will be notified through the radiology report. At this point, a referral to respirology or a thoracic surgeon for a biopsy would be appropriate.

Appropriate staging investigations should be undertaken based on the common locations for lung cancer metastases and presence of symptoms.  Contrast enhanced CT of the chest and upper abdomen including the liver and adrenal glands is appropriate for most patients suspected of having lung cancer. Further imaging may be conducted based on clinical suspicion of metastasis secondary to symptoms or focal findings, or because of extensive disease on initial imaging. A PET scan or MRI may be ordered by a specialist to further characterize the cancer and burden of disease. For example, an MRI may be used to assess a Pancoast tumour and a PET scan may be used to look for nodal or distant metastases to determine appropriate treatment options for non-small cell lung cancer.

Summary

Lung cancer diagnosis is done by complete history, physical examination, and relevant tests. Imaging tests include X-ray and CT scan with confirmation by biopsy. Staging investigations will vary depending on the extent and type of disease and may include CT, PET scan, and/or MRI.

Imaging of the chest is important both for identifying the presence of a primary lung tumour as well as evaluating lymph node status. Staging of the tumour involves assessment of nodal involvement, and staging is important as it directs treatment.

TABLE 1: LUNG CANCER WORKUP TESTS

Both posterior-anterior (PA) and lateral view x-rays of the chest should be done. Peripheral lesions or large central obstructing lesions will be easily visible on a chest x-ray (CXR). However, having a normal CXR does not rule out the possibility of having a primary lung tumour because small tumours may be obscured by the radio-opaque nature of the mediastinal structures.

CT scans of the chest and upper abdomen should also be obtained because it has a higher sensitivity (60%) and specificity (80%) than chest x-rays for detecting primary lung cancers. In terms of diagnostic accuracy, higher-resolution techniques can be employed, increasing the sensitivity and specificity to 85% and 100%, respectively, for detecting the primary tumour. A limitation of CT scans is that they do not reliably detect mediastinal lymph node metastases. Enlarged lymph nodes causing symptoms through mass effect can be histologically benign while other smaller lymph nodes (< 1cm) can contain malignant cells. CT can provide information about tumour size, presence or absence of separate tumour nodules, presence or absence of atelectasis or obstructive pneumonia, invasion of adjacent structures, and proximal extent of the tumour which are important for staging of the tumour. Identification of sites of involvement can help to select the optimal site for biopsy to confirm the diagnosis.

To search for lymphatic spread, patients can undergo fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in order to detect areas of higher metabolic activity, consistent with cancer. FDG-PET is best for detecting N1 nodes but only moderately capable of detecting N2 nodes. However, the negative predictive value (NPV) of not detecting “hot spots” is 90%. FDG-PET interpretation can be confounded in two ways. Other lung disease (eg. granulomatous inflammation, silicosis and sinus histiocytosis) can manifest high metabolic activity on these scans resulting in false positives. Or, tumours can be slow-growing (eg. bronchoalveolar carcinoma) resulting in a false negative. Hypermetabolic inflammatory lymph nodes may result in false positive on PET scans and thus require biopsy to confirm the presence of nodal metastases [3].

To take advantage of the benefits of both CT and FDG-PET, these scans can be used in combination. The sensitivity is 80%, specificity is 85%, and accuracy is 90% for the integration of these two techniques.

Magnetic resonance imaging (MRI) is not generally helpful in making the diagnosis of lung cancer, but is useful for detecting the extent of invasion into the chest wall, spine, nerves, soft-tissues, brain or blood vessels. It is most often used when symptoms or previous imaging indicate possible involvement of one of these structures.

Bone scan is used when patients have symptoms, signs, laboratory or imaging findings suggestive of bony metastases. However, FDG-PET is often used instead of bone scan for identification of bony metastases as it has better specificity and can also identify metastases to other organs.

A new, less invasive technique for investigating lymph nodes, is endoscopic ultrasound (EUS) guided fine needle aspiration of mediastinal lymph nodes. Results are promising as EUS seems able to identify more of the mediastinal lymph nodes that contain malignant cells than either CT or FDG-PET[1].

While imaging technology is constantly improving and evolving, definitive diagnosis of lung cancer still depends on obtaining a tissue sample and getting histological confirmation.

Summary

Chest x-ray and CT scan of the chest are always used for evaluating lung cancer. PET scans may be used to assess lymph node involvement and search for metastases. MRI can also be used to assess local spread and distant metastasis.

Tissue biopsy of the tumour is required in order to make the diagnosis of lung cancer. This sample can be obtained through various techniques.

TABLE 1: PATHOLOGY SPECIMEN SAMPLING TECHNIQUE COMPARISON

Summary

Sputum samples, bronchoscopy, thorascopy, thoracotomy, mediastinoscopy, and FNA may all be used to biopsy lung cancer tissue for pathologic examination. A biopsy is needed to make a definitive diagnosis of lung cancer.

TNM Staging in Lung Cancer

Utilizing a universal staging practice for lung cancer is beneficial for use in determining treatment regimes, informing prognosis, and for selection of patients for research studies (3). It allows physicians and other health care workers to know how much cancer is present and where it is located (ie. how advanced the disease is) which influences management. It also allows health care professionals to communicate effectively with each other using a universal language to delineate the progression of a patient’s disease.

The TNM staging system includes assessment of tumour size (T), involvement of lymph nodes (N) and presence of metastases (M). The T component of the staging system represents the primary tumour with size being a significant component determining T status. The T designation is also influenced by the relationship of the tumour with the airway, invasion into surrounding structures and presence of multiple nodules in the lung. The N component of staging represents the nodal status. The N designation is influenced by the location of nodes involved with N1 representing hilar lymph nodes and N2 representing mediastinal lymph nodes. The M designation represents metastases. A TX, NX or MX indicates that the tumour, nodal, or metastatic state is unknown.

The three components of the staging system together determine the ultimate summary stage of the cancer. It is important that patients have a thorough work up assessing the tumour, lymph node involvement and presence of metastases so that the cancer can be accurately staged. Presence of a metastasis is always considered stage IV disease. The different summary stages were developed based on prognosis [3].

A chest CT is used to characterize the primary tumour, an abdominal CT searches for metastases in common sites such as liver and adrenal glands, and EUS biopsy may be undertaken to investigate nodal involvement. Laboratory evidence or signs and symptoms can also indicate the presence of bone, liver or brain metastases. Further imaging in search of metastases can be undertaken if any focal symptoms are reported. The more advanced FDG-PET scan may be ordered by the physician who will be treating the patient, whether that is a thoracic surgeon, medical oncologist, and/or radiation oncologist. FDG-PET can be used to find “hot spots” or potential metastatic tumours and lymph nodes. Knowing how advanced the patient’s disease is and the prognosis changes how the patient will be managed.

Staging varies between NSCLC and SCLC.

Non-Small Cell Lung Cancer

• Staged using the TNM staging system
• Stage 0 = cancer cells have been found in the lining of the lungs (ie. the respiratory epithelium) but there is no evidence of disease within the lung parenchyma. This stage is also know as “carcinoma in situ”.
• Stage I = cancer in its earliest stage of local disease, primary tumour less than or equal to 4cm, limited to one lung with no nodal or distant metastases
• Stage II = tumour less than or equal to 5cm or with spread to ipsilateral intraparenchymal or hilar nodes
• Stage III = cancer has spread past its surrounding membranes (ie. to the chest wall or diaphragm) but not outside the chest, and/or to the mediastinum and/or mediastinal lymph nodes (eg. heart, blood vessels, trachea, esophagus)
• Stage IV = cancer has spread to the contralateral lung and/or to a distant site (metastasis)
• For a more detailed description, see table below provided for reference

Table 1: T Staging of NSCLC

‍

Table 2: N Staging of NSCLC

Table 3: M Staging of NSCLC

Table 4: Prognostic Staging of NSCLC

Small Cell Lung Cancer

We have traditionally staged small cell lung cancer as limited or extensive disease based on the ability to treat small cell lung cancer within a single radiation treatment field, “radioencompassable”.

• Limited disease = cancer is only present in one side of the chest in a “radioencompassable volume”
• Extensive disease = cancer is present bilaterally in the chest, there is a pleural effusion, and/or there are distant metastases

Summary

The TNM staging system has been recently updated and is used for classifying non small cell lung cancer. As the cancer spreads into the central lung and mediastinum, the T stage increases. Hilar lymph nodes are N1 and mediastinal lymph nodes are N2. M1 indicates distant metastasis. Small cell lung cancer is classified as limited stage, where the cancer is radioencompassable and limited to one lung, while extensive stage indicates distant metastasis or bilateral lung involvement.

There are three main modalities used for curative and/or palliative treatment in lung cancer: surgery, radiation and systemic therapies (chemotherapy, immunotherapy, targeted therapies). The choice of modality or combination of modalities depends on a number of factors including patient and tumour factors.

The main intents of treatment are cure or palliation (symptom control). Adjuvant treatment is given in addition to the primary treatment in order to decrease the chance of recurrence. Neoadjuvant treatment is used before the primary treatment.

Treatment: Non-Small Cell Lung Cancer

Surgery

Surgery serves two main purposes in the treatment of NSCLC: to completely remove a tumour with the aim for cure, or to reduce symptoms for palliative treatment [2]. Prior to surgery it must be determined if the cancer is resectable, which is based on size, location and spread of the cancer. It must also be determined if the patient is an operable candidate: if they are healthy enough to proceed with surgery.

Patients with early stage NSCLC are appropriate candidates for consideration of surgical resection of the tumour. Surgery is appropriate for patients with tumours that can be completely resected, and are in a location suitable for resection. Surgical resection is indicated when the disease has not spread beyond one lung, the tumour is small enough to ensure resection will be feasible, there is limited spread to local lymph nodes, and patient and other tumour factors are favourable. Lymph node dissection is performed for ipsilateral nodes during surgery to look for nodal involvement of the cancer as adjuvant chemotherapy is indicated when there is nodal involvement[3]. Surgical resection is not considered a curative treatment approach for patients with metastases; however it is occasionally used for palliation in removal of metastatic lesions causing symptoms.  

The most common method of surgery is through thoracotomy [2]. Anterior limited thoracotomy is a less invasive procedure that can be done instead of thoractomy and uses only a small opening through the front of the chest. Video-assisted thoracoscopic surgery (VATS) is used instead of conventional surgery in patients who will not be able to tolerate a thoracotomy or have poor pulmonary reserve as measured on pulmonary function tests (PFTs). Some advantages include decreased postoperative pain, better preservation of pulmonary function, and shorter recovery time.

A lobectomy is the most common surgery for lung cancer [3]. For very small, early lung cancers, or for patients unable to tolerate removal of a lobe due to reduced lung function segmentectomy or wedge resection can be considered. A pneumonectomy can be considered for larger, more extensive tumours but there is increased morbidity and mortality. Extended pulmonary resection may be used for tumours which have spread to nerves, blood vessels or other tissues surrounding the lungs. A sleeve resection is used to remove cancer in the bronchus. A chest wall resection may be required for tumours that have spread to the bones, muscles or other tissues of the chest.

Preoperative factors to assess include the presence of postoperative morbidity and mortality (M&M) risks such as cardiovascular disease, the extent of resection and the patient’s recovery ability.

Pulmonary function tests (PFTs) are usually done to assess lung reserve. A forced expiratory volume (FEV1) of greater than or equal to 1.2 and a diffusing capacity of the lung for CO (DLCO) of greater than 60% predicted are all indicators of a good outcome post-surgery.

For both stage I and stage II disease, surgery is the modality of choice and gold-standard in treatment. For stage I disease, there are 5-year survival rates of up to 60%. For stage II tumours, the 5-year survival rates are typically around 30%, but surgery remains the recommended course of action [2]. For some stage III tumours, resection may be possible and this should be assessed on an individual basis; unfortunately despite resection, many of these patients have recurrence. Variability within Stage III cancer makes it difficult to state definitive treatment options. Surgery is not indicated for patients with Stage IV disease because survival benefits have not been demonstrated. Other modalities can be used for palliative treatment.

The surgical procedure carried out for Stage I disease is typically a lobectomy or complete resection of the affected lung lobe.

Stage II disease is usually treated by surgical resection by lobectomy however, more extensive procedures may be required depending on the spread of the tumour. Stage IIIA disease is often treated with a more extensive surgery after chemoradiation given that the tumour responded well to chemoradiation and the patient is fit for surgery. Stage IIIB patients do not usually receive surgery as chemotherapy and radiation therapy are the treatment modalities of choice.

Lymph Node Assessment

Lymph node systematic sampling involves routine sampling of lymph nodes at predetermined nodal sites (eg. superior mediastinum, aorta, inferior mediastinum). A complete mediastinal lymph node resection involves the removal of all lymph node tissue at sites specified by the surgeon. Lymph node sampling should always be done at the time of surgery to determine the need for adjuvant chemotherapy.

Radiotherapy

Radiation acts to kill cancer cells by causing DNA damage. Although normal cells are also damaged by radiation, they are believed to have better repair capabilities/mechanisms that permit quicker recovery. Radiation therapy (RT) is used in treating cancer to improve local tumour control, to increase possibility of cure (eg. as adjuvant treatment after surgical resection) and for palliative care (eg. improve symptoms and quality of life).

The therapeutic ratio is based on how much damage the normal surrounding tissue can sustain compared to the damage the radiotherapy is supposed to inflict upon the cancerous cells. The dose and fractionation schedules (ie. dividing the total dose over a set number of days) are determined by radiation oncologists in conjunction with technologists. Computer programs are used to help determine the location (radiation fields), dosages, and schedules by the members of the radiation oncology team, including physicists and dosimetrists.

The two main delivery methods of RT are external beam radiation therapy and brachytherapy. External beam radiation therapy refers to the projection of radiation to the tumour from a source outside the body. Brachytherapy refers to the insertion of radioactive sources into the body next to the tumour to closely irradiate the cancer cells.

Radiation therapy can be used at all stages of lung cancer, whether it is the first-line, curative, adjuvant, or palliative treatment. RT is a first-line treatment for patients who are deemed inoperable despite having stage I and II disease (eg. due to age). This may or may not be given in combination with chemotherapy depending on the situation [3]. The five-year survival rates for patients receiving RT are around 20-25% for T1 disease and 15% for T2 disease.

RT and chemotherapy is the current “gold-standard” treatment for patients with stage III disease. For stage IIIB disease, combined modality chemotherapy and RT can be considered to be curative therapy. Even if the cancerous cells can be encompassed within a reasonable radiation volume, chemotherapy should be added in order to improve the outcome.

RT is sometimes given pre-operatively with the goal of shrinking the tumour, making it easier to resect. Pre-operative RT has been shown to be advantageous for patients with Pancoast syndromes.

RT may also be used as an adjuvant treatment. In patients with T3 disease and incomplete resection, radiation has been shown to improve survival rates.

Radiotherapy is often used for palliation in more advanced NSCLC to improve symptoms. Endobronchial brachytherapy has been shown to help with symptom palliation for symptoms such as dyspnea, cough and hemoptysis although there is a risk of side effects such as bronchoesophageal fistulas. RT is also used for patients at risk for disease progression (eg. prophylaxis for superior vena cava syndrome).

External beam whole brain radiation therapy (WBRT) is used for those patients who have evidence of brain metastases to reduce the size of metastases with the hope of improving symptom control [2]. RT is also used for bone metastases with the goals of decreasing pain, increasing mobility and preventing pathologic fractures.

Chemotherapy

Most patients with NSCLC will receive chemotherapy. Chemotherapy may be used for any of the following (4):

• To shrink a tumour prior to surgery or radiation
• To kill cancer cells that were not removed during surgery to reduce the risk of recurrence
• As the primary treatment for those unable to have surgery
• To relieve pain of advanced cancer
• As maintenance therapy in those with advanced cancer that is responsive to chemotherapy

Chemotherapy has been used in the treatment of NSCLC for several decades. Treatment most commonly involves the use of two drugs, one platinum based (usually cisplatin and alternatively carboplatin) in combination with a second drug (etoposide, gemcitabine, docetaxel, paclitaxel or pemetrexed). Single drugs are sometimes used in metastatic cancer when combination drugs would not be tolerated or resistance has developed. Treatment with chemotherapy can be adjuvant, neoadjuvant, or part of a multimodality treatment plan.

Studies have shown that with post-operative adjuvant treatment for stage IB to stage III disease, there was an increase in 5-year survival rates, but for stage IA disease there seemed to be a detrimental effect of chemotherapy. For some stage I and most stage II and III patients who have completely-resected NSCLC, the standard of care is adjuvant cisplatin-based chemotherapy.

Patients at the IIIB stage are treated with chemo-radiation alone since surgery is not usually possible. The primary treatment for patients with stage IV disease is chemotherapy, despite extremely low survival rates.

Neoadjuvant chemotherapy (or induction chemotherapy pre-operatively) has been shown to improve survival for  some patients with stage II or IIIA disease. Neoadjuvant chemotherapy plus RT has been shown to be superior to just RT alone.

Targeted Therapies

Targeted therapies utilize specific molecular mutations present in certain non small cell lung cancer cells to stop growth and spread of cancer cells [4]. It is usually given to patients with nodal spread or metastases, to those whose cancer does not respond to chemotherapy, or to those who have had recurrence of cancer after chemotherapy. There are multiple different targeted drugs that are specific to different molecules. Molecular testing of cancer cells determines if a specific cancer will respond to an available targeted therapy.

Targets include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), BRAF and ROS1 which are commonly mutated genes involved in control of cell growth and division [3]. Targeting these pathways with inhibitors has resulted in prolonged progression free survival and improved response rates compared with chemotherapy, although median survival has not been significantly improved in comparison with standard chemotherapy [3]. Angiogenesis inhibitors are also used and their mechanism is to prevent the growth of new vessels to supply cancers.

Immunotherapy

Immune checkpoints serve to prevent excessive inflammatory responses and autoimmunity; however, some cancers have taken advantage of this to evade immune system detection [3]. Overexpression of inhibitory ligands and receptors are often present in the tumour microenvironment. These can be targeted with antibodies for cancer treatment. The most commonly targeted pathways are CTLA-4 and PD-1 pathways. Immunotherapy has been shown to have improved progression free survival, response rates and survival at 6 months compared to standard chemotherapy [3].

Immunotherapy can have different roles in treatment [4]. Some immunotherapies kill or alter the behaviour of cancer cells while others strengthen the immune system, control symptoms or reduce treatment side effects. Immunotherapy is available for advanced or metastatic NSCLC which has stopped responding to chemotherapy or targeted therapies. It is used to shrink advanced or metastatic NSCLC tumours or for symptom control.

Table 5. Summary of Treatment Options for Different Stages of NSCLC

Summary

Surgery is the primary treatment modality for NSCLC if the disease is localized. Chemotherapy and radiation, alone or in combination, may be used for patients who are not surgical candidates or as adjuvant therapy. Immunotherapy and targeted therapies are available for more advanced staged cancers not responsive to standard treatments.

Treatment: Small Cell Lung Cancer

Chemotherapy

Chemotherapy is the primary treatment for both limited and extensive SCLC. Chemoradiation is used to treat limited stage disease. The two treatments are given concurrently with RT initiated in cycle 1 or 2 of chemotherapy. Chemotherapy is generally used alone to treat extensive stage SCLC. SCLC is usually treated with combinations of chemotherapy agents. Even in extensive-disease stage SCLC, complete remissions rates up to 30% have been achieved [1], and a substantial portion (60-80%) of SCLC tumours respond to treatment. Overall survival rates are still very low, with median survival lengths of one year.

Platinum-based chemotherapy agents (cisplatin or carboplatin) are used in conjunction with etoposide as first line therapy. More than six cycles of chemotherapy have not shown benefit nor have maintenance doses.

Essentially all patients with extensive stage disease will eventually relapse after first line chemotherapy. Consolidative thoracic radiation in selected patients achieving complete responses to induction chemotherapy may be considered to improve survival [3]. There is one FDA approved agent for second line use in SCLC which is a topoisimerase I inhibitor called Topotecan, while many other agents are currently being investigated in clinical trials. In addition, the National Comprehensive Cancer Network has included immunotherapy agents including nivolumab and nivolumab plus ipilimumab as treatment for SCLC patients who have had progressive disease after one or more previous regiments, or have relapsed within 6 months of initial treatment. These agents have shown promise in phase I/II trials and there are very few options for these SCLC patients.

Radiotherapy

Radiation is also not the primary treatment modality of choice for extensive-stage SCLC disease. However, for both extensive-stage and limited-stage disease, radiation used in conjunction with chemotherapy resulted in decreased mortality.

For limited-stage disease, radiation therapy and chemotherapy combined increases median survival to around 1.5 years.

Radiation to the brain is also recommended for patients with limited stage disease. This is given when there is no evidence of spread to the brain and therapy is completely confined to the chest. The purpose of this is to decrease the chance of developing brain metastases. This is called prophylactic cranial irradiation (PCI). PCI is not routinely recommended used for patients with extensive stage disease even if they have a good response to chemotherapy; however, this decision warrants discussion and shared decision making with the patient [3].

Surgery

Surgery is not useful in the treatment of most cases of SCLC. For patients with stage I SCLC and no nodal involvement surgery in addition to chemotherapy may be considered.

Summary

Surgery is not a standard treatment option for SCLC. Chemotherapy is the main therapy used, with radiotherapy being used as an adjuvant therapy in some situations.

The net five year survival for lung cancer in Canada is 17%. Survival rates depend on the stage, treatment and whether the cancer is small cell or non small cell lung cancer. Both patient and cancer characteristics influence survival. The following list includes the main factors that influence prognosis [4]:

• Stage is the most important prognostic factor
• Presence and location of metastases
• Presence of specific markers with targeted therapies
• Function of the patient at the time of cancer diagnosis
• Sex: females have slightly better outcomes
• Weight loss: significant weight loss prior to diagnosis is associated with worse outcomes
• Lung disease: preexisting lung disease is associated with worse outcomes

There is a lack of strong evidence from well designed trials to recommend a specific protocol for follow up and surveillance of NCSLC with most evidence being based off of retrospective data. However, it is generally agreed that surveillance with history, physical exam and chest CT is appropriate [3]. Patients with NSCLC who have been treated with curative intent should undergo history, physical and CT chest every 6 months for 2 years, and every year thereafter. It is estimated that 27% of patients treated for stage I NSCLC will develop a second primary lung cancer within 10 years with the greatest risk being in the first 2-3 years; therefore this is another consideration in planning follow up.

There is little evidence to support a protocol for surveillance for patients with locally advanced tumours treated with radiotherapy with curative intent such as stage IIIB tumours. As recurrence is more likely in this population it would be reasonable to complete surveillance at more frequent intervals such as every 4-6 months for the first several years.

It is also important to provide supportive treatment for survivors. Multidisciplinary teams that can aid with smoking cessation, encourage a healthy lifestyle, provide age appropriate screening for other cancers and provide psychological support are an important part of cancer treatment [2].  

Epidemiology

1. Brooks, DR et al. Influence of Type of Cigarette on Peripheral v. Central Lung Cancer. Cancer Epidemiology Biomarkers & Prevention [serial online].:2005,14:576-581. Available at: http://cebp.aacrjournals.org/cgi/content/full/14/3/576 Accessed July 2008.
2. Bach PB, Kattan MW, Thornquist MD, Kris MG, Tate RC, Barnett MJ, Hsieh LJ, Begg CB. Variations in Lung Cancer Risk Among Smokers. J Natl Cancer Inst: 2003; 95(6): 470-478.
3. DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles & Practice of Oncology 7th Edition Vol 1. Lippincott Williams & Wilkins, Philadelphia; 2005.
4. Canadian Cancer Society. Lung Cancer: Risk Factors. 2019. Available at: http://www.cancer.ca/en/cancer-information/cancer-type/lung/risks/?region=on. Accessed March 2019.
5. de Groot, P., Wu, C., Carter, B., and Munden, R. The epidemiology of lung cancer.Translational Lung Cancer Research. 2018; 7(3). doi: 10.21037/tlcr.2018.05.06

Screening

1. DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles & Practice of Oncology 7th Edition Vol 1. Lippincott Williams & Wilkins, Philadelphia; 2005.
2. Roberts HC et al. Lung Cancer Screening With Low-DoseComputed Tomography: Canadian Experience. Chest Radiol Jour [serial online].:2007,58:226-235. Available at: http://www.carj.ca/issues/2007-Oct/225/225.pdf. Accessed July 2008.
3. Reduced Lung – Cancer Mortality with Low – Dose Computed Tomographic Screening. New England Journal of Medicine. 2011. 365: 395-409. DOI: 10.1056/NEJMoa1102873
4. Lewin, G., Morissette, K., Dickinson, J., Bell, N., Bacchus, M., Singh, H., Tonelli, M., Garcia, A. Recommendations on Screening for Lung Cancer. Canadian Medical Association Journal. 2016.
5. Canadian Cancer Society. Lung Cancer: Screening. 2019. Available at: http://www.cancer.ca/en/cancer-information/cancer-type/lung/ Accessed March 2019.

Classification

1. Stithman SO. Metastatic cancer to the lung. US National Library of Medicine – Medline: Metastatic Cancer to the Lung. 2008. http://www.nlm.nih.gov/medlineplus/ency//article/000097.htm Accessed July 2008.

Signs & Symptoms

1. Thomas KW. UpToDate: Lung cancer risks, symptoms, and diagnosis. 2008. Available at: http://www.uptodate.com Accessed July 2008.
2. Canadian Cancer Society. Lung Cancer: Signs and Symptoms. 2019. Available at: http://www.cancer.ca/en/cancer-information/cancer-type/lung/. Accessed March 2019.

Diagnosis

1. ‍DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles & Practice of Oncology 7th Edition Vol 1. Lippincott Williams & Wilkins, Philadelphia; 2005.
2. Bury, T., Barreto, A., Daenen, F., et al. Fluorine-18 deoxyglucose positron emission tomography for the detection of bone metastases in patients with non-small cell lung cancer. European Journal of Nuclear Medicine. 1998; (25)9: 1244
3. Thomas, KW., Gould, MK. Uptodate: Overview of the initial evaluation, diagnosis and staging of patients with lung cancer. 2018.

Staging

1. Lababede O et al. TNM Staging of Lung Cancer. Chest [serial online]. 1999;15:233-235. Available at: http://www.chestjournal.org/cgi/content/full/115/1/233 Accessed July 2008.
2. Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest [serial online]. 2009;136:6-8. Available at: http://www.chestjournal.org/content/136/1/260.full Accessed July 24, 2009.
3. Detterbeck, F., Boffa, D., Kim, A., and Tanoue, L.The Eight Edition Lung Cancer Stage Clasification. Chest. 2017; 151(1): 193-203

Treatment: Non-Small Cell Lung Cancer

1. Swierzewski SJ. Oncology Channel: Lung Cancer treatment. 1999. Available at: http://www.oncologychannel.com/lungcancer/treatment.shtml
2. Houlihan NG. Site-Specific Cancer Series: Lung Cancer. Oncology Nursing Society, Pittsburgh; 2004.
3. Tanoue, L.,Detterbeck, F. Lung Cancer: A Practical Approach to Evidence Based Clinical Evaluation and Management. 2018.
4. Canadian Cancer Society.

Treatment: Small Cell Lung Cancer

1. ‍Houlihan NG. Site-Specific Cancer Series: Lung Cancer. Oncology Nursing Society, Pittsburgh; 2004.
2. Canadian Cancer Society. Lung Cancer: Treatment. 2019. Available at: http://www.cancer.ca/en/cancer-information/cancer-type/lung/risks/?region=on. Accessed March 2019.
3. Tanoue, L.,Detterbeck, F. Lung Cancer: A Practical Approach to Evidence Based Clinical Evaluation and Management. 2018.