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Objectives

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 reccomendations 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.

Epidemiology

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 initiation of lung cancer.

Figure 1: Lung Cancer Pathogenesis

Cigarette smoking is far and away the most important risk factor in developing lung cancer, with some studies suggesting causation in up to 90% of cases. However, not all smokers get lung cancer, indicating genetics may play a role. Non-modifiable risk factors such as gender, age, and race are all independently correlated with increased incidence of lung cancer. Lifestyle factors such as occupational hazards, poor diet, and low physical activity are associated with increased risk of lung cancer. Prior lung dysfunction is also a risk factor for lung cancer.

Cigarettes

The number one risk factor for lung cancer is cigarette smoking, which is a modifiable risk factor. The evidence supporting this includes case-control studies that were later substantiated by cohort studies .

There are more than 300 chemicals in one cigarette and at least 40 of those are 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 mechanisms and cell cycle regulation mechanisms.

The duration and intensity of smoking both influence the risk of lung cancer. For patients with similar pack year histories, the patient who has smoked for more years is at greater risk for developing lung cancer. Smoking cessation lowers the risk of lung cancer and should always be recommended to patients.

Modern cigarette formulations are not better for patients in terms of risks for lung cancer. They actually seem to increase the risk of adenocarcinoma, and the reason for this appears to be threefold1. First, low-tar and nicotine cigarettes have a lower yield of nicotine so smokers tend to compensate for this by inhaling more deeply, frequently, and vigorously. Secondly, filters in cigarettes select for smaller particles which, combined with the deeper and stronger inhalations, results in these particles being deposited in more peripheral regions of the lung. Thirdly, modern formulations use a different type of tobacco, which contain more nitrates that are converted to nitrosamines upon burning.

*FOR MORE INFORMATION SEE ARTICLE: 
INFLUENCE OF TYPE OF CIGARETTE ON PERIPHERAL VS. CENTRAL LUNG CANCER

Genetics

Genetics are believed to play a role in the development of lung cancer because only 5-10% of heavy smokers develop lung cancer2. While the exact genes involved have yet to be identified, the greatest risk for lung cancer occurs in patients with a positive family history of lung cancer and who are non-smokers. A locus on chromosome 6 has been implicated in such families.

Mutations in the p53 genes and CYP450 metabolism genes can also contribute to the development of lung cancer.

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 (eg. during WWII in Japan or a previously treated breast cancer patient) 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 some of these hazards will develop lung cancer, with substantial exposure leading to higher risk. The variable occurrence of cancer in patients who have been exposed also supports the theory that there could be a genetic predisposition towards developing lung cancer.

Diet

Data surrounding the role of diet in the pathogenesis and progression of lung cancer is controversial. Low folate levels have been associated with increased DNA damage, but there is no definitive evidence that folate supplementation decreases the risk of lung cancer development. Still, folate continues to be recommended as a preventative measure for developing lung cancer3. This observation could partially be explained by folate’s role in DNA repair, which is typically low in lung cancer patients.

Copper, selenium, and zinc have demonstrated a correlation with reduced lung cancer risk.

Risk Factors Summary

Non-Modifiable

  • Genetic predisposition
  • Age
  • Gender
  • Ethnicity
  • Prior lung dysfunction

Modifiable

  • Cigarette smoking
  • Occupational exposure
  • Physical activity
  • Diet
  • Environmental exposure

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.

Screening

In Canada, lung cancer annually causes the most deaths of all types of cancers. Survival rates after diagnosis are low. While it would be extremely beneficial to be able to screen for lung cancer to allow for early detection and early intervention due to the aggressive nature of this tumour, there remains no good screening test agreed upon for lung cancer. Neither sputum cytology1 nor frequent chest x-rays have been found to have consistently good predictive value in North American randomized-control studies. Further research into the efficacy of screening is necessary and currently being conducted.

While the international jury is still undecided about recommending serial CT scans as a lung cancer screening tool, there is some evidence that CT scans may be useful for early detection of lung cancer leading to a reduction in mortality.

Evolution of Screening Guidelines

In 2003, the findings of the Canadian Task Force on Preventive Health Care was that there was FAIR evidence (D recommendation) against screening asymptomatic people for lung cancer with chest x-rays, but that there was INSUFFICIENT evidence to draw any conclusions about the efficacy of spiral CT scans.

Most recently, a multi-national study has been undertaken, the International Early Lung Cancer Action Program (I-ELCAP). Princess Margaret Hospital in Toronto hosts the Canadian arm of this screening program for lung cancer, which involves low-dose CT scans (LDCT). They believe that their program is successful because of “the number of early-stage lung cancers detected”2. Further, this screening regimen has allowed people to avoid unnecessary invasive procedures, complications, and costs, with 90% of biopsies done due to findings on screening exams confirming malignancy.

*FOR MORE INFORMATION SEE: LUNG CANCER SCREENING WITH LDCT

Summary

Screening is used to detect cancer in asymptomatics individuals. Lung cancer screening is not currently done in Canada, because there is sufficient evidence recommending against screening by X-ray and insufficient evidence for screening using CT scans.

Classification

The first consideration in management of lung cancer patients is determining the type and stage of their lung cancer. The main division in types of lung cancer 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.

The logic behind the broad division of lung parenchyma cancers into SCLC and NSCLC is that the two categories of cancers typically behave differently, so treatment options and management also differ. Lung cancers that are not SCLC can all generally be treated in the same way and so are grouped together. SCLC is generally more aggressive, growing and metastasizing extremely 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.

The classification system (SCLC v. NSCLC) generally holds true, but as with all aspects of medicine, there is a grey area when tumours have features of both SCLC and NSCLC. In these situations, the tumours are referred to as “mixed” tumours. Another type of lung cancer is a mesothelioma, which is a rare cancer of the lung pleura.

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 primary tumours that progress to lung invasion. However, almost any tumour can metastasize to the lungs through hematogenous spread1.

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 very differently than other adenocarcinomas.

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

Histologic Features of SCLC

Small Cell Carcinoma:

  • Accounts for about 10-15% 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 sooner to distant sites (often distant metastases present at time of diagnosis)
  • More responsive than NSCLC to chemotherapy and radiotherapy BUT prognosis still extremely grim

Summary

Lung cancer can be divided into small cell (SCLC) and non small cell lung cancer (NSCLC). More than 85% of cancers 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.

Signs & Symptoms

The presentation of lung cancer can be very subtle with many of the symptoms and signs being non-specific. The variety of presentations depends on the type of lung cancer, location and size of the tumour, and presence of distant metastasis. Thus, clinicians should ask patients about their risk factors for developing lung cancer and take care to rule out this serious disease.

Symptoms in lung cancer can vary depending on the extent of disease spread. If the tumour is confined to the thorax, lung and chest symptoms will be the dominant complaints. On the other hand, once the tumour has spread to other parts of the body, aches, pains, and weaknesses in other areas may be noted. As with any tumour, there are the indirect systemic effects such as fatigue, night sweats, and weight-loss, which an astute clinician should inquire about in patients.

Some cases of lung cancer may 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 is intense research into finding appropriate screening investigations.

Localized Symptoms

Cough

The most common symptom is a cough. Moreover, the cough should in some way be new. This means that the cough is either of recent-onset, or there has been a change in a longstanding, chronic cough such as an increase in frequency or severity. Other causes of new cough development should be ruled out, such as beginning of new medications such as ACE-inhibitors. Whether the cough is productive is not necessarily definitive, but often yellowish-green coloured sputum would lower cancer on one’s differential in favour of an infectious cause. If the cough is bloody (hemoptysis), this is more worrisome, and further details must be elicited.

Shortness of Breath

Patients can also come in complaining of shortness of breath, chest pain, and wheezing1. Dyspnea can occur due to mass effects of the tumour if it is 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 (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 determining 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, including: vague complaints of confusion, headache, nausea and vomiting to personality changes and seizures.

Indirect (Paraneoplastic) Signs and Symptoms

Paraneoplastic symptoms and signs are those caused indirectly by the tumour and are not due to the local presence of cancerous cells. Examples include the cardinal cancer red-flags of weight loss, decreased appetite, fatigue, and night sweats. A patient’s fingers and toes may also display clubbing. Other symptoms that may be present are: joint pain and swelling, muscle pain/weakness/stiffness, breast enlargement, blood pressure changes, and electrolyte imbalance.

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 symptoms and constitutional symptoms that should be asked about when taking a respiratory history. Asymptomatic individuals are not commonly diagnosed as there is currently no recommended screening test. 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 and can vary greatly between individuals.

Diagnosis

History

Typically, a patient with lung cancer will come in to his/her family doctor with a new respiratory complaint. The family doctor will take a history of this presenting complaint (onset, duration, alleviating/aggravating factors, associated symptoms, etc.) and a complete medical history, including risk factor assessment and discussion of possible co-morbid illnesses. Risk factors that are important to inquire about include a family history of cancer and potential occupational, environmental and lifestyle hazards. To help 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.

Physical Examination

A physical exam should be done to find clinical signs that may help rule in/out the diagnosis 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 looked for due to metastases (eg. osteoarthropathies) and indirect effects of having a tumour (eg. weight loss and hypercoagulopathy leading to DVTs). Absence of clinically significant findings does NOT rule out the diagnosis of lung cancer.

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. For example, a bone scan should be used to search for bony metastasis, head and neck CT for brain metastasis, and abdominal CT for liver metastasis. A PET scan or MRI may be ordered by a specialist to assess for local tumour extent. For example, an MRI may be used to assess a Pancoast tumour and a PET scan may be used for assessing 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 head, neck, abdominal CT, PET scan, and/or MRI.

Radiology

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 nodal involvement assessment, and staging is important as it directs treatment. The radiologist reading the chest films is thus a key player in the work-up of a patient with lung cancer.

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 effects can be histologically benign while other smaller lymph nodes (< 1cm) can contain many malignant cells.

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 cancerous spots. 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 metabolical activity on these scans resulting in false positives. Or, tumours can be slow-growing (eg. bronchoalveolar carcinoma) and show up as a false negative.

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 if the tumour has invaded the spine, nerves, soft-tissues or blood vessels, MRI can be beneficial.

A new, less invasive technique for investigating lymph nodes, is endoscopic ultrasound (EUS). Results are promising as EUS seems able to identify more of the mediastinal lymph nodes that contain malignant cells than either CT or FDG-PET1.

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

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. MRI can also be used to assess local spread and distant metastasis.

Pathology

Tissue biopsy of the tumour is required in order to make the diagnosis of lung cancer. This sample can be obtained through various techniques. The most important for pathologists to make is the distinction between small cell lung cancer and non-small cell lung cancer.

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.

Staging

TNM Staging in Lung Cancer

  • As the tumour increases in size (the threshold is 3cm), the stage increases due to the increase in T
  • As the tumour gets closer to the central lung structures or mediastinal structures, the stage increases due to the increase in T
  • N1 lymph nodes are within the hilum, N2 nodes are within the mediastinum
  • If there are metastases present, the stage automatically increases to IV due to the increase in M
  • A TX, NX or MX indicates that the tumour, nodal, or metastatic state is unknown

The logic behind staging lung cancer is two-fold:

  • 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 and treatment
  • It allows health care professionals to communicate effectively with each other using a universal language to delineate the progression of a patient’s disease.

Staging is also informative of a patient’s prognosis, which pertains to patient care. The stage of a patient’s disease is determined through diagnostic testing. For lung cancer, the most common locations for metastases are the bone, adrenals, liver, skin, and the brain. Therefore, appropriate workup diagnostic tests include CT scans of the chest (looking for affected lymph nodes and spread of cancer to other lung lobes), CT scans of the upper abdomen (for assessment of the adrenals and liver), CT/MRI of the head (for brain metastases), and bone scans (for bone metastases).

It is especially important to assess for metastases immediately if the patient is complaining of symptoms from these regions. Liver metastases are usually asymptomatic at the time of diagnosis, but bone pain can be present in the vertebrae, femurs and ribs. Brain metastases have variable presentations but can include anything from vision problems to unilateral weakness or twitches to seizures.

The more advanced FDG-PET scan is typically 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, limited to one lung with no metastases outside the chest
  • Stage II = cancer has metastasized to ipsilateral lymph nodes, invaded tissues around the ipsilateral lung (eg. pleura), or invaded central structures of the lung (eg. main bronchi, but NOT mediastinal structures)
  • 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
Table 1: TNM Staging of NSCLC1,2

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”.

  • Staged as limited or extensive disease due to its different growth pattern
  • 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

For more details, see the table below:

Table 2: Staging of SCLC

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.

Treatment

There are three main modalities used for curative and/or palliative treatment in lung cancer: surgery, radiation and chemotherapy. 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

The first requirement to be considered for surgery is whether there is evidence of distant metastasis. If metastases are present, the patient is not a surgical candidate. Provided there is no evidence of metastasis, the next step is inspecting the mediastinum for positive lymph nodes, usually through mediastinoscopy.1 If these are present, the patient’s status as a surgical candidate is questionable.

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.

Surgical resection is indicated when the disease has not spread beyond one lung, the disease 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.

Pulmonary function tests (PFTs) are usually done to assess lung reserve post-surgery. 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. Preoperative pulmonary rehabilitation (eg. teaching breathing exercises) is not currently an “evidence-based” medical practice, but it is done for the possibility of benefit.

Surgical resection is typically done through thoracotomy, complete opening of the chest wall. 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.

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 still remains the recommended course of action.2 For stage IIIA 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 IIIA cancer makes it difficult to state definitive treatment options.

Surgery is not indicated in 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.

Other possible surgical procedures include more limited procedures such as wedge resections and segmentectomy but these methods are associated with greater morbidity and mortality.

Stage II disease is usually treated by surgical resection by pneumonectomy, the complete removal of one lung. Stage IIIB patients do not usually receive surgery and chemotherapy and radiation therapy are the modalities of choice.

Video-assisted thoracoscopic surgery (VATS) is used instead of conventional surgery for diagnosis and treatment. It is indicated in patients who will not be able to tolerate a thoracotomy or have poor pulmonary reserve as measured on pulmonary function tests (PFT). Some advantages include decreased postoperative pain, better preservation of pulmonary function, and shorter recovery time.

Combination Therapy

Surgical treatment can be combined with chemotherapy and/or radiation. Mixed results have been seen with combination therapy, but adjuvant chemo seems to have a 4-5% overall survival benefit according to meta-analyses . If negative surgical margins cannot be achieved, radiation should be administered or surgical re-resection should be done.

Lymph Node Assessment

Lymph node systematic sampling involves routine sampling of lymph nodes at predetermined nodal sites (eg. superior mediastinum, aorta, inferior mediastinum) or a complete mediastinal lymph node resection involves the removal of all lymph node tissue at sites specified by the surgeon.

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 is used in treating cancer to improve local tumour control and 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 (RT) 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 (RT) can be used at all stages of lung cancer, whether it is the first-line, curative, adjuvant, or palliative treatment.

Radiation therapy (RT) is a first-line treatment for patients who are deemed inoperable despite having stage I and II disease (eg. due to age). These patients are not candidates for chemotherapy. The five-year survival rates for patients receiving RT are around 20-25% for T1 disease and 15% for T2 disease.

Other indications for RT include patients:• With early-stage but unresectable disease (often in combination with chemotherapy)• Who are at risk for disease progression (eg. prophylaxis for superior vena cava syndrome)• Who require palliative treatment

Radiotherapy combined with chemotherapy is the standard of care for patients with stage IIB and higher disease.

Whether the treatments are concurrent or sequential, the results show survival benefits, so RT and chemo is the current “gold-standard” treatment for patients with stage III disease. For stage IIIB disease, combined modality (chemo + RT) can be considered to be curative therapy. Even if the cancerous cells can be encompassed within a reasonable radiation volume, chemo 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 earlier stages of lung cancer, clear survival benefits over surgery alone have yet to be demonstrated, but radiation is often given to improve chances of survival. In patients with T3 disease and incomplete resection, it has been shown to improve survival rates.

Radiotherapy is often used for palliation in more advanced NSCLC to improve symptoms since the radiation fields are simply too large for the benefit to outweigh the risks. There is a slight survival benefit of RT as opposed to no RT, regardless of whether the RT is given immediately or delayed. Endobronchial brachytherapy has been shown to help with symptom palliation for symptoms such as dyspnea to cough and hemoptysis although there is a risk of side effects such as bronchoesophageal fistulas.

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 control2. RT is also used for bone metastases with the goals of decreasing pain, increasing mobility and preventing pathologic fractures.

Chemotherapy

Chemotherapy has been used for several decades with the compounds being used changing frequently. The newer generation of chemotherapy drugs is platinum-based, which have been shown to be quite useful along with taxanes, and vinorelbine. The current agents used are cisplatin with etoposide; docetaxel is sometimes used in post-radiotherapy cycles instead of etoposide. 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 those 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 patients in stage II or IIIA disease. Neoadjuvant chemotherapy plus XRT has been shown to be superior to just RT alone.

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.

Treatment: Small Cell Lung Cancer

Surgery

Surgery is not the primary treatment modality of choice. Five year survival rates are dismal, and at ten years, there are usually no survivors. Even with preoperative radiation, long-term survival rates are low.

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 used for patients with extensive stage disease if they have a good response to chemotherapy.

Chemotherapy

SCLC is usually treated with combinations of chemotherapy agents. Even in extensive-disease stage SCLC, complete remissions rates up to 30% have been achieved1, 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 and carboplatin) are often used in conjunction with etoposide and with other drug combinations using vincristine, doxorubicin, and cyclophosphamide. More than six cycles of chemotherapy have not shown benefit nor have maintenance doses. More than three drugs are not typically used.

Chemotherapy has a 90% fail rate in extensive-stage disease, so radiation therapy is used in conjunction with medical treatment. It has been proven to increase survival and the question is usually how to integrate the two modalities together. The importance of communication between radiation and medical oncologists comes into play here. Concurrent therapy as compared to sequential therapy or sandwich therapy (chemo-radiation-chemo) is superior. Radiation typically starts about a month after chemotherapy starts2. Long-term survival rates exceed 20% at five years with such treatment.

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.

Virtual Patient Case

This case study was designed to supplement your knowledge on the workup of lung cancer and test what you have learned after going through module. Use your mouse to click through the slides and answer each question in the text box provided.

Note: This case can be completed on an iPad. To do this download the (free) Articulate Mobile Player for the iPad by clicking here.

References

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.

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.

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.

Radiology

  1. ‍DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles & Practice of Oncology 7th Edition Vol 1. Lippincott Williams & Wilkins, Philadelphia; 2005.

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.

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.

Treatment: Small Cell Lung Cancer

  1. ‍Houlihan NG. Site-Specific Cancer Series: Lung Cancer. Oncology Nursing Society, Pittsburgh; 2004.

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