Lung Cancer: A Review of Current Treatment Modalities with a Focus on New Strategies

Rennette Timbrell, RT(T), M.Rad (South Africa)

    ^*Supervisor-Radiation Therapy, Radiation Oncology Department, University of Colorado Hospital Denver, Aurora, Colorado.
   Address correspondence to: Rennette Timbrell, RT(T), M.Rad (South Africa), Supervisor-Radiation Therapy, Radiation Oncology Department, PO Box 6510, MS-F-706, University of Colorado Hospital Denver, Aurora, CO 80045. E-mail: Rennette.Timbrell@uch.edu.

Disclosure: Ms Timbrell reports having no significant financial or advisory relationships with corporate organizations related to this activity.

ABSTRACT

Lung cancer is one of the leading causes of cancer deaths in the world and is by far the most common cancer in the Western world. In the United States, lung cancer is responsible for more deaths annually than those due to cancers of the breast, colorectal cancer, and prostate cancer combined. The American Cancer Society estimated that in 2008, the number of deaths due to cancers of the lung and bronchus will be approximately 161 840, as opposed to 119 550 deaths from breast, prostate, and colorectal cancers combined.

Between 1972 and 1997 the incidence of lung cancer continued to rise, peaking in the 1990s. Historically, the incidence of the disease was higher in males than in females, but in the last 2 decades, the incidence and mortality rates for lung cancer have decreased for men and increased for women. These figures correlate with a rise in the incidence of smoking among women. Another interesting change in the incidence of specific lung cancer pathologies has been noted. For instance, squamous cell carcinoma (SCC) was previously the most common lung cancer diagnosed, but since the mid to the end of the 1980s, SCC has undergone an absolute decline resulting in adenocarcinoma now being the most common type of lung cancer, which is also attributable to changes in smoking habits.

This article will provide a summary of the epidemiology, pathology, and staging of lung cancer and the current radiation treatment options available to patients, with special reference to stereotactic body radiation therapy and accelerated dose regimens for non-resectable early stage lung cancer and lung metastases. Also, new strategies involving biological molecular targeting will be addressed.

Introduction
Lung cancer, or bronchogenic carcinoma, is the most common cause of cancer deaths in the world, accounting for 15% of all new cancer diagnoses in men and women combined.¹ It is the second most common cancer for males and females behind cancers of the prostate and breast, respectively. In the United States, this disease remains the most frequent cause of death^1-3; according to the American Cancer Society, in 2008 it is estimated that there will be 215 020 new cases diagnosed and death due to lung cancer will claim some 161 840 lives, accounting for 29% of all deaths (Figure 1).^1,4 According to the National Cancer Institute, the incidence of lung cancer increased by 28% between 1973 and 1997 compared to an overall increase of 23.4% in all sites combined.

Historically, the incidence and mortality rates due to lung cancer were both higher in males than in females; however, in the last 2 decades, these figures have changed, and the incidence and mortality rate is now higher in females. Currently, lung cancer incidence rates are declining in men and appear to be plateauing in women after increasing for many years. The lag in the temporal trend of incidence in men and women reflects the historical differences in cigarette smoking between men and women.¹ Cigarette smoking for women peaked 20 years later than for men. For example, around 1953, lung cancer was the most common cause of death in men, and by 1987, lung cancer surpassed breast cancer as the leading cause of death in females.¹ These figures appear to correlate with the increase in the number of women who smoke cigarettes, with this increase being significant from the 1950s to the present.

It has been well documented that cigarette smoking is the most common risk factor in the etiology of lung cancer and it is estimated that 87% to 90% of all lung cancers are attributable to cigarette smoking.⁵ However, approximately 10% of patients with lung cancer in the United States are lifelong non-smokers.⁶ 

Gross Anatomy of the Respiratory System: An Overview
The bronchi and paired lungs comprise a major portion of the respiratory system; other parts of the respiratory system include the nose, pharynx, larynx, and trachea. The trachea terminates and divides at the sternal angle into the right and left bronchi, which enter the right and left lungs, respectively. Upon entering the lungs, the bronchi divide into smaller branches called bronchioles, resembling the branches of a tree, and this structure is often referred to as the bronchial tree.⁷ The bronchi are lined by pseudostratified ciliated epithelium.

The lungs are the paired organs of respiration that are situated in the thoracic cavity. They are separated by the mediastinum which contains the heart, large vessels, trachea, esophagus, thymus gland, and lymph nodes.⁸ The lungs are enclosed by the serous membrane, which is made up of 2 layers collectively called the pleural membrane.^7,8 Between the 2 layers is a space called the pleural cavity, which contains a lubricating fluid. This fluid prevents friction and allows for easy movement during respiration. The lungs extend from the diaphragm to a point approximately 0.5-inch superior to the clavicle. Each lung is divided into lobes by 1 or more fissures. Both lungs have an oblique fissure and the right also has a horizontal fissure dividing the lung into 3 lobes whereas the left lung has 2 lobes. Each lobe receives its own secondary (lobar) bronchus and within the substance of the lung the secondary bronchi give rise to the tertiary bronchi.⁷ The segment of lung that each bronchus supplies is called the bronchopulmonary segment. These segments in turn are broken into small compartments called lobules. The tertiary bronchioles further subdivide to form the respiratory bronchioles, which terminate in alveolar ducts. Around each alveolar duct are numerous alveoli and alveolar sacs through which the exchange of gases takes place as part of the function of respiration. The blood supply to the lungs is from 2 sources: the pulmonary vessels that support the respiratory tissue and the bronchial vessels that supply blood to the non-respiratory tissue.

Lung Cancer Etiology
The development of lung cancer has been attributed to several environmental and lifestyle factors, of which cigarette smoking is the most important. Other factors, such as exposure to asbestos, radon, arsenic, nickel, cooking fumes, and environmental tobacco smoke (ETS; passive exposure), have been cited as playing a role in the development of lung cancer. Genetic disposition and diet have also been studied with regard to having a role in the etiology of lung cancer.

It is estimated that close to 90% of lung cancers are caused by tobacco smoke, with factors such as duration and intensity of smoking playing an important role in the development of disease. The risk of developing lung cancer for a current smoker of 1 pack of cigarettes per day for 40 years is approximately 20 times that of someone who has never smoked. However, it has recently been estimated that 15% of men and 53% of women with lung cancer worldwide are individuals who have never smoked.⁶ Former smokers make up approximately 50% of new cases. ETS exposure or passive smoking and lung cancer risk appears to be somewhat controversial.⁹ Studies indicate that ETS contributes to 25% of all lung cancers in non-smokers. Outdoor air pollution, which includes combustion-generated carcinogens, is also considered to contribute to the lung cancer burden in urban dwellers.¹⁰

In the last decade, there has been a significant decline in smoking in the United States, resulting in a decline in the incidence of lung cancer, especially among young males. Today there are numerous anti-tobacco health policies in effect in the United States that could account for this decline in smoking. However, any major difference in the mortality rate due to lung cancer will only be seen in the next decade. Anti-tobacco policies are being adopted by other Western countries, although there is still resistance to the banning of smoking in some countries. Presently, China is the largest producer and consumer of tobacco products, and it is predicted that in the next few decades, the incidence of lung cancer in China will increase dramatically.⁹

The 5-year survival rate figures for lung cancer in general are dismal, with a 5-year survival rate of 15%, according to figures from the National Cancer Institute. People who smoke tobacco products live approximately 10 years less than those who do not smoke and are also at risk of developing other smoking related illnesses, such as chronic bronchitis and emphysema.⁸

In light of these statistics, there has been an increased effort to improve the outlook for lung cancer sufferers by spotlighting the need for better lung cancer screening techniques in an attempt to diagnose the disease earlier when the odds of successful treatment are greater. Meanwhile, efforts have also been made to improve the current treatment options for all stages of lung cancer.

Lung Cancer Pathology
Lung cancer or bronchogenic carcinoma is comprised of a group of malignancies that originate mainly in the bronchi or the lung parenchyma. There are 4 major types of bronchogenic carcinomas: squamous cell carcinoma (SCC), adenocarcinoma, large-cell anaplastic carcinoma, and small-cell carcinoma.^9,11 In making therapeutic decisions, there are 2 major categories to consider: non–small-cell lung cancer (NSCLC), which includes SCC, adenocarcinoma, and large-cell undifferentiated carcinoma; and small-cell lung cancer (SCLC).¹¹ These 2 categories account for 95% of lung malignancies. The other 5% are made up by other cell types that arise in the lungs.⁹ All lung carcinomas are aggressive, locally invasive, and metastasize widely if left untreated. Commonly they tend to spread by local invasion and by lymphatic and hemotogenous routes to the liver, adrenal glands, brain, and bones.

Non–small-cell Lung Cancer
Squamous cell carcinoma. Until the mid 1980s, SCC was the most common type of lung cancer worldwide, but since that time, SCC has undergone an absolute decline. Recent data from large cooperative studies indicate that adenocarcinoma now exceeds SCC of the lung in frequency. The decrease in the incidence of SCC is particularly evident in women.

Squamous cell carcinoma arises from the bronchial epithelium, and 60% to 80% are proximal to or involve the hilus and often arise in the large bronchi. A minority of SCC may present clinically in the periphery of the lung.⁹ 

Adenocarcinoma. Over the past 2 decades, the incidence of adenocarcinoma has increased more rapidly than SCC. Adenocarcinoma is now the most common type of lung cancer in many recently reported series. It is the most frequent type of lung cancer in women and in non-smokers of either sex¹² and has a better prognosis that SCC.

The rise in the incidence of adenocarcinoma is thought to be due to the introduction of filter cigarettes with substantially reduced "tar" and nicotine in the smoke from cigarettes.^12,13 Filter cigarettes were introduced in the late 1940s and 1950s. The lower nicotine yield of filtered cigarettes enticed the smokers to take more frequent and larger puffs and to retain the smoke in the lungs for longer to compensate for the lower nicotine yield per puff. This in turn led to an altered pattern of deposition of particulate matter within the lungs.¹³ The higher nitrate content of the low-tar cigarettes has been shown to produce adenocarcinoma in laboratory animals, which is another factor considered to contribute to the rise in the incidence of adenocarcinomas.

Adenocarcinomas tend to be located in the periphery of the lung, frequently invading the pleura and may metastasize widely at an early stage to the contralateral lung, liver, bone, and brain. Bronchioloalveolar carcinoma (BAC) is a special category of adenocarcinoma, which is distinguishable by specific histologic features.¹² BAC has a better prognosis than other bronchogenic carcinomas.

Large-cell anaplastic carcinoma. This type of lung cancer represents a group of neoplasms, which represent squamous cell or glandular neoplasms that are too anaplastic to permit categorization. Histologically, they may be composed of clear cells or giant cells.¹¹ The prognosis for this type of cancer is very poor, with a 5-year survival rate of 2% to 3%.

Small-Cell Lung Carcinoma
Small-cell lung carcinoma accounts for 20% to 25% of all bronchogenic cancers. SCLC correlates strongly with cigarette smoking and is extremely rare in non-smokers.¹²

This is an aggressive and rapidly growing neoplasm with metastases usually present at the time of diagnosis. This type of cancer is also known as "oat cell" lung cancer due to the histologic cellular staining properties that resemble a grain of oats. The prognosis of SCLC is very poor, with a 2-year survival rate of 5% to 8%.

Mixed Histology
A minority of bronchogenic neoplasms reveal 1 or more lines of differentiation. The most common of these is adenosquamous carcinoma, which is made up of both squamous and glandular components. Adenosquamous carcinoma has a low incidence, and it is unclear whether the behavior of these cancers is any more aggressive than other non-small-cell tumors.¹²

Diagnosis and Staging of Lung Cancer
Diagnosis
A lung tumor may be silent for many years with the patient being asymptomatic. In fact, the presence of a lung malignancy may be discovered incidentally when chest radiography is needed for some other complaint. The most common symptoms are a persistent cough with dyspnea, hemoptysis, and chest pain, depending on the site and size of the tumor. Pain may arise from invasion of the mediastinum and atelectasis. Growths in the apex of the lung may cause a severe pain radiating to the shoulder and down the arm from involvement of the brachial nerve plexus. These tumors are referred to as "Pancoast tumors" or "superior sulcus tumors," and patients often present with weakness of the handgrip and Horner's syndrome due to involvement of the sympathetic nerve chain.¹⁴ Some patients also experience unexplained weight loss.

The diagnosis of lung cancer is made using chest radiography and computed tomography (CT) scan. Sputum cytology has largely been ruled out as a diagnostic tool. Positron emission tomography (PET) scans are done to evaluate and stage patients with known lung malignancy.⁹ Methods to establish histology include percutaneous fine-needle aspiration and bronchoscopy.

Staging
In 1985, the tumor-node-metastases staging system (TNM; T = tumor size, N = lymph node involvement, and M = presence of distant metastases), was established worldwide and is used extensively in lung cancer management (Figure 2).¹⁵ This system was revised in 1997 by the American Joint Committee on Cancer and the International Union Against Cancer and is currently the system used most often to stage lung cancer (Figure 3).^9,15

The Role of Imaging Modalities for Staging Lung Cancer
Optimal management of lung cancer is dependent upon histologic identification and staging of the tumor, as well as physiologic assessment of the patient, especially if surgery is to be considered. The decision to use surgery for treatment is strongly influenced by the health of the patient. Many tests will be done to establish whether the patient is likely to withstand the surgical procedure. These tests may include exercise, spirometry, and lung function tests.

Imaging plays a vital role in the staging of lung cancer, with the most common modalities including chest radiography, CT, PET, magnetic resonance imaging (MRI), and radionuclide bone scanning.¹⁴

Chest radiography will show most lung tumors, but CT is superior in that it is more sensitive in demonstrating tumor size (Figure 4) and the presence of lymph node metastases.¹⁴ Bepler et al stated that low-dose CT results in an approximately 3-fold higher detection rate than conventional chest X ray and, furthermore, a 5-fold increase in the identification of resectable lung cancers.¹⁶ However, CT is not always able to distinguish the limits between malignant tumor and normal tissue, particularly when atelectasis is present.

Positron emission tomography has been widely evaluated with studies indicating that PET is superior to CT in detecting pathology of metastatic mediastinal lymph nodes. The use of combined PET/CT scanning may improve the detection of intrathoracic lymph node metastases compared with CT or PET alone, allowing for more accurate staging of the disease. Meanwhile, bone metastases are best detected by radioisotope and/or PET scanning, and brain metastases are best diagnosed using MRI scans.¹⁷

For patients with SCLC, because there is early widespread dissemination, the rationale for staging is based mainly on establishing the degree of dissemination.

Lung Cancer Screening Efforts
A remarkable feature of lung cancer is that it is the most avoidable among the frequent diseases.¹⁸ Smoking is the cause of 90% of lung cancer cases, and it has been widely accepted that the most effective strategy for reducing the incidence of lung cancer is the cessation of smoking. However, the role of screening continues to be developed and pursued due to the fact that the mortality rate from lung cancer remains high and there is a relationship between survival and tumor size. These facts suggest that screening for early stage lung cancer should be effective from a public health perspective. Nevertheless, testing for the early presence of lung cancer remains a controversial issue, and the evolving diagnostic technology plays an important role in this debate.

Since the 1960s the chest X ray has been used as a tool for screening and several studies, most notably in England, reviewed the effectiveness of either biannual or annual screening for lung cancer by chest X ray. Sputum cytology was often used in conjunction with chest X rays. However, the use of chest X ray, with or without sputum cytology, has failed to show a reduction in lung cancer mortality.^9,18-20

Low-dose CT (LDCT) has also been evaluated as a tool for lung cancer screening in several studies, the largest of which was conducted in Japan. In 2005, a study was conducted by Swensen et al using low-dose helical chest CT for lung cancer screening.  The results from this study concluded that the level of false-positive diagnosis and overdiagnosis was still high, with rates of 90% to 94%.²¹ Overdiagnosis refers to the detection of small lesions that do not grow, spread, or result in death.²² The Early Lung Cancer Action Project and the Mayo Clinic CT studies indicated that CT did, in fact, demonstrate an increase in the number of patients diagnosed with early lung cancer; however, these results failed to contribute to a decrease in the mortality rate due to lung cancer. Other technologies, such as LDCT followed by PET with fluorodeoxyglucose have also been evaluated with similar results.

Overall, screening interventions have failed to alter the mortality rates due to lung cancer, and there have been no major calls for mass screening programs, such as those instituted for colon or breast cancers. The programs offered to help smokers stop smoking are a more effective tool to prevent death and complications as a result of lung cancer, as opposed to screening campaigns designed to detect early lung cancer. Aside from the inability of widespread screening to prevent lung cancer deaths, these programs are contraindicated due to the high cost of screening and follow-up, as well as the anxiety associated with false-positive results.²³ Nevertheless, there are a number of current lung cancer screening trials in progress, including the National Lung Screening Trial sponsored by the National Cancer Institute and the New York Early Lung Cancer Project sponsored by New York State.

Treatment Options and General Management
The therapeutic approach to lung cancer depends largely upon histology and staging of the tumor. If surgery is a viable option, the patient's functional status and potential risks with surgery are very important considerations. Overall, the treatment of lung cancer involves a multifaceted approach that encompasses surgery, radiation therapy, and chemotherapy.

Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with a median survival from diagnosis of only 2 to 4 months. Compared with other cell types of lung cancer, SCLC has a greater tendency to be widely disseminated by the time of diagnosis but is much more responsive to chemotherapy and radiation therapy.²⁴

Surgery
Surgical resection is a standard component to the treatment regimen of patients with stage 1 and stage 2 NSCLC and may be used with or without chemotherapy.²⁵ Selection of patients for resection of the primary tumor depends on the stage of the disease, in addition to the patient's general health status.

The optimal surgical procedure is lobectomy, which is the removal of an anatomical section of the lung; in some cases a pneumonectomy, or removal of a whole lung, will be carried out.^8,9,24-28 An important factor to be considered is the preservation of lung function to the greatest possible degree. The availability of video-assisted thorascopic surgery (VATS) allows for less invasive surgery and may be useful in selected patients. However, comparative results with VATS and conventional surgery have yet to be resolved.^9,27

Patients with stage IIIA disease may be considered for surgery dependent on the site of the primary tumor whereas stage IIIB disease, by virtue of evidence of lymph node metastases or invasion of the carina, heart, or great vessels, is typically inoperable. In general, most patients who present with stage III NSCLC are considered inoperable. If surgery is possible, these patients may be more suitable for postoperative radiation therapy, or for radiation therapy alone if surgery is not possible. Stage IV disease has metastasized to distant sites, such as the brain, bones, or liver, and is largely considered to be incurable by surgery.⁹

Results following surgery are favorable, with a 50% to 70% 5-year survival for stage 1 NSCLC,⁸ and this remains the treatment of choice for this population.

For patients diagnosed with SCLC, surgery plays a very minor role with fewer than 10% of patients being suitable for staging thoracotomy.⁹

Chemotherapy
Most lung cancers, especially SCLC, develop systemic metastases, which, at the time of presentation, are associated with a very high risk of widespread metastases. Chemotherapy therefore plays a significant role in the treatment of both NSCLC and SCLC in light of the high probability of systemic disease. Although chemotherapy regimens often induce a response in patients with NSCLC, with modest improvements in survival, no regimen is completely effective and none has been associated with a cure.

Postoperative adjuvant chemotherapy has been shown to improve survival for patients with stage II disease and may also have a role in the treatment of stage IB NSCLC.²⁹ Adjuvant chemotherapy, with or without radiation therapy, is also used as a standard treatment for later-stage NSCLC, and several different combination chemotherapy strategies have been employed. Combination regimens, including platinum-based chemotherapy, have become the standard of care for treating NSCLC, and these drugs have modestly improved survival.²⁸ The most common platinum-based drugs are cisplatin and carboplatin. Cisplatin-based adjuvant chemotherapy has been shown to improve survival among patients with completely resected stages I, II or IIIA NSCLC.³⁰

Many clinical trials have been conducted to assess the value of combination chemotherapy. However, there does not appear to be an advantage to using more than 2 drugs in a chemotherapy regimen.⁹ Modern drugs used in combination may include cisplatin, carbo/taxol, etopiside, gemcitabine, taxane agents, and vinorelbine.

Neoadjuvant chemotherapy, which involves the administration of cycles of chemotherapy before definitive local therapy with surgery or radiation therapy, appears to be beneficial for locally advanced NSCLC, while chemotherapy administered concomitantly with radiation is being intensively investigated to improve local control.⁹

The management of SCLC involves systemic treatment, and combination chemotherapy is now recognized as the primary strategy. The standard of care for patients with SCLC includes systemic chemotherapy in addition to locoregional radiation therapy.²⁸ The chemotherapy drugs used in the management of SCLC are similar to those used for NSCLC treatment.

Radiation Therapy
Radiation therapy (RT) is used for patients with early stage NSCLC who are not surgical candidates and is also used definitively for later-stage lung cancer. In lung cancer, the goal of RT may be either radical or palliative care.^8,31

The outcome for early stage disease with RT alone is not as favorable as with surgery alone. In general, the 5-year survival rate for RT alone in lung cancer is approximately 20%.²⁸

The use of radiation therapy alone for later stage (stage III) NSCLC consistently results in a median survival of 10 months, and a 5-year survival rate of approximately 5%.³² The utility of post-operative adjuvant RT for stage I NSCLC has been evaluated in several studies with mostly negative results.²⁵ At best, the 2-year survival rate for lung cancer, with surgery and adjuvant RT, is 48%.²⁸

For early stage disease, the primary object of RT is to achieve local control of the tumor. For patients with non-resectable early or late-stage lung cancer or metastatic disease, the therapeutic aim is to ablate the tumor or, at the least, to shrink the tumor to a significant degree while sparing the surrounding healthy tissue.

The standard approach of RT for both early and advanced disease stages involves administering doses in the region of 54 to 66 Gray (Gy) in 30 to 33 daily fractions of 1.8 to 2 Gy per daily fraction. However, it has been reported that 30% to 50% of patients with either early stage or advanced stage NSCLC undergoing RT at these doses will develop local failure within the primary tumor, or will fail treatment due to the development of distant metastases.³¹ Meanwhile, with conventional radiation techniques, increases in radiation dose have been inversely correlated with local tumor control.

Radiation treatment fields generally encompass the primary tumor and regional lymphatics in the ipsilateral hilum and mediastinum, and also account for lung motion due to respiration. This necessitates large treatment fields to be used, often not less than 10 x 10 cm. However, a larger volume of tissue irradiated is associated with a lower degree of tolerance in the normal tissue to doses of radiation. One substantial side effect of radiation intolerance, radiation pneumonitis, is a potentially fatal complication of lung irradiation, and its occurrence is proportional to the volume of lung irradiated.³¹

The standard radiation treatment is often poorly tolerated, especially in patients with poor performance status and those with limited pulmonary reserves, such as those with chronic heart failure or emphysema. The protracted length of the treatment, which can be 5 to 6 weeks in some cases, adds further burden and stress to patients.

Patient set-up for RT. When preparing a patient for RT, the primary aim is to achieve good immobilization of the patient to allow reproducible positioning on a day-to-day basis, thereby allowing for a high degree of accuracy in treating the patient and the tumor according to the treatment plan.

Radiation therapy management options exist in which the highly accurate treatment of lung cancer can be achieved using high doses of radiation per fraction, decreasing the volume of tissue being irradiated, and decreasing the number of fractions delivered. In addition, the motion of the lungs due to breathing can be controlled, increasing the degree of accuracy in delivering radiation treatment. There are several methods available to control lung motion, including the use of an occlusion valve to stop the breathing at a particular phase of the respiration cycle, or the use of a device that electronically monitors breathing and triggers the delivery of the radiation dose during a specific phase of the respiration cycle.

Stereotactic body radiation therapy. Stereotactic body radiation therapy (SBRT) is image-guided RT with the use of 3-dimensional conformal treatment planning and stereotactic targeting of the beam. SBRT allows for highly accurate localization of the tumor, which in turn allows for a substantial reduction in the volume of irradiated lung tissue and delivery of higher radiation doses. The use of SBRT for the treatment of solitary lung tumors represents a potential opportunity to improve clinical outcomes. Many studies have been conducted over the past 2 decades to assess the efficacy of SBRT and, for the most part, indicate that SBRT increases the biological effectiveness of RT. SBRT has a proven safety record² and is a promising option for many patients with lung cancer who are considered unsuitable for surgery.

Patients who may be viable candidates for SBRT include those who refuse surgery; those who have significant medical problems or comorbidities; patients suffering from cardiac dysfunction, vascular disease, or diabetes mellitus; patients with a limited pulmonary reserve (emphysema); elderly patients with compromised  performance status (general frailty); and patients with lung metastases who are suitable candidates for RT, have good performance status, and those who have solitary lesions or lesions that are amenable to RT.

Dose fractionation regimens using SBRT vary from 10 to 60 Gy, delivered in 1 to 5 fractions. SBRT requires a system that accounts for the position of the patient and motion of the internal organs. Immobilization, reproducible positioning, and localization are the most important aspects of the treatment process. The University of Colorado Hospital uses a frameless system with real-time optical tracking of an object by means of infrared markers attached to the patient. The position of the markers is tracked by means of a camera system in the treatment room. Kilovoltage X rays are taken from both sides of the patient, and these are fused with the images from CT treatment planning (Figure 5). The X rays and fusion are done every day to ensure that the patient is positioned accurately and correctly according to the original treatment plan. If any changes occur on a day-to-day basis, the machine will correct for these changes by giving adjustment requirements in millimeters.

One concern in administering SBRT is the uncertainty of the effects of the altered fractionation with the higher doses.^33,34 However, the observed rate and severity of pulmonary complications after the high dose per fraction in SBRT is surprisingly low. Radiation pneumonitis is seen in most patients, and it is often difficult to differentiate on diagnostic images between radiation pneumonitis and residual tumor.³³ Only after 3 to 6 months of follow-up has it been possible to determine that irregular densities, reduced in size over time, were most likely to be related to radiation pneumonitis. In most clinical studies of SBRT, the pulmonary changes that have occurred are very similar to those observed with conventional RT and are generally not severe. In one Japanese study during which the CT appearance of tumors and lung injury after SBRT were evaluated, the investigators concluded that the pulmonary reaction to SBRT was similar to reactions observed with conventional RT.³⁵

A full literature survey to assess the value of SBRT for early stage NSCLC and solitary lung lesions is beyond the scope of this article. However, SBRT has been accepted as an option for select patients with NSCLC.

Recent Advances: Biological Molecular Targeting
As previously discussed, the mortality rate for patients with NSCLC is high. The 5-year survival rate for NSCLC hovers at approximately 15%, and this figure drops dramatically with advancing stage.³⁶ In light of these facts, there has been aggressive research done to find new and effective treatments to improve the outcome for this disease.

Research into cancer at the cellular and genetic level offers new advances whereby specific cellular processes are manipulated using biological agents.

Evidence strongly suggests that growth factors and receptors play a central role in malignancy. Growth factors are polypeptide molecules that regulate cell growth, differentiation and survival. They are found on cell membranes and approximately 40 different growth factors have been identified. The effects of growth factors are mediated by receptors, one of which is the epidermal growth factor receptor (EGFR).

Many epithelial malignancies display increased EGFR on the cell surface (overexpression), and lung cancer is one, particularly in NSCLC, SCC, and adenocarcinoma. In NSCLC, EFGR is overexpressed in 50% to 81% of tumors,³⁶ and this is thought to lead to changes in cell growth, invasion, angiogenesis, and metastases.

Epidermal growth factor receptor inhibitors (anti-EGFR) block the ability of the growth factor to bind to the receptor, and the growth and survival of the cells is effectively stopped. The latest anti-EGFR drugs that are in use include gefitinib, erlotinib, and sorafenib.³⁶ Several studies have been conducted (IDEAL [Dose Evaluation in Advanced Lung Cancer] 1 and 2) in which gefitinib was used in conjunction with chemotherapy and radiation, with response rates of between 11% and 18%.⁹ Gefitinib was well tolerated in these trials, with the most prominent side effects including skin rash and diarrhea.

A second biologic process that has been targeted is the arrest of the blood supply to the tumor with the use of angiogenesis inhibitors. In addition, biological agents that target vascular endothelial growth factor (VEGF), which plays a role in the proliferation and maintenance of neovasculature, are being developed. Bevacizumab is one VEGF inhibitor that continues to be extensively tested in conjunction with chemotherapy. However, the ability to obtain definitive results has been challenging, indicating that further work needs to be done before these drugs can be accepted for use in all patient populations. As a result, these treatments are presently used largely for patients with NSCLC who have failed primary treatment and in those who have metastatic lung cancer.

Conclusions
Over the past 2 decades, there has been a modest improvement in the treatment of lung cancer. Improved technology in diagnostic imaging, the development of new chemotherapy drugs, and improvements in radiation treatment planning and delivery have all played a role in improving outcomes. The role of drugs that achieve specific molecular biological targeting is receiving attention, and clinical trials with these agents are in progress for all stages of lung cancer. Although innovative new treatment strategies are under development, the best route to improving mortality rates due to lung cancer continues to be prevention and cessation of smoking, with improved screening methods for the early detection of lung cancer.

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