Lung cancer is the leading cause of cancer-related death and is responsible for more than a quarter of all deaths due to cancer in the United States. Patients whose cancer is diagnosed early, before it spreads, have a 5-year survival rate of 52%; however, just 15% of lung cancers are diagnosed at this stage. Overall, the 5-year survival rate for small cell lung cancer (6%) is lower than for non-small cell lung cancer (18%).

Integrative interventions like vitamin D, melatonin, and soy isoflavones have been shown in studies to affect survival rates in lung cancer patients.

Causes and Risk Factors

• Smoking and tobacco smoke, which are implicated in approximately 85% of all lung cancers
• 50‒80% increased risk of lung cancer if first-degree relative or sibling has the disease
• Emphysema increases risk 2.44-fold and chronic bronchitis 1.47-fold
• Exposure to asbestos, diesel engine exhaust, air pollution, pesticides, and heavy metals are associated with lung cancer development

Note: Recent evidence suggests e-cigarettes can harm the lungs. In one study, never-smokers and regular smokers demonstrated a significant increase in airway resistance in response to e-cigarettes. Lab studies have also shown that the nicotine vapor from e-cigarettes enhanced the “aggressive” behavior of epithelial lung tissue that already contained mutations.

Signs and Symptoms

• chest discomfort or pain, persistent cough, trouble breathing, wheezing, bloody sputum
• loss of appetite, unexplained weight loss
• fatigue
• hoarseness, trouble swallowing
• swelling in the face and/or veins in the neck

Diagnosis and Staging of Lung Cancer

A number of tests and diagnostic tools may be used to identify lung cancer and determine how advanced it is, including:

• Imaging: X-rays, magnetic resonance imaging (MRI), chest computed tomography (CT), and positron emission tomography (PET) scans
• Staging: The extent of the cancer is determined by tumor size, whether cancer cells have spread to nearby lymph nodes, and whether additional metastatic events have occurred.

Note: Annual screening with low-dose computed tomography (LDCT) is recommended in current smokers with a 30 pack per year smoking history and most former smokers ages 55 to 80.

Conventional Treatment

• Lung cancer treatment depends on the subtype of the cancer and its stage, but can involve surgery, chemotherapy, and radiation.

Novel and Emerging Strategies

• Vaccines, with several in late-stage trials
• Quantitative circulating tumor cell (CTC) analysis counts the number of CTCs in a patient’s blood.
• Metformin, with studies showing that people with type 2 diabetes who use it have a significantly lower risk of developing lung cancer

Dietary and Lifestyle Changes

• Smoking cessation
• Controlling glucose levels, as studies find that people with diabetes and lung cancer have a worse prognosis
• Adhering to a Mediterranean diet may reduce lung cancer risk

Integrative Interventions

• Vitamin D: An epidemiological study found that patients with lung cancer who underwent surgery during the summer and had higher vitamin D intake (greater than 596 IU daily) had a significantly longer period of recurrence-free survival and overall survival than those who underwent surgery during the winter and had low vitamin D intake (less than 239 IU daily and no vitamin D supplements).
• Melatonin: A study of lung cancer patients found significantly higher 5-year survival rates and tumor regression rates in those who received melatonin each evening while undergoing chemotherapy compared with those who received chemotherapy alone.
• Soy Isoflavones: A study of women with lung cancer found that those whose diets were highest in soy products and isoflavones (average 31.4 g of soy foods and 53.5 mg isoflavones daily) before diagnosis had mortality rates at the 2-year follow-up that were 81% lower than those with the median intake (average 16 g soy foods and 26.5 mg isoflavones daily).
• Vitamin E: A large study on male smokers found that those whose blood levels of alpha-tocopherol were in the top 20% had a 19% reduction in the risk of developing lung cancer compared with those whose levels were in the bottom 20%.
• Zinc: A study of lung cancer patients compared with an equal number of healthy individuals found that those with the highest dietary intake of zinc (greater than about 12 mg daily) had a 43% lower risk of lung cancer.

Lung cancer is the leading cause of cancer-related death and is responsible for more than a quarter of all deaths due to cancer in the United States (ACS 2013a). It accounts for 13-14% of all cancer diagnoses, making it the second most commonly diagnosed malignancy in both men and women (not counting skin cancers) (ACS 2013a; ACS 2014a). Until the 20th century, however, lung cancer was a relatively rare disease. That changed with the advent of wide-scale cigarette smoking, which remains the leading cause of lung cancer today (Proctor 2001; A.D.A.M. 2013a; Hill 2003; OSH 2006).

There are two main types of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The majority of lung cancer patients have NSCLC, which usually grows and spreads more slowly and has a better 5-year overall survival rate than SCLC (NCI 2013a; NCI 2013c; A.D.A.M. 2013a; ACS 2013a).

The primary treatments for lung cancer are the same as those for most solid tumors: surgery, chemotherapy, and radiation. Their applicability and effectiveness depend on the stage at which the cancer is diagnosed, subtype classification, and genetic characteristics (A.D.A.M. 2013a; Hofmann 2006; Ellis 2012).

Although 1-year survival rates for lung cancer have improved in the past 3 decades thanks to better surgical techniques and treatments, the 5-year survival rate for all stages combined is still relatively poor at only about 16%. Patients whose cancer is diagnosed early, before it spreads, have a 5-year survival rate of 52%; however, just 15% of lung cancers are diagnosed at this stage. Overall, the 5-year survival rate for small cell lung cancer (6%) is lower than for non-small cell lung cancer (18%) (ACS 2013a; Dela Cruz 2011; American Lung Association 2014c; Youlden 2008; NCI 2014d).

Several efforts are underway to improve outcomes in lung cancer patients. Recommendations for routine screening of current and former smokers, emphasis on personalized genomic medicine with targeted therapies, and the development of highly specific drugs focused on destroying malignant tissue while sparing healthy cells represent key opportunities in the battle against lung cancer (Schabath 2014; Moyer 2013; Ma 2013; Clinical Lung Cancer Genome Project 2013; Heuvers, Hegmans 2012; Heuvers, Aerts 2012; Wouters 1999; Nascimento 2014).

In this protocol, you will learn about the fundamentals of lung cancer and lung cancer treatment, novel and emerging strategies such as cancer vaccines, as well as scientifically studied integrative interventions that may target some of the underlying mechanisms that drive lung cancer.​

Lung cancer tends to develop slowly, though there are very aggressive types of lung cancer that grow and metastasize rapidly (Hayabuchi 1983; Lozic 2010; Cooper 2000; Alberts 2002). The transformation of healthy lung tissue into cancerous tissue occurs at the cellular level as DNA is damaged by various possible mechanisms, including environmental carcinogens such as those found in tobacco smoke, with the likelihood of cancer development dependent upon each individual’s genetic predisposition. Prolonged DNA insults eventually lead to disruption of signaling pathways that control cellular growth in lung tissue. Once genes and pathways that control cellular growth are sufficiently damaged, malignancy emerges (Horn 2013a; Sato 2007).

Researchers have identified numerous molecular changes that drive lung cancer development, many of which have become targets of biologic drugs designed to destroy cancerous cells or arrest their growth. Several gene mutations have been associated with lung cancer, but two have been particularly well studied (Davidson 2013; Horn 2013a):

• KRAS – Mutations in the KRAS gene primarily occur among smokers with adenocarcinomas;
• EGFR – Mutations in the EGFR gene are more common in patients who never smoked, women, and Asians.

Both genes control cellular growth, so mutations in these genes can cause cells to grow and divide rapidly and continuously, eventually leading to tumor formation (Horn 2013b; Bacchi 2012; Martinsson 2010; Sunaga 2011; Yoon 2010).

Types of Lung Cancer

The types of lung cancer include non-small cell lung cancer (NSCLC), which is the most prevalent; small cell lung cancer (SCLC), which accounts for 15-20% of lung cancers in the United States; as well as some rare neuroendocrine tumors accounting for less than 5% of cases (Horn 2013a; Mayo Clinic 2014; NCI 2014e; Skirecki 2009). NSCLC and SCLC are further classified based on their pathology (NCI 2013a; NCI 2013c; Horn 2013b). The type of cancer helps determine the treatment used as well as the prognosis.

Non-small cell lung cancer. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, arising from the bronchial surface epithelium or bronchial mucous glands (Bunn 2008; O'Hanlon 2013). It tends to grow and spread to other sites (metastasize) more slowly than SCLC. The 5-year survival rate for NSCLC is 18%, compared to 6% for SCLC (ACS 2013a; A.D.A.M. 2013a).

• Adenocarcinoma. Adenocarcinoma is the most common type of lung cancer in the United States and Japan. It predominantly occurs in smokers, although never-smokers may also develop this form. This type typically develops in the mid-lung zone and periphery of the lung. Patients with solid and micropapillary adenocarcinomas (many small tumor loci) tend to have a worse prognosis (Horn 2013a).
• Squamous cell carcinoma. Squamous cell carcinoma is strongly associated with smoking (Herbst 2008) and typically occurs within the central part of the lung (Horn 2013a).
• Large cell carcinoma. Large cell carcinoma usually occurs in the periphery of the lung and accounts for less than 10% of lung cancers (Horn 2013a).

Small cell lung cancer. Small cell lung cancer (SCLC) arises from neuroendocrine cells in the lungs and is sometimes referred to as oat-cell carcinoma because of the flatness and small oval shape of the cancer cells (O'Hanlon 2013). SCLC accounts for 15-20% of lung cancer cases (Skirecki 2009). SCLC is more aggressive than NSCLC, with the cells dividing more rapidly, although it is generally more responsive to chemotherapy and radiation therapy. However, the potential for metastasis and the rate of recurrence after treatment are both high, and overall survival rate is poor (ACS 2013a; A.D.A.M. 2013a; NCI 2013c).

Neuroendocrine tumors of the lung. SCLC is a type of neuroendocrine cancer and there are three other less common neuroendocrine tumor types: typical carcinoid, atypical carcinoid, and large cell neuroendocrine carcinoma. The first two are less common in smokers and generally less aggressive, while the latter is more likely to be seen in smokers and carries a worse prognosis (Horn 2013b; ACS 2013b; Rekhtman 2010).

Lung Cancer among Never Smokers

Rates of lung cancer in never smokers vary depending on gender, ethnicity, and geographic location. Approximately 40% of females in Asia diagnosed with lung cancer are never smokers, while about 10% of males diagnosed with lung cancer in Western countries never smoked (Pallis 2013a; Larsen 2011). A study published in 2012 found that the increased risk of lung cancer in never-smoking women in Asia was linked to three genetic alterations that are prevalent in this population – a mutation on chromosome 10 and two separate mutations on chromosome 6 (Lan 2012). Lung cancer in never smokers generally displays a different profile of mutations and molecular changes than those which occur among smokers (Larsen 2011).

Risk factors for lung cancer among never smokers include exposure to secondhand smoke, hormonal and genetic factors, air pollution, radon exposure, and occupational exposure to carcinogens (Pallis 2013a; Brennan 2011; CDC 2006; Kligerman 2011; Cohen 1995). Never smokers diagnosed with lung cancer are more likely to have adenocarcinomas. Several reports have demonstrated a better survival rate compared with smokers (Pallis 2013a).

There are striking differences in the pathophysiology and biology of lung cancer in patients who never smoked compared to patients who ever smoked. A small study found, on average, a 10-fold higher rate of genetic mutations in smokers with lung cancer compared to never smokers (Govindan 2012). Moreover, comparisons of the 2 groups showed marked differences in the profile of mutations. For instance, overexpression of epidermal growth factor receptor (EGFR) is more common in lung cancer among never smokers (Pallis 2013a; Larsen 2011).

In addition to differences in the genetic profiles of smoking-associated lung cancers and those not associated with smoking, there are also differences in the location of these tumors within the lung. Smoking-related cancerous lesions, whether SCLC or NSCLC, most often develop in the central airway of the lungs, while most lung cancers in never smokers develop in the distal airways (Usuda 2010; Gonzalez 2012; Samet 2009; Larsen 2011; Brambilla 2009).​

Smoking

Although there are a variety of causes and risk factors for lung cancer, none are more clearly defined than smoking, which is implicated in approximately 85% of all lung cancers (Larsen 2011). Overall, smokers are about 25 times more likely than nonsmokers to develop lung cancer (Larsen 2011; ACS 2013a; ACS 2014c). Over half of newly-diagnosed lung cancers in the United States, however, occur in people who have already quit smoking, a testament to the long-term damage caused by tobacco smoke (Larsen 2011). Those exposed to secondhand smoke are at increased risk of developing lung cancer as well; one study estimated that workers exposed to atypically high levels of secondhand smoke may have up to a 13-fold increased risk of dying from lung cancer (NCI 2014e; Mayo Clinic 2014; O'Hanlon 2013; Siegel 2003).

Tobacco smoke has been reported to contain over 6000 chemicals, more than 70 of which have been shown to be carcinogenic. These include arsenic, benzene, benzo(a)pyrene, cadmium, and formaldehyde (Sanders 2008; Health Canada 2011). When inhaled, these compounds contribute to DNA damage, resulting in the mutation of genes involved in controlling cellular growth (Landi 2006).

Fortunately, long-term smoking cessation mitigates lung cancer risk; after 10 years without smoking, the likelihood of developing lung cancer is decreased 30–50% (NCI 2013d). However, it is unclear if former smokers have a better prognosis than patients still smoking at diagnosis. It is clear, however, that smoking cessation after diagnosis improves outcomes (Parsons 2010).

Family History and Genetic Predisposition

Several large studies have identified inherited genetic variations that increase the risk of lung cancer, some of which also increase the risk of nicotine dependence (Larsen 2011). Studies have found at least 3 key chromosomal regions that in populations of European descent are associated with the risk of lung cancer: sequence variants within the nicotinic acetylcholine receptor genes on chromosome 15, which are associated with the number of cigarettes smoked per day, nicotine dependence, and smoking-related diseases; sequence variants in a region on chromosome 5, which includes the TERT and the CLPTM1L genes; and a region on chromosome 6. Neither of the two latter regions appeared to be associated with smoking behavior (Rafnar 2011). Having a first-degree relative with lung cancer is associated with a roughly 50% increased risk of acquiring the disease; the risk increases to about 80% when the affected relative is a sibling (Cote 2012).

Previous Lung Disease

Many lung diseases, including chronic bronchitis, emphysema, pneumonia, and tuberculosis are associated with lung cancer development (Brenner 2012; Koshiol 2009). Specifically, people with emphysema and chronic bronchitis have a 2.44-fold and 1.47-fold increased risk, respectively, of developing lung cancer. Never smokers with a history of emphysema, pneumonia, or tuberculosis demonstrate a higher risk of lung cancer than those without (Brenner 2012). These diseases are major sources of inflammation in lung tissue, which is thought to contribute to cellular changes resulting in malignancy (Brenner 2012; Koshiol 2009; Engels 2008).

Carcinogenic Environmental Factors and Toxins

Several environmental factors are associated with lung cancer development, including exposure to asbestos, diesel engine exhaust, air pollution, pesticides, and heavy metals such as cadmium and nickel (Vermeulen 2014; Raaschou-Nielsen 2013; Clapp 2008; Offermans 2014; Wild 2009).

Radon, a radioactive gas released from the decay of uranium, thorium, and radium, can damage epithelial lung cells, leading to cancer. In fact, exposure to radon is the second leading cause of lung cancer in the United States, after smoking (NCI 2011).

Symptoms of lung cancer include chest discomfort or pain, persistent cough, trouble breathing, wheezing, bloody sputum, hoarseness, loss of appetite, unexplained weight loss, fatigue, trouble swallowing, and swelling in the face and/or veins in the neck (NCI 2013c). Individuals with SCLC sometimes exhibit other symptoms, including the syndrome of inappropriate antidiuretic hormone secretion (SIADH). (Antidiuretic hormone, or vasopressin, helps regulate reabsorption of water in the kidneys, as well as blood pressure.) Abnormal antidiuretic hormone secretion leads to excess fluid buildup in tissues (Canadian Cancer Society 2014).

Sometimes patients present with symptoms that are due to the cancer but are not caused by the local presence of cancer cells. The term “paraneoplastic syndrome” refers to the collection of symptoms that result from substances produced by the tumor, and occur remotely from the tumor itself. Sometimes, paraneoplastic syndromes can appear before the cancer is diagnosed and may be the presenting symptom of the cancer. These conditions include Cushing syndrome, caused by excessive cortisol levels; paraneoplastic cerebellar degeneration (a rare neurologic disorder); or Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder resulting in muscle weakness in the limbs (Yoh 2003; Marchioli 1997; Thomas 2004; Gandhi 2006; Gilhus 2011; NCI 2013c).​

Diagnosis

A number of tests and diagnostic tools may be utilized to identify lung cancer and determine how advanced it is. Blood testing is routinely ordered as part of the workup and includes a complete blood count (CBC) and chemistry panel (includes several parameters such as liver and renal function tests and electrolytes) (O'Hanlon 2013).

Imaging. X-rays, magnetic resonance imaging (MRI), chest CT, and positron emission tomography (PET) scans are used in the diagnosis and staging of lung cancer (Horn 2013a). In addition, a bone scan may be performed to see if the cancer has moved into the bones (Horn 2013a; American Lung Association 2014b). PET scans can also help determine if cancer has metastasized to other areas of the body (Schrevens 2004). A PET scan involves injecting the patient with a radioactive tracer compound called fluorodeoxyglucose, or FDG, which is a modified glucose molecule that can still be taken up by cells. Shortly after being injected with FDG, the patient is analyzed with computer-aided scanning technology that detects gamma rays emitted by the radioactive FDG. Since cancer cells are more metabolically active than most normal cells, the FDG, which cells recognize simply as glucose, is taken up more rapidly into cancerous tissue. Thus, a PET scan will reveal areas of cancer metastasis by detecting higher concentrations of FDG in affected tissues (Lucignani 2004; Avril 2001; Huang 2000; Bustamante 1977; Lopez-Lazaro 2008; Verhagen 2004; Zhu 2011).

A tissue sample is necessary to accurately diagnose the type of lung cancer, plan treatment, and predict prognosis (O'Hanlon 2013).  

Biopsy. Fine needle biopsy uses a long, thin needle to remove a piece of tissue from the lungs, which can then be examined under a microscope (American Lung Association 2014b). A biopsy may not be necessary if tissue will be obtained during surgery to remove the tumor (NCCN 2014a).

Tissue samples can be obtained several different ways. The type of procedure or biopsy performed depends on characteristics of the suspected cancer based on radiographic and clinical findings (Rivera 2013):

• Bronchoscopic biopsy. Bronchoscopy involves insertion of a flexible tube down the throat into the lungs to allow the physician to view the airways and lungs (A.D.A.M. 2013b). It is typically performed prior to surgery (NCCN 2014a).
• Endobronchial ultrasound (EBUS)-guided lung biopsy. Endobronchial ultrasound is similar to a bronchoscopy except an ultrasound device is fitted onto the end of the bronchoscope. It is used to see if the cancer has spread to the lymph nodes and/or nearby tissues in the chest (American Lung Association 2014b). Endobronchial ultrasound (EBUS)-guided lung biopsy is a minimally invasive procedure in which a thin catheter with a balloon at the end is inserted into the airways to obtain detailed images. A biopsy instrument can be inserted through the catheter to obtain a biopsy sample (Gomez 2009).
• Mediastinoscopy is performed by a surgeon inserting a small camera through tiny incisions to visualize the mediastinum (ie, the part of the chest between the sternum and spine and between the lungs). This procedure is useful for removing lymph nodes and looking for abnormal growth on the outside of the lungs and in the chest (A.D.A.M. 2012a; A.D.A.M. 2012b).
• Thoracoscopy, video-assisted thoracic surgery (VATS). A surgical procedure in which the surgeon looks for and removes tumors in the chest wall (American Lung Association 2014b).

Sputum cytology. Mucus coughed up from the lungs is examined under a microscope for any cancer cells (American Lung Association 2014b).

Thoracentesis. The doctor slips a needle between the ribs to drain fluid and assess it for cancer cells (American Lung Association 2014b).

Staging

The extent of the cancer is determined by tumor size, whether cancer cells have spread to nearby lymph nodes, and whether additional metastatic events have occurred. NSCLC is staged from I to IV, with stage IV representing advanced, metastatic cancer. Stages are further subdivided based on specific characteristics of the tumor and lung as well as where the cancer has spread (NCCN 2014a; NCI 2013a).

SCLC cases are divided into either a limited disease stage, in which the cancer is limited to the lungs and nearby lymph nodes, or extensive disease stage, in which metastasis to areas outside the chest cavity has already occurred (NCCN 2014b).

Staging is completed after several tests, including MRI, CT, or PET scans; bone scans; pulmonary function tests; endoscopic ultrasound; mediastinoscopy; lymph node biopsy; and sometimes, bone marrow aspiration and biopsy to see if the cancer has metastasized to the bone marrow (NCI 2013c).

Lung cancer treatment depends on the subtype of the cancer and its stage. The initial treatment for stage I or II NSCLC is surgery, usually followed by chemotherapy and radiation. Although surgery in patients with stage III cancer is controversial, national guidelines suggest its use in certain cases (McCloskey 2013). Either way, these patients will generally receive chemotherapy and often drugs that specifically target signaling pathways known to be involved in lung carcinogenesis such as bevacizumab (Avastin), erlotinib (Tarceva), or crizotinib (Xalkori) (NCCN 2014a; ACS 2013a).

Early-stage (stage I) SCLC may be treated with surgery to remove the affected lobe followed by chemotherapy, with a combination of chemotherapy and radiation, or chemotherapy alone (ACS 2014d). More advanced SCLC is often treated with chemotherapy alone or with radiation therapy to the whole brain (to treat/prevent metastasis) or other parts of the body to shrink tumors and reduce symptoms (NCCN 2014b).

Surgery

Surgical removal of a primary lung tumor by a thoracic surgeon is the standard treatment for early-stage NSCLC (Belani 2005; He 2012; NCCN 2014a; Liberman 2006). The preferred method is anatomic pulmonary resection (thoracotomy), also called pneumonectomy or segmentectomy depending on how much lung tissue is removed. It is the most common surgical procedure in general thoracic surgery. It can be performed with a minimally-invasive approach called VATS (video-assisted thoracoscopic surgery) (He 2012; NCCN 2014a). An advantage of VATS is that it requires only a minimal incision in the thorax. Thus, it takes less time to perform the surgery, with fewer post-surgical complications and faster recovery (Detterbeck 2013; NCCN 2014a).

Only about 5% of patients with SCLC are diagnosed at stage I, which is the only stage for which surgery is an option (NCCN 2014b).

More than half of patients with either type of lung cancer are not eligible for surgery due to local spread (ie, extended beyond the lungs into the thoracic cavity) or distant metastasis (Shamji 2013). Other contraindications include patient age (particularly 75 and older), general physical and mental health, and certain characteristics of the cancer. In addition, the patient may elect not to undergo surgery (Dell'amore 2013; Shamji 2013; Mehta 2012).

Readers are encouraged to also review the Cancer Surgery protocol, which contains detailed information about important considerations for those preparing to undergo surgery to remove cancerous tissue.

Radiation Therapy

Radiation therapy may be administered alone or in combination with chemotherapy and/or surgery, depending on the type of lung cancer, stage, and the presence and nature of complications. In combination with surgery, a regimen of radiation therapy is designed to maximize lung cancer cell killing in the surgical zone (ie, area of the tumor that will be removed). Radiation therapy may be given before surgery (neoadjuvant therapy) to shrink the tumor before the surgical procedure or after surgery (adjuvant therapy) to destroy tumor cells that were left behind (O’Hanlon 2013).

NSCLC. Radiation can be used in NSCLC patients who undergo surgery, as a primary treatment modality when surgery cannot be performed, postoperatively when the cancer was not completely removed, or as a palliative treatment to help keep the patient comfortable (O’Hanlon 2013).

SCLC. In SCLC, radiotherapy administered concurrently with chemotherapy is considered the standard and preferred therapeutic approach, and a shorter time between the start of any treatment and end of radiation therapy was significantly associated with improved survival (NCCN 2014b).

In addition, in all patients, radiation therapy can be used to treat brain metastases, spinal cord compression, or local lesions that cause symptoms, such as nerve paralysis or the obstruction of airways (NCCN 2014a; O'Hanlon 2013; Baskar 2012). Cranial radiation may be implemented preventively as well; patients whose SCLC can be controlled outside of their brain have about a 60% chance of developing central nervous system metastasis within 2 – 3 years of treatment. Preventive cranial radiation therapy has been reported to substantially reduce this risk (NCI 2014a).

Conventional radiotherapy fails to control unresectable NSCLC about 70% of the time. Only around 40% of people with unresectable NSCLC who receive conventional radiotherapy survive 2 years (Ferri 2013). Radiation therapy improves survival for patients with limited-stage SCLC and is recommended soon after diagnosis (ACR 2012). It is typically delivered in conjunction with chemotherapy in patients with limited disease and for a select group of patients with extensive stage disease who respond to chemotherapy (NCCN 2014b; Provencio 2011).

High dose radiation therapy may be associated with some side effects depending on the area(s) of the body targeted. Fortunately, many modern radiation therapy techniques such as intensity-modulated radiation therapy (IMRT), helical tomotherapy, and volumetric-modulated arc therapy target cancerous tissue more precisely, reducing damage to nearby tissues and organs (Chi 2013). A form of targeted radiation therapy called stereotactic body radiation therapy is gaining attention as a useful tool for treatment of early stage lung cancer. A technique called Gamma Knife radiosurgery is used to deliver targeted radiotherapy, while sparing the surrounding healthy tissue, and has been intensively studied in the context of brain metastases originating from lung cancer (Abacioglu 2010; Serizawa 2000; Serizawa 2002). A 3-year postoperative study on 59 patients with early stage but inoperable lung cancer found a survival rate of 55.8%, with a tumor control rate of 97.6% with stereotactic body radiation therapy, about twice that found with conventional radiotherapy (Timmerman 2010).

The Cancer Radiation Therapy protocol provides a comprehensive discussion about radiation therapy and outlines a number of steps that can be taken to maximize its benefits and minimize its side effects.

Chemotherapy

Chemotherapy describes the treatment of disease with chemicals (drugs). In the case of cancer chemotherapy, the drugs administered to the patient typically cause damage to cancer cells by interfering with the process of cell division (Goodin 2007). Although chemotherapy can affect malignant and healthy cells, those cells afflicted with cancer-causing mutations tend to be more vulnerable to these medications because they grow and divide much more rapidly than most normal cells. However, certain cell types, such as those in the hair follicles, gastrointestinal tract, and oral mucosa, divide rapidly under normal conditions, thus begetting the common side effects associated with chemotherapy (Mukherjee 2010; Hanahan 2011; PubMed Health 2012).

Chemotherapy, both in the neoadjuvant (prior to surgery) and adjuvant (post-surgical) settings remains a mainstay of lung cancer therapy (Ripley 2013; Daly 2011; Reungwetwattana 2011).

NSCLC. Patients with NSCLC undergoing adjuvant chemotherapy typically receive cisplatin (Platinol) with vinorelbine (Navelbine); carboplatin may be used in place of cisplatin in some cases, although available evidence suggests that cisplatin may be somewhat more effective (NCI 2014b). Other drugs used include gemcitabine (Gemzar), docetaxel (Taxotere), and pemetrexed (Alimta). Those receiving concurrent chemotherapy/radiation treatment are typically prescribed cisplatin and etoposide (Etopophos, Toposar), cisplatin and vinblastine (Velbe), cisplatin and pemetrexed, or carboplatin (Paraplatin) and pemetrexed (NCCN 2014a). Cisplatin is often part of neoadjuvant chemotherapy (Daly 2011).

SCLC. Patients with limited SCLC typically undergo chemotherapy with cisplatin or carboplatin with etoposide. Those with extensive stage disease may receive other regimens such as irinotecan (Camptosar, CPT-11) with cisplatin (NCCN 2014b; NCI 2014c).

Most chemotherapeutic agents are generally active in fast-growing cells, including healthy cells. They can have serious and often life-threatening side effects (such as anemia, immunosuppression, and heart damage). The Chemotherapy protocol outlines several integrative strategies that may help mitigate some of the adverse effects of chemotherapy.

Targeted Therapy

The success of treatment of NSCLC and SCLC with surgery, radiation therapy, and traditional chemotherapy is largely dependent on diagnosing lung cancer as early as possible (Daniels 2013; Yasufuku 2010; Herbst 2008). However, just a third of NSCLC cases are diagnosed in the early stages when remission with surgical resection alone is possible (Byron 2014). Even then, up to 40% of patients with stage I, 66% of those with stage II, and 75% of those with stage III NSCLC die within 5 years (Byron 2014).

In recent years, however, new classes of drugs that target signaling pathways within cancer cells and are specific to tumor type and genetic makeup provide more options for lung cancer patients, even those diagnosed in later stages (Majem 2013; Larsen 2011). They are typically used as second- or third-line treatments after traditional chemotherapy fails and are often combined with traditional chemotherapies (Majem 2013).

Targeted treatments may be determined by the molecular footprint of the tumor; thereby enabling clinicians to choose an agent based on specific mutation(s) (Table 1). For instance, patients with EGFR (epidermal growth factor receptor) mutations benefit from treatment with drugs that block pathways that activate the receptor, including erlotinib, cetuximab (Erbitux), and afatinib (Gilotrif) (NCCN 2014a; ACS 2014b; Rengan 2011; Majem 2013; Gao 2012; Domvri 2013).

Key molecular biomarkers include KRAS mutations, ALK rearrangements, and MET and EGFR immunohistochemistry, all of which can help identify sensitivity to various chemotherapies, radiotherapy, and molecularly-targeted drugs (Vincent 2012).

The ability to individualize treatment based upon the genetic profile of a patient’s tumor is ushering in a new age of personalized medicine.

Table 1. Targeted Agents for Patients with Genetic Alterations (NSCLC) (Gadducci 2013; Pirrotta 2011; NCI 2012; Elisei 2013; NCCN 2014a; Douillard 2014; Drilon 2013)

Osimertinib for NSCLC. Osimertinib (Tagrisso) is approved as a first-line treatment in patients with metastatic NSCLC with certain EGFR mutations. In December 2020, the FDA approved osimertinib as the first adjuvant treatment for patients with metastatic EGFR T790M mutation-positive NSCLC (Pazdur 2020). Osimertinib was evaluated in the phase 3, double-blind, randomized ADAURA trial of 682 patients with early-stage NSCLC with this specific mutation (Wu 2020). Patients underwent surgery for complete tumor removal and following recovery received standard-of-care chemotherapy or osimertinib. The results showed those who received osimertinib had significantly longer disease-free survival compared with patients in the standard-of-care group. At 24 months, disease-free survival was 89% in the osimertinib group compared with 52% in the placebo group among the overall population of patients with stage IB to IIIA disease.

Bevacizumab for NSCLC. The formation of new blood vessels, known as angiogenesis, is the result of a complex equilibrium between factors that stimulate (pro-angiogenic) and factors that inhibit (anti-angiogenic) this process (Carmeliet 2000; Pallis 2013b). Normally, angiogenesis occurs during very specific times, such as development, reproduction, and wound healing, but it is also pivotal in the development of solid tumors and during their metastatic dissemination (Pallis 2013b).

Vascular endothelial growth factor (VEGF) is a protein that drives angiogenesis upon interaction with its cellular receptors (VEGF receptors). The VEGF receptor pathway is considered the most powerful mediator of angiogenesis in tumors (Das 2012; Pallis 2013b).

Bevacizumab is an antibody against VEGF; it is FDA approved for the first-line systemic treatment of unresectable NSCLC in combination with carboplatin and paclitaxel (FDA 2013; Das 2012; Ferrara 2004; Pallis 2013b; Planchard 2011; NCI 2013e). Bevacizumab is able to inhibit angiogenesis by directly binding to VEGF and preventing it from activating its receptor. In addition to NSCLC, bevacizumab has shown clinical benefits in other cancers, including breast cancer, renal cancer, and metastatic colorectal cancer (Wang 2013). Several studies suggest that combination therapies based on bevacizumab offer clinical benefits in NSCLC (Sandler 2006; Reck 2009), and long-term therapy with this compound showed benefits even in patients with late-stage NSCLC (Fan 2013). Hypertension, an increased risk of bleeding, and gastrointestinal perforation are adverse effects associated with bevacizumab treatment (Wang 2013; Planchard 2011).

Crizotinib for NSCLC. In NSCLC, mutations can occur in several different genes that can contribute to the development of the disease. One of these genes, ALK, was implicated in 2007 in a small but significant proportion of patients with NSCLC (Gupta 2014). In NSCLC, certain genetic alterations involving ALK were reported in 3-7% of patients, particularly in younger people who never smoked or were light smokers; these findings helped define a new subtype of NSCLC (Shaw 2013; Gupta 2014; Iwama 2014). In advanced NSCLC patients who previously received treatment, and who present with alterations in the ALK gene, crizotinib was found to be superior to standard chemotherapy.

Crizotinib inhibits the gene function of the gene product of ALK. It was approved by the FDA in late 2011, less than 4 years after the discovery of its target (Gandhi 2012). Adverse effects with crizotinib include nausea, diarrhea, constipation, vomiting, water retention in the extremities, and visual problems. Also, 1.6% of patients had life-threatening or fatal interstitial lung disease that was related to the treatment (Iwama 2014).

Sotorasib for NSCLC. In May 2021, the FDA approved the first drug ever that targets tumors with KRAS mutations. The drug sotorasib (Lumakras) was approved to treat NSCLC patients with a specific KRAS mutation, called G12C, who have been previously treated with another chemotherapy drug. Approximately 30% of lung adenocarcinomas carry a KRAS mutation, with 13% carrying the specific mutation, KRASG12C, targeted by sotorasib (Veluswamy 2021).

Researchers have attempted to target KRAS for decades, but have not been successful until recently (Veluswamy 2021). Before then, tumors with KRAS mutations were thought to be resistant to chemotherapy. The FDA’s accelerated approval was based on a study in 124 patients with locally advanced or metastatic NSCLC with the KRASG12C mutation who had previously been treated with an immune checkpoint inhibitor or a platinum-based chemotherapy. Thirty-six percent of participants experienced an objective response (meaning the tumor was reduced or destroyed), and of those, 58% sustained that response for at least six months (FDA 2021). As this was an accelerated approval, further studies are needed to clarify the degree of clinical benefit conferred by sotorasib. The most common adverse reactions in the trial, occurring in 20% or more of participants, included diarrhea, musculoskeletal pain, nausea, fatigue, liver toxicity, and cough. Nine percent of participants experienced adverse reactions significant enough to require discontinuation of sotorasib.

Maintenance Therapy

Maintenance therapy is a term used to refer to treatment provided once patients achieve tumor response or have stable disease. However, definitions vary slightly, and the National Cancer Institute defines it as therapy that is given to prevent the cancer from progressing once it has been successfully controlled. It may use the same drug administered previously, or a different drug, and it may include, besides drugs, treatment with vaccines or antibodies (Novello 2011; Stinchcombe 2011; Hirsh 2010). Several large trials have evaluated the use of various drugs as maintenance therapy in NSCLC patients, including docetaxel, pemetrexed, bevacizumab, erlotinib, and cetuximab, all of which demonstrated improved progression-free and/or overall survival in patients receiving the treatment, primarily those with progression-free disease. No such benefits have been observed in patients with extensive-stage SCLC (Horn 2013b).

Vaccines

One of the most exciting frontiers in cancer medicine is the emerging field of cancer vaccines and immunotherapies (Emens 2008). This cutting-edge approach involves reprogramming a cancer patient’s immune system to more aggressively target his or her cancer (Bodey 2000; Butterfield 2014). The basic idea behind therapeutic cancer vaccines is more or less similar to that of vaccination against infectious diseases. However, instead of aiming to prevent disease, cancer vaccines are designed to initiate an immune response against a disease already present in a patient (Palucka 2013).

New technology and improved understanding of lung cancer and its interactions with the immune system have led to new opportunities in immunotherapy, with several vaccines in late-stage clinical trials (Brahmer 2013). Specifically, researchers have identified scores of proteins selectively expressed or modified by tumor cells but not by normal, noncancerous cells. These proteins, which are referred to as tumor-associated antigens (TAAs), can be exploited with cancer vaccines to act as “flags” for the immune system to recognize cancers and eliminate them as if they were virally-infected cells (Buonaguro 2011; Brahmer 2013; Palucka 2013).

Two types of vaccines are under investigation: tumor cell vaccines (composed of actual cancer cells, sometimes the patient’s own) and antigen-based vaccines (target specific proteins expressed by the tumor cells) (Brahmer 2013).

Vaccines in late-stage clinical trials include belagenpumatucel-L (Lucanix), made with four irradiated NSCLC cell lines that, in a phase II clinical trial with 75 patients, elicited a 15% response rate and significantly improved the median overall survival in those who received a high dose as compared to those who received a lower dose (Brahmer 2013). A phase III trial comparing belagenpumatucel-L to placebo following front-line chemotherapy in NSCLC patients is ongoing as of the time of this writing (Fakhrai 2012). Antigen-specific vaccines include melanoma-associated antigen-A3 (MAGE-A3), which targets a tumor-specific antigen expressed only on some tumors, including about a third of NSCLCs; the BLP-25 liposome vaccine and TG4010 vaccine, both of which target an abnormal protein expressed on epithelial cells; and CimaVax EGF, which induces antibodies against EGF to block the binding between EGF and its receptor EGFR (Brahmer 2013; Fernandez Lorente 2013; Mancebo 2012).

Personalizing Cancer Care with Circulating Tumor Cell Testing

The one word that cancer patients dread most is “metastasis.” Metastasis is the spread of cancer cells from the primary tumor into distant organs or tissues. In most cases of cancer-related death, it is not the primary tumor but rather the emergence of distant metastasis that claims the lives of cancer victims (Liberko 2013).

In order for cancer to metastasize, cells of the primary tumor must break away and infiltrate the circulatory system to be transported to another part of the body. These cancer cells flowing through the bloodstream are called circulating tumor cells (CTCs) (Wang, Liu 2011). In recent years, technological advances have given clinicians the ability to collect and evaluate CTCs from a cancer patient’s blood sample. These innovations have been paving the way for new diagnostic and therapeutic strategies based upon quantitative and qualitative analysis of CTCs in several types of cancer (Liberko 2013).

Quantitative CTC analysis allows for the enumeration of CTCs in a patient’s peripheral blood and provides some prognostic insight in several types of cancer. Generally, greater numbers of CTCs in peripheral blood correlate with worse prognosis. An analytical methodology called CellSearch has been approved by the US FDA to enumerate CTCs in breast, colon, and prostate cancer patients (Janssen Diagnostics 2014). CellSearch CTC quantitation counts the number of CTCs in the patients’ peripheral blood and contextualizes the result within evidence-based reference ranges.

Unfortunately, not enough studies have been completed on lung cancer patients to allow meaningful prognostic reference ranges and CTC count thresholds to be established as of the time of this writing, but additional research is underway and lung cancer patients may soon be able to benefit from CTC analysis using CellSearch or other methodologies (Hashimoto 2014). For example, one study published in 2014 showed that NSCLC patients with higher numbers of CTCs at baseline, as determined using the CellSearch methodology, demonstrated worse overall and progression-free survival than patients with lower CTC counts. This study also revealed that patients with lower CTC counts during chemotherapy had better overall and progression-free survival than those with higher counts (Muinelo-Romay 2014). Similarly, a study on 21 limited-stage and 38 extensive-stage SCLC patients employed the CellSearch methodology to detect CTCs before, after one cycle, and at the end of chemotherapy. CTC count after one cycle of chemotherapy was found to be a strong predictor of response to chemotherapy and survival. Moreover, patients with low baseline CTC counts survived longer than those whose CTC counts were higher (Hiltermann 2012). Another study, this time using a different CTC detection methodology called TelomeScan, revealed that SCLC patients with fewer than 2 CTCs per 7.5 mL of blood prior to the initiation of treatment survived significantly longer (14.8 months) than patients with 2 or more CTCs per 7.5 mL of blood (3.9 months). The researchers who conducted the study concluded “…CTC count prior to treatment appears to be a strong prognostic factor” (Igawa 2014).

Another aspect of CTC testing – qualitative CTC analysis – can be used to help guide cancer treatment decisions. Recent technological advances have allowed CTC testing to evolve from simply counting numbers to characterizing intricate molecular properties of CTCs (Dong 2012; Rahbari 2012; Boshuizen 2012).

A major hurdle in the treatment of metastatic cancer is that tumor cells that break away from the primary site may develop different metabolic properties than the original tumor from which they emerged. This presents several problems because physicians often rely upon molecular analysis of a tissue sample from a primary tumor to guide treatment. For example, once a patient is diagnosed with cancer and a tumor is identified, a tissue sample (biopsy) is often taken from the tumor and sent to a pathologist for molecular analysis. This elucidates the properties of the tumor cells and allows oncologists to select interventions with a higher likelihood of success based upon the molecular characteristics of the cancer cells. However, in several cancer types, molecular differences have been observed between primary and metastatic tumors, even within the same patient (Cavalli 2003; Smiraglia 2003). Interventions based upon molecular analysis of the primary tumor may, therefore, not be effective against metastatic tumors (Biofocus 2011).

Qualitative CTC analysis is a step toward overcoming this barrier. Characterization of the molecular and genetic properties of CTCs allows oncologists to select a drug regimen that may be more effective against metastatic tumors. Using a process known as “chemosensitivity testing,” pathologists can analyze the properties of CTCs and determine which chemotherapeutic drugs are likely to kill the cells based upon their specific genetic makeup. Oncologists can then develop a treatment regimen consisting of drugs to which the patient’s CTCs are susceptible (Biofocus 2011; Rüdiger 2013).

Metformin

Prescribed to over 100 million people with type 2 diabetes worldwide, metformin (Glucophage) lowers serum levels of glucose by making cells more sensitive to insulin and reducing the production of glucose by the liver (Viollet 2012).

Metformin has also been shown to potently activate a cellular protein called adenosine monophosphate-activated protein kinase (AMPK) (Hardie 2012). This inhibits a protein called mammalian target of rapamycin (mTOR), which drives cellular metabolism and promotes cellular growth (Gwinn 2008). AMPK activation was also shown to selectively inhibit cancer cells that are deficient in the tumor suppressor gene p53 (Buzzai 2007).

Epidemiological studies have found that people with type 2 diabetes who use metformin have a significantly lower risk of developing lung cancer (Mazzone 2012; Noto 2012). In addition, studies on lung cancer cells have found that metformin promotes the anti-cancer properties of the chemotherapeutic agent cisplatin and radiation therapy regimens (Storozhuk 2013; Lin 2013).

Preliminary results from a small study of 16 patients with diabetes and stage III NSCLC found that adding metformin to chemo-radiotherapy dramatically reduced local recurrence, with just 2 recurrences during a median follow-up of 10.4 months (Penn Medicine 2013; Csiki 2013). Another study that evaluated data on 99 patients with NSCLC and type 2 diabetes found that those who received chemotherapy and metformin had significantly longer progression-free survival compared to subjects receiving insulin and chemotherapy (Tan 2011).

Non-steroidal Anti-inflammatory Drugs and Aspirin

Cyclooxygenase-2 (COX-2) is an enzyme that converts an omega-6 fatty acid called arachidonic acid into prostaglandin H2 (PGH2), a messenger molecule involved in inflammation and pain; COX-2 enzyme activity is generally increased in cancer cells (Khan 2011; Mazhar 2005). A reason non-steroidal anti-inflammatory drugs (NSAIDs) possess significant anti-inflammatory and analgesic properties is because they inhibit COX-2 (Mao 2011; Menter 2010; Dionne 2001; Ishiguro 2014). Aspirin in particular has been associated with a reduced risk of lung cancer (Xu 2012). Several epidemiological studies have also found that use of the selective COX-2 inhibitor celecoxib (Celebrex) was associated with as much as a 72% reduced risk of developing lung cancer (Harris 2007).

Additionally, several studies have found that COX-2 expression increases during lung cancer progression and high levels of COX-2 are associated with a poorer prognosis (Takahashi 2002; Jiang 2013; Mao 2011). Specifically, these studies found that high levels of COX-2 were significantly associated with the development of squamous cell carcinoma, early-stage NSCLC, and the adenocarcinoma subtype of NSCLC (Jiang 2013). A COX-2 inhibitor, apricoxib (Capoxigem), has completed a phase II study in patients who failed a platinum-containing regimen for advanced disease. The study found that combination therapy with apricoxib and erlotinib in 120 patients with advanced lung cancer who showed a reduction in the urinary biomarker for PGEM, an indication of high COX-2 activity, demonstrated a 71% improvement in disease control rate; 93% improvement in median progression-free survival; and 205% improvement in median overall survival (Gitlitz 2011).

However, COX-2 inhibitors are not without their own risks. In fact, drugs that specifically inhibit COX-2 such as celecoxib and rofecoxib (Vioxx), which has been withdrawn from the US market, are associated with an increased risk of cardiovascular events like heart attack. To this effect, in 2004 and 2005, the US FDA and other public health authorities advised physicians and patients that selective COX-2 inhibitors should be used with caution in persons at risk for cardiovascular events (Bennett 2005; Antman 2007).

Aspirin, which nonselectively inhibits COX-1 and COX-2, also appears to confer protection against lung cancer (Harrington 2008). Evidence from an animal model showed that aspirin reduces lung cancer metastasis to regional lymph nodes. This same experiment also found that aspirin treatment significantly lowered the mortality rate of lung cancer among mice (Ogawa 2014).

Epidemiological evidence indicates that regular aspirin use may reduce lung cancer risk. In one study, 398 Chinese women with lung cancer were compared to healthy control subjects. Women who regularly used aspirin were 50% less likely to have lung cancer. The researchers concluded “Our results suggest that aspirin consumption may reduce lung cancer risk in Asian women and are consistent with current understanding of the role of cyclooxygenase in lung carcinogenesis” (Lim 2012). Aspirin has also been shown to improve post-surgical prognosis for lung cancer patients. Researchers analyzed data from a thoracic surgery database and found that individuals using aspirin before undergoing potentially curative lung cancer surgery had a significantly increased survival rate compared to those not using aspirin. This finding was especially meaningful considering that aspirin users tended to have a higher cardiovascular risk profile, which generally increases mortality risk (Fontaine 2010).

More Information about repurposing drugs for use in the context of cancer in general is available at Life Extension’s Drug Repurposing in Cancer protocol.

Enhancing Immune Function with GM-CSF and IL-2

The evasion of the immune system by malignant cells is thought to be an important aspect of tumor development (Arens 2012). The immune system kills the majority of malignant cells that emerge within the body; only those capable of neutralizing immune cells or avoiding detection give rise to a progeny of tumor cells (Hanahan 2011). Indeed, studies on genetically modified mice have shown that deficiencies in NK cells, CD8+ cytotoxic lymphocytes, or CD4+ helper T cells all increase susceptibility to carcinogen-induced cancer (Teng 2008; Hanahan 2011). This is troubling for cancer patients because numerous studies document that cancer surgery results in substantial reduction in NK cell number and/or activity (Da Costa 1998; Shakhar 2003; McCulloch 1993; Rosenne 2007). In one investigation, NK cell activity in women having surgery for breast cancer was reduced by over 50% on the first day after surgery (McCulloch 1993). A group of researchers stated that “we therefore believe that shortly after surgery, even transitory immune dysfunction might permit neoplasms [cancer] to enter the next stage of development and eventually form sizable metastases” (Shakhar 2003). In another study, colorectal cancer patients with reduced NK cell activity before surgery had a 350% increased risk of metastasis during the following 31 months (Koda 1997).

Interleukin-2 (IL-2), an endogenous cytokine that can also be administered as a drug, helps promote the expansion of a subpopulation of NK cells in the body (Caligiuri 1990; Fehniger 2000; Choi 2008; Cheever 1986), while granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances the ability of the immune system to attack cancer cells (Rowe 1995; Buchsel 2006; Arellano 2008; Freeman 2007). A clinical trial on 26 patients with advanced non-small cell lung cancer whom had previously received treatment tested gemcitabine plus docetaxel with or without IL-2 and GM-CSF. Recipients of IL-2 and GM-CSF demonstrated a greater objective response and increased numbers of several immune cells (eosinophils, basophils, and activated mononuclear blood cells). The researchers concluded that “Addition of immune-adjuvant cytokines'[IL-2 and GM-CSF] may enhance the activity of [gemcitabine plus docetaxel]” (Correale 2009). Animal model experimentation has shown that GM-CSF and IL-2, when administered together, confer robust immunological benefits. In one study on immunocompromised mice deficient in NK cells, the combination of IL-2 and GM-CSF prevented Epstein-Barr virus-induced lymphoproliferative disease, which is a cancer-like condition (Baiocchi 2001).

Several dietary and lifestyle management strategies may help reduce the risk of lung cancer and/or improve treatment outcomes.

Smoking Cessation

Smoking cessation is one of the key strategies for preventing lung cancer and an important component in lung cancer treatment (Risser 1996; Leone 2013). Smoking can also affect the quality of life for patients already diagnosed who continue to smoke, and some surgeons will not even operate on someone who continues to smoke (Leone 2013; NCCN 2014a). Fortunately, there are several evidence-based approaches shown to help people quit and stay tobacco-free.

Several forms of nicotine replacement therapy are available by prescription or over the counter, including chewing gum, patches, inhalers, nasal sprays, and lozenges. In addition, the prescription drugs bupropion (Wellbutrin, Zyban) and varenicline (Chantix) are approved for smoking cessation and often used in conjunction with nicotine replacement. Although varenicline appears more effective than bupropion or the nicotine patch, it is more likely to cause nausea (Leone 2013; Stead 2008; NCCN 2014a). The antidepressants nortriptyline (Pamelor, Aventyl), paroxetine (Paxil), and venlafaxine (Effexor), while not specifically approved for smoking cessation, are also used (Hughes 2014; Killen 2000; Cinciripini 2005).

The government website http://smokefree.gov provides additional information on smoking cessation.

Controlling Glucose Levels

Studies find that people with diabetes and lung cancer have a worse prognosis. One study found that NSCLC patients with fasting blood glucose levels of 126 mg/dL or higher were 69% more likely to die from lung cancer than those with a normal level (Luo 2012). Another study found that people with diabetes who underwent resection of NSCLC had 5-year local recurrence rates of 56% compared to 26% in those without diabetes (Varlotto 2012).

Healthy Diet

Several studies found that good nutrition after surgical removal of primary lung cancers can significantly improve quality of life (Sanchez-Lara 2012). Moreover, preventing malnutrition and having a well-balanced diet can lower the risk of post-surgery complications such as infection and death (Bagan 2013; Sanchez-Lara 2012).

Adhering to a Mediterranean diet may reduce lung cancer risk. In a study of 4336 current smokers or individuals who recently quit smoking, greater adherence to a Mediterranean-style diet was associated with an up to 90% reduced risk of lung cancer (Gnagnarella 2013). Another study examined specific aspects of the Mediterranean diet and found that exclusive use of olive oil and consumption of the sage spice were significantly associated with reduced lung cancer risk (Fortes 2003).​

Astragalus

Astragalus, an herb used in traditional Chinese medicine, possesses significant immune-stimulating properties. Preclinical studies found that astragalus can promote anti-tumor immune responses in tumor-bearing mice, likely by restoring T cell function, an important component of the immune system (Cho 2007a; Cho 2007b).

There is also some clinical evidence suggesting that astragalus may improve survival rates in patients with advanced-stage NSCLC. Specifically, researchers found that patients who received 60 mL intravenous astragalus daily for 3 months combined with conventional treatment had a 1-year survival rate of 46.8% compared to a survival rate of 30% in the conventional treatment only group (Zou 2003). An analysis of 12 studies involving 940 patients with advanced NSCLC investigated the effects of astragalus in combination with platinum-based chemotherapy; researchers found an average 33% increase in 1-year survival rates in the astragalus groups compared to patients receiving platinum-based chemotherapy alone (McCulloch 2006). In another study, 136 patients with NSCLC received either vinorelbine and cisplatin or both chemotherapy drugs in combination with astragalus. Researchers noted significant improvement in patients’ overall quality of life, physical function, fatigue, nausea and vomiting, pain, and loss of appetite (Guo 2012).

Vitamin B6

A study assessed B-vitamin (B2, B6, B9, and B12) and methionine levels in blood samples of 899 patients with lung cancer, then compared them to a healthy group. People with the highest blood levels of B6 had a 56% reduced risk of lung cancer, while those with the highest levels of methionine had a 48% reduced risk, compared to those with the lowest levels (Johansson 2010).

Vitamin B6 appears to regulate the response of lung cancer cells to cisplatin by depleting glutathione within the cell, as well as exacerbating intracellular stress. The mechanism may be related to levels of pyridoxal kinase (PDXK), an enzyme required to make B6 biologically active. Evaluation of patients with NSCLC found that those with low PDXK expression had markedly worse disease-free and overall survival (Galluzzi 2012).

Vitamin D

An increasing body of evidence suggests that vitamin D may be chemoprotective against several types of cancer (Fleet 2012; NCI 2013b). Skin cells naturally produce vitamin D in the presence of ultraviolet radiation from sunlight. However, relying on sunshine alone is often insufficient to achieve optimal blood levels of vitamin D. It is also difficult to obtain adequate levels of vitamin D from diet alone (Nair 2012).

An epidemiological study found that patients with NSCLC who underwent surgery during the summer and had higher vitamin D intake (greater than 596 IU daily) had a significantly longer period of recurrence-free survival and overall survival than those who underwent surgery during the winter and had low vitamin D intake (less than 239 IU daily and no vitamin D supplements) (Zhou, Suk 2005). In addition, analysis of data from the Third National Health and Nutrition Examination Survey (1988-1994) found that higher blood levels of vitamin D in people with lung cancer was associated with a 47% reduced risk of death in former and never smokers as well as a 69% reduced risk in distant-former (quit ≥20 years) and never smokers (Cheng 2012).

Green Tea

Made from the leaves of Camellia sinensis, green tea contains a variety of antioxidant phytochemicals called polyphenols. Epigallocatechin gallate (EGCG), the principal active ingredient in green tea, appears to possess significant growth-inhibitory effects on lung cancer cells, particularly in conjunction with chemotherapy (Yamauchi 2009; Shim 2010; Wang, Bian 2011; Anderson 2008; Suganuma 2011). Several mechanisms are responsible for its anti-cancer properties in lung cancer, primarily its ability to suppress the EGFR signaling pathway, suppressing EGFR, AKT, and ERK1/2 activation, all of which are associated with lung cancer development (Ma 2014). It also appears to reduce VEGF (vascular endothelial growth factor) expression (Li 2013), increase expression of the tumor suppressor protein p53, and inhibit COX-2 expression (Lu 2012). Another laboratory study found that it inhibited tumor migration as well as increased the effectiveness of docetaxel (Deng 2011). In addition, topical application of green tea may help radiation burns heal faster (Fritz 2013). However, a 2009 study found that green tea blocked the anticancer effects of certain types of chemotherapy agents, boronic acid-based proteasome inhibitors, with bortezomib (Velcade) being the most prominent in this category. The research found no negative effects with non–boronic acid proteasome inhibitors they studied (Golden 2009).

Melatonin

Melatonin, a hormone produced by the pineal gland, is integral to the proper regulation of sleep. Several studies have found that melatonin may slow tumor progression thanks to its ability to protect cells from oxidation, induce cell death, and stimulate the immune system. It also protects red blood cell precursors during chemotherapy (Srinivasan 2008).

In a study of 12 lung cancer patients, researchers assessed urinary markers of melatonin and found that low levels were associated with faster cancer growth (Bartsch 1997). A study of 100 patients with lung cancer found significantly higher 5-year survival rates and tumor regression rates in those who received 20 mg of melatonin each evening while undergoing chemotherapy compared to those who received chemotherapy alone (Lissoni 2003). Other studies also found that daily oral doses of melatonin between 10 and 50 mg for 3-5 weeks with chemotherapy seemed to enhance the response to chemotherapy and even demonstrated some disease stabilization and tumor regression (Vijayalaxmi 2002).

Silymarin

Traditionally used in the treatment of certain liver diseases, silymarin is a mixture of flavonoids from the medicinal plant milk thistle. Several studies show that silymarin’s primary active ingredient, silibinin, possesses potent antioxidant properties that may prevent the formation of reactive oxygen species, subsequent DNA damage, and the growth of tumor cells (Kaur 2010; Dagne 2011; Li 2011). Studies have found that silibinin inhibits the growth of lung cancer cells in the laboratory and in mice, with one study reporting that it worked as well as the targeted biologic drug gefitinib (Mateen 2010; Chittezhath 2008; Cufi 2013). It also appears to enhance apoptosis, or programmed cell death, of SCLC cells and reverse resistance to the chemotherapy drugs etoposide and doxorubicin (Adriamycin), as well as EGFR inhibitors gefitinib and erlotinib (Sadava 2013; Rho 2010). Silibinin has been noted to suppress nuclear factor-kappa B (NF-κB), which is involved in numerous steps of carcinogenesis and which contributes to chemotherapy and radiotherapy resistance (Chen 2012). It also appears to reduce the activity of EGFR-related proteins and has an anti-angiogenesis effect, preventing or slowing the growth of vascular tissue (Rho 2010; Tyagi 2009).

Soy Isoflavones

Isoflavones are a class of plant polyphenols found in soy and other plants. A study of 444 women with lung cancer found that those whose diets were high in soy products and isoflavones (average 31.4 g of soy foods daily) before diagnosis had mortality rates during the 2-year follow-up that were 81% lower than those with the lowest intake (average 6.3 g soy foods daily) (Yang 2013).

In addition, studies in mice found that soy isoflavones given before and after radiation can make NSCLC cells more sensitive to radiotherapy and protect against radiation-related lung tissue injury and other side effects, while laboratory studies in human lung cancer cells show that soy increased radiation-related cell death (Hillman 2013; Hillman 2011; Singh-Gupta 2011). A study of 1674 patients with lung cancer found that those with the highest dietary intake soy bioactives, including phytosterols, isoflavones, lignans, and phytoestrogens, were 21-46% less likely to develop lung cancer than those consuming the least (Schabath 2005).

N-Acetylcysteine

N-acetylcysteine (NAC) is a form of the sulfur-containing amino acid cysteine. It can act as a precursor for glutathione and has well-established oxidative stress-reducing and antitoxic effects (Raghu 2021; Tenorio 2021). NAC is often used to counteract poisoning due to acetaminophen overdose and has shown promise as an antidote to toxic mushroom ingestion (Tenorio 2021; Akin 2013). Unlike most other antioxidants, NAC has the ability to break disulfide linkages (Tenorio 2021; Aldini 2018). Disulfide bond disruptors are a class of agents being investigated for potential anticancer effects (Wang 2019). NAC is also known as a mucus-thinning agent, a property that is related to disulfide bond reduction (Tenorio 2021). Furthermore, NAC lowers levels of inflammatory cytokines involved in cancer growth, including IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, and suppresses signaling by the protein NF-ĸB, which has been implicated in tumor initiation and progression (Tenorio 2021; Zhang 2020). NAC has demonstrated a variety of anticancer mechanisms. In addition to free radical-scavenging and anti-inflammatory activities, it has been shown to inhibit angiogenesis and may help regulate cell differentiation, proliferation, and apoptosis by replenishing glutathione levels (Radomska-Lesniewska 2017; Morales-Borges 2022). These combined effects make it a useful therapeutic in respiratory conditions such as COPD, cystic fibrosis, and severe respiratory infections, as well as possibly lung cancer (Izquierdo-Alonso 2022; Guerini 2022; Kiyokawa 2021).

An observational study examined the presence of circulating compounds known as albumin adducts (which form when various molecules become attached to the blood protein albumin) in 106 individuals who later developed lung cancer and 106 matched healthy individuals. The study found lower levels of albumin-NAC adducts, in particular, were associated with smoking, the presence of smoking-related DNA damage, and increased risk of lung cancer years later, indicating a potential role for NAC in lung cancer prevention in smokers (Dagnino 2020). In a placebo-controlled trial in 41 smokers, 600 mg NAC twice daily for 6 months lowered levels of other cancer-associated adducts in lung cells (Van Schooten 2002). However, in a subset of a randomized controlled trial that included 1,270 lung cancer patients (most of whom were smokers), 600 mg NAC once daily for two years did not affect outcomes (van Zandwijk 2000).

NAC may have a role in supporting conventional chemotherapy. In a randomized controlled trial, 60 patients with advanced non-small cell lung, prostate, or pancreatic cancer were assigned to receive a standard chemotherapy protocol or standard chemotherapy plus so-called induction therapy, consisting of 50 mg cyclophosphamide (Cytoxan) daily, 400 mg celecoxib twice daily, and 400 mg NAC twice daily. The goal of induction therapy was to inhibit angiogenesis and promote anti-tumor immune activity. Patients who received induction therapy were found to have slightly longer survival: in participants with lung cancer, average survival was 16.7 months in those who received induction therapy and 12.1 months in those who did not (Lasalvia-Prisco 2012).

Animal studies suggest NAC may protect lungs against carcinogens including cigarette smoke and radiation (Radomska-Lesniewska 2017; Morales-Borges 2022). In laboratory research, NAC was found to restore sensitivity to the EGFR-inhibiting drug gefitinib in NSCLC cells that had developed gefitinib resistance (Miller 2013; Balansky 2010). In an animal model, the combination of NAC plus doxorubicin was found to synergistically reduce cancer metastases (Li 2020).

Overall, however, the preclinical evidence for a benefit of NAC in the context of lung cancer is mixed. Two experiments in mice genetically modified to have elevated susceptibility to cancer found that NAC (and vitamin E, in one of the studies) exerted pro-cancerous effects (Sayin 2014; Breau 2019). On the other hand, several other preclinical experiments have shown that NAC and related thiol compounds exerted a protective effect in lung cancer models. Thus, available preclinical evidence does not allow for firm conclusions regarding NAC’s role in lung cancer (Breau 2019).

It is equally important to note that NAC use in clinical settings has not been associated with an increased risk of lung cancer. Clinical trials exploring the use of NAC at doses as high as 3,000 mg per day for as long as 12 months in patients with chronic respiratory diseases have not detected any safety concerns (Calverley 2021). Similarly, a genome-wide association study published in late 2022 did not find a significant causal association between vitamin E intake and lung cancer risk (Zhao 2022).

Nevertheless, out of an abundance of caution, Life Extension suggests that people at high risk of lung cancer, as well as those who have or have had lung cancer, consult their physician before supplementing with vitamin E or NAC, especially at high doses. This is particularly pertinent for people with a K-Ras mutation, which is observed in approximately 30% of people with NSCLC.

Pomegranate

Pomegranate extract, containing high levels of antioxidants, has been shown to possess anti-lung cancer properties in experimental models of lung cancer in mice. A study in mice found that combining pomegranate fruit extract (in water) with chemotherapy reduced tumor growth 61.6-65.9% more than chemotherapy alone. The authors speculated that pomegranate’s anti-inflammatory effects are due to its actions on several biochemical pathways related to cellular proliferation (Khan, Afaq 2007; Khan, Hadi 2007). Specifically, daily consumption of pomegranate extract was associated with a 66% reduction in the incidence of lung tumor formation in mice exposed to carcinogenic compounds (Khan, Afaq 2007).

Quercetin

Quercetin, a flavonoid found in certain fruits, vegetables and grains, possesses significant antioxidant and anti-inflammatory properties that have been proposed to prevent the biological effects caused by many cancer-causing chemicals (Kamaraj 2007; Zheng 2012; Yang 2006; Jeong 2009; Saponara 2002).

In addition, epidemiological studies found that consumption of quercetin-rich foods was associated with a significant reduction in smoking-related cancer risk. A review of 35 studies found that smokers with the highest daily intake of quercetin-containing foods had an approximately 34% lower risk of developing lung cancer than those with the lowest intake (Woo 2013). Potential mechanisms include its ability to scavenge free radicals, modify signal transduction pathways that control cellular growth and apoptosis, and inhibit enzymes that activate carcinogens while inducing enzymes that break down carcinogens (Lam 2010).

Vitamin E

A large study on 29,133 male smokers found that those whose blood levels of alpha-tocopherol were in the top 20% of the distribution had a 19% reduction in the risk of developing lung cancer compared with those whose levels were in the bottom 20% of the distribution (Woodson 1999). Another study showed vitamin E (alpha-tocopherol; 300 mg twice daily during radiation therapy followed by 300 mg once daily for 3 months), when combined with the anti-inflammatory drug pentoxifylline (Trental) (400 mg three times daily during radiation therapy followed by 400 mg once daily for 3 months), helped reduce toxicity due to radiation therapy in lung cancer patients (Misirlioglu 2007). This same combination may also confer a survival advantage for patients with advanced-stage NSCLC; in a group of these patients undergoing radiotherapy, use of pentoxifylline along with alpha-tocopherol increased median survival to 12 months compared to 8 months in a control group receiving radiation alone (Misirlioglu 2006). The gamma-tocopherol form of vitamin E demonstrated impressive results in an animal model of lung cancer. In this study, a tocopherol mixture rich in gamma-tocopherol that was incorporated into the diet reduced tumor growth up to 80% in mice after 50 days of treatment. Moreover, microscopic analysis of tumor samples revealed that the gamma-tocopherol-enriched mixture increased the death rate of lung cancer cells up to 240% compared with the control (Lambert 2009).

It is important to note that some preclinical evidence suggests supplementation with vitamin E and/or NAC may not be appropriate for people with a history of certain kinds of lung cancer. An animal model study published in 2019 found that supplemental NAC and synthetic alpha-tocopherol promoted lung cancer metastasis in mice with genetically elevated lung cancer risk (via increased K-Ras expression). On the other hand, a genome-wide association study published in late 2022 did not find a significant causal association between vitamin E intake and lung cancer risk (Zhao 2022). Nevertheless, out of an abundance of caution, Life Extension recommends that people who have or have had lung cancer consult their physician before supplementing with vitamin E or NAC, especially at high doses. This is especially pertinent for people with a K-Ras mutation, which is observed in approximately 30% of people with NSCLC.

Zinc

Zinc is an important component in several enzymes that help maintain normal DNA replication. A study of 1676 people with lung cancer compared to an equal number of healthy individuals found that those with the highest dietary intake of zinc (greater than 12 mg daily) had a 43% lower risk of lung cancer (Mahabir 2006). A similar study found a 33% reduced risk (Zhou, Park 2005). Another study analyzed hair samples of lung cancer patients and healthy control subjects. Individuals with lung cancer were found to have significantly lower zinc levels in their hair samples compared to control subjects (Piccinini 1996).

Curcumin

Curcumin is an active constituent of the Indian culinary spice turmeric. It has been extensively studied and shown to possess considerable antioxidant and anti-inflammatory properties (Aggarwal 2013; Prasad 2014). Curcumin has also generated interest among cancer researchers due to its apparent chemopreventive properties (Gupta 2013). A number of studies have investigated curcumin’s activity against lung cancer in experimental models. One intriguing aspect of curcumin’s bioactivity is its ability to inhibit a signaling pathway called Stat3. Stat3 has been shown to be active in nearly 50% of lung cancers, and curcumin was shown in preclinical in vitro and animal experiments to function as a potent suppressor of the Stat3 pathway (Alexandrow 2012; Yang 2012). Other evidence shows that pretreating lung cancer cells with curcumin may enhance sensitivity to the chemotherapy drug cisplatin. It is thought to accomplish this by downregulating a protein called Bcl-2, which interferes with programmed cell death (Chanvorachote 2009). Additional evidence from a preclinical model shows that curcumin may reduce the invasive potential of lung cancer (Chen 2008).

Fish Oil

Fish oil, a rich source of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), significantly increased the efficacy of first-line chemotherapy in patients with advanced NSCLC in one trial. The dose of fish oil used was sufficient to supply 2.5 g of EPA plus DHA daily. The study also found that fish oil increased the 1-year survival rate by about 20% compared to standard-of-care, although the difference was not statistically significant (Murphy 2011a). In another study by the same primary researcher, supplementation with 2.2 g of EPA daily was shown to help NSCLC patients receiving chemotherapy maintain their body weight and muscle mass more effectively than standard-of-care (Murphy 2011b). An experimental laboratory study showed that incubation of lung cancer cells with EPA and DHA dose- and time-dependently decreased the viability of the cancer cells. The researchers concluded “… DHA and EPA inhibited the proliferation of [lung cancer] cells and induced cell apoptosis and autophagy, which may provide new safe and effective options for the treatment of lung cancer in the future” (Yao 2014).

Honokiol

Derived from magnolia trees, honokiol is a bioactive phytochemical shown to initiate apoptosis and inhibit growth of several cancer cell lines; it possesses anti-angiogenic and anti-carcinogenic properties (Bai 2003; Yang 2002). Honokiol also appears to hamper migration of NSCLC cancer cells; one study identified COX-2 inhibition as a mechanism possibly responsible for this effect (Singh 2013). In an animal model of lung cancer, honokiol alone conferred antitumor activity, which was enhanced when combined with cisplatin. The scientists who conducted the study postulated that the effects of honokiol were attributable to induction of apoptosis and inhibition of angiogenesis (Jiang 2008).

Maitake Mushroom

The maitake mushroom contains polysaccharides called beta-glucans (particularly, beta-1,6 glucan), which have been shown to possess potent immunomodulating and anticancer properties (Kodama 2002). A few clinical trials have studied the impact of maitake extracts on various immunologic and cytologic (relating to the properties of cells) outcomes in cancer patients including one in breast cancer patients and another in patients with various types of cancer (Deng 2009; Kodama 2002). In the latter study, maitake extract and whole maitake powder were given to 36 patients with stage II – IV cancers, including 8 lung cancer patients, whom had discontinued chemotherapy due to side effects. Following treatment with maitake, cancer regression or symptomatic improvement was observed in 5 of the 8 lung cancer patients (Kodama 2002).

Additional Suggestions

Some additional ingredients have a sound mechanistic basis for potential benefit in the context of lung cancer.

Reishi mushroom. Reishi mushroom (Ganoderma lucidum) may support host antitumor immunity, and since it is generally well-tolerated and nontoxic, may be a worthwhile adjunct to conventional cancer treatment (Jin 2012).

Arabinoxylan. Arabinoxylan, a non-starch component of dietary fiber in whole grains, may also favorably modulate anticancer immunity (Lattimer 2010; Ghoneum 2011). It has been shown to sensitize cancer cells to chemotherapeutic agents and enhance apoptosis (Ghoneum 2005; Gollapudi 2008).

Mistletoe. Mistletoe preparations (eg, Iscador) have been shown to reduce side effects of chemotherapy in NSCLC patients (Piao 2004; Bar-Sela 2013). Although more studies are needed to determine whether mistletoe preparations confer a survival benefit in lung cancer patients, several studies have identified mechanisms suggestive of enhanced immunity (Gardin 2009; Huber 2011; Matthes 2010).

Intravenous vitamin C. Intravenous vitamin C is sometimes used as an anticancer therapy in integrative medical clinics. Some research suggests that this approach may mitigate inflammatory responses in cancer patients and decrease levels of tumor markers, and several cases of cancer remission after intravenous vitamin C treatment have been reported (Mikirova 2012; Fritz 2014). A systematic review published in 2014 concluded that available data suggest potentially important antitumor activity of intravenous vitamin C as well as a good safety profile. One area that makes it difficult to draw firm conclusions about the benefit of intravenous vitamin C in cancer patients is the lack of consistency across trials with regard to methodology, and especially, dosing, which ranges from 1 g to more than 200 g two to three times weekly (Fritz 2014). More studies are needed to clarify these discrepancies and determine the best approach to intravenous vitamin C therapy in the context of cancer.