Lung Cancer-1

Each year, an estimated 93,000 men and 82,000 women in the United States will be diagnosed with lung cancer, with a median age of 70 years of age (Jemal A et al 2006; Gloeckler Ries LA et al 2003). To date the prognosis is grim for most forms of lung cancer as the five-year overall survival rate of only 14 percent has hardly changed in the past 50 years (Sugimura H et al 2006). Cigarette smoking is the main cause of lung cancer; however, nonsmokers also develop the disease due to genetics, secondhand smoke, and exposure to toxins and radon gas (Toh CK et al 2006; Vukovic B et al 2005).

Novel approaches are urgently needed that reverse, suppress, or prevent lung cancer development (van Zandwijk N 2005). Early detection offers the best chance for long-term survival (Saba NF et al 2005). The conventional choices of treatment include surgery, chemotherapy, and radiotherapy and depend on the type and stage of the cancer (European Lung Cancer Working Party 2006). Irrespective of the treatment method used, complementary therapy, such as nutritional supplementation and the use of bioresponse modifiers, is an important addition to traditional treatment that could help control symptoms, enhance quality of life, and improve overall survival (Jatoi A et al 2005b).

What Is Lung Cancer?
Lung cancer is a disease in which cells in the lungs begin to grow out of control and interfere with normal lung functions such as breathing. The vast majority of lung cancer cases fall into one of two categories: non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

NSCLC. NSCLC is the most common type of lung cancer, making up nearly 80 percent of all cases. This type of lung cancer grows and spreads more slowly than the other major type and is therefore more treatable. NSCLC is divided into three subtypes: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. The five-year survival rate for patients with NSCLC is less than 25 percent (Jemal A et al 2006).

SCLC. SCLC accounts for 20 percent of all lung cancer cases. Its small cells can rapidly reproduce to form large tumors that quickly spread to the lymph nodes and other parts of the body. This type of lung cancer is almost always caused by smoking or secondhand smoke. SCLC responds well to chemotherapy and radiotherapy treatment initially. However, less than 5 percent of SCLC patients survive five years past diagnosis; a patient with untreated SCLC has an average survival time of two to three months (Toyooka S et al 2001).

Mesothelioma. Mesothelioma is diagnosed when cancer cells are found in pleural fluid or tissue. It is associated with asbestos exposure (70 percent of cases), and asbestos workers have a lifetime risk of 8 percent; tumors arise 20 to 40 years after asbestos exposure. Mesothelioma has a poor prognosis, with 75 percent of patients dying within one year and five-year survival being about 5 percent. Long-term survival has been reported in 50 percent of patients who receive a combination of surgical removal of cancer followed by chemotherapy during surgery and intraperitoneal chemotherapy soon after surgery.

What Causes Lung Cancer?
Lung cancer is a multistep process that involves cancer-causing agents (environmental carcinogens), inherited genes, and tumor promoters (e.g., inflammatory mediators) (Miller YE 2005; Philip M et al 2004; Tokuhata GK et al 1963). Cigarette smoking may cause as many as 90 percent of male and 79 percent of female lung cancers (Ozlu T et al 2005).

Smoking. Cigarette smoke contains potent cancer-causing derivatives of nicotine, and nicotine itself is directly involved in lung cancer development (Minna JD 2003). Smoking cessation is difficult because nicotine is highly addictive; however, nicotine replacement therapy combined with Zyban® (bupropion) enables a higher smoking cessation rate (L F et al 2005). Medicinal herbal tea made from cloves and milk vetch reduces smoking withdrawal symptoms and increases the rate of smoking cessation (Lee HJ et al 2005). In 2006, the Food and Drug Administration approved a new smoking cessation drug called Chantix™ (varenicline). This new drug is the first prescription medication approved for smoking cessation in almost a decade. It works by partially activating the nicotine receptors in the brain, thus reducing the craving for nicotine and reducing withdrawal symptoms. It also reduces the satisfaction gained by smoking, which may lessen addiction.

Nonsmokers get lung cancer too. Nonsmokers make up 10 to 15 percent of all lung cancer cases (Vastag B 2006). Many nonsmokers who develop lung cancer appear to carry a genetic tendency (Gorlova OY et al 2006).

Some cancer risk is inherited. A two- to threefold increase in lung cancer risk is associated with having a relative with lung cancer (Matakidou A et al 2005). Adults with retinoblastomas (inherited mutations in the retinoblastoma-1 (RB1) gene) and those with Li-Fraumeni syndrome (inherited mutations in the tumor suppressor p53 gene) may develop lung cancer (typically bronchial cancers) at a higher rate than the general population, suggesting a family association (Kleinerman RA et al 2000; Zalcman G et al 1994). The p53 and RB1 genes are both mutated in more than 90 percent of SCLCs, while p53 is mutated in more than 50 percent and RB1 in 20 percent of NSCLCs (Campling BG et al 2003; Horowitz JM et al 1990).

Some lung cancer is caused by exposure to toxins and viruses. Indoor exposure to secondhand smoke, radon gas, asbestos, and heavy metals (e.g., arsenic, nickel, chromium, iron oxide) and exposure to petrochemicals, polycyclic aromatic hydrocarbons, and human papillomavirus all cause lung cancer (Miller YE 2005; Vukovic B et al 2005; Chen YC et al 2004; Minna JD et al 2002; Hertz-Picciotto I et al 1993).

Understanding and Reducing Your Risk

Smoking and secondhand smoke. More than 90 percent of lung cancers are unquestionably caused by tobacco and the 4000 cancer-causing substances in cigarette smoke (van Zandwijk N et al 2000). The risk of developing lung cancer increases 20- to 40-fold for lifelong smokers and 1.5-fold for people with long-term passive exposure to cigarette smoke. Population studies show that approximately 15 percent of heavy smokers will ultimately develop lung cancer but that, interestingly, 85 percent of heavy smokers will not develop lung cancer because of innate differences in cancer susceptibility, or in other words, genetics. If a family member has lung cancer, chances are your genes render you susceptible to cancer, and you should stop smoking.

The lung cancer death rate is related to the total number of cigarettes smoked, and the risk for a man smoking two packs daily for 20 years is 60- to 70-fold the risk run by a nonsmoker. Among individuals who smoke 15 or more cigarettes per day, reducing smoking by 50 percent significantly reduces the danger of lung cancer (Godtfredsen NS et al 2005). In addition, stopping smoking may prolong survival of cancer patients (Ozlu T et al 2005).

To reduce risk:

1)Stop smoking. Use nicotine replacement therapy, Zyban®, counseling, and herbal tea made of cloves and milk vetch (Lee HJ et al 2005). A new smoking cessation drug, Chantix™ (varenicline), is available by prescription.

2)Increase intake of citrus fruits and tomatoes, which are high in beta-cryptoxanthin, lycopene, alpha-carotene, and lutein (Mannisto S et al 2004; Yuan JM et al 2001; Knekt P et al 1999; Le ML et al 1993).

3)With the approval of your physician, take aspirin regularly (Moysich KB et al 2002).

4)Take folate and vitamin B12, which improve abnormal bronchial cell growth in smokers (Heimburger DC et al 1988).

5)Consume green tea, whose polyphenols prevent DNA damage in lung cells exposed to oxidants from cigarette smoke.

6)Test your home for radon gas.

Dietary factors. A low intake of fruits and vegetables and consumption of red meat and preserved and fatty foods increase risk (Kubik A et al 2004; Wang J et al 2004). Therefore, your diet should consist mostly of vegetables, fruits, raw foods, and fresh fish (Takezaki T et al 2003; Gao CM et al 1993). However, the genes one inherits play an important role in individual susceptibility to lung cancer (Lam WK et al 2004).

- The overall risk of lung cancer decreases by one half among those with a high intake of lettuce and cabbage, even among current smokers (Gao CM et al 1993).

- Chinese leek (Allium tuberosum Rottler), also known as Chinese chives, reduced lung cancer metastasis (spread) in mice by 40 percent and prevented cancer cell growth in experimental conditions (Shao J et al 2001).
See the section below titled “Preventing Lung Cancer” for more recommendations.

Genetics. Especially among nonsmokers, a genetic predisposition increases an individual’s susceptibility to cancer-causing agents (carcinogens) in the environment. Nonsmokers with a close family member stricken by cancer might reduce their lung cancer risk by about 25 to 50 percent by taking the following steps:

- Increasing intake of darkly colored vegetables and fruits

- Consuming carotene-containing fruits and vegetables—spinach, kale, carrots, cantaloupes, and sweet potatoes (Fabricius P et al 2003; Fontham ET 1990).

Lung disease. Lung diseases such as chronic obstructive pulmonary disease and infections such as tuberculosis, human papilloma virus, and Microsporum canis (skin fungus) are linked with a proinflammatory state and a high risk of lung cancer (Lam WK et al 2004; Biesalski HK et al 1998). Although most of these conditions are easily diagnosed and fairly well managed, smoking cessation is a must.

Environmental carcinogens. Certain elements in the environment further increase one’s risk of developing lung cancer. See the discussion under “Some lung cancer is caused by exposure to toxins and viruses” above.

How Is Lung Cancer Diagnosed?Approximately 5 to 15 percent of lung cancers are discovered in the course of a routine chest x-ray of people with no symptoms. However, more than 50 percent of new lung cancer cases will be diagnosed by the presence of symptoms that indicate cancer spread (metastasis).

Symptoms. Lung cancer symptoms are caused by tumor growth in the lungs, invasion or obstruction of nearby structures, and tumor growth in lymph nodes and in distant sites after cancer spreads through the blood. Symptoms include worsening or chronic cough, shortness of breath, wheezing, coughing up blood, back pain, and weight loss.

Screening. Screening methods include examination of a sputum (spit) sample, chest x-ray, and low-dose spiral computed tomography (CT) lung scanning. A biopsy of the tumor tissue is necessary to confirm a diagnosis of lung cancer. Physical examination, bone scans, brain CT, and bone marrow examination are performed when SCLC is suspected. Positron emission tomography scans are also useful in detecting cancer spread.

What If Lung Cancer Is Detected?

Blood tests. Blood tests should measure levels of electrolytes (sodium, potassium, calcium, magnesium, phosphorus, chloride, and bicarbonate), indicators of liver function (aspartate aminotransferase, alanine aminotransferase, prothrombin time, bilirubin, and alkaline phosphatase), and level of lactate dehydrogenase.

A complete blood count will determine most of these values. However, the prothrombin time is a separate test that measures how quickly the blood clots. A prolonged prothrombin time, in the absence of vitamin K deficiency, and an elevated D-dimer level are associated with a poor outcome after surgery for lung cancer (Ferrigno D et al 2001; Kostecka IA et al 2000). An elevated alkaline phosphatase level suggests cancer spread to the bone. Blood tests can be performed via National Diagnostics: http://www.lef.org/bloodtest/.

What You Have Learned So Far

- Smoking is the major cause of lung cancer; thus, most lung cancers are preventable.

- Genetics, secondhand smoke, human papillomavirus infection, an unhealthy diet, and exposure to chemicals, heavy metals, and radon gas cause lung cancer in nonsmokers.

- All these risk factors are modifiable.

- Symptoms include worsening or chronic cough, shortness of breath, wheezing, coughing up blood, back pain, and weight loss.

- Tests for lung cancer include sputum sample, chest x-ray, and computed tomography lung scanning, but a biopsy is needed for diagnosis.

- In the past 50 years, the five-year survival rate for lung cancer has not improved significantly.

- A healthy lifestyle and diet (citrus fruits, tomatoes, spinach, carrots, cantaloupes, and sweet potatoes), in addition to supplementation with folate and vitamin B12, may help prevent lung cancer.


How Advanced Is the Cancer?
How extensive or advanced a cancer is can be determined by “staging,” which is important in determining the proper treatment approach. NSCLC is staged according to tumor size, whether lymph nodes are affected, and whether the cancer has spread (metastasized). NSCLC has five stages, numbered 0 through IV, with 0 being the earliest stage and having the best chance of cure and IV being the most advanced.

SCLC is divided into two stages: limited disease (25 to 30 percent of cases), in which the cancer is limited to the chest and nearby lymph nodes, and extensive disease (70 to 75 percent of cases), in which the cancer extends beyond the chest.

What Is the Prognosis?
Lung cancer generally has a grim prognosis, which can be defined by means of the blood tests mentioned above as well as the following tests:

Tumor markers. Tumor markers are substances produced by cancer cells. They reflect the presence or absence of cancer, and indicate whether a cancer returns (recurs) after treatment. Measuring the following six tumor markers is essential to daily lung cancer management. They are measured either by blood testing or by testing the tumor biopsy sample:

- Carcinoembryonic antigen: High carcinoembryonic antigen (CEA) levels in the blood (>10 ng/mL before and after surgery) are linked with poor survival (Tomita M et al 2005).

- Neuron-specific enolase: Neuron-specific enolase (NSE) in the tumor biopsy sample is a significant predictor of survival (Komagata H et al 2004; Ferrigno D et al 2003).

- Sialyl Lewis X-i antigen: Sialyl Lewis X-i antigen (SLX) identifies the presence of lung metastasis (Satoh H et al 1998).
- Serum cytokeratin fragment 21.1: Serum cytokeratin fragment 21.1 (CYFRA) diagnoses NSCLC, especially squamous cell and adenocarcinoma (Chantapet P et al 2000).

- Squamous cell carcinoma antigen: Some 85 percent of patients with squamous cell carcinoma antigen (SCC) levels higher than 2 ng/mL have squamous tumors (Molina R et al 2003).

- Pro-gastrin-releasing peptide: High levels of pro-gastrin-releasing peptide (ProGRP) are found in SCLC patients, and this test is more specific than NSE for SCLC (Molina R et al 2004).

Cyclooxygenase-2. Cyclooxygenase-2 (COX-2) is associated with a worsening prognosis in lung cancer. Therefore, COX-2 inhibitors, taken as either prescription medication or nutritional supplements, may be beneficial in addition to standard treatments and in the prevention of lung cancer (Scagliotti GV et al 2003). COX-2 inhibitors enhance the cancer-killing effects of chemotherapy and radiation therapy in lung cancer cell lines with high levels of COX-2 (Saha, P et al 2005).

Advanced lung cancer patients who took Celebrex® (celecoxib; 200 mg twice daily), medroxyprogesterone (500 mg twice daily), and oral food supplementation for six weeks had stable weight (±1 percent) or gained weight and had significant appetite improvement and relief from nausea and fatigue (Cerchietti LC et al 2004). Consequently, clinical trials are currently assessing Celebrex® alone for preventing lung cancer in heavy smokers and Celebrex® in combination with chemotherapy or after radiation therapy in lung cancer treatment. More information on ongoing clinical trials may be found at www.clinicaltrials.gov.

The following may also inhibit the effects of COX-2:

- Eicosapentaenoic acid (EPA) from fish oil (Yang P et al 2004), alpha-tocopheryl succinate (Lee E et al 2006); and a tea made from clove (Banerjee S et al 2006) hinder COX-2 in lung cancer cells.

- Aspirin also slows down COX-2 activity in lung cancer cells and may prevent tobacco carcinogenesis (Harris RE et al 2005).

Gene abnormalities. Mutations in K-ras genes are associated with a poor prognosis in NSCLC (Mascaux C et al 2005; Slebos RJ et al 1990), while tumor amplification of c-myc is associated with a poor prognosis in SCLC (Zajac-Kaye M 2001) and shorter survival in NSCLC (Yakut T et al 2003). The p16/CDKN2 gene is abnormal in 10 percent of SCLCs and in more than 50 percent of NSCLCs, and its detection may improve early diagnosis (Su C et al 2002).

Detection of K-ras mutations may help predict treatment outcome. For example, tumors in patients with a mutant ras gene are more difficult to kill with radiation than are tumors in people without the mutation. K-ras mutations can be detected in blood, sputum, lavage fluids, stool sample (Minamoto T et al 2000), and the tumor itself. Testing can be performed through the Harvard Medical School-Partners Healthcare Center for Genetics and Genomics Laboratory for Molecular Medicine (http://www.hpcgg.org/LMM/tests.jsp?name=LMM&subname=genetictests#Cancer). Several gene therapies are under investigation:

- Perillyl alcohol, found in lavender, cherries, and mint, slowed down ras activity and prevented lung cancer in experimental studies. Because it stimulated lung cancer cell death, it is being tested in clinical trials as an anticancer agent (Xu M et al 2004; Lantry LE et al 1997).

- Theaflavins and epigallocatechin gallate (EGCG), black tea components, alter c-myc levels, resulting in a decreased occurrence and delayed onset of preinvasive lung cancers (Saha P et al 2005; Lin JK 2002).

-Grape seed proanthocyanidins alter c-myc activity and protect against tobacco-induced death of healthy cells (Bagchi D et al 2002).