Lung Cancer And The Link With Vitamin A Biology Essay


The most common type of cancer in the Western world is lung cancer. (1) Lung cancer is the 2nd leading killer among all the cancers in both men and women. (2) In the United States, during the year of 2007, 203,536 people were diagnosed with lung cancer (109,643 men and 93,893 women) and 158,683 people died from lung cancer (88,329 men and 70,354 women).

Lung cancer develops in the lungs; however, other cancers metastasize from other organs to the lungs. (2) In addition, lung cancer often metastasizes to the brain, bone, liver, and skin. (1) Two main types of lung cancer exist: non-small cell lung cancer and small-cell lung cancer. "Non-small-cell lung cancer (NSCLC) has three major subtypes: adenocarcinoma (40% of cases), squamous carcinoma (30-35% of cases, slow growing, and formerly called epidermoid carcinoma), and large-cell carcinoma (affecting 5-15% of cases)." (1)

Over the years, research has identified several risk factors for lung cancer. One of the main risk factors is smoking and secondhand smoke. (1,2) In the United States, smoking causes about 90% of deaths from lung cancer in men and almost 80% of deaths from lung cancer in women. (2) In fact, heavy smokers of tobacco or marijuana are 25 times more likely to develop lung cancer or die from lung cancer than people who do not smoke. (1) Due to secondhand smoke, approximately 3,000 nonsmokers expire from lung cancer each year. (2) Risk of lung cancer increases as the number of cigarettes per day increase as well as the number of years people continue to smoke. However, the risk of lung cancer lowers when people quit smoking. Although, it is still greater compared to the risk of people who never smoked.

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"High lung cancer rate in Taiwanese women, despite a low prevalence of smoking, are positively related to Chinese quick-frying cooking without using fans to ventilate the oils." (1) Another risk factor for lung cancer is the exposure to hazardous chemicals, radon gas, asbestos, arsenic, and some forms of silica and chromium. (1,2) Radon is a radioactive, odorless, colorless, tasteless gas that comes from the natural breakdown of uranium in the rocks, soil and water, and then can get trapped in houses and buildings. (2,3) After smoking, radon gas is the 2nd leading cause of lung cancer. (2) An additional environmental risk factor is exposure to nickel. "Nickel depletes intracellular ascorbate, which inhibits cellular hydroxylases that are important for lung surfactant; depletion of ascorbate by chronic exposure to nickel could be deleterious for lung cells and may lead to lung cancer." (1)

Last, but not least, risk factor of lung cancer is personal traits, for instance family history. (2) The risk of developing lung cancer may be greater if a person's parents, siblings, or children have lad lung cancer, which may be due to one or multiple contributing factors. They may share behaviors, like smoking; may live in the same place where there are carcinogens, such as radon; may have inherited increased risk of lung cancer in their genes.

Screening refers to the detection of a disease in individuals without signs and symptoms or history of that disease. (2) Lung cancer is diagnosed using various screening tests, like chest X-rays, sputum cytology (examines a sample of mucus from the lungs under a microscope to determine whether cancerous cells are present), and spiral (helical) CT scans of the lungs (CAT scans are x-ray procedures that combine many x-ray images with the aid of a computer to generate cross-sectional views and, if needed, three-dimensional images of the internal organs and structures of the body). (2,4) Screening tests help discover a disease in the early stages, when treatment is more likely to be effective. (2) However, the downside of screening is that the tests do not always reveal the difference between cancers and other abnormalities that are not cancers. Therefore, a biopsy (a surgical procedure that removes a small piece of tissue for laboratory examination) must be done to determine that abnormality is cancerous. (2,5) During this time, it is unknown if the benefits of screening outweigh the potential risks. (2) In addition, experts have reviewed studies that assessed these several screening tests determining that more information is needed because there is very little evidence whether these tests help prevent death from lung cancer.

Signs and symptoms of lung cancer include: depression, dyspnea, fatigue, and fever of unknown cause, bloody sputum, chest pain, recurring pneumonia or bronchitis, hoarseness, shortness of breath, persistent cough, swelling of neck or face, and weight loss. (1)

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Currently, there are several ways to treat lung cancer, such as surgery (a surgical operation to cut out and remove the cancerous tissue), chemotherapy (the use of drugs to shrink or kill the cancer), and radiation (the use of high-energy rays in an attempt to kill the cancerous cells). (2) The treatment options rely on the type of cancer and how far it has advanced. However, for the majority of lung cancer cases, radiation and chemotherapy are required because the caner is detected too late for surgical treatment or surgery is not clinically recommended. (1) All of these treatments for lung cancer are provided by different specializing doctors, for instance pulmonologists - experts in diseases of the lungs, surgeons - experts in surgical operations, medical oncologists - expert in chemotherapy, and radiation oncologists - experts in radiation therapy. (2) Lung cancer's 5-year survival rate is only 15%, which is worse than many other types of cancer. (1)

In addition, researchers are searching for associations between the risk of developing lung cancer and various foods in the diet. (2) Nonetheless, any outcomes diet may produce on lung cancer are minute when measured up to with the risk of smoking. For example, high consumption of cholesterol may increase the chances of developing lung cancer. Another example is high consumption of alcohol, but it is difficult to quantify how much of the risk is related to smoking in people who consume high amount of alcohol, since many people drink alcohol and smoke.

Nevertheless, several food items in the diet possess a protective role against lung cancer, which means they may help prevent lung cancer. (1,2) "Foods rich in flavonoids may protect again certain types of lung cancer, possibly by inhibiting P450 enzymes, which decrease bioactivation of carcinogens. Onions and apples have quercetin; white grapefruit provides naringin." (1) Decreased levels of vitamin C, an antioxidant, have been linked to smoking. Vitamin E food sources are important; gamma-tocopherol seems protective, whereas alpha-tocopherol from supplements is not. Studies with omega-3 fatty acids are needed as well."

Vitamin A is a common term used to describe a large group of compounds associated through the biological activity of all-trans retinol. (6,7) Retinol, retinal, retinoic acid, and related compounds are structurally similar and identified as retinoids.

"Retinol (an alcohol) and retinal (an aldehyde) are often referred to as preformed vitamin A. Retinal can be converted by the body to retinoic acid, the form of vitamin A known to affect gene transcription." (7) Preformed vitamin A food sources include: liver, whole milk, cheese, eggs, butter, fish such as tuna, sardines, and herring, and some fortified food products, margarine. (6,8,9)

"Beta-carotene and other carotenoids that can be converted by the body into retinol are referred to as provitamin A carotenoids. Hundreds of different carotenoids are synthesized by plants, but only about 10% of them are provitamin A carotenoids." (7) Provitamin A carotenoids food sources include: a colorful variety of fruits and vegetable, like carrots, sweet potatoes, spinach, kale, collard greens, tomatoes, watermelon, papayas, squash, pumpkins, broccoli, cantaloupe, peas, peppers, corn, etc. (6,8,9)

In 2001, new recommendations for vitamin A were published by the Institute of Medicine's Food and Nutrition Board. (6,7,8) Recommendations of vitamin A consumption are expressed in retinol activity equivalents (RAE). "The RAE equivalents of retinol, Beta-carotene, and other provitamin A carotenoids are as follows: 1 RAE = 1 μg retinol = 12 μg β-carotene = 24 μg α-carotene or β-cryptoxanthin." (6) The RDA recommendations for vitamin A are 900 μg and 700 μg RAE for men and women, respectively. (6,7,8) During pregnancy and lactation, the RDA recommendations for vitamin A in adult women increase to 770 μg and 1,300 μg RAE, correspondingly. A daily Tolerable Upper Intake Level (UL) for preformed vitamin A has been instituted at 3,000 μg RAE for adults.

Vitamin A performs an essential role in vision, gene expression, bone growth, reproduction, antioxidant functions, and cell proliferation, growth, and differentiation. (6,7,8,9) Vitamin A helps regulate the immune system by developing and differentiating white blood cells, such as lymphocytes, which help prevent or fight off infections by destroy harmful bacteria and viruses. In addition, vitamin A maintains healthy skin, mucous membranes, and surface linings of the eyes and the respiratory, urinary, and intestinal tracts. (8) It is much easier for bacteria and viruses to penetrate the body and trigger infections when those membranes and linings are damaged.

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A deficiency of vitamin A is rarely observed in the United States, but rather common in the developing countries. (6,7,8,9) "Selected signs and symptoms of deficiency include xerophthalmia (dryness of the eye and abnormalities of the conjunctiva and cornea of the eye; it includes conjunctival and corneal xerosis, Bitot's spots, corneal scarring and ulcerations, and night blindness), anorexia, retarded growth, increased susceptibility to infections, obstruction and enlargement of hair follicles, and keratinization of epithelial (mucous) cells of the skin with accompanying failure of normal differentiation." (6) In developing countries, the main origin of blindness is a prolonged vitamin A deficiency. (6,7,8,9)

Over the years, an abundance of research has been completed to determine a correlation between a lower incidence of lung cancer and diets rich in beta-carotene and vitamin A or supplementation of beta-carotene and vitamin A. For instance, one of the hypotheses is that "a higher intake of green and yellow vegetables or other food sources of beta-carotene and/or vitamin A may decrease the risk of lung cancer." (8) However, numerous studies investigated the protective functions of vitamin A and beta-carotene supplements in lung cancer, but the outcomes did not discover vitamins to guard against lung cancer, unfortunately. Currently, the correlations between diet and lung cancer risk, prevention, or treatment continue to be controversial. (1,2)

Two large, randomized, placebo-controlled trials implemented in well-nourished populations (primarily cigarette smokers) with a lung cancer endpoint, the Alpha-Tocopherol, Beta-Carotene (ATBC) Prevention Study and the Beta-Carotene and Retinol Efficacy Trial (CARET), reported that supplementation of antioxidants showed no differences in the incidence of lung cancer, but rather increased the rates of lung cancer. (1)

In 1994, a study published in the New England Journal of Medicine, titled "The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers" evaluated whether daily supplementation of alpha-tocopherol, beta-carotene, or both would decrease the incidence of lung cancer and other cancers utilizing a randomized, double-blind, placebo-controlled primary-prevention trial, the Alpha-Tocopherol, Beta-Carotene (ATBC). (11) The subjects were recruited from 14 various geographic areas in southwestern Finland. A total of 29,133 subjects, ages 50 to 69, participated in the study. At each of the 14 sites, the subjects were randomized to receive one of the four regimens daily: 50mg of alpha-tocopherol alone (n=7286), 50 mg alpha-tocopherol and 20 mg beta-carotene (n=7278), 20 mg beta-carotene alone (n=7282), and placebo (n=7287). The study followed the subjects for 5 to 8 years, until death, or April 30, 1993. At the 4 month follow up appointments, the subjects would receive a new supply of capsules. Compliance was assessed by analyzing the remaining capsules at each visit, serum alpha-tocopherol and beta-carotene levels after 3 years of supplementation, and random serum assessments during the study. In order to evaluate safety and efficacy, questionnaires were provided at each follow up visit, which included questions about symptoms, and interviews, which included discussions about recent illnesses. (11)

The outcomes of the study showed that there was no decrease in the incidence of lung cancer among male smokers after 5 to 8 years supplementing beta-carotene daily, but rather may have harmful effects in this population. (11) In the entire study, 876 newly established cases of lung cancer and 564 deaths due to lung cancer were discovered. In the subjects receiving beta-carotene supplementation daily, the death rate was 8% higher compared to those receiving the placebo regimen. (11)

In 1996, a multicenter, randomized, double-blind, placebo-controlled primary prevention trial, the Beta-Carotene and Retinol Efficacy Trail (CARET), was executed to assess the effects of 30 mg beta-carotene and 25,000IU of retinol (vitamin A) supplementation daily versus placebo on the incidence of lung cancer, which was published in the New England Journal of Medicine, titled, "Effects of a Combination of Beta-Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease". (12) The study included 18,314 subjects, ages 45-69, who were smokers, former smokers, and workers exposed to asbestos. The subjects were randomly assigned, on a 1:1 basis, to receive one of the two regimens. The subjects were followed for 4 years, on average. Four month follow up appointments and two phone calls were the methods used to monitor the subjects' safety and end points of the study. (12)

The results of the study demonstrated that there was no decrease in the incidence of lung cancer among the subjects evaluated after 4 years (average) supplementing beta-carotene and vitamin A daily, but rather may have harmful effects in this population on risk and incidence of lung cancer. (12) In the entire study, 254 subjects died about the 388 newly diagnosed cases of lung cancer that were discovered during the trial. "The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P = 0.02), as compared with the placebo group. This result includes relative risks of 1.40 (95 percent confidence interval, 0.95 to 2.07) for workers exposed to asbestos, 1.42 (95 percent confidence interval, 1.07 to 1.87) for heavy smokers who were smoking at the time of randomization, and 0.80 (95 percent confidence interval, 0.48 to 1.31) for heavy smokers who were no longer smoking at the time of randomization. There was no statistically significant effect of the intervention on survival after the diagnosis of lung cancer (relative risk of survival after diagnosis of lung cancer in the active-treatment group as compared with the placebo group, 1.05; 95 percent confidence interval, 0.80 to 1.37)." In the subjects receiving beta-carotene and vitamin A supplements daily, the death rate was 17% higher compared to those who were receiving the placebo. (12)

Additionally, in 1996, a study published in the New England Journal of Medicine, titled "Lack of Effect of Long-Term Supplementation with Beta Carotene on the Incidence of Malignant Neoplasms and Cardiovascular Disease" evaluated whether supplementation of 50 mg beta-carotene on alternated days in male physicians, ages 40-84, would lower the incidence of malignant cancers, including lung cancer. (13) A total of 22,071 subjects participated in this randomized, double-blind, placebo-controlled trial. Participants were excluded from the study if they had history of cancer (except nonmelanoma skin cancer), myocardial infarction, stroke, or transient cerebral ischemia. In 1982, at baseline, 11% of the subjects were smokers and 39% were former smokers. The subjects were randomized in one of the four treatment groups: aspirin and beta-carotene placebo, beta-carotene and aspirin placebo, aspirin and beta-carotene, or both placebos. The trial end date was December 21, 1995. The subjects received the newly capsule packs monthly by mail, which included red capsules for even-numbered days, and white capsules for odd-numbered days. Follow up were performed every 6 months for the first year and yearly thereafter. Compliance was assessed via questionnaires or telephone interviews, plasma beta-carotene levels during the study.

The study established that beta-carotene supplementation had no significant effect on the incidence of malignant cancers, including lung cancer. In addition, the study determined that beta-carotene supplementation has no significant effect of the mortality rate due to malignant cancer, including lung cancer. In conclusion of the study, the authors stated that 12 years of beta-carotene supplementation created no improvement or damage in the incidence of malignant cancers or death from malignant cancers. (13)

Furthermore, in 2005, in India, a randomized controlled trial, was implemented to evaluate whether supplementation of high-dose multiple antioxidants vitamin C (ascorbic acid) 6100 mg/day; vitamin E (dl-alpha-tocopherol succinate) 1,050 mg/day; vitamin A (synthetic beta-carotene) 60 mg/day promotes further benefits when treating lung cancer with chemotherapy, which was published in the Journal of the American College of Nutrition, titled, "Chemotherapy alone vs. chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer". (14) A total of 73 subjects participated in the study, ages 26-65. Inclusion criteria included: previously untreated, ≤65 years of age, cytologically or histologically confirmed advanced stage (IIIB or IV) non-small-cell lung cancer with measurable lesions, Karnofsky's Performance Status > 60, adequate organ function, and informed consent. Exclusion criteria included: interstitial pneumonia, pulmonary fibrosis, myocardial infarction within the preceding 3 months, uncontrolled diabetes mellitus, and massive pleural or peritoneal effusion, symptomatic brain metastases requiring whole-brain irradiation, pregnant and lactating. Subjects were randomized to receive chemotherapy alone or chemotherapy and multiple high-dose antioxidants. In both treatment groups, subjects received "paclitaxel 225 mg/m2 over 3 hours on the first day and carboplatin dosed to AUC of 6 on the second day. Chemotherapy was repeated every three weeks for a maximum of 6 cycles". (ADA) Data was collected by the use of history and physical examinations, clinical and radiological evaluations, such as complete blood count and serum chemistry, chest radiograph, CT scans of chest and upper abdomen, toxicity assessments. (14)

The outcomes of the study confirmed that there were no significant differences between the chemotherapy treatment group and high-dose antioxidant supplementation with chemotherapy treatment group in response to treatment, survival, and survival time or toxicity. (14) Overall survival in the chemotherapy treatment group was 32.9% and 11.1% at year one and year two, respectively. Overall survival in the high-dose antioxidant supplementation with chemotherapy treatment group was 39.1% and 15.6% at year one and year two, respectively. (14)

In conclusion, the lack of evidence may be explained by too short of a time period of supplementation to truly observe the effects, the application of wrong dosage, or the population may be inappropriate. (11, 12,13,14) However, the benefits of vitamin A supplementation are truly inconclusive. Therefore, additional research must be employed to address the delimitations of the current studies available. For example, analyzing the effects of vitamin A supplementation and the incidence of lung cancer in the nonsmoking populations or testing various dosages of vitamin A supplementation.