Cancer Prevention

Because each cancer type is different in origin, composition, and responsiveness to treatment, reliable prevention techniques are very difficult to identify. Evidence that an activity or dietary item prevents cancer is difficult to confirm because the goal of cancer prevention is to produce an outcome where nothing changes (i.e. cancer does not develop). Additionally, because cancer prevention cannot usually be accomplished by a single event,  preventative measures must be taken for many years to give results that can be examned. Even if something is shown to help prevent a certain type of cancer, there is no guarantee that eating or behaving in a certain way will absolutely assure freedom from cancer development.

Much of the evidence for cancer prevention is not definitive. As an example, a diet low in fat 12 but high in fiber 34, fruits and vegetables 56 has been associated with lower risks for several cancers. There have also been a number of studies that have shown no connection between these kinds of diets and reduced cancer cases 789. Exercise has been shown to reduce cancer occurrence in some studies; in others, exercise does not seem to make a difference 1011.

Despite the conflicting evidence, the National Cancer Institute contends that the best way to help prevent cancer is to exercise, as well as eat a low calorie diet containing fiber, fruits, and vegetables. They also suggest that people should avoid a sedentary lifestyle, animal fats, and grilled meats to lessen the risk of developing cancer 12. Research suggests that a combination of different essential nutrients is better than consuming a large amount of a single item. 13

Another way to help prevent cancer is to avoid behaviors that are generally accepted to increase your risk of cancer. Some of the behaviors linked to cancer development are tobacco use 141516, alcohol consumption 1718, obesity 171920, and sun exposure. 2122 A study on Swedish families shows that an increased risk of cancer is more associated with environmental factors, diet and exercise rather than heredity. 23 The American Cancer Society suggests that a third of all American cancer deaths are linked to poor diet and lack of exercise. Additionally, another third of all cancer deaths are preventable by avoiding tobacco products. 24 The World Health Organization believes that 40% of cancer deaths world-wide could be prevented with proper diet, exercise, and tobacco avoidance. 25

View a 2015-2016 American Cancer Society publication on cancer prevention statistics.

In addition to these general guidelines, there are several specific compounds that have exhibited evidence that they may contribute to cancer prevention. 26

The following pages describe cancer prevention methods in more detail.

If you find the material useful, please consider linking to our website

Antioxidants

       The possible role of antioxidants in the prevention and treatment of a variety of medical conditions has been very highly publicized.  For some diseases, anti-oxidants may well play an important role.  Unfortunately, some of the excitement is not based on scientific evidence.  In order to understand how antioxidants work, it is first important to understand the process of oxidation.

 

What is Oxidation?

Oxidation is a chemical process.  Oxidation is the reason that metals rust and apples turn brown. When this same process happens inside your body, it can harm cells and tissues.  Free radicals are small chemicals that are responsible for oxidative damage. Free radicals can be contained in (or caused to form by) a variety of things including tobacco smoke, radiation (like sunlight or x-rays) and even the normal functioning of the human body.  Free radicals are unstable and they can interact with, and alter, other molecules.  Targets of free radicals include DNA, lipids and proteins.  When free radicals interact with other molecules, they can cause changes  (called oxidation) that interfere with the normal activity of the altered  target molecules.  The altered activity of the affected cell parts can cause severe problems for the cell and ultimately the entire body.  You can learn more about oxidation in the Closer Look on this page.

 

What are Antioxidants?
Antioxidants are molecules that, as the name suggests, prevent or reverse oxidation.  Examples of dietary antioxidants include vitamins C and E. Antioxidants are able to interact with and neutralize free radicals in vitro 2728, improve health and prolong life in animals 2930, and many studies are underway to investigate the potential of these compounds to prevent cancer in humans. Antioxidants are important to humans because they stop 'radicalized' molecules before they cause damage. Compounds that exhibit antioxidant properties do this by donating an electron to a free radical without needing to steal another electron. Unlike most compounds, antioxidants are stable with or without the electron they donate. Some antioxidants function in a "suicidal" manner, neutralizing free radicals by forming permanent bonds with them.

 

Sources and Uses of Antioxidants
There are many good sources of antioxidants including green tea, berries, tomatoes and soy. Antioxidants can be found in many fruits and vegetables because plants produce antioxidants to help protect themselves from free radicals created by radiation from the sun. The body naturally produces some antioxidants that help protect against free radical damage. Unfortunately, these do not provide complete protection. Humans must consume antioxidants from other sources if they wish to decrease their risk of developing diseases that are increased by free radical damage 31. Outside of the body, antioxidants can also be used for many practical purposes: museum curators use them to preserve artifacts derived from living things, they can prevent food from spoiling. They are also used to make better rubbers, plastics, automobile fuels and paint 31.

NOTE: Just because something is healthy does not mean more is better. Even the healthiest substances can cause harm if taken in large amounts. In fact, there has been some recent evidence linking antioxidants to the spread of cancer. The benefits of antioxidants aren't limited to healthy cells; it seems they can support the survival and spread of cancer cells too. In one study, mice were given an anti-diabetic drug that activated a protein, called NRF2, in their cells. This protein increases the levels of antioxidants in cells. NRF2 activation seemed to increase cell migration and metastasis in mice with pre-existing tumors. Be sure to tell your physician about any drugs you may be taking, and always ask before starting any supplements. 32

Watch the full interview about antioxidants with urologist Dr. John Petros.

A Closer Look at Free Radicals

Atoms are composed of a nucleus, containing particles called protons and neutrons, and a  group of particles (electrons) that constantly circle the nucleus like satellites around the earth. In most molecules electrons travel in pairs around the nucleus.Free radicals are an exception.  At least one atom in a free radical has a single (unpaired) electron circling the nucleus. This single electron gives the atom a charge, making it very attracted to other molecules. A molecule with an unpaired electron is said to be 'radicalized'. These radicalized compounds, or free radicals, can quickly react with other molecules. For this reason these compounds are also called reactive species. Oxygen is the most common reactive species found in the human body and when it acquires an extra electron it is called a reactive oxygen species (ROS).

Free radicals 'steal' an electron from a nearby molecule so that all of their electrons are in pairs. The affected target molecule would then become a radical.  A chain reaction of electron 'theft' can occur within a cell. Free radicals can affect just about any structure in a cell, including DNA. If free radicals steal an electron from DNA, the genetic code can be damaged and cell function damaged. DNA damage caused by free radicals has been associated with aging, rheumatoid arthritis, inflammatory bowel disease, acute respiratory distress syndrome (ARDS), emphysema, and some types of cancer. 333134


Plant Products (Phytochemicals)

Phytochemicals are compounds found in plants. The phytochemicals below are being investigated to see if they are beneficial to human health; even when extracted from the plant from which they originate. In recent years, there has been a large amount of research to investigate the usefulness of specific natural compounds in the prevention and treatment of cancer.  The list below is not meant to be complete.  There are numerous other chemicals that are being examined.  We have chosen some of the best-studied and most widely publicized agents:

Choosing an item from the list below will take you to the Plant Products page in our Integrative Oncology section.


Drugs

Drugs that are used to help prevent cancer are highly regulated by the federal government to insure quality and safety. Most drugs that are suggested by doctors to help prevent cancer are for a specific population that is at a high risk of developing certain cancer types. These drugs are not suggested for all people because they can cause other problems that may not be worth the cost of protection. Nevertheless, some drugs have been shown to decrease the risk for cancer and have been approved by the US Food and Drug Administration for cancer prevention. These include non-steroidal anti-inflammatory drugs (NSAIDs) and the hormonal antagonists tamoxifen and raloxifene, discussed in more detail below.

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Non-steroidal anti-inflammatory drugs

 

Types of NSAIDs
COX-1 Inhibitors:

   
Structure of Acetaminophen                          Structure of Diclofenac                           

   
Structure of Ibuprofen                                           Structure of Salicylic Acid     

COX-2 Inhibitors:

   
         Structure of Celecoxib                            Structure of Naproxen

  
   Structure of Rofecoxib                                Structure of Valdecoxib

Intro and Background
The inflammatory response is a normal function of the human immune system. This process helps repair the body after injury. When you get cut or hurt, the area usually becomes red, hot, and swollen. In part, this is caused by the immune system as it works to heal the damaged area of your body. This response brings nutrient rich blood to the area so injured tissues can be repaired and new cells can grow 35. Despite its normally positive function, research has shown that the human inflammatory response is important in controlling the environment of cancer cells. Inflammation can promote tumor angiogenesis, initiation, growth and metastasis. Cells of the immune system, such as macrophages, may also be negatively affected by inflammation. 36373839. Also, the same cells that are stimulated by the immune response to grow and replicate may malfunction and grow without proper regulation; this behavior may lead to the initiation of a cancerous growth. 40.

Learn MORE about angiogenesis and metastasis

Non-steroidal anti-inflammatory drugs interfere with the activity of a family of enzymes called cyclooxygenases (COX). COX inhibitors prevent the enzymes from producing chemical signals responsible for inflammation, pain and possibly tumor growth 41. There are two types of NSAIDs, grouped by the form of COX they inhibit (COX-1 or COX-2). NSAIDs are quite common and are commonly known as pain relievers [acetaminophen (Tylenol®), diclofenac (Voltaren®), ibuprofen (Advil® ), salicylic acid (Aspirin®), celecoxib (Celebrex®), naproxen (Aleve®), rofecoxib (Vioxx®), and valdecoxib (Bextra®)]. Aspirin is also taken for the prevention of heart disease. For this use, the average, safest, and most effective dose of aspirin usually recommended by doctors is 81 mg/day 42.

Scientific Research
Research suggests that NSAIDs are effective chemopreventative agents but significant negative effects have also been identified. Regular use of aspirin has been shown to reduce the risk of colorectal cancer and recurrent colorectal cancer in humans 43444145464748. Exactly how these drugs reduce cancer risk is still unclear but seems to be linked to their ability to block the cyclooxygenase (COX) enzymes.49

COX-1 inhibitors are associated with digestive problems such as excessive bleeding and ulcers.42

COX-2 inhibitors have recently come under scrutiny because they were identified as increasing the risk of heart attacks and strokes 50. Because of the risks associated with NSAIDs, only people at high risk of cancer are typically given these drugs as a preventative measure. Researchers are now working to identify the sub-population of people who should take NSAIDS to lower their risk of colon cancer. 51

Aspirin, a type of NSAID, has been documented in some cases to reduce the risk of certain cancers, notably colorectal cancer, and potentially cancers of the oesophagus, stomach, breast, ovary, and lung. Aspirin has also been shown to reduce the risk of Barrett's esophagus, a precursor to esophageal cancer.52. Though daily aspirin use has been shown to decrease cancer mortality,53 aspirin is nevertheless a drug, and long-term use may lead to other problems. Aspirin was even proposed to increase risk for kidney cancer 54

Studies have shown that individuals with an increased risk of colorectal cancer may be able to reduce recurrence of adenomas or advanced adenomas in the colon with the use of aspirin 55. However, its effectiveness in prevention may be dependent on its duration of use and the dose taken.5657 The long term use of aspirin has been documented to reduce the incidence of colorectal cancer. Long-term use was even associated with decreased abnormal methylation of genes related to cancer. 58In contrast, studies with smaller, short term usage have not yielded these results.5960 The US Preventative Services Task Force has concluded, though, that overall, taking aspirin to reduce the risk for colorectal cancer may be doing more harm than good for individuals with an average risk of developing colorectal cancer.61 More research is needed to determine if the benefits outweight the possible risks for people with an increased risk of colorectal cancer. In summary, aspirin has been shown to  reduce the risk of developing colorectal cancer and adenomas, and reduce the chance of recurrence of colorectal cancer and adenomas in individuals with a history of colorectal cancer. However, taking aspirin for colorectal cancer prevention depends on an individual's risk of developing cancer; the possible negative effects of aspirin need to be weighed against its chemoprevention benefits.

Results of studies on the ability of aspirin to reduce the risk of prostate cancer have been inconsistent.62 Some research indicates that aspirin may be able to reduce the level of prostate specific antigen (PSA) in individuals with latent cancer, and thus affect the detection of prostate cancer.63 Other research indicates that, as with colorectal cancer, the dosage and duration of aspirin intake may play a role in its protective effect 64. For example, researchers found that exposure to an average dose of at least 80 mg of aspirin for 8 years led to a decline of 18% in prostate cancer risk. However, one year after ending the 7 year regular aspirin intake, no protective effect was found. 

It is unclear whether aspirin reduces the risk of breast cancer. Some studies have found that aspirin use is associated with reduced risk for breast cancer 65, but others have found no significant reduction in risk with use of aspirin 64.It is possible that the effects are different for different types of breast cancer. For example, daily intake of aspirin was associated with reduction in risk for ER-positive breast cancer 64. Recent research also indicates that aspirin may prevent the metastasis of breast cancer 66

US Food and Drug Administration Approval
Celecoxib (Celebrex®) is the only NSAID that has been approved to treat cancer. It is used to reduce polyps for people with a rare genetic disorder (adenomatous polyposis)67. In 2007, the US Preventive Services Task Force recommended against the use of aspirin for the prevention of colorectal cancer.68


Hormonal Antagonists

phytoestrogens

Drugs:
 Tamoxifen- Nolvadex®
 Raloxifene- Evista®, Keoxifene, Raloxifene Hydrochloride

Classified as:
Hormonal Antagonists

   
                         Structure of Tamoxifen                                              Structure of Raloxifene

Intro and Background
Tamoxifen and Raloxifene are both prescription drugs that are structurally similar to the hormone estrogen. Tamoxifen was originally developed in the 1960s as a possible contraceptive. After it was found to be inneffective for this use, doctors began researching it as a way to fight estrogen stimulated cancers. 6970 In the 1970s, it was tested on late stage breast cancer and was found to be a potent treatment. In 1998, it was approved as the first chemopreventative agent for women with a high risk of breast cancer. 7071

Tamoxifen and Raloxifene are classified as selective estrogen receptor modulators (SERMs) because they are able to block a cell's response to estrogen. Tamoxifen is also known to trigger uterine cancer and blood clots that may block blood vessels (thromboemboli). Because of these negative side-effects, doctors suggest that only women with a high risk of breast cancer should take the drug as a preventative measure 7172.

Scientific Research
Early studies showed that breast cancer tumorogenesis was inhibited in rats treated with tamoxifen 73. In addition to the positive effects of tamoxifen, it has been found to increase the risk of endometrial and uterine cancers. This may be due to its ability to damage DNA in healthy cells 74. Both tamoxifen and raloxifene have both been shown to reduce the incidence of invasive breast cancer by as much as fifty percent in high risk women.75767778

US Food and Drug Administration Approval
Tamoxifen was approved by the FDA for breast cancer treatment in 1977. Tamoxifen was subsequently approved as a way to help prevent surgically removed breast cancer from reoccurring as well to help prevent breast cancer in high risk women 70. Raloxifene has been approved by the FDA to help prevent and combat cancer and bone loss (osteoporosis). 7976


Cancer Vaccines

The prevention of cancer is the ultimate goal of cancer researchers and clinicians. One good way to accomplish this is to prevent infection with agents (viruses, bacteria, and parasites) known to cause cancer.  Vaccines have been developed and approved to prevent infection with hepatitis B virus,  a cause of liver cancer, and the human papillomavirus, the major cause of cervical cancer and a cause of cancers of the head/neck and urogenital tract of men and women. Learn more about the approved vaccines:

Cervical Cancer Vaccines

The development of vaccines against HPV is a major step in the fight against cervical cancer.

Currently, there are two vaccines approved for the prevention of infection with HPV, Gardasil® and Cervarix®.

Gardasil® is FDA approved for the prevention of HPV types 6, 11, 16 and 18 infection in young women aged 9-26. On October 16, 2009, the FDA also approved Gardasil® to prevent genital warts caused by HPV types 6 and 11 in young men aged 9-26.8081  In 2016, the CDC changed their recommendation for 11- to 12-year-olds, allowing them to take only two doses of HPV vaccine instead of three doses. People vaccinated at 15 through 26 years of age, still need to get three doses of of the vaccine.82

Cervarix® also prevents infection by HPV 16 and 18. Cervarix® was approved for use in the United States in October 2009.83

Importantly, the vaccinations are prophylactic  and are not effective against the progression of pre-existing HPV infection or cervical dysplasia, and should not deter women from annual screening tests, especially since not all cancer causing (oncogenic) forms of HPV are included in the vaccines.8485

Watch the video to learn more about HPV vaccines. Click here to watch the full interview with Dr. Ira Horowitz.

Because of exciting recent developments in this field, we will cover this treatment in more depth than some others and will discuss the development of the treatment

The majority of cervical cancer is believed to be caused by the Human Papillomavirus (HPV). There are more than 100 variants (subtypes) of HPV but only a small subset are associated with human cancer. HPV subtypes 16 and 18 are the variants most commonly associated with human cervical cancer. Several characteristics of HPV make it a good target for vaccine development. The virus is simple, small, and has a stable genome. HPV vaccine development and clinical trials are currently underway.

Gardasil®

The Strategy

As discussed in the previous sections, the goal of vaccines is to increase the response of the immune system to particular antigens. The idea is that if our immune system 'sees' the protein again, it will respond very strongly. In the case of viruses, the immune system often reacts to the proteins on the outside of the virus particle.

In a laboratory, it is possible to construct non-infectious virus-like particles (VLPs) that are similar to the infectious virus but are free of viral DNA and can therefore not reproduce. These VLPs contain viral proteins and are capable of generating the same natural humoral immune response following injection into the body. Two different VLP-based Human Papilloma Virus vaccines are at advanced stages of development/usage.

The Agents

Gardasil®
The first preventative cancer vaccine to receive FDA approval was Gardasil®. Gardasil® was designed to prevent infection by four different subtypes of HPV (6, 11, 16, and 18). HPV types 6 and 11 together, cause 90% of the cases of genital warts while 16 and 18 combined, are responsible for 70% of cervical cancer cases. Gardasil® contains VLPs containing the capsid protein of each of these four strains of HPV.

Gardasil® is produced by Merck Pharmaceuticals. The agent was approved by the FDA on June 8, 2006 for the prevention of cervical cancer (and genital warts) in females 9-26 years old and is being tested for its effectiveness in other age groups and in combination with other vaccines. On October 16th,2009 Gardasil® was approved for use in boys and men 9-26 years of age.

More on Gardasil® from Merck
Search for clinical trials involving Gardasil® at the NCI

The Data
Following positive phase I and II clinical trials, a total of 12,167 women, aged 16-26 years, enrolled in a phase III trial at 90 different study centers in Brazil, Colombia, Denmark, Finland, Iceland, Mexico, Norway, Peru, Poland, Singapore, Sweden, the United Kingdom and the United States. Of the more than 12,000 participants, 6,082 females received a three dose regimen of Gardasil while the remaining 6,075 received a placebo. The study evaluated the occurrence of HPV 16/18 associated cervical pre-cancers and non-invasive cancers.

Specifically, participants were screened for moderate (2) and high (3) grade cervical intraepithelial neoplasia (CIN), Grade 3 CIN is also known as carcinoma in situ (CIS). CIS is an immediate precursor to invasive squamous cell cervical cancer. Participants were also examined for the occurrence of AIS adenocarcinoma in situ (AIS), a precursor to glandular cervical cancer. The results of the trial showed that Gardasil® prevented 100 percent of high-grade pre-cancer and non-invasive cancers associated with HPV 16/18. Gardasil® was also found to reduce the risk of developing high-grade pre-cancer and non-invasive cancer in women who may have violated the protocol or become infected with the virus during the time of the trial. The treatment received FDA approval in the summer of 2006.86878884

Gardasil 9®

Gardasil 9, an improved version of Gardasil®, was developed to protect against five additional types of HPV-31, 33, 45, 52, and 58-not accounted for in the original vaccine. Targeting an even broader range of HPV types, Gardasil 9 prevents approximately 90 percent of cervical, vulvar, vaginal, and anal cancers, up 20 percent from Gardasil.
 
Gardasil 9® is produced by Merck Pharmaceuticals. The agent was approved by the FDA in December 2014 for use in females 9-26 years of age, and males 9-15 years of age.
 

Cervarix®

A second HPV vaccine, Cervarix®, produced by GlaxoSmithKline, was approved by the U.S. Food and Drug Administration (FDA) in October 2009 for use in girls age 10 to 25.79 The vaccine is designed to protect against infection by HPV types 16 and 18, these two subtypes of HPV are responsible for 70% of cervical cancer cases. In addition to two VLPs, the vaccine also contains chemicals (aluminum hydroxide and 3-deacylated monophosphoryl lipid A (AS04)) designed to increase the immune response to the viral proteins.

A Phase III double-blind, placebo-controlled trial of Cervarix® was conducted with more than 1,100 women in North America and Brazil between the ages of 15 and 25. Those receiving Cervarix® received three doses of the vaccine over a six month period, similar to the manner in which Gardasil® is administered. Follow-up was conducted for 27 months. Researchers found a 92 percent efficacy rate against new infection and 100 percent protection against persistent HPV infection. The results also showed that AS04 helped the vaccine to elicit a stronger antibody response than would occur with natural infection.89

Search for clinical trials involving Cervarix® at the NCI

 

Liver Cancer (Hepatitis Virus)

Chronic infection with hepatitis viruses is a major risk factor for the development of liver cancer.  Both hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with liver cancer.9091 Gobally, infection with hepatitis B virus is extremely common, with an estimated 240 million people infected worldwide in 2005.92

A vaccine against hepatitis B virus was approved in 1981, making it the first cancer prevention vaccine.93  Today, babies in the US are routinely vaccinated against hepatitis B shortly after birth.  It is also recommended that adults receive vaccinations against hepatitis B9495 There is no vaccine available to prevent infection with hepatitis C.

 


Cancer Prevention Tables

Classification

Chemical

Drugs NSAIDs, Tamoxifen, Raloxifene
Phytochemicals Anthocyanin, Curcumin, EGCG, Lycopene, Phytoestrogens, Pycnogenol, Resveratrol, Selenium, Vitamin E

 

Biological Process Affected

Chemical

Angiogenesis Curcumin, EGCG, Resveratrol
Apoptosis Anthocyanin, Curcumin, EGCG, Lycopene, Resveratrol, Selenium
Inflammation Anthocyanin, Pycnogenol, NSAIDs
Metastasis Curcumin, NSAIDs, Vitamin E, Resveratrol
Oxidation
(i.e. Antioxidants)
Anthocyanin, Curcumin, EGCG, Lycopene, Phytoestrogens, Pycnogenol
Proliferation Anthocyanin, Curcumin, NSAIDs, EGCG, Selenium,
Enzyme Activity NSAIDs
Hormone Activity Tamoxifen, Raloxifene
  • 1. Littman AJ, Beresford SA, White E: The association of dietary fat and plant foods with endometrial cancer (United States). Cancer Causes Control 12 (8): 691-702, 2001 [PUBMED]
  • 2. McCann SE, Freudenheim JL, Marshall JR, et al.: Diet in the epidemiology of endometrial cancer in western New York (United States). Cancer Causes Control 11 (10): 965-74, 2000. [PUBMED]
  • 3. Howe GR, Benito E, Castelleto R, et al.: Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case-control studies. J Natl Cancer Inst 84 (24): 1887-96, 1992. [PUBMED]
  • 4. Morse DE, Pendrys DG, Katz RV, et al.: Food group intake and the risk of oral epithelial dysplasia in a United States population. Cancer Causes Control 11 (8): 713-20, 2000. [PUBMED]
  • 5. Buiatti E, Palli D, Decarli A, et al.: A case-control study of gastric cancer and diet in Italy: II. Association with nutrients. Int J Cancer 45 (5): 896-901, 1990. [PUBMED]
  • 6. Neuhouser ML, Patterson RE, Thornquist MD, et al.: Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the beta-carotene and retinol efficacy trial (CARET). Cancer Epidemiol Biomarkers Prev 12 (4): 350-8, 2003. [PUBMED]
  • 7. Fuchs CS, Giovannucci EL, Colditz GA, et al.: Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med 340 (3): 169-76, 1999 [PUBMED]
  • 8. Michels KB, Edward Giovannucci, Joshipura KJ, et al.: Prospective study of fruit and vegetable consumption and incidence of colon and rectal cancers. J Natl Cancer Inst (2000) 92(21): 1740-52. [PUBMED]
  • 9. Jain MG, Rohan TE, Howe GR, et al.: A cohort study of nutritional factors and endometrial cancer. Eur J Epidemiol (2000) 16 (10): 899-905. [PUBMED]
  • 10. Friedenreich CM: Physical activity and cancer prevention: from observational to intervention research. Cancer Epidemiol Biomarkers Prev 10 (4): 287-301, 2001. [PUBMED]
  • 11. Schouten LJ, Goldbohm RA, van den Brandt PA: Anthropometry, physical activity, and endometrial cancer risk: results from the Netherlands Cohort Study. J Natl Cancer Inst 96 (21): 1635-8, 2004. [PUBMED]
  • 12. Vainio H, Weiderpass E. Fruit and Vegetables in Cancer Prevention. Nutrition and Cancer. (2006) 54(1):111-42 [PUBMED]
  • 13. Greenwald P, Anderson D, Nelson SA, Taylor PR. Clinical trials of vitamin and mineral supplements for cancer prevention. Am J Clin Nutr. (2007) 85(1):314S-317S. [PUBMED]
  • 14. Boffetta P, Pershagen G, Jöckel KH, et al.: Cigar and pipe smoking and lung cancer risk: a multicenter study from Europe. J Natl Cancer Inst 91 (8): 697-701, 1999 [PUBMED]
  • 15. Anthonisen NR, Skeans MA, Wise RA, et al.: The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med 142 (4): 233-9, 2005. [PUBMED]
  • 16. Koh HK: The end of the "tobacco and cancer" century. J Natl Cancer Inst 91 (8): 660-1, 1999. [PUBMED]
  • 17. a. b. Morimoto LM, White E, Chen Z, et al.: Obesity, body size, and risk of postmenopausal breast cancer: the Women's Health Initiative (United States). Cancer Causes Control 13 (8): 741-51, 2002. [PUBMED]
  • 18. Bagnardi V, Blangiardo M, La Vecchia C, et al.: Alcohol consumption and the risk of cancer: a meta-analysis. Alcohol Res Health 25 (4): 263-70, 2001 [PUBMED]
  • 19. Purdie DM, Green AC: Epidemiology of endometrial cancer. Best Pract Res Clin Obstet Gynaecol 15 (3): 341-54, 2001 [PUBMED]
  • 20. Bergström A, Pisani P, Tenet V, et al.: Overweight as an avoidable cause of cancer in Europe. Int J Cancer 91 (3): 421-30, 2001. [PUBMED]
  • 21. Preston DS, Stern RS: Nonmelanoma cancers of the skin. N Engl J Med 327 (23): 1649-62, 1992 [PUBMED]
  • 22. English DR, Armstrong BK, Kricker A, et al.: Case-control study of sun exposure and squamous cell carcinoma of the skin. Int J Cancer 77 (3): 347-53, 1998. [PUBMED]
  • 23. Czene K, Lichtenstein P, Hemminki K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int J Cancer 2002;99:260266 [PUBMED]
  • 24. Lawrence H. Kushi, Tim Byers, Colleen Doyle, Elisa V. Bandera, Marji McCullough, Ted Gansler, Kimberly S. Andrews, Michael J. Thun and The American Cancer Society 2006 Nutrition and Physical Activity Guidelines Advisory Committee. CA Cancer J Clin (2006) 56; 254-281 [PUBMED]
  • 25. World Health Organization. Cancer Fact Sheet No. 297. February 2006. Accessed 2 June 2010. [http://www.who.int/mediacentre/factsheets/fs297/en/index.html]
  • 26. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortaily from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. (2003) 348: 1625-38 [PUBMED]
  • 27. Valcheva-Kuzmanova S.V., Belcheva A. Colon-available raspberry polyphenols exhibit anti-cancer effects on in vitro models of colon cancer. Journal of Carcinogenesis (2007) Apr 18; 6: 4 [PUBMED]
  • 28. Lin Y.G., Kunnumakkara A., et al. Curcumin Inhibits Tumor Growth and Angiogenesis in Ovarian Carcinoma by targeting the Nuclear Factor-ºB Pathway. Clin Cancer Res 2007 13: 3423-3430 [PUBMED]
  • 29. Yanase S, Yasuda K, Ishii N: Adaptive responses to oxidative damage in three mutants of Caenorhabditis elegans (age-1, mev-1 and daf-16) that affect life span. Mech Ageing Dev. (2002) 123:1579-1587 [PUBMED]
  • 30. Missirlis F, Phillips JP, Jackle H: Cooperative action of antioxidant defense systems in Drosophila. Curr Biol. (2001) 11:1272-1277 [PUBMED]
  • 31. a. b. c. Halliwell, Barry. (May 3, 2005) Free radicals and other reactive species in disease. In: Encyclopedia of Life Sciences. John Wiley & Sons, Ltd: Chichester http://www.els.net/ [doi:10.1038/npg.els.0006101] [http://www.els.net/ [doi:10.1038/npg.els.0006101]]
  • 32. Wang, H., X. Liu, M. Long, Y. Huang, L. Zhang, R. Zhang, Y. Zheng, X. Liao, Y. Wang, Q. Liao, W. Li, Z. Tang, Q. Tong, X. Wang, F. Fang, M. R. De La Vega, Q. Ouyang, D. D. Zhang, S. Yu, and H. Zheng. "NRF2 Activation by Antioxidant Antidiabetic Agents Accelerates Tumor Metastasis." Science Translational Medicine 8.334 (2016). [http://www.ncbi.nlm.nih.gov/pubmed/?term=NRF2+activation+by+antioxidant+antidiabetic+agents+accelerates+tumor+metastasis] [PUBMED]
  • 33. Ramsey MR, Sharpless NE: ROS as a tumour suppressor? Nat Cell Biol. (2006) 8: 1213-1215 [PUBMED]
  • 34. Irminger-Finger I. Science of cancer and aging. J Clin Oncol. 2007 May 10;25(14):1844-51 [PUBMED]
  • 35. Villarreal G, Zagorski J, Wahl Sm (January 29, 2003). Inflammation: Acute. In: ENCYCLOPEDIA OF LIFE SCIENCES. John Wiley & Sons, Ltd: Chichester [http://www.els.net/ [doi:10.1038/npg.els.0006101]]
  • 36. Fox JG, Wang TC. Inflammation, atrophy and gastric cancer. J Clin Invest. (2007) 117: 60-9 [PUBMED]
  • 37. Dobrovolskaia MA, Kozlov SV. Inflammation and cancer: when NF-ºB amalgamates the perilous partnership. Current Cancer Drug Targets. (2005) 5:325-44 [PUBMED]
  • 38. de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nature Reviews. Cancer. (2006) 6: 24-37. [PUBMED]
  • 39. MacDonald N. Cancer cachexia and targeting chronic inflammation: a unified approach to cancer treatment and palliative/supportive care. J Support Oncol. (2007) 5(4): 157-62 [PUBMED]
  • 40. Villarreal G, Zagorski J, Wahl Sm (January 29, 2003). Inflammation: Acute. In: ENCYCLOPEDIA OF LIFE SCIENCES. John Wiley & Sons, Ltd: Chichester [http://www.els.net/ [doi:10.1038/npg.els.0006101]]
  • 41. a. b. Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med (2003) 348: 891-9. [PUBMED]
  • 42. a. b. Campbell CL, Smyth S, Nontalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA. (2007) 297(18): 2018-24 [PUBMED]
  • 43. Chan AT. Aspirin, non-steroidal anti-inflammatory drugs, and colorectal neoplasia: future challenges in chemoprevention. Cancer Causes Control (2003) 14: 413-8 [PUBMED]
  • 44. Bertagnolli MM. Chemoprevention of colorectal cancer with cyclooxygenase-2 inhibitors: two steps forward, one step back. Lancet Oncol. (2007) May;8(5):439-43. [PUBMED]
  • 45. Sandler RS, Halabi S, Baron JA, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med (2003) 348: 883-90. [PUBMED]
  • 46. Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med (2006) 355: 873-84 [PUBMED]
  • 47. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med (2006) 355: 885-95 [PUBMED]
  • 48. Leibowitz B, Qiu W, Buchanan ME, Zou F, Vernon P, Moyer MP, Yin XM, Schoen RE, Yu J, Zhang. BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16520-5. [PUBMED]
  • 49. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. (2007) 356(21): 2131-42. [PUBMED]
  • 50. Couzin J. Drug Safety. FDA panel urges caution on many anti-inflammatory drugs. Science. (2005) 307(5713): 1183-5 [PUBMED]
  • 51. Markowitz SD. Aspirin and colon cancer--targeting prevention? N Engl J Med. (2007) 356(21): 2195-8. [PUBMED]
  • 52. Omer ZB, Ananthakrishnan AN, Nattinger KJ, Cole EB, Lin JJ, Kong CY, Hur C. Aspirin Protects Against Barrett's Esophagus in a Multivariate Logistic Regression Analysis. Clin Gastroenterol Hepatol. 2012 Jul;10(7):722-7. Epub 2012 Mar 15. [PUBMED]
  • 53. Baron JA. Aspirin and cancer: trials and observational studies. J Natl Cancer Inst. 2012 Aug 22;104(16):1199-200. [PUBMED]
  • 54. Bosetti C, Gallus S, La Vecchia C. Aspirin and cancer risk: a summary review to 2007. Recent Results Cancer Res. 2009;181:231-51. [PUBMED]
  • 55. Cooper K, Squires H, Carroll C, Papaioannou D, Booth A, Logan RF, Maguire C, Hind D, Tappenden P. Chemoprevention of colorectal cancer: systematic review and economic evaluation. Health Technol Assess. 2010 Jun;14(32):1-206. [PUBMED]
  • 56. Chan AT, Giovannucci EL, Meyerhardt JA, et al. Aspirin dose and duration of use and risk of colorectal cancer in men. Gastroenterology 2008;134:21¿28.
  • 57. Chan AT, Giovannucci EL, Meyerhardt JA, et al. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 2005;294:914¿923.
  • 58. Noreen F, Röösli M, Gaj P, Pietrzak J, Weis S, Urfer P, Regula J, Schär P, Truninger K.Modulation of age- and cancer-associated DNA methylation change in the healthy colon by aspirin and lifestyle. J Natl Cancer Inst. 2014 Jun 28;106(7). [PUBMED]
  • 59. Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: the Women¿s Health Study: a randomized controlled trial. JAMA 2005;294:47¿55.
  • 60. Gann PH, Manson JE, Glynn RJ, et al. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst 1993;85:1220¿1224.
  • 61. Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology. 2010 Jun;138(6):2029-2043.e10. [PUBMED]
  • 62. Brasky TM, Velicer CM, Kristal AR, Peters U, Potter JD, White E. Non-Steroidal Anti-Inflammatory Drugs and Prostate Cancer Risk in the VITamins And Lifestyle (VITAL) Cohort. Cancer Epidemiol Biomarkers Prev. 2010 Oct 8. [PUBMED]
  • 63. Fowke JH, Motley SS, Smith JA Jr, Cookson MS, Concepcion R, Chang SS, Byerly S. Association of nonsteroidal anti-inflammatory drugs, prostate specific antigen and prostate volume. J Urol. 2009 May;181(5):2064-70 [PUBMED]
  • 64. a. b. c. Takkouche B, Regueira-Méndez C, Etminan M.Breast cancer and use of nonsteroidal anti-inflammatory drugs: a meta-analysis. J Natl Cancer Inst. 2008 Oct 15;100(20):1439-47. [PUBMED]
  • 65. Zhao YS, Zhu S, Li XW, Wang F, Hu FL, Li DD, Zhang WC, Li X. Association between NSAIDs use and breast cancer risk: a systematic review and meta-analysis. Breast Cancer Res Treat. 2009 Sep;117(1):141-50. [PUBMED]
  • 66. Bhattacharyya M, Girish GV, Ghosh R, Chakraborty S, Sinha AK. Acetyl salicyclic acid (aspirin) improves synthesis of maspin and lowers incidence of metastasis in breast cancer patients. Cancer Sci. 2010 Oct;101(10):2105-9. [PUBMED]
  • 67. US Food and Drug Adminstration website. Accessed 6/20/2016. [http://www.fda.gov/]
  • 68. Routine Aspirin or Nonsteroidal Anti-inflammatory Drugs for the Primary Prevention of Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine. 2007 Mar;146(5):361-364. [http://www.uspreventiveservicestaskforce.org/uspstf/uspsasco.htm]
  • 69. Jordan VC . Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov. (2003) 2: 205-13 [PUBMED]
  • 70. a. b. c. Wozniak K, Kolacinska A, Blasinska-Morawiec M, Morawiec-Bajda A, Morawiec Z, Zadrozny M, Blasiak J. The DNA-damaging potential of tamoxifen in breast cancer and normal cells. Arch Toxicol. (2007) 81(7): 519-27 [PUBMED]
  • 71. a. b. Jordan VC. SERMs: meeting the promise of multifunctional medicines. J Natl Cancer Inst. (2007) 99(5): 350-6. [PUBMED]
  • 72. Hu H, Jiang C, Ip C, Rustum YM, Lu J. Methylseleninic acid potentiates apoptosis induced by chemotherapeutic drugs in androgen-independent prostate cancer cells. Clinical Cancer Research (2005). 11: 2379-2388. [PUBMED]
  • 73. Jordan, V. C., Allen, K. E. & Dix, C. J. Pharmacology of tamoxifen in laboratory animals. Cancer Treat. Rep. (1980) 64: 745-759. [PUBMED]
  • 74. Poirier MC, Schild LJ. The genotoxicity of tamoxifen: extent and consequences. Mutagenesis. (2003) 18: 395399 [PUBMED]
  • 75. Cuzick J, Forbes J, Edwards R, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomized prevention trial. Lancet. (2002) 360:81724. [PUBMED]
  • 76. a. b. Richardson H, Johnston D, Pater J, Goss P. The National Cancer Institute of Canada Clinical Trials Group MAP.3 trial: an international breast cancer prevention trial. Curr Oncol. (2007) 14(3): 89-96 [PUBMED]
  • 77. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl CancerInst (1998) 90: 1371-88 [PUBMED]
  • 78. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomesthe NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA. (2006) 295: 272741. [PUBMED]
  • 79. a. b. US Food and Drug Administration. FDA Approves raloxifene to prevent osteoporosis. U.S. Department of Health and Human Services. Dec 10, 1997. [http://www.fda.gov/bbs/topics/ANSWERS/ANS00838.html]
  • 80. Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP).Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007 Mar 23;56(RR-2):1-24. [PUBMED]
  • 81. U.S. Food and Drug Administration. News Release: FDA Approves New Indication for Gardasil to Prevent Genital Warts in Men and Boys. October 16, 2009. [http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm187003.htm]
  • 82. Centers for Disease Control and Prevention Newsroom. Accessed 11/1/2016. [http://www.cdc.gov/media/releases/2016/p1020-hpv-shots.html]
  • 83. Food and Drug and Administration Vaccines, Blood, & Biologics Accessed October 21st, 2009 [http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm186991.htm]
  • 84. a. b. Food and Drug and Administration Vaccines, Blood, & Biologics Accessed October 21st, 2009 [http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm186991.htm]
  • 85. Gardasil® Website Registered by Merck & Co., Inc. Site accessed 12/04/07 [http://www.gardasil.com/index.html]
  • 86. Lowndes CM. "Vaccines for cervical cancer." Epidemiology and Infection. (2006) 134: 1-12. [PUBMED]
  • 87. "Merck's investigational vaccine GARDASIL" prevented 100 percent of cervical pre-cancers and non-invasive cervical cancers associated with HPV types 16 and 18 in new clinical study." Merck website. Accessed 3 August 2006. [http://www.merck.com/newsroom/press_releases/research_and_development/2005_1006.html]
  • 88. Schmiedeskamp, MR and DR Kockler. "Human Papillomavirus vaccines." 2006, The Annals of Pharmacotherapy 40(7):1344-52 [PUBMED]
  • 89. Harper DM, et al. "Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial." The Lancet (2004) Nov 13; 364:1757-65. [PUBMED]
  • 90. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012 May;142(6):1264-1273.e1. [PUBMED]
  • 91. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006 Oct;45(4):529-38. Epub 2006 Jun 23. [PUBMED]
  • 92. Vaccine. 2012 Mar 9;30(12):2212-9. Epub 2012 Jan 24. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012 Mar 9;30(12):2212-9. Epub 2012 Jan 24. [PUBMED]
  • 93. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, Wolfe S, Hamborsky J, eds. 12th ed. Washington DC: Public Health Foundation, 2011. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hepb.pdf Accessed July 20, 2011. [http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hepb.pdf]
  • 94. Mast EE, Margolis HS, Fiore AE, Brink EW, Goldstein ST, Wang SA, Moyer LA, Bell BP, Alter MJ; Advisory Committee on Immunization Practices (ACIP). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005 Dec 23;54(RR-16):1-31. [PUBMED]
  • 95. Mast EE, Weinbaum CM, Fiore AE, Alter MJ, Bell BP, Finelli L, Rodewald LE, Douglas JM Jr, Janssen RS, Ward JW; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep. 2006 Dec 8;55(RR-16):1-33; quiz CE1-4. [PUBMED]