Cancer Adjuvant Therapy
Repurposing Common Drugs as Adjuvant Cancer Therapies
A few widely used medications have received attention for their apparent correlations with lower rates of cancer and better cancer outcomes. The advantages of repurposing the drugs listed below is that each has a long history of use, is relatively inexpensive, and carries a low potential for toxicity.
Statin drugs, such as atorvastatin (Lipitor) and rosuvastatin (Crestor), block the production of cholesterol in the liver and are widely prescribed to lower high cholesterol levels. Statins work by inhibiting an enzyme critical to cholesterol synthesis (NIH 2018g). Cancer cells, especially CSCs, appear to rely on the cholesterol-synthesis pathway to promote proliferation and tumor growth, and blocking this important enzyme may therefore suppress cancer activity (Gruenbacher 2017).
Findings from dozens of studies and numerous research reviews suggest that individuals with a history of cancer who are also taking a statin drug have longer survival and lower rates of cancer recurrence (Cardwell 2015; Wu QJ 2015; Cai, Zhang 2015; Sakellakis 2016).
A thorough review of research into the effects of statin use in patients with cancer was published in 2017. The review included data from 1,111,407 participants in 95 studies. Analysis of the data showed strong consistency in evidence of benefits of statins, regardless of tumor location, publication type, study design, sample size, stage of disease, country of recruitment, or time of follow-up (Mei 2017).
The benefits the review found for statin users compared with non-users were:
- 30% reduction in all-cause mortality.
- 40% decrease in cancer-specific mortality.
- 33% improvement in progression-free survival.
- 26% improvement in recurrence-free survival.
However, although statins are generally safe and usually cause no problems, some people experience negative side effects from statin therapy. The most common of these are muscle spasms, muscle pain, and new-onset diabetes (Toth 2018). Because all statin drugs decrease production of coenzyme Q10 (CoQ10), long-term statin users will likely benefit from CoQ10 supplementation (see below) (Banach 2015; Muller 2017; Garrido-Maraver 2014).
Histamine (H2) receptor antagonists such as cimetidine (Tagamet) became popular in the late 1970s to treat gastrointestinal ulcers and other benign conditions of the stomach, esophagus, and duodenum. In 1985, Life Extension noted that cimetidine had merit as part of cancer treatment. Since then, many studies have supported the potential use of cimetidine to extend survival rates in patients with cancer (Tonnesen 1988; Yoshimatsu 2003; Pantziarka 2014).
Cimetidine may interfere with cancer progression by several mechanisms. These include: inhibiting cancer cell proliferation; stimulating immune cell activity by reducing T-regulatory cell function; preventing tumor growth by blocking histamine's action as a growth factor; and preventing the attachment of cancer cells to blood vessel walls (Siegers 1999; Kobayashi 2000).
Given the vast improvements in our understanding of molecular mechanisms of cancer and immune function, it is not surprising that multiple approaches using combinations of drugs, and possibly natural agents, are emerging. In one study that used such an approach, cimetidine was administered alongside other drugs that inhibit an enzyme involved in a type of brain tumor known as glioblastoma. The enzyme, called glycogen synthase kinase-3beta (GSK-3b), makes these brain tumor cells more aggressive. The combination of cimetidine, lithium (Eskalith, a mood stabilizer), olanzapine (Zyprexa, an antipsychotic medication), and valproate (Depakote, an antiseizure medication) appeared to improve survival in patients with brain tumor that had active GSK-3b (Furuta 2017).
A randomized controlled trial performed in Japan looked at the effects of cimetidine on survival and cancer recurrence in 64 patients undergoing surgery for colorectal cancer. The cimetidine group received 800 mg a day of cimetidine along with 200 mg of the chemotherapy drug 5-fluorouracil (5-FU) and the control group received only 5-FU, for one year, beginning 2 weeks after surgery. The 10-year survival rate was significantly higher in the cimetidine group (84.6%) than in the control group (49.8%) (Matsumoto 2002).
Cimetidine treatment is particularly effective in patients whose tumor cells have high numbers of surface proteins called Lewis A and Lewis X antigens. These antigens are seen particularly in some breast and pancreatic cancers, as well as about 70% of the colon cancers. Cimetidine is thought to reduce the amount of a protein on inner blood vessel walls that interacts with Lewis A and Lewis X antigens and promotes tumor cell attachment and invasion (Kobayashi 2000; Matsumoto 2002; Nakagoe 2000; Sozzani 2008; Pour 1988). In the trial described above, a second analysis was performed using only data from participants with high concentrations of Lewis antigens. In patients with Lewis X antigens, the 10-year survival rate was 95.5% with cimetidine and 35.1% without cimetidine; in patients with Lewis A antigens, 10-year survival was 90.9% with cimetidine and 20.1% without cimetidine (Matsumoto 2002).
Cimetidine may also improve the immune response to cancer by stimulating dendritic cell function (Kubota 2002). Dendritic cells are immune cells with the critical job of activating other immune cells that then recognize and target invaders and infected and damaged cells, including cancer cells (Goyvaerts 2015). For more information about dendritic cells, please see the "Cancer Immunotherapy" protocol.
Although cimetidine is available without a prescription, it is important to talk with a doctor before adding cimetidine to your treatment program. Cimetidine can interact with several commonly prescribed medications, such as digoxin (Lanoxin), theophylline (Theobid or Theo-Dur), phenytoin (Dilantin), warfarin (Coumadin), lidocaine (Xylocaine), and certain high blood pressure medications and antidepressants. These drug interactions can result in increased risk of toxicity or decreased efficacy of the medications (NIH 2018e).
Aspirin has been used for more than 100 years to reduce pain, fever, and inflammation, and a small daily dose of aspirin is recommended for some people at increased risk of heart attack or stroke (Desborough 2017; Walker 2018). Scientists have recently begun to explore how aspirin might help people with cancer (National Cancer Institute, Aspirin, 2017; Dulai 2016; Smith 2017).
Aspirin works by inhibiting an enzyme family called cyclooxygenases. Cyclooxygenases produce chemical messengers called prostaglandins and thromboxanes that transmit pain signals to the brain, play a role in blood clotting, and increase inflammation (Misra 2014; Regulski 2016). Aspirin may fight cancer partly by reducing the inflammation that is critical to the development and progression of tumors (Todoric 2016; Moris 2016). Other studies suggest that aspirin might interrupt interactions between platelets and tumor cells that contribute to metastasis (Guillem-Llobat 2016; Lichtenberger 2017).
Because many patients with cancer take aspirin daily for prevention of stroke or heart attack, researchers have been able to study whether aspirin improves cancer-related outcomes (Sleire 2017). For example, one study that included 4,164 women previously treated for stage 1, 2, or 3 breast cancer found that women who happened to be taking daily aspirin were 64% less likely to have a recurrence of their breast cancer than women in the study who never used aspirin (Holmes 2010).
Other studies have evaluated whether daily aspirin can help men with prostate cancer. In one study in 823 men with prostate cancer, those taking aspirin daily were less likely to develop advanced prostate cancer and have a recurrence of their disease after treatment (Smith 2017). Another observational study found that patients with prostate cancer treated with radiation therapy were less likely to have a cancer recurrence within 18 months if they were taking aspirin daily (Zaorsky 2012). Daily aspirin may also reduce the risk of death from prostate cancer (Jacobs 2014).
Regular aspirin use can prevent the development of colorectal cancer, and recent data suggest aspirin may also help patients after diagnosis of colorectal cancer (McCowan 2013; Chan 2009). In one study of 799 patients with stage 3 colon cancer, those who used aspirin regularly were significantly less likely to have disease recurrence or die from the disease (Ng 2015). An analysis of data from multiple studies of patients with colorectal adenomas found that taking aspirin at a dose of 80–160 mg per day for two to four years significantly reduced the risk of additional colorectal adenomas (Veettil 2017).
Aspirin may enhance the immune response to cancer. Prostaglandins can promote tumor growth by suppressing T cells that fight cancer (Zelenay 2015), which suggests aspirin may be especially effective in combination with powerful new immunotherapies (Hamada 2017). For more information about aspirin in relation to immunotherapy, please see the "Cancer Immunotherapy" protocol.
Research on the promising effects of aspirin is increasing (Hamada 2017; Xu 2018). At the time of this writing, the ADD-ASPIRIN trial has recruited about 5,000 participants, with a goal of 9,000, with breast, prostate, colorectal, and gastroesophageal cancers at sites all over the world to further test whether aspirin, at doses of 100 or 300 mg per day, can prevent cancer recurrence and increase chances of survival (Coyle 2016).
Although aspirin is available without a prescription, it is important to talk with a doctor before adding it to your treatment regimen. Because aspirin inhibits blood clot formation, daily aspirin can increase the risk of serious bleeding. It can also cause irritation and erosion of the stomach lining. People taking blood thinners, those who are at risk for gastrointestinal bleeding, and those who have blood disorders may not be good candidates for daily aspirin use.
Metformin (Glucophage) is a medication used to treat diabetes. After metformin was first approved by the US Food and Drug Administration in 1994, doctors began to notice that cancer rates were lower than expected among people with diabetes taking metformin (Evans 2005; Zi 2018). Researchers have since demonstrated cellular effects of metformin that may explain these unexpected observations (Zhao 2018).
Metformin has many molecular effects related to the growth and survival of cells, including cancer cells. The drug is effective for the treatment of diabetes because it reduces blood glucose levels and improves the responsiveness of cells to insulin (Viollet 2012; Adak 2018). These changes inhibit signaling along two critical pathways that cancer cells rely on to grow (Zhao 2018; Bi 2018). Metformin may also fight cancer by increasing levels of a protein called AMP-activated protein kinase, which controls how cells use energy and regulates cell growth and reproduction (Zakikhani 2006; Kheirandish 2018).
Promising data from early studies demonstrated that people taking metformin for diabetes were less likely to develop cancer (Evans 2005; Zi 2018). Later studies found that metformin use improved survival in patients with diabetes who had several forms of cancer, including breast, colorectal, lung, and prostate cancers (Tang 2018; Raval 2015; Tian 2017; Margel 2013; Levy 2018).
Recent randomized clinical trials have begun to examine whether metformin can also help patients with cancer who do not have diabetes:
- Among 200 women with an early form of breast cancer, a marker of proliferation was significantly reduced in breast tissue surrounding tumors after 28 days of treatment with 1,700 mg per day of metformin compared with placebo (DeCensi 2015).
- In 44 men with treatment-resistant prostate cancer, treatment with 1,000 mg per day of metformin appeared to stabilize their cancer and slow the increase of prostate-specific antigen (PSA), a tumor marker used to monitor prostate cancer growth (Rothermundt 2014).
- In 18 patients with advanced or metastatic non-small cell lung cancer who received metformin at doses of 1,000 to 2,000 mg per day along with standard chemotherapy for one year, 47% experienced no cancer progression. This rate of non-progression was better than the historical rate of about 15% seen in people with this type of cancer (Marrone 2018).
More studies are underway to determine the optimal doses of metformin, define which types of cancers are most responsive to metformin, and test the effects of metformin in combinations with radiation therapy and chemotherapy (Roberts 2016; Kim 2014; Gillessen 2016).Metformin can cause negative side effects such as upset stomach and diarrhea (NIH 2018h), and doses that are higher than needed can result in hypoglycemia (low blood sugar). In addition, metformin may not be safe for patients with abnormal kidney or liver function (Diabetes Prevention Program Research Group 2012).