Efforts to develop new cancer therapies are costly and not always successful. Therefore, repurposing existing drugs with potential anti-cancer effects to expand the armamentarium of cancer therapeutics is an appealing strategy. Common drugs that show promise as repurposed adjuvant cancer therapies are often inexpensive and have well-documented safety and drug-interaction profiles.¹

Given the appeal of established and well-characterized drugs from a cost and safety perspective, several research collaborations have emerged to study the potential of repurposed drugs for use in cancer. Among the most well-known of these collaborative efforts is the Repurposing Drugs in Oncology (ReDO) Project, which was launched by an international group of researchers in 2014.² More recently, high-throughput computer-aided drug screening efforts continue to reveal the potential of repurposing existing drugs as cancer therapeutics.³

A major challenge in advancing research on repurposed drugs for cancer is that there is often little commercial interest in this strategy from pharmaceutical companies. Repurposing old drugs is not as financially lucrative as developing new drugs and bringing them to market. Therefore, research on repurposing existing drugs gets little financial support from the private sector. Some support for drug repurposing research is provided through federal funding in the United States: both the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) have drug repurposing programs.⁴

The purpose of this protocol is to highlight several drugs with track records of safe use in other conditions that may have utility in the context of cancer. The drugs discussed in this protocol should not be incorporated into any cancer treatment regimen unless done so under the supervision of qualified oncology-care clinicians.

Note: Refer also to Life Extension’s other cancer-related protocols, including Cancer Adjuvant Therapy, Chemotherapy, Cancer Radiation Therapy, Cancer Surgery, Cancer Treatment: The Critical Factors, and the protocol on the specific type of cancer you are interested in.

Background

Metformin (Glucophage) is a medication used to treat diabetes, and has been shown to reduce the progression from pre-diabetes to overt diabetes.⁵ After metformin was first approved by the FDA in late 1994, evidence emerged suggesting people taking metformin for diabetes were less likely to develop certain types of cancer.^6,7 Subsequent studies showed that metformin use was associated with improved survival in diabetic patients with several different types of cancer.⁶ These unexpected observations may be explained by cellular effects of metformin that have since come to light.

Metformin decreases blood glucose levels by inhibiting glucose production and release by the liver; in addition, metformin increases cells’ sensitivity to insulin. These effects can reduce high insulin levels in people with insulin resistance and type 2 diabetes.⁸ Because cancer cells have high glucose requirements and insulin can promote tumor initiation and progression, lower glucose and insulin levels may protect against cancer development and growth.^9,10

Metformin has also been shown to affect signaling pathways that influence the activity, growth, and survival of cancer cells. Although its exact mechanisms are not completely understood, metformin’s actions are likely due in part to suppression of mitochondrial energy production and activation of AMP-activated protein kinase (AMPK), an enzyme that slows down cellular energy use and regulates cell growth and proliferation.^7,11-13 In addition, metformin has been shown to inhibit cell signaling via a pathway known as mammalian target of rapamycin (mTOR). Signaling via the mTOR pathway is involved in regulating cell division and survival, and dysregulated mTOR signaling is a common characteristic of cancer cells. Studies in cancer cells suggest metformin-induced AMPK activation and mTOR inhibition can inhibit cancer cell initiation, proliferation, and metastasis, and induce apoptosis (normal cell death).^6,7,9,12 Metformin also impacts the tumor microenvironment, reducing inflammatory immune function, quieting tumor-supportive regulatory T cells, and stimulating anti-cancer T cells.^11,14,15

In addition, metformin has been shown to modulate the microbiome in ways that may mitigate inflammation and confer some protection against cancer. In the context of colorectal cancer, for example, researchers have recently proposed a “metformin-gut microbiota-colorectal cancer (in type 2 diabetes) axis.”¹⁶ In this new theoretical framework, “the gut microbiota plays a key role as a bridge that affects not only the pharmacological effects of metformin but also the occurrence of colorectal cancer” in patients with type 2 diabetes. This model proposes that metformin’s inhibition of colorectal cancer in people with type 2 diabetes may be mainly due to manipulation of populations of several microbiota genera in the gut, including Bacteroides, Ruminococcus, Clostridium, Firmicute, Lactobacillus, and E. coli. More research is needed, but evidence available as of early 2021 increasingly suggests manipulation of the gut microbiome may be a principal mode of action for metformin’s influence on metabolic activity and an important component of the drugs’ anti-cancer actions.^17-20

Observational (Correlational) Evidence

The growing body of research is varied in methodologies and definitions, such as how metformin use is defined and what characterizes the control group; therefore, more research is needed to clarify metformin’s potential as an adjuvant therapy for cancer. The following summary describes recent findings from observational studies of the effects of metformin in the context of specific types of cancer in people with type 2 diabetes.

Metformin and colorectal cancer: A meta-analysis of 50 studies with a combined total of more than 238,000 participants found metformin use was associated with lower risk of colorectal cancer and longer overall and cancer-specific survival in patients with type 2 diabetes. Greater protective effects were seen with higher doses and longer duration of use in Asian populations.²¹ Findings from another meta-analysis suggest women may benefit more than men.²² In other studies in diabetic colorectal cancer patients, metformin use was linked to better responsiveness to chemotherapy and radiation therapy, a lower rate of cancer recurrence, fewer metastases, and longer survival.^23,24

Metformin and breast cancer: Although there have been conflicting findings, some observational studies have reported lower breast cancer incidence and mortality in type 2 diabetic patients treated with metformin than in those not treated with metformin, and the benefits may pertain particularly to hormone receptor-positive and HER2-positive breast cancers.^658-660 However, randomized controlled trials and meta-analyses have shown metformin is not likely to improve outcomes in non-diabetic breast cancer patients.^661-663

Metformin and ovarian cancer: A meta-analysis of five studies with a combined total of 3,582 ovarian cancer patients found consistent evidence for improved survival in those using metformin as an anti-diabetes treatment after their cancer diagnosis compared with both diabetic and non-diabetic non-metformin users. Two other meta-analyses that each included 13 studies found an association between metformin use and lower ovarian cancer incidence, as well as a link between metformin use and improved prognosis in ovarian cancer patients.^26,27 However, one meta-analysis of six studies with 2,638 participants reached another conclusion, finding no correlation between metformin use and ovarian cancer outcomes.²⁸

Metformin and liver cancer: A meta-analysis of eight studies found metformin use was correlated with reduced risk of hepatocellular carcinoma (the most common type of primary liver cancer) in type 2 diabetic subjects.²⁹ In another meta-analysis that included results from six studies in diabetic patients with hepatocellular carcinoma, the pooled data indicated metformin use was related to increased overall and recurrence-free survival in those treated with measures intended to cure the cancer; however, metformin had no association with survival in those whose cancer treatment was palliative.³⁰ A retrospective cohort study of 164 individuals with diabetes and single nodular hepatocellular carcinoma who underwent transarterial chemoembolization (TACE) found those who took metformin (median duration 32 months and median dosage 250 mg daily) had significantly higher response rates—79% versus 60% in those who did not take metformin. Metformin use was found to be an independent predictor of response rates to TACE and was associated with a 72% lower risk of local tumor recurrence. Although metformin use prior to TACE reduced local tumor recurrence, its use did not appear to affect overall recurrence rate or progression-free survival.⁶⁸⁴

Metformin and pancreatic cancer: Metformin use has been linked to reduced risk of pancreatic cancer.³¹ In a case-control study based at the University of Texas MD Anderson Cancer Center in Houston, diabetic patients with a history of metformin use had considerably lower odds of pancreatic cancer than those who had not taken metformin (OR: 0.38, 95% CI: 0.22-0.69). On the other hand, diabetic patients in this study who had taken insulin or insulin secretagogues had significantly greater odds of pancreatic cancer.³² A meta-analysis of 14 studies including nearly 36,800 participants with type 2 diabetes and pancreatic cancer found metformin use was correlated with increased overall survival, with stronger effects in those with less-advanced tumors. A second analysis of the data, however, showed the protective effect was only present in Asians.³³ Another study found no benefit from metformin in diabetic African Americans with pancreatic cancer; however, in diabetic Caucasian patients who started metformin after the time of cancer diagnosis, an increase in overall survival was observed.³⁴

Metformin and gastric cancer: A meta-analysis of findings from 11 studies found metformin use was associated with a reduced risk of gastric cancer and longer cancer-specific and overall survival in type 2 diabetics in Asian, but not Western, populations.³⁵ A study done in the Baltic country of Lithuania found, compared with the general population, that people using metformin for type 2 diabetes had lower incidence of gastric cancer, while those using sulfonylureas (another type of anti-diabetes drug) had a higher incidence.³⁶

Metformin and lung cancer: Lithuanian researchers reported the risk of death was reduced in lung cancer patients with diabetes being treated with metformin, but was increased in those treated with sulfonylureas, compared with non-diabetic lung cancer patients.³⁷ A small study performed in the United States found, in 50 patients with non-small cell lung cancer, those simultaneously receiving metformin for diabetes had better cancer treatment response, better disease control, and longer progression-free and overall survival compared with non-diabetics.³⁸ An observational registry study that assessed data from over 730,000 subjects found that metformin use was associated with lower lung cancer incidence and mortality. Moreover, increasing metformin dose was associated with more pronounced reductions in lung cancer risk in this study. This study also showed that combined use of metformin, statins, and aspirin was associated with greater reductions in lung cancer mortality than use of any of the three alone; this effect was greater with longer duration use.³⁹

Metformin and prostate cancer: Several meta-analyses have found metformin use does not significantly influence prostate cancer risk^40-42; however, in one meta-analysis, diabetic prostate cancer patients using metformin were found to have prolonged cancer-specific, recurrence-free, and overall survival.⁴¹

Metformin and brain cancer: In patients with high-grade glioma (the most common type of brain cancer), metformin use was associated with longer progression-free and overall survival in those with grade III but not grade IV disease.⁴³ (Grade IV is the most malignant form of glioma; it is also known as glioblastoma.) In addition, a meta-analysis of three studies involving newly diagnosed glioblastoma patients found no benefit associated with metformin use.⁴⁴

Metformin and endometrial cancer: Findings from meta-analyses suggest there is no relationship between metformin use and endometrial cancer risk,^45-47 but metformin use has been consistently found to be associated with better survival in endometrial cancer patients.^47-51

Metformin and blood cancers: In Taiwanese people with type 2 diabetes, metformin use was associated with lower risk of non-Hodgkin lymphoma compared with other diabetes treatments⁵²; however, a similar study done in Canada found no relationship.⁵³ In addition, metformin use does not appear to correlate with improved outcomes in patients with non-Hodgkin lymphoma.^54,55 In people with a precancerous condition called monoclonal gammopathy of undetermined significance (MGUS), those treated with metformin were found to have slower progression from MGUS to multiple myeloma.^56,57 In addition, some evidence suggests metformin use may be linked to better outcomes in diabetics with multiple myeloma.⁵⁸

Metformin and other cancers: A study done in Sweden found metformin users had a lower risk of esophageal cancer than non-metformin users.⁵⁹ In a Taiwanese study, people with type 2 diabetes were less likely to be diagnosed with esophageal cancer than those treated with other medications.⁶⁰ A meta-analysis of seven studies found metformin use was unrelated to survival in patients with head and neck cancer.⁶¹

Causal Evidence - Clinical Trial Data

Recent randomized clinical trials have begun to examine whether metformin can also help non-diabetic cancer patients:

• Among 200 women with an early form of breast cancer, a marker of tumor aggressiveness and potential for 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.⁶²
• In 58 women with HER2-positive breast cancer treated with standard chemotherapy, the addition of 1,700 mg of metformin for 24 weeks increased the likelihood of a complete response⁶³; in addition, even those who did not have a complete response expressed lower amounts of a marker of tumor aggressiveness.⁶⁴
• 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) levels, a tumor marker used to monitor prostate cancer growth.⁶⁵
• 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.⁶⁶
• A controlled trial in 139 patients with advanced lung cancer found adding 500 mg of metformin twice daily to chemotherapy resulted in longer progression-free survival.⁶⁷
• In 102 patients with acute lymphoblastic leukemia (ALL), 850 mg of metformin three times daily improved the response to chemotherapy and reduced the rate of relapse compared with chemotherapy alone. Furthermore, this trial identified a genetic marker associated with poorer outcomes in general but greater benefit from metformin.⁶⁸
• In a placebo-controlled trial, 151 individuals with recurrent precancerous colon polyps were treated surgically and then given low-dose metformin (250 mg per day) or placebo for one year; those who received metformin had fewer benign and precancerous polyps at 1-year follow-up colonoscopy.⁶⁹
• A small early clinical trial in ovarian cancer patients reported no improvement in progression-free survival with the addition of metformin to chemotherapy.⁷⁰

More studies are underway to determine optimal doses of metformin, define which types of cancer and types of patients are most responsive to metformin, and test the effects of metformin in combinations with radiation therapy and chemotherapy.⁷¹

Safety Considerations

Metformin may cause side effects such as gastrointestinal upset including bloating, flatulence, and diarrhea.⁷² Uncommonly, it may also cause lactic acidosis (high levels of lactic acid), particularly when used in high doses.^71,73 Metformin may raise homocysteine concentrations as well, but supplementation with B vitamins may counteract this side effect.⁷⁴ Metformin may reduce testosterone levels as well (which may be beneficial among women with polycystic ovary syndrome).^75-77 In addition, patients with impaired kidney function and elderly individuals with heart failure or other serious conditions should be closely monitored while using metformin.^9,78

Background

Statins are a family of cholesterol-lowering drugs that work by inhibiting an enzyme called HMG-CoA reductase, which is critical to cholesterol synthesis in the liver. There are currently seven drugs in the statin family approved for treating high cholesterol levels: simvastatin (Zocor), lovastatin (Mevacor), pravastatin (Pravachol), fluvastatin (Lescol), atorvastatin (Lipitor), rosuvastatin (Crestor), and pitavastatin (Livalo). They differ somewhat in degree of lipid-solubility, metabolism, and clearance, and have different effects on lipid profiles.⁷⁹

Cholesterol is needed for cell membrane structure, energy storage, and as a substrate for signaling molecules. Cancer cells, especially cancer stem cells, are dependent on the cholesterol-synthesis pathway to support proliferation, migration, and invasion. By interfering with cholesterol synthesis, statins may therefore suppress cancer activity.^80-82 There is also evidence that statins lower immune signaling and help regulate epigenetic mechanisms related to cells’ proliferative potential. Because their effects on HMG-CoA reductase impact multiple fundamental cellular processes, statins are considered pleiotropic agents.^83,84

In a meta-analysis of seven studies with a combined total of 23,555 participants, all of whom had type 2 diabetes, cancer incidence was found to be lower in those taking any of the statin medications, with rosuvastatin showing the strongest association.⁸⁵ Another meta-analysis reported people taking statins for high cholesterol levels had lower incidences of 10 out of 18 types of cancer, although the evidence for these correlations was mostly weak.⁸⁶ Although not all studies agree,⁸⁷ findings from dozens of studies and numerous research reviews suggest the incidental use of statins to lower high cholesterol levels may reduce cancer risk and, in cancer patients, prolong survival and lower rates of cancer recurrence.^88-90

Despite many positive findings, much remains to be learned about the relationship between statin use and cancer initiation and progression. For example, there is conflicting evidence for cancer-related benefits with long-term statin use: while multiple studies suggest a protective effect, a recent meta-analysis of 15 studies with a total of 358,544 participants found those taking statins for a minimum of 10 years experienced no benefit on cancer incidence or cancer-related mortality.⁹¹ Importantly, some evidence suggests long-term statin use may be associated with new-onset diabetes.⁹² More research is needed to clarify the risk-benefit profile in terms of potential cancer risk reduction or treatment benefit against the potential detrimental effect of long-term statin use on glucose and insulin metabolism. Statins have a well-documented favorable risk-benefit in the context of cardiovascular risk, but more evidence is needed to establish their utility in the prevention and/or treatment of cancer in otherwise healthy individuals, especially with long-term use.

Observational (Correlational) Evidence

Statins and liver cancer: Statin users have consistently been found to have a substantially lower incidence of hepatocellular carcinoma, the most common form of cancer originating in the liver.^93-95 A meta-analysis of data from 24 studies with a total of 59,073 participants found statin use was associated with a 46% hepatocellular carcinoma risk reduction, and the association was even stronger in patients with increased liver cancer risk due to diabetes, cirrhosis, or viral hepatitis.⁹⁶ In one large study, the correlation between statin use and reduced liver cancer risk was only evident in those taking highly lipid-soluble statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, and simvastatin) and the reduction was greatest in those who took a cumulative total of 600 or more daily doses. In addition, 10-year mortality was reduced in users of all types of statins compared with non-users.⁹⁷

Statins and esophageal cancer: A large meta-analysis examined data from 22 studies that followed a total of more than 6 million people and identified 372,206 esophageal cancer cases. The analysis found statin users, including those at high risk due to Barrett’s esophagus (a precancerous condition of the esophagus), had a lower incidence of esophageal cancer.⁹⁸ A meta-analysis of data from four studies with a total of 20,435 esophageal cancer patients found statin use after cancer diagnosis was correlated with better cancer-specific and overall survival.⁹⁹

Statins and gastric cancer: A relationship between long-term statin use and reduced gastric cancer risk was reported in a Korean study that included 21,149 participants with high cholesterol levels and followed them for 12–13 years.¹⁰⁰ In another Korean study that included people at high risk of gastric cancer due to Helicobacter pylori, those taking statins were less likely to develop gastric cancer after H. pylori treatment compared with those not taking statins.¹⁰¹ Another Korean study found an association between statin use and reduced recurrence rate during 5–12 years of follow-up in gastric cancer patients treated surgically.¹⁰² An analysis of two populations in the United Kingdom, however, found evidence for a modest benefit of statins on risk of gastric cancer.¹⁰³

Statins and pancreatic cancer: Despite some conflicting evidence,¹⁰⁴ statin use was found by two large meta-analyses to be correlated with reduced risk of pancreatic cancer.^105,106 Statin use may also be associated with lower incidence of pancreatic cancer in patients at high risk due to chronic pancreatitis,^107,108 though not all studies agree.¹⁰⁹ There is also evidence suggesting statins may improve the course of pancreatic cancer. A meta-analysis of 14 studies with a combined total of 33,137 pancreatic cancer patients found statin use was associated with a lower mortality rate in those treated surgically, but not those with advanced cancer. Some data in the analysis suggested rosuvastatin specifically was linked to better survival.¹¹⁰ In an analysis of two studies comparing outcomes in a combined total of 156 pancreatic cancer patients who used statins during cancer treatment with 641 patients who did not, statin use was associated with better progression-free and overall survival.¹¹¹ Regular statin use prior to cancer diagnosis was also associated with a small increase in survival time in pancreatic cancer patients participating in the Nurses’ Health Study and the Health Professionals’ Follow-Up Study.¹¹²

Statins and prostate cancer: Long-term statin use (10 years or longer) has also been associated with reduced prostate cancer risk in some, but not all, studies.^113,114 While some research suggests statins may protect against aggressive prostate tumors, metastatic disease, and mortality,^115,116 studies in men with elevated PSA levels or those under active surveillance for low-risk tumors have not demonstrated a link between statin use and prostate cancer occurrence or progression.^117,118 Statin use following prostate cancer diagnosis has been correlated with better survival outcomes in multiple observational studies.^119-122 For example, a study that followed 44,126 men for 24 years found no relationship between statin use and prostate cancer risk, but among men who developed prostate cancer, those using statins at the time of cancer diagnosis were less likely to die from their cancer than those who never used statins or had stopped using them prior to their cancer diagnosis. The study also identified an epigenetically controlled marker on tumor cells that may indicate responsiveness to statin therapy.¹²³ One study found relationships between statin use and improved survival outcomes in those taking statins for 11 months or longer or who had taken a higher cumulative dose of statins, and in those with more aggressive tumors.¹²⁴

Statins and breast cancer: Although statins do not appear to impact the overall risk of breast cancer, there is some evidence that statin use may reduce breast cancer-related mortality.^125,126 Findings from a meta-analysis of data from seven studies, including a combined total of 197,048 breast cancer patients, suggest statins with high lipid solubility (atorvastatin, fluvastatin, lovastatin, pitavastatin, and simvastatin) are more strongly associated with increased survival than those with low lipid solubility (rosuvastatin and pravastatin).¹²⁷ In one study, disease-free and overall survival were higher in breast cancer patients who had taken statins for five years or longer.¹²⁸ A study performed in Sweden evaluated data on statin use among 20,559 breast cancer patients. Women who took statins regularly within the six months prior to their cancer diagnosis had a lower risk of breast cancer-related death during approximately five years of monitoring compared with those who never or irregularly used statins during the six months prior to diagnosis. In addition, those who initiated statin use after their cancer diagnosis also had a lower risk of breast cancer-related death.¹²⁹ In breast cancer survivors, statin use was associated with reduced risk of new cancer in the other breast, and the association was stronger with long-term (five years or longer) use.¹³⁰ However, according to a retrospective cohort study, statin use may not influence breast cancer risk in women with type 2 diabetes.¹³¹

Statins and lung cancer: Long-term statin use has been observed to be correlated with lower lung cancer risk in Korean men, particularly smokers, as well as in a Taiwanese population with chronic obstructive pulmonary disease (COPD).^132,133 In addition, two large meta-analyses found statin use before or during cancer treatment was associated with lower cancer-specific and all-cause mortality, particularly in patients with non-small cell lung cancer and those with more advanced cancer.^134,135 However, statin use did not appear to impact survival in patients who underwent surgery for lung cancer.¹³⁶

Statins and colorectal cancer: Studies of the effect of statin drugs on colorectal cancer risk and outcomes have produced varying results ranging from some benefit to no effect.^{140,143,650-654} Variables that may influence results include differences in dosage; pharmacological differences among different statin drugs; treatment history (eg, duration and initiation before vs. after diagnosis); tumor-specific factors like location and genetics; and comorbid conditions such as diabetes, inflammatory bowel disease, and cardiovascular disease.^{140,145,652,655}

One example of statins’ potential benefit in colorectal cancer patients comes from a retrospective cohort study that included nearly 12,000 patients who underwent surgical resection for rectal cancer. This study found that statin use within the year before surgery was significantly associated with a reduced risk of 90-day all-cause mortality (0.7% with statins vs. 5.5% without statins).⁶⁵⁶

As of 2021 the American Gastroenterological Association recommends statins not be used to prevent colorectal cancer in those at average risk, and that statins should not be prescribed to reduce mortality in colorectal cancer patients.⁶⁵⁷

Statins and endometrial cancer: While statin use does not appear to be correlated with endometrial cancer risk in the general population,^146,147 it may have a protective effect against endometrial cancer in women with type 2 diabetes.^148,149 In addition, a meta-analysis of data from nine studies found statins had a positive impact on overall and disease-specific survival.³² In one study with 6,694 participants, those who used statins before and after endometrial cancer diagnosis had a higher chance of survival, with a more pronounced association more than five years after diagnosis compared with years 1 through 5 after diagnosis.¹⁵⁰ Not all studies agree, however: a study that included data from 2,017 endometrial cancer patients found no relationship between statin use and recurrence-free or overall survival during an average follow-up time of 6.2 years.¹⁵¹

Statins and ovarian cancer: Although not all studies have linked statin use to lower ovarian cancer risk,^146,152 one study that followed 2,040 women with and 2,100 without ovarian cancer for 16 years found statin use for six months or longer was more common in women who did not develop ovarian cancer than those who did.¹⁵³ There is also evidence statins may improve the course of ovarian cancer. In a study that included data from 2,195 women with ovarian cancer monitored for an average of 2.2 years, cancer-related mortality was lower in those who began taking a statin within one year after their cancer diagnosis.¹⁵⁴ A meta-analysis of eight other studies with a combined total of 19,904 ovarian cancer patients also noted improved survival in those who used statins after their cancer diagnosis.¹⁵⁵

Statins and other cancers: There is also evidence that statin use is associated with lower incidence and better survival rates in head and neck cancer,^156,157 lower risk and better survival rates in kidney cancer,^158-160 and lower incidences of blood cancers including chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma.^161-163 However, statin use does not appear to be correlated with lower risk of, or better treatment outcomes for, brain cancer.^164-166

Causal Evidence - Clinical Trial Data

Despite intriguing preclinical research suggesting statins have pleotropic effects that may be beneficial in the context of cancer,¹⁶⁷ prospective clinical trials have not suggested statin use reduces cancer risk or provides benefit as adjunctive cancer therapy. A meta-analysis of 10 randomized controlled trials in patients with advanced cancers found adding statins to cancer treatment had no impact on survival outcomes.¹⁶⁸ In a meta-analysis of eight randomized, controlled, phase II and III trials, adding statins at typical doses to cancer treatment was not found to improve outcomes in patients with solid tumors including liver, gastric, lung, prostate, and colorectal cancers.¹⁶⁹ Another meta-analysis of 21 randomized controlled trials involving over 65,000 subjects found that “… there was no significant association between statin use and risk of cancer (RR: 0.97; 95% CI: 0.92-1.02).¹⁷⁰ Most trials included in these meta-analyses used standard cholesterol-lowering doses of either simvastatin or pravastatin; at least one of the included trials used lovastatin. Whether use of higher doses or other statin drugs might result in different outcomes remains to be investigated.

Future research will provide needed information about the optimal choice of drug, dose, and timing with regards to diagnosis and treatment for best results in cancer patients. Large, well-designed clinical trials are needed to clarify the potential role of statins in the context of cancer treatment.

Safety Considerations

Although statins are generally safe and usually cause minimal adverse events, some people experience negative side effects from statin therapy. The most common of these are muscle spasms, muscle pain, and new-onset diabetes.¹⁷¹ Because all statin drugs decrease production of coenzyme Q10 (CoQ10), long-term statin users benefit from CoQ10 supplementation.^172-174

Background

Aspirin has been used for more than 100 years to treat pain, fever, and inflammation. Scientists have more recently begun to explore how aspirin might help people with cancer.^175-177

Aspirin works by inhibiting a family of enzymes called cyclooxygenases (COXs). Cyclooxygenases help turn fatty acids into chemical messengers called prostaglandins and thromboxanes, which help promote pain signaling, blood clotting, and inflammation.¹⁷⁸ Aspirin may fight cancer partly by reducing the inflammation that is critical to the development and growth of tumors.^179,180 At the same time, by reducing platelet activity, aspirin may enhance anti-tumor immune activity and may have a role in supporting other anti-cancer immunotherapies.^181,182 (For more information about aspirin in relation to immunotherapy, please see the "Cancer Immunotherapy" protocol.) Aspirin has also been shown to reduce cancer cell production of certain growth factors.¹⁸³ In numerous preclinical studies, aspirin has demonstrated the ability to suppress a range of tumor cell activities and disrupt the tumor microenvironment in ways that interfere with tumor cell proliferation and metastasis.¹⁸⁴ Because it exerts multiple effects on the biology of cancer cells, aspirin is considered to have pleiotropic anti-cancer properties.¹⁷⁸

Observational (Correlational) Evidence

Numerous observational studies have linked low-dose aspirin use with reduced cancer incidence. A meta-analysis of 218 studies found regular low-dose aspirin use was correlated with lower overall cancer risk, as well as specific risks of gastric, esophageal, colorectal, pancreatic, ovarian, endometrial, breast, and prostate cancers.¹⁸⁵ In addition, a large study performed in China that followed 204,170 people using low-dose aspirin and 408,339 age- and sex-matched non-aspirin users for about 10 years found low-dose aspirin use was associated with lower incidences of liver, stomach, colorectal, lung, pancreatic, and esophageal cancers, as well as leukemia; was not associated with incidences of multiple myeloma or cancers of the kidney, bladder, or prostate; and was associated with a slight increase in breast cancer incidence.¹⁸⁶ However, an exploratory analysis of cancer outcomes in 10 studies from a meta-analysis of aspirin use and cardiovascular outcomes found no statistically significant effect of aspirin use on cancer incidence or mortality, compared with no aspirin use.¹⁸⁷

Low-dose aspirin has also been correlated with better survival outcomes in multiple studies in people with cancer. In a study performed in the United States with 146,152 participants aged 65 years and older, regular low-dose aspirin use was linked to lower risks of cancer-related and all-cause death over 8.7–16.4 years of follow-up.¹⁸⁸ Similarly, a study performed in France that included 111,025 participants aged 50–80 years found the 10-year risk of cancer and overall mortality were lower in low-dose aspirin users compared to non-users, with the protective association becoming stronger with each year of aspirin use.¹⁸⁹ In a meta-analysis of 13 studies with a combined total of 65,768 cancer patients, low-dose aspirin use after cancer diagnosis was associated with lower mortality in patients with digestive tract cancers including colorectal, esophageal, and gastric cancers; however, an analysis of findings from four other studies that included 16,654 cancer patients failed to find an impact of low-dose aspirin use prior to cancer diagnosis.

Aspirin and gastrointestinal cancers: For many years, it appeared promising evidence was building for aspirin’s anti-cancer effects on gastrointestinal cancers. In 2016, accumulating research led the US Preventive Services Task Force (USPSTF) to recommend regular use of low-dose aspirin to prevent colorectal cancer in people 50–69 years with a low risk of bleeding. This was followed by similar recommendations by the US Multi-Society Task Force on Colorectal Cancer and the National Institute for Health and Care Excellence for patients with Lynch syndrome, a genetic disorder characterized by increased risk of colorectal cancer.¹⁹⁰ Unfortunately, since then, large randomized controlled trials have not been able to demonstrate a protective effect for aspirin: one placebo-controlled clinical trial in 19,114 healthy older participants found long-term low-dose aspirin users had an increase in cancer-related and all-cause mortality rates.¹⁹¹ Another trial in 15,480 participants with type 2 diabetes reported no difference in risk of gastrointestinal cancer or any cancer with low-dose aspirin compared with placebo.¹⁹² In addition, in a randomized controlled trial in 2,536 Japanese patients with type 2 diabetes, low-dose aspirin did not impact cancer incidence.¹⁹³ The USPSTF is in the process of updating its 2016 recommendations; although, the contents of the new recommendations have not been released as of mid-2020.

Aspirin and liver cancer: A meta-analysis of eight studies including data from more than 2.6 million participants found a strong association between aspirin use and lower incidence of hepatocellular carcinoma, the most common form of primary liver cancer. The analysis found aspirin users were 41% less likely to develop hepatocellular carcinoma than non-users during an average monitoring period of 8.9 years.¹⁹⁴ Even in patients with high risk of liver cancer due to alcoholic cirrhosis or viral hepatitis, aspirin appears to reduce cancer risk.^195-197 Aspirin use has also been reported to lower recurrence rate in liver cancer patients treated surgically.¹⁹⁸

Aspirin and ovarian cancer: The Ovarian Cancer Cohort Consortium examined the findings from 12 observational studies with a total of 758,829 participants and found low-dose aspirin use six or more times per week was associated with a 10% reduction in ovarian cancer risk.¹⁹⁹ A previous meta-analysis of 23 studies also found a correlation between regular use of low-dose aspirin and reduced incidence of ovarian cancer.²⁰⁰ An analysis of findings from the Nurses’ Health Study and Nurses’ Health Study II, which followed a total of 205,498 women, also found low-dose, but not regular-dose, aspirin was linked to lower ovarian cancer risk.²⁰¹ Few studies have examined the relationship between aspirin use and survival in ovarian cancer patients. Some, but not all, evidence suggests aspirin use after ovarian cancer diagnosis may be linked to lower cancer-related mortality.^202,203 In a small study that tracked outcomes in 77 women with clear cell ovarian cancer, an uncommon and typically aggressive form of ovarian cancer, aspirin use was found to be associated with lower mortality.²⁰⁴ Aspirin use before ovarian cancer diagnosis, on the other hand, does not appear to impact survival.^202,205

Aspirin and gallbladder and biliary tract cancers: Two meta-analyses have found aspirin use may protect against the development of gallbladder cancer.^206,207 Researchers have also reported better survival outcomes in biliary tract cancer patients who used aspirin regularly after their cancer diagnosis.²⁰⁸

Aspirin and gastric cancer: Two large meta-analyses of observational studies have found an association between long-term, regular, low-dose aspirin use and reduced risk of gastric cancer.^209,210 The evidence for a protective effect comes from studies performed in China, Korea, and Sweden.^211-214 Aspirin may have a particular role in protecting patients at increased risk due to their need for long-term treatment with proton-pump inhibitor (PPI) drugs to reduce gastric acid production. Aspirin’s effect on mortality in gastric cancer patients is unclear: a study performed in the United Kingdom found aspirin use was not associated with survival outcomes in those with gastric or esophageal cancers.²¹⁵

Aspirin and breast cancer: Some evidence suggests low-dose, but not regular-dose, aspirin may lower the risk of breast cancer.²¹⁶ A meta-analysis of 13 studies with a total of 857,831 participants found the use of low-dose aspirin two to seven times per week for more than five years was associated with a lower risk of breast cancer, and the relationship was stronger with more regular and longer duration of use.²¹⁷ A study in 8,233 women whose risk of breast cancer was increased due to family history found regular aspirin users were less likely to develop breast cancer than non-aspirin users.²¹⁸ However, one study in breast cancer survivors found no link between aspirin use and risk of a new cancer diagnosis involving the other breast.²¹⁹ A systematic review of observational studies suggests low-dose aspirin during breast cancer treatment may also reduce metastases and cancer-related death.²²⁰ However, not all of the research is in agreement.²²¹ Researchers are just beginning to explore the role of genetics and epigenetics in predicting whether individuals will benefit from aspirin in cancer prevention or treatment.²²²

Aspirin and prostate cancer: In a review and meta-analysis of data from observational studies, use of low-dose aspirin for three or more years was associated with reduced prostate cancer incidence.²²³ One study included men with PSA levels of 3 ng/mL or higher and monitored them for about 10 years. The study found men using low-dose aspirin had lower PSA levels at the beginning and end of the study; unexpectedly, overall mortality was higher in aspirin users compared with non-users.²²⁴ Other research has reported a link between daily low-dose aspirin use for cardiovascular protection and lower prostate cancer mortality.^225,226 In one study, a protective association was only measurable after five years of aspirin use.²²⁷ But not all of the research is in agreement, and two meta-analyses of studies have failed to show a correlation between aspirin use and cancer-related or overall mortality in men with prostate cancer.^228,229

Aspirin and pancreatic cancer: In two meta-analyses of observational studies, long-term, regular, low-dose aspirin use was associated with reduced risk of pancreatic cancer.^230,231 One study performed in China found the risk in aspirin users was 46% lower than non-users.²³² Nevertheless, not all studies have observed a relationship.^108,233,234 For example, an analysis of data from 141,940 participants in the Nurses’ Health Study and the Health Professionals Follow-Up Study found no correlation between aspirin use and pancreatic cancer incidence; however, a possible protective effect in people with diabetes was noted.²³³

Aspirin and lung cancer: Findings from meta-analyses of observational studies regarding aspirin use and risk of lung cancer have been inconclusive.^235,236 One large study performed in Korea that included data from nearly 1.3 million people found regular aspirin use was associated with a small reduction in risk of lung cancer.²³⁷ In a study performed in the United States, regular low-dose aspirin use was associated with lower lung cancer incidence only in men.²³⁸ Notably, in a study that included 19,894 people with COPD, a condition that raises the risk of lung cancer, aspirin use was correlated with a further increase in lung cancer risk.²³⁹ So far, studies in lung cancer patients have failed to find a relationship between low-dose aspirin use, before or after cancer diagnosis, and risk of cancer-related death.^240-242

Aspirin and endometrial cancer: Although not all findings are in agreement, aspirin use has been found in multiple studies and meta-analyses to be correlated with reduced risk of endometrial cancer, particularly in overweight and obese women and with higher frequency and dosing of aspirin.^243-247 There is conflicting evidence regarding the relationship between aspirin use and endometrial cancer survival.^248,249

Aspirin and other cancers: A limited body of evidence also suggests aspirin use may be associated with a lower risk of brain cancer,²⁵⁰ and better outcomes in head and neck cancer patients,^251-253 but may not be correlated with risk of thyroid cancer or survival in esophageal cancer patients.^215,254

Causal Evidence - Clinical Trial Data

Few clinical trials of aspirin in cancer patients have been undertaken to date. The most recent trials have evaluated gastrointestinal cancer or overall cancer as endpoints, and results have not been promising.^191-193

The ASPREE trial, a large clinical trial involving over 19,000 participants, first published in 2018, showed that 100 mg aspirin daily was associated with increased all-cause mortality in heathy older adults.²⁵⁵ In 2020, the authors of the ASPREE trial published an analysis of secondary endpoints covering cancer incidence and mortality. Among subjects randomized to aspirin therapy in ASPREE, there was no difference in overall cancer incidence or mortality compared with placebo. However, those taking aspirin were more likely to be diagnosed with metastatic cancer and to die from cancers that were diagnosed at stages III or IV than those taking placebo (although this remains a controversial finding and more research is still needed). The ASPREE authors suggested aspirin may have an adverse effect on later-stage cancers in older adults.²⁵⁶

In a trial that included 709 participants with a history of precancerous colon polyps, 300 mg aspirin daily for one year did not reduce polyp recurrence.²⁵⁷ At the time of this writing, the ADD-ASPIRIN placebo-controlled trial, which has enrolled 11,000 survivors of breast, prostate, colorectal, and gastroesophageal cancers, is underway in the United Kingdom, Republic of Ireland, and India to further test whether aspirin, at doses of 100 or 300 mg daily, can prevent cancer recurrence and increase chances of survival.²⁵⁸ Other randomized controlled trials in colorectal cancer patients are also underway.^259-261

Safety Considerations

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 use increases the risk of serious bleeding.²⁶² 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 with blood disorders may not be good candidates for daily aspirin use.

Background

Diclofenac (Zipsor, Cataflam, Voltaren, and others) is a non-steroidal anti-inflammatory drug (NSAID). Oral, topical, and injectable preparations of diclofenac are used to treat inflammation, pain, and fever. Conditions such as arthritis, gout, migraine headache, and menstrual pain are often treated with diclofenac.^263,264 In cancer care, diclofenac is used for post-operative and cancer-related pain and has an established role in treating actinic keratosis, a precancerous skin condition caused by chronic sun exposure.²⁶⁴

Diclofenac appears to interact with cellular pathways that regulate factors such as metabolism, equilibrium, pH, chemosensitivity, cell signaling, and inflammation.²⁶⁵ It is well known to inhibit COX enzymes, particularly COX-2, and thereby reduces production of prostaglandin E2 (PGE2) from arachidonic acid. PGE2 is a pro-inflammatory molecule that occurs in high levels in the tumor microenvironment and is involved in tumor initiation and progression.^264,266 Diclofenac also decreases platelet function, which is important in the context of cancer because platelet activation can promote tumor growth through several mechanisms. Through these effects, diclofenac enhances anti-cancer immune function, reduces tumor-related new blood vessel formation, and increases cancer cells’ sensitivity to chemotherapy agents. Diclofenac has also been found to reduce glucose utilization, increase apoptosis, and suppress proliferation in cancer cells.²⁶⁴

Diclofenac has demonstrated anti-cancer effects in laboratory studies involving melanoma, leukemia, neuroblastoma, brain cancer, colorectal cancer, and prostate cancer cells.^264,267,268 One study looked at the combined effects of metformin and diclofenac on brain cancer cells and found they had complementary cancer-killing effects on cellular metabolism.²⁶⁹ Other cell studies indicate diclofenac may work synergistically with the kinase inhibitor sorafenib (Nexavar) and platinum-based chemotherapy agent cisplatin (Platinol) to increase cancer cell death.^270,271 Diclofenac has also demonstrated positive effects in animal models of colorectal, ovarian, brain, pancreatic, prostate, and oral cancers, as well as melanoma and neuroblastoma.^264,272

Observational (Correlational) Evidence

Observational studies examining the link between diclofenac and cancer occurrence, recurrence, and mortality have had mixed findings.

Diclofenac and colorectal cancer: A study examining data from 2,308 patients undergoing surgery for colorectal cancer found those who took either ibuprofen (Advil) or diclofenac for at least two days around the time of surgery were 24% less likely to have a recurrence of their cancer compared with those who did not use any NSAIDs around surgery; however, NSAID use had no effect on five-year survival.²⁷³

Diclofenac and breast cancer: Diclofenac may lower breast cancer risk, but has not been found to lower risk of recurrence at distant sites in women treated for breast cancer. In 24,662 women with autoimmune disorders, those who reported using NSAIDs for at least three months during the previous nine years had a 63% lower incidence of breast cancer. Diclofenac, ibuprofen, piroxicam (Feldene), and selective COX-2 inhibitors (like celecoxib [Celebrex]) were each associated with decreased breast cancer risk, and even the women with low cumulative daily use appeared to be protected.²⁷⁴ A study that followed 34,188 breast cancer patients for a median period of 7.1 years after treatment found no relationship between use of NSAIDs post-diagnosis (with diclofenac being one of the most commonly used) and risk of breast cancer recurrence; however, NSAID use before diagnosis was associated with reduced rates of recurrence.²⁷⁵ Another study found use of diclofenac around the time of surgery to remove breast cancer had no effect on later development of distant metastases; however, use of another NSAID, ketorolac (Toradol), was correlated with decreased risk of metastatic recurrence, particularly in overweight and obese women.²⁷⁶

Causal Evidence - Clinical Trial Data

The only clinical trials investigating the role of diclofenac in cancer prevention have been in patients with precancerous actinic keratosis. COX activity is increased in skin cells exposed to UV light, raising levels of PGE2, and high PGE2 levels are associated with transformation to actinic keratosis and progression to squamous cell carcinoma of the skin.²⁶⁶ Multiple clinical trials and case reports show topical treatment with 3% diclofenac in a 2.5% hyaluronic acid solution produces high rates of response and remission and decreases long-term risk of progression to skin cancer in patients with actinic keratosis with few adverse effects.^266,277 In two placebo-controlled trials, complete improvement was noted in 31–47% of participants treated with diclofenac/hyaluronic acid for 60 or 90 days, versus 8–19% of participants receiving placebo.^278,279 Because of the strength of the evidence, topical 3% diclofenac/2.5% hyaluronic acid is FDA approved for use in actinic keratosis.²⁶⁶ However, compared with other available treatments, diclofenac may be less effective for achieving lasting remission.^280,281

Although existing evidence suggests diclofenac may have anti-cancer properties related to its anti-inflammatory actions and other effects on cancer cell function, its potential benefits in the treatment of other types of cancer have yet to be explored in clinical trials.

Safety Considerations

Diclofenac can cause mild-to-moderate adverse side effects including abdominal pain, headache, dizziness, fluid retention, and a range of digestive symptoms. In rare cases, diclofenac can cause severe adverse effects such as gastrointestinal ulceration and bleeding, severe allergic reaction, anemia, pancreatitis, pneumonia, liver failure, and kidney damage and failure.^263,264,282 Some evidence suggests diclofenac has greater toxicity to the heart and blood vessels than most other NSAIDs, and chronic use increases risk of heart attack, stroke, and cardiovascular death.²⁸²

Background

Antihistamines interfere with interactions between histamine and either H1 or H2 histamine receptors. In general, H1 receptor blockers, like loratadine (Claritin), suppress histamine’s effect on the immune system and are used for treating allergic and anaphylactic reactions, while H2 receptor blockers, like cimetidine (Tagamet), inhibit gastric acid secretion and are used to treat gastrointestinal ulcers and other benign conditions of the stomach, esophagus, and duodenum. Both types of antihistamines are currently being studied for their potential utility in cancer care.

H1 Blocker: Loratadine

Many types of cancer cells express histamine receptors, through which histamine may increase cancer cell proliferation and tumor growth.²⁸³ The antihistamine loratadine, an H1 histamine receptor antagonist, has been found in preclinical research to induce cancer cell death by disabling cellular components called lysosomes (reservoirs of enzymes that break down intracellular molecules and dismantle the cell after cell death). Loratadine causes lysosomes to leak, releasing their cytotoxic contents into the cancer cell, and works synergistically with chemotherapy agents to cause cancer cell death.²⁸⁴ Loratadine has also been shown to damage cancer cell DNA, inhibit cancer cell proliferation, and enhance the cancer-killing effect of radiation and chemotherapy in preclinical research.^285,286

A study performed in Denmark found the incidental use of either loratadine or astemizole (Hismanal) (a related antihistamine) by cancer patients was associated with reduced risk of death from any cause, and the association was stronger in those treated with chemotherapy.²⁸⁴ A similar 15-year study found ovarian cancer patients using loratadine or a related antihistamine were less likely to die from cancer.²⁸⁷ However, H1 blocker antihistamine use was not found to correlate with risk of new breast cancer in women who previously had cancer in the other breast.²⁸⁸

Loratadine may reduce some side effects of chemotherapy, increasing treatment tolerance. In women with ovarian cancer treated with paclitaxel (Taxol), those already using loratadine had a lower risk of developing treatment-related muscle and joint pain; furthermore, 75% of those who started loratadine after developing chemotherapy-induced joint and muscle pain had pain reduction. In a pilot trial, 600 women with breast cancer who were scheduled to undergo chemotherapy with pegfilgrastim (Neulasta) were randomly assigned to receive naproxen, loratadine, or no other treatment. Loratadine and naproxen both reduced chemotherapy-related bone pain, but loratadine caused fewer adverse side effects.²⁸⁹

Loratadine is generally well-tolerated but may cause headache or drowsiness in some individuals.²⁹⁰

H2 Blocker: Cimetidine

Cimetidine is an antacid medication that reduces acid production in the stomach by inhibiting the action of H2 histamine receptors. Cimetidine has demonstrated several effects that may interfere with cancer progression: inhibiting cancer cell proliferation; reducing T-regulatory cell function and thereby stimulating immune cell activity; preventing tumor growth by blocking histamine's action as a growth factor; and preventing the attachment of cancer cells to blood vessel walls.^1,291 Cimetidine may also improve immune response to cancer by stimulating dendritic cell activity.^292,293 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. For more information about dendritic cells, please see the "Cancer Immunotherapy" protocol.

In a study that evaluated a combined treatment 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-3 beta (GSK-3β), makes brain tumor cells more aggressive. The combination of cimetidine, lithium (Eskalith, a mood stabilizer), olanzapine (Zyprexa, an antipsychotic medication), and valproate (Depakote, an anti-seizure medication) appeared to improve survival in patients with brain tumor that had active GSK-3β.²⁹⁴

Several trials have investigated the effect of cimetidine in colon cancer treatment. One study reported on outcomes in 38 colon cancer patients who did or did not receive cimetidine therapy, along with chemotherapy, around the time of cancer surgery; the addition of cimetidine was associated with longer time to cancer recurrence and longer cancer survival.²⁹⁵ A meta-analysis of five randomized controlled trials with a combined total of 421 participants found cimetidine, as an adjunct to surgery, prolonged survival in colorectal cancer patients.

Although findings have been mixed, researchers continue to investigate the possible role of cimetidine in the treatment of kidney cancer. In one promising trial, cimetidine was combined with a COX-2 inhibitor (meloxicam [Mobic]) and either an ACE inhibitor (perindopril [Aceon]) or angiotensin II receptor blocker (candesartan [Atacand]) and used adjunctively with the chemotherapy agent interferon in 51 patients with advanced kidney cancer. Four patients achieved a complete response, seven achieved a partial response, and the remaining 24 had no disease progression for at least six months. Another pilot trial investigated cimetidine, at a dose of 600 mg four times daily, as the only treatment in 42 patients with advanced kidney cancer; two participants had complete remission lasting more than two years.

Adjuvant treatment with cimetidine has been noted to prolong survival in gastric cancer patients, and this effect may be more pronounced in individuals with more advanced cancer.^296,297 However, in one controlled trial that included 442 gastric cancer patients, the addition of cimetidine to treatment had no effect on survival.²⁹⁸

Cimetidine treatment may be 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 colon cancers. Cimetidine is thought to inhibit interactions between Lewis A and Lewis X antigens and blood vessel walls that can lead to tumor cell attachment and invasion.^299,300 One clinical trial in gastric cancer patients found that, in a subgroup of participants expressing Lewis X antigens, the 10-year survival rate was 95.5% in those receiving cimetidine and 35.1% in those not receiving cimetidine; in participants with Lewis A antigens, 10-year survival was 90.9% with cimetidine and 20.1% without cimetidine.³⁰¹

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), propranolol, and antidepressants. These drug interactions can result in increased risk of side effects and altered efficacy of the medications.³⁰² Because of cimetidine’s potential for many drug-drug interactions, other H2 blockers are now preferred in the general clinical setting. However, other H2 blockers have generally not been studied in the context of cancer to the extent cimetidine has.

Background

Beta-blockers are a class of medications that inhibit a type of adrenaline receptor known as beta-adrenergic receptors. These receptors are activated by neurohormones called catecholamines, particularly epinephrine and norepinephrine. Two subtypes of beta-adrenergic receptors, β1 and β2, are found throughout the body, and different drugs within the beta-blocker family have different effects. Non-selective beta-blockers, such as propranolol (Inderal), inhibit both β1 and β2 receptors; selective beta-blockers, like atenolol (Tenormin) and metoprolol (Lopressor), inhibit only β1 receptors. Beta-blockers have a long history of use in treating hypertension, but certain drugs in this class are also used to prevent migraine headaches, reduce anxiety, and treat essential tremor. Most recently, beta-blockers have attracted interest for their potential anti-cancer effects.³⁰³

Levels of norepinephrine and epinephrine rise in response to stress, and cancer diagnosis and treatment are often accompanied by intense psychological and physical stress and loss of quality of life. Beta-adrenergic receptors are found on cancer and immune cells, allowing norepinephrine and epinephrine to influence cancer progression by enhancing tumor-related inflammatory signaling, tumor cell invasion and migration, and formation of new blood and lymph vessels, while disrupting anti-cancer immune activity.^303-305 Decreasing the cancer-promoting effects of these stress-response neurohormones has the potential to improve cancer outcomes.³⁰⁶ Preclinical evidence suggests beta-blockers may alter the tumor microenvironment in ways that inhibit cancer growth and spread.^303,304 Furthermore, beta-blockers have been found to reduce cardiac toxicity from anthracyclines, a widely used class of chemotherapy drugs.³⁰⁷

Observational (Correlational) Evidence

The potential anti-cancer benefits of beta-blockers were first identified when correlations were reported between incidental propranolol use and reduced risk of many types of cancer. Non-selective beta-blocker use has since been associated with reduced cancer recurrence in melanoma, ovarian cancer, and breast cancer patients, and increased cancer-related survival in patients with melanoma and ovarian, pancreatic, colorectal, liver, and breast cancers.^303,308-310 On the other hand, studies in patients with lung,^311,312 prostate,^311,312 head and neck,^313,314 and endometrial³¹⁵ cancers have reported no benefit from beta-blocker use as of early 2021. An observational study that used data from 30,020 subjects with breast, colorectal, or lung cancers did not find a survival advantage in those who were incidentally taking beta-blockers around the time of surgery to remove their tumors.³¹⁶

Studies in women with ovarian cancer have had mixed findings. In one observational study, women with ovarian cancer who used non-selective beta-blockers during the year following their cancer diagnosis were more likely to survive their cancer than women taking no blood pressure-lowering medications.³¹⁷ Another study involving ovarian cancer patients found certain factors were associated with a benefit from beta-blocker use; specifically, in those over 60 years old, those with existing cardiovascular or other chronic disease, and those who used beta-blockers for one year or longer, beta-blockers were linked to increased survival during at least three years of monitoring.³¹⁸ However, a large study that followed 6,197 ovarian cancer patients found both selective and non-selective beta-blocker use during the five years after cancer diagnosis were associated with lower rates of cancer-related and overall survival.³¹⁹

Propranolol and other beta-blockers may be helpful in cancers with few treatment options and poor prognoses. One study found propranolol use was correlated with improved survival in liver cancer patients with metastatic disease, but not those whose tumors were amenable to surgery.³²⁰ In colorectal cancer patients requiring emergency surgery, those who had been taking beta-blockers prior to surgery had better short-term (30-day) and long-term (one-year) survival.³²¹ In women with triple-negative breast cancer, a type of breast cancer that is difficult to treat and particularly aggressive, beta-blocker use was also linked to better outcomes. However, the link between cancer outcomes and beta-blocker use is challenging to interpret. Adequately controlled hypertension has been associated with better cancer outcomes, so the apparent benefits could be related to better blood pressure control in general.³²²

Causal Evidence - Clinical Trial Data

A small randomized controlled trial published in June 2020 found propranolol plus the COX-2 inhibitor etodolac (Lodine) improved tumor molecular markers of malignant and metastatic potential and non-significantly reduced recurrence rates among individuals who underwent surgery for colorectal cancer. The propranolol and etodolac were administered for 20 days perioperatively, starting five days before surgery. Although the trial was small and not initially designed to assess differences in survival, the trends toward increased survival in the recipients of propranolol and etodolac warrant larger trials sufficiently powered to assess clinical outcomes in colorectal cancer patients.³²³

Some evidence suggests beta-blockers may have a role as an adjunctive therapy for breast cancer.^324,325 In a randomized placebo-controlled trial, 60 women with early-stage breast cancer received either propranolol or placebo for seven days prior to surgical tumor removal. Cells from tumors of women who received propranolol were found to express fewer markers associated with cancer progression than cells from tumors of women who received placebo.³²¹

In a small randomized controlled trial that enrolled 25 patients undergoing hematopoietic cell transplantation (HCT) for multiple myeloma, propranolol administered before and after the transplant led to changes in cellular and molecular pathways that are generally associated with favorable outcomes. In this study, 13 subjects received placebo and 12 subjects received propranolol starting seven days before HCT. The starting dose of propranolol was 20 mg twice daily, which was increased to 40 mg twice daily after one week if there were no adverse effects observed on the 20 mg dose. Propranolol was continued until 28 days after HCT. After analyzing the data, the authors concluded that, “Peri-HCT propranolol inhibits cellular and molecular pathways associated with adverse outcomes. Changes in these pathways make propranolol a potential candidate for adjunctive therapy in cancer-related HCT.”³²⁶

The body of research on beta-blockers and cancer outcomes is still in an early stage. Future research will help elucidate the anti-cancer potential of specific beta-blockers and how type of cancer, timing of beta-blocker use, and use of other therapies (surgery, radiation, chemotherapy) influence the effects.^310,327

Safety Considerations

Propranolol and other beta-blockers have a long history of safe use. Typical side effects, such as fatigue, insomnia, cold extremities, and less commonly digestive symptoms, are mild. These effects can often be avoided by starting with a low dose and building slowly to a therapeutic dose. Discontinuing beta-blockers must also be done slowly. Beta-blockers are contraindicated in people with low blood pressure, asthma, uncontrolled heart failure, metabolic acidosis, severe peripheral artery disease, and cardiogenic shock.³²⁸

Background

Valproic acid, a short-chain fatty acid with anticonvulsant activity, is used to treat epilepsy, as well as bipolar disorder and migraines. Preclinical studies indicate valproic acid inhibits cancer by inducing normal cell maturation and apoptosis. Its apparent anti-cancer effects are likely to be due in part to its ability to affect epigenetic regulation of gene expression by inhibiting enzymes involved in gene activation.^329,330

Valproic acid has been found to increase sensitivity to chemotherapy agents in ovarian, pancreatic, and breast cancer cells, and increase radiation sensitivity in breast cancer cells cultured in the laboratory.^331-334 In liver cancer cells, valproic acid was found to suppress tumor cell signaling and induce expression of receptors that could be targets of other anti-cancer drugs.³³⁵ In prostate cancer cells, valproic acid inhibited cell proliferation, migration, and invasion, and its effects were enhanced by combining it with other anti-cancer agents.³³⁶

Causal Evidence - Clinical Trial Data

In preliminary clinical research, valproic acid has been found to have synergistic effects with the chemotherapy drug combination 5-azacytidine (Vidaza) plus all-trans retinoic acid in patients with blood cancers (myelodysplastic syndromes and acute myeloid leukemia),³³⁷ and with 5-fluorouracil (5-FU, Adrucil) in pancreatic cancer patients.³³⁸ In a pilot trial, treatment with valproic acid led to disease stabilization for one year in four of eight individuals with low-grade carcinoid or pancreatic tumors.³³⁹ In another pilot trial that included 32 patients with advanced solid tumors that were unresponsive to standard therapies, valproic acid combined with two chemotherapy drugs (azacitidine and carboplatin [Paraplatin]) led to minor responsiveness or disease stabilization lasting four months or longer in six participants.³⁴⁰ As of late-2020, a trial is ongoing to test valproic acid in combination with bevacizumab (Avastin) and oxaliplatin/fluoropyrimidine regimens in people with RAS-mutated metastatic colorectal cancer³⁴¹; the estimated completion date for this trial is August 2022.

Not all available evidence supports the use of valproic acid as a cancer adjunct therapy. Valproic acid was tested in combination with paclitaxel in 66 individuals with advanced gastric cancer. Outcomes were no different in the group receiving paclitaxel plus valproic acid than in the paclitaxel-only group.³⁴²

Safety Considerations

Valproic acid’s usefulness can be limited by adverse side effects such as fatigue and low white blood cell numbers, as well as neurological symptoms such as disorientation, memory loss, lethargy, and loss of muscular control.^340,343 Valproic acid has also been linked to liver failure, and liver function tests should be monitored regularly during use. Valproic acid may also cause serious pancreatic damage. It is contraindicated in women who are pregnant or may become pregnant.

Background

Dichloroacetate, a drug used to treat lactic acidosis, genetic conditions affecting mitochondrial function, and diabetes, has demonstrated anti-cancer effects in laboratory and animal studies. In animal research, dichloroacetate has been shown to decrease tumor size, slow tumor cell proliferation, and inhibit metastasis.³⁴⁴

Dichloroacetate appears to work by interfering with cancer cell metabolism. Cancer cells disproportionately use glycolysis to metabolize glucose, which leads to accumulation of lactic acid in the tumor microenvironment. Lactic acid stimulates tumor growth and inhibits apoptosis.^344-346 Dichloroacetate shifts metabolism away from glycolysis toward mitochondrial energy production and reduces lactic acid accumulation, altering the tumor microenvironment away from one that supports cancer growth and spread. Furthermore, by promoting mitochondrial metabolism of glucose, dichloroacetate induces cellular changes that favor normal apoptotic processes.^344,347

Multiple preclinical studies have found dichloroacetate can increase sensitivity and reduce resistance to chemotherapy drugs and radiation therapy in certain cancer types, and may enhance the actions of other potential anti-cancer agents such as propranolol and metformin.^344,348 Importantly, dichloroacetate may even sensitize cancer stem cells—which are thought to be central to the development of resistance and cancer recurrence—to anti-cancer treatment.^349,350

Observational (Correlational) Evidence

Several case studies using dichloroacetate in cancer patients have been published. One case report describes a 32-year-old man with malignant melanoma who experienced remission and disease stabilization for more than four years after adding dichloroacetate to a naturopathic treatment program. Similarly, in a 57-year-old woman with stage IV colon cancer, dichloroacetate therapy in combination with chemotherapy, bevacizumab, and metformin resulted in stabilization of disease for almost four years. Positive responses to dichloroacetate therapy have also been reported in patients with recurrent cancers that were unresponsive to standard cancer care.^351,352

Causal Evidence - Clinical Trial Data

In a pilot trial, seven participants with multiple myeloma were treated with dichloroacetate; one had a full response and two had partial responses to treatment after one month. The researchers also noted specific genetic markers related to drug metabolism and efficacy.³⁵³

Safety Considerations

The usefulness of dichloroacetate is limited mainly by its neurotoxicity. Neurological side effects from dichloroacetate resolve after it is discontinued.^344,354

Background

Naltrexone is an opioid antagonist used to treat alcohol and opioid dependence. However, at low doses (roughly 1/10^th of the typical addiction treatment dosage, commonly 4.5 mg/day), naltrexone has been used for off-label treatment of a variety of pain-related conditions, including fibromyalgia, multiple sclerosis, and Crohn’s disease.^355-357 At this dosage level, naltrexone also exhibits immunomodulatory effects and has shown early promise for the treatment of autoimmune disorders and cancer.³⁵⁸

Naltrexone has high affinity for μ-opioid receptors, which are overexpressed in a number of different cancers.^359-363 In healthy cells, interactions between opioid growth factor (OGF) and opioid growth factor receptor (OGFr) help regulate DNA synthesis and cell renewal. In fact, OGF has been shown to depress tumor proliferation and possess broad immune modulating properties, with important implications for regulating the tumor microenvironment and promoting anti-tumor immunity.³⁶⁴ Targeting the OGF-OGFr axis with naltrexone is being actively investigated in preclinical models.^365,366 Naltrexone has also been found to bind toll-like receptor 4, disrupting cellular pro-inflammatory responses.^367-369 In a mouse colorectal cancer xenotransplant model, low-dose naltrexone increased macrophage activity and expression of pro-apoptotic factors, suggesting a multi-faceted immunoregulatory function.^370,371 In vitro, low-dose naltrexone enhanced the cell-killing activity of the chemotherapy drug oxaliplatin in colorectal cancer cells, whereas higher-dose naltrexone was not as effective.³⁷¹

Low-dose naltrexone has been used successfully in multiple animal models of carcinomas. In a mouse model of solid Ehrlich carcinoma, treatment with low-dose naltrexone resulted in reduced tumor weight and volume. In combination with the chemotherapeutic drug 5-FU, low-dose naltrexone was also associated with reduced expression of an important antiapoptotic factor in treated mice.³⁷² Similar results were seen in a mouse model of ovarian cancer, in which low-dose naltrexone in combination with the chemotherapeutic drug cisplatin reduced DNA synthesis and inhibited tumor progression.³⁷³ In a study of 60 dogs with mammary carcinomas, the addition of low-dose naltrexone to chemotherapy was associated with prolonged survival, fewer chemotherapy-related adverse events, and better quality of life.³⁷⁴

Observational (Correlational) Evidence

Studies examining the efficacy of low-dose naltrexone as an anti-cancer agent in humans have been lacking, and current evidence for its clinical use is based on several case reports. The earliest of these reports described the use of low-dose naltrexone in combination with alpha-lipoic acid in four patients with metastatic and non-metastatic pancreatic cancer. As early as four and five months after beginning the combination treatment, two of the patients demonstrated no evidence of disease on position emission tomography (PET) scan, and no appreciable progression of malignancy was reported up to 78 months after initial presentation.^375,376 Use of a similar protocol was also described in a 64-year-old man diagnosed with metastatic renal cell carcinoma, which resulted in stable disease and disappearance of radiological evidence of malignancy for up to nine years after diagnosis.³⁷⁷ Treatment with low-dose naltrexone has also been described for a 50-year-old man with a history of prostate and lung cancer. The patient began low-dose naltrexone treatment after halting standard chemotherapy due to intolerable side effects and exhibited no signs of disease recurrence almost four years after initiating treatment. This patient has been maintained throughout on an array of 11 other medications for other chronic conditions.³⁷⁸ Successful use of low-dose naltrexone treatment has also been reported in two cases of hepatoblastoma, in an infant and a young child. At the time of the report, the children had disease-free survival of 10 and five years, respectively.³⁷⁹

Safety Considerations

The preliminary reports described above also suggest low-dose naltrexone exhibits a favorable safety profile as an anti-cancer agent and is associated with minimal side effects.^375-379 A systematic review of randomized controlled trials of naltrexone use in various conditions, compared with placebo, found that naltrexone does not increase the risk for serious adverse events, providing a firm basis for researchers to further investigate low-dose naltrexone’s therapeutic potential.³⁸⁰

Background

Phosphodiesterases (PDEs) are a family of cellular enzymes that catalyze the breakdown of two cyclic nucleotide compounds: cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP). For this reason, PDEs are also called cyclic nucleotide phosphodiesterases. cAMP and cGMP are important second messengers—a specific type of signaling molecule—that regulate the transmission of signals within cells and in this way modulate such fundamental cellular activities as cell division, apoptosis, metabolism, inflammation, and gene expression.^381,382 Nearly 100 distinct PDEs have been identified, and these are broadly categorized according to their ability to break down cAMP, cGMP, or both. The PDE-5 category targets cGMP.^381,382

PDE-5 inhibitors are used to treat erectile dysfunction, pulmonary hypertension, and benign prostatic hyperplasia. They are also under investigation as possible agents for treating diabetes, atherosclerosis, metabolic syndrome, heart failure, and stroke, as well as lower urinary tract symptoms.^381-383 Three PDE-5 inhibitors are currently of particular interest for cancer therapy:

• Sildenafil (Viagra)
• Tadalafil (Cialis)
• Vardenafil (Levitra)

Impaired production of cyclic nucleotides or overexpression of PDEs may contribute to cancer cell growth and migration, and targeted PDE inhibition may promote tumor cell apoptosis and decrease uncontrolled tumor cell growth.^382,383 High levels of PDE-5 are reported to be present in several types of cancer cells, including breast, prostate, lung, and colorectal cancers, as well as melanoma.³⁸³

PDE-5 inhibition has been found to trigger both cancer cell apoptosis and anti-cancer immune activation. PDE-5 inhibitors, mainly in combination with various chemotherapy drugs, have been shown to enhance suppression of cancer cell activity and increase apoptosis in cancer cells or other preclinical models of cancers such as lung, breast, prostate, colorectal, bladder, liver, thyroid, head and neck, and brain cancers, as well as several blood cancers.^383,384

Observational (Correlational) Evidence

The incidental use of PDE-5 inhibitors, usually for erectile dysfunction, may be associated with lower risk of some cancers as well as better outcomes in certain cancers. There is evidence for a benefit in colorectal cancer; their effects on prostate cancer risk is less clear. However, observational studies have found an association between the use of PDE-5 inhibitors for erectile dysfunction, and a higher risk of malignant melanoma and possibly other skin cancers.^385-387 Although plausible mechanisms by which PDE-5 inhibition could promote melanoma have been described, multiple authors suggest this relationship is likely a result of confounding and thus non-causal.^384,388,389

PDE-5 inhibitors and colorectal cancer: In a study that included more than 221,000 men, having used a PDE-5 inhibitor for erectile dysfunction was associated with an 18% lower risk of colorectal cancer compared with never having used one.³⁹⁰ In a study that examined data from 36,020 men diagnosed with benign colorectal polyps during a 10-year period, those taking PDE-5 inhibitors were found to have a 35% reduced incidence of colorectal cancer. Greater cumulative PDE-5 inhibitor doses were associated with greater protection.³⁹¹ However, another study in 200,000 male participants whose data were collected for The Health Improvement Network found no association between PDE-5 inhibitor use and colorectal cancer incidence.³⁹²

A 2020 study investigated the relationship between PDE-5 inhibitor use and colorectal cancer outcomes. The study, which included 12,465 male colorectal cancer patients, found those who used PDE-5 inhibitors after their cancer diagnosis had an 18% lower chance of colorectal cancer-specific death and a 15% lower risk of distant metastasis during 4.25 years of monitoring. These associations were stronger in those who had undergone open surgery to remove their tumor.³⁹³

PDE-5 inhibitors and prostate cancer: A study that followed 6,501 men for four years found PDE-5 inhibitor use was not correlated with prostate cancer incidence overall, but was associated with a 33% risk reduction in North American participants; however, this risk reduction was not statistically significant.³⁹⁴ A systematic review and meta-analysis found no link between PDE-5 inhibitor use and prostate cancer risk or risk of recurrence in prostate cancer patients.^395,396 Although one study found that PDE-5 inhibitor use increased the risk of biochemical recurrence (a rise in PSA level) in men treated surgically for prostate cancer,³⁹⁷ multiple other studies and a meta-analysis have failed to confirm that increased risk.^398-402

PDE-5 inhibitors and other cancers - case reports: The use of sildenafil for erectile dysfunction was reported to improve the clinical course in five cases of men with a rare incurable blood cancer called Waldenström’s macroglobulinemia. In one case, complete remission occurred after starting sildenafil.⁴⁰³ In another case series, sildenafil use was associated with long-term disease-free survival in two of three cases of penile cancer, which was attributed to possible sensitization to radiation treatment by the drug.^404,405 A case report described how the addition of tadalafil led to enhanced treatment response in a patient with relapsed multiple myeloma that had previously been unresponsive to treatment. The researchers suggested tadalafil likely induced an anti-myeloma immune response by reducing the function of myeloid-derived suppressor cells, which suppress anti-tumor immunity and promote tumor progression.^405,406

Causal Evidence - Clinical Trial Data

The effect of tadalafil treatment, at gradually diminishing doses starting at 40 mg and eventually lowered to 5 mg, on melanoma was investigated in an open trial that included 12 patients with metastatic melanoma, 11 of whom had already received standard cancer treatment and all of whom had evidence of cancer progression. Tadalafil was associated with increased tumor targeting by immune cells, and three participants experienced stabilization of their condition. The tadalafil dose did not correlate with clinical response in this study.⁴⁰⁷ Tadalafil has similarly been found to reduce tumor-related immune suppression in patients with head and neck cancer in two placebo-controlled trials.^408,409 A number of clinical trials that include tadalafil in patients with various types of cancer are underway as of mid-2020.⁴¹⁰

Safety Considerations

Adverse side effects such as nausea and vomiting, headache, back pain, fatigue, and weight loss have been reported in men using PDE-5 inhibitors.^407,409 Other known side effects include dizziness, visual disturbance, red eyes, heart palpitations, rapid heartbeat, high or low blood pressure, and nose bleeds. In rare cases, PDE-5 inhibitors have been linked to cardiovascular events, retinal vascular occlusion (blood clot in a tiny vessel in the eye), and sudden hearing loss.³⁸⁴

Background

Chloroquine (CQ, Avloclor) has historically been used to prevent and treat malaria, and its safer metabolite, hydroxychloroquine (HCQ, Plaquenil), has more recently been used to treat autoimmune diseases such as systemic lupus erythematosus, discoid lupus, Sjögren’s syndrome, and rheumatoid arthritis.^411,412 These medications inhibit an important cellular process called autophagy, through which cells clean up and recycle misfolded proteins, damaged organelles, and other degraded components as a strategy to adapt to stressful conditions.⁴¹³ Autophagy functions as a tumor suppressor, preventing the initiation of cancer. However, autophagy could support cancer progression by contributing to the maintenance of cancer stem cells, helping tumors survive cellular stresses, and stimulating resistance to chemotherapeutic agents.^413-415 This dual effect complicates the use of autophagy-inhibiting medications in cancer therapy.⁴¹³ In addition to inhibiting autophagy, some evidence suggests CQ and HCQ may suppress cancer growth and activity by inhibiting certain signaling pathways in cancer cells, altering the tumor microenvironment, and interfering with tumor blood vessel supply.⁴¹¹ Importantly, while autophagy is overactive in many tumor cells, only certain types are sensitive to autophagy inhibitors, and these considerations are important to clinical practice.⁴¹²

CQ and HCQ have been found to suppress tumor initiation and growth in numerous cell culture and animal models of various types of cancer, including brain, liver, breast, pancreatic, and colorectal cancers, as well as lymphoma and melanoma. On the other hand, some studies have shown CQ and HCQ can promote cancer growth and metastasis of some types of cancer, indicating the importance of identifying the tumor characteristics associated with a likely benefit from CQ or HCQ. One proposed indicator of potential HCQ/CQ efficacy is p53 status (p53 is an important tumor-suppressor protein). Another is the degree to which different tumor cells and tumor types are dependent on autophagy. Dose timing relative to chemotherapy may be important as well, with some authors hypothesizing that CQ should be administered after chemotherapy, not before.⁴¹¹

Multiple preclinical studies have noted CQ and HCQ can enhance the efficacy of other cancer treatments by increasing cancer cell sensitivity to therapeutic agents. In fact, CQ and HCQ have been tested in combination with more than 40 anti-cancer therapies, including chemotherapy drugs, radiation therapy, monoclonal antibodies, hormone therapies, and tyrosine kinase inhibitors, and have led to decreased tumor growth and improved survival in some cases.^411,413 However, some of this work has been criticized, as the positive results were obtained primarily in immune-deficient animals, while some results were disappointing in immune-competent hosts.⁴¹³

Causal Evidence - Clinical Trial Data

CQ and brain cancer: A randomized controlled trial in 18 patients with glioblastoma multiforme found survival time was significantly increased in those whose post-surgical treatment with radiation and chemotherapy was augmented by 24 to 50 months of CQ therapy.⁴¹⁶ A similar trial by the same research group found CQ therapy for 12 months after surgery markedly prolonged survival time relative to placebo in 30 glioblastoma multiforme patients under age 60 who were treated with chemotherapy and radiation after surgery.⁴¹⁷ This research group published a retrospective report describing significantly increased survival time in 41 glioblastoma multiforme patients who received CQ in addition to standard treatment compared with 82 patients who did not.⁴¹⁸

Several case reports and some preclinical research indicate the addition of CQ may restore sensitivity to the targeted cancer drug vemurafenib (Zelboraf) in brain cancer patients who developed resistance to the drug.^419,420

Two clinical trials have examined the effect of CQ in patients with brain metastases (secondary brain tumors). In one placebo-controlled trial, 39 cancer patients with brain metastases received whole brain irradiation plus CQ or placebo for four weeks; although the CQ group did not have a higher response rate or overall survival, they did have longer progression-free survival.⁴²¹ An uncontrolled trial found CQ in combination with whole brain radiation therapy for three months led to a complete response in two of 16 patients with brain metastases, partial response in 13, and tumor stabilization in one.⁴²²

CQ and multiple myeloma: Two clinical trials evaluated CQ as add-on therapy in multiple myeloma patients. In an uncontrolled trial, eight evaluable participants with relapsed and unresponsive multiple myeloma had CQ added to chemotherapy with bortezomib (Velcade) plus cyclophosphamide (Cytoxan). Three subjects had a partial response and one had tumor stabilization, while the other four progressed.⁴²³ A controlled trial in 38 multiple myeloma patients, however, found adding CQ to treatment with cyclophosphamide plus prednisone had no impact on treatment response.⁴²⁴

CQ and pancreatic cancer: In an uncontrolled trial in nine patients with metastatic or non-surgically treatable pancreatic cancer, three participants had a partial response and two had tumor stabilization following treatment with the chemotherapy drug gemcitabine (Gemzar) plus CQ.⁴²⁵

HCQ and solid tumors: In 25 stage IV cancer patients with various solid tumors who had not responded to standard treatment, the addition of rapamycin plus HCQ to treatment for at least three months led to partial response in 10 participants and tumor stabilization in 11 participants. In all, 84% of evaluable participants showed a positive clinical effect.⁴²⁶ Another trial in 27 patients with solid tumors was designed as a safety, tolerability, and pharmacology study of HCQ plus the chemotherapy agent vorinostat (Zolinza). The authors reported a partial response in one patient with kidney cancer and prolonged tumor stabilization in two patients with colorectal cancer.⁴²⁷ A pilot trial tested a combination of HCQ and the investigational drug MK-2206 in 35 patients with advanced solid tumors, but found minimal evidence of anti-tumor activity and a substantial number of adverse side effects.⁴²⁸

HCQ and pancreatic cancer: In a clinical trial in 20 previously treated metastatic pancreatic cancer patients, HCQ as a stand-alone therapy had little therapeutic efficacy, was associated with serious adverse side effects in two participants, and did not reliably inhibit autophagy.⁴²⁹ Another trial in 35 pancreatic cancer patients deemed unlikely to benefit from surgery tested the combination of gemcitabine with HCQ for 31 days prior to surgery. Nineteen participants had reductions in levels of a cancer biomarker, and 29 proceeded to surgery. Among surgically treated participants, 77% had a successful surgical outcome with clean margins, and those who had a significant increase in an autophagy marker in response to HCQ had significantly longer disease-free and overall survival. According to the study’s authors, gemcitabine plus HCQ resulted in better outcomes than historical treatments in similar patients.⁴³⁰ Another randomized controlled trial included 64 pancreatic cancer patients and compared treatment with gemcitabine and paclitaxel to the same chemotherapy regime plus HCQ for two cycles, followed by surgery. Those who received HCQ had better responses than those who did not; however, there were no differences in overall survival or time to relapse.⁴³¹ An open-label trial with 112 participants also found no survival benefit from adding HCQ to pancreatic cancer treatment with gemcitabine and paclitaxel after one year, although the overall response rate was significantly greater in the HCQ group. Severe adverse effects were considerably greater in the HCQ arm.⁴³²

HCQ and colorectal cancer: In 20 participants with metastatic colorectal cancer that was unresponsive to treatment, HCQ plus vorinostat appeared to enhance anti-tumor immune activity. Although no partial or complete treatment responses were noted, five of the participants had stable disease for more than 16 weeks.⁴³³

HCQ and multiple myeloma: A safety and preliminary efficacy trial in 21 participants with relapsed or unresponsive multiple myeloma found that two weeks of HCQ alone, followed by the addition of bortezomib for a median of 14 weeks (range: 1‒77 weeks), led to very good partial response in three patients, minor response in three, periods of no progression in 10, and immediate progression (no treatment response) in six.⁴³⁴

HCQ and sarcoma: An uncontrolled trial enrolled 10 patients with soft tissue sarcoma that had not responded to standard treatment. After two weeks of therapy with a combination of sirolimus (Rapamune, also known as rapamycin) and HCQ, six participants had partial response, three had cancer stabilization, and one had cancer progression. Although tumor cells’ use of glucose for energy production was reduced with treatment, none of the tumors decreased in size. Nausea, diarrhea, constipation, and skin rash were reported as mild side effects of treatment.⁴³⁵

HCQ and melanoma: In a trial designed to study the safety, tolerability, and pharmacology of a combination of HCQ plus temozolomide in 40 patients with solid tumors, 27 of whom had malignant melanoma, treatment resulted in partial response or cancer stabilization in 38% of those with melanoma.⁴³⁶ A similar trial, performed by the same research group, in patients with advanced solid tumors and melanoma found cancer stabilization in 14 of 19 melanoma patients treated with temsirolimus (Torisel, a derivative of sirolimus) plus HCQ. However, no partial or complete responses were noted.⁴³⁷

HCQ and lung cancer: In a safety, tolerability, and pharmacology study in 27 patients with advanced non-small cell lung cancer treated with HCQ alone or in combination with the chemotherapy agent erlotinib (Tarceva), only one patient receiving combination therapy experienced a partial response.⁴³⁸ In another uncontrolled trial in 40 untreated metastatic non-small cell lung cancer patients given four to six cycles of standard chemotherapy augmented by HCQ, 10 patients had some treatment response and six others had cancer stabilization.⁴³⁹

HCQ and kidney cancer: In patients with advanced clear cell renal cell carcinoma who had undergone at least one prior anti-cancer protocol, treatment with HCQ plus everolimus (Afinitor, Zortress) resulted in partial response in two of 33 participants, stabilization in 20, and progression-free survival for six months in 15.⁴⁴⁰

Safety Considerations

Multiple clinical trials have been initiated to study the safety of CQ and HCQ in cancer treatment, mainly in combination with other anti-cancer therapies, and to identify tolerable doses. It is important to note that few of these trials were designed to evaluate the efficacy of CQ and HCQ in cancer treatment. CQ and HCQ, though tolerable for most patients in these studies, were associated with several adverse side effects, including fatigue, loss of appetite, and digestive symptoms. Higher and longer-duration doses in particular appeared to cause more serious adverse effects.⁴⁴¹ In addition, serious side effects such as heart rhythm abnormalities, hypoglycemia, bone marrow toxicity leading to decreased blood cell production, heart muscle damage, and irreversible damage to eye tissue causing visual impairment have been reported in some patients treated with CQ or HCQ.^411,442,443

Background

Clarithromycin (Biaxin) is a member of the class of antibiotics known as macrolides. It is widely used as part of therapy to eradicate gastric H. pylori infection, and is also used to treat other bacterial infections, as well as Lyme disease. Because H. pylori infection increases the risk of gastric cancer, clarithromycin can play a role in gastric cancer prevention.^444,445 In addition, a growing body of evidence suggests it may help treat other types of cancer, including lymphoma, multiple myeloma, chronic myeloid leukemia, and non-small cell lung cancer.⁴⁴⁶

Studies in cancer cells and animals show clarithromycin slows tumor growth, induces tumor cell apoptosis, and inhibits tumor-associated formation of new blood vessels in models of cancers such as melanoma, lymphoma, lung, and colorectal cancers.^446,447 Clarithromycin has also been found to enhance the anti-cancer effects of some chemotherapy agents and modulate levels of inflammatory cytokines related to cancer progression in animals with melanoma and lung, breast, and head and neck cancers.^446,448

Causal Evidence - Clinical Trial Data

Clarithromycin and gastric cancer: In contrast to its apparent mechanisms of action in other cancers, clarithromycin exerts its protective effects in gastric cancer through its antibacterial action against H. pylori. In a placebo-controlled trial that included 552 H. pylori-infected patients who were monitored for 10 years, one week of triple therapy with clarithromycin, amoxicillin (Amoxil), and omeprazole (Prilosec, a proton pump inhibitor) to eradicate H. pylori reduced gastric cancer risk.⁴⁴⁹ In a controlled trial that included 898 gastric cancer patients treated with surgery, those who received one week of clarithromycin, amoxicillin, and omeprazole to eradicate H. pylori were half as likely to develop new gastric cancer compared with those who did not receive triple therapy during a median follow-up period of almost six years.⁴⁵⁰ Another placebo-controlled trial in 396 surgically treated gastric cancer patients performed by the same research group found triple therapy with clarithromycin, amoxicillin, and rabeprazole (Pariet, another proton pump inhibitor) reduced the risk of subsequent new gastric cancer compared with placebo during a median of 5.9 years of monitoring.⁴⁵¹ Unfortunately, because of widespread resistance to clarithromycin, its usefulness in reducing gastric cancer risk through H. pylori eradication may be limited.⁴⁵²

Clarithromycin and multiple myeloma: Several clinical trials using clarithromycin alone in patients with multiple myeloma have reported no survival benefits^446,453; however, combinations of clarithromycin with the anti-inflammatory steroid dexamethasone (Decadron), with and without chemotherapy agents, have shown promising results in preliminary uncontrolled trials.⁴⁴⁶

Treatments for multiple myeloma that combine clarithromycin and dexamethasone with either lenalidomide (Revlimid) or thalidomide (Thalomid) appear to result in similar outcomes and may be more beneficial than protocols that do not include clarithromycin.⁴⁵⁴ One study compared outcomes from 72 patients who received clarithromycin plus lenalidomide and dexamethasone to treat newly diagnosed multiple myeloma to 72 similar patients who received lenalidomide and dexamethasone without clarithromycin. Among those receiving clarithromycin, 73.6% had a very good partial response or better, with 45.8% having a complete response; among those not receiving clarithromycin, only 33.3% had a very good partial response or better, and 13.9% had a complete response.⁴⁵⁵ A follow-up report after a median of 6.6 years found 68% of patients treated with clarithromycin continued to exhibit a very good partial response or better.⁴⁵⁶

An uncontrolled trial analyzing 50 patients with untreated or previously treated multiple myeloma or Waldenström’s macroglobulinemia found the combination of clarithromycin plus thalidomide and dexamethasone resulted in a 93% response rate, with 53% achieving a complete or near complete response.⁴⁵⁷ In 26 patients with newly diagnosed multiple myeloma, clarithromycin in combination with dexamethasone and both thalidomide and lenalidomide was associated with an overall response rate of 80% and four-year overall survival rate of 74.9%. In addition, 100% of 11 patients who also underwent a treatment known as autologous stem cell transplantation responded to treatment with clarithromycin plus chemotherapy.⁴⁵⁸

One study included 31 multiple myeloma patients and 17 patients with a related condition known as primary systemic light chain amyloidosis, all of whom had not responded to treatment with dexamethasone plus either thalidomide, lenalidomide, or pomalidomide (Pomalyst). The addition of clarithromycin to their treatment resulted in a response rate of 48% in multiple myeloma patients and 94% in amyloidosis patients.⁴⁵⁹ In an uncontrolled trial, 120 patients with relapsed or treatment-resistant multiple myeloma were given clarithromycin plus a standard chemotherapy protocol that included pomalidomide and dexamethasone. This combination resulted in an overall response rate of 60%, and 23% of patients achieved at least a very good partial response.⁴⁶⁰

In contrast, clarithromycin may increase toxicity of some chemotherapy agents. In a placebo-controlled trial in 58 patients with newly diagnosed multiple myeloma, the addition of clarithromycin to standard care with a chemotherapy protocol using cyclophosphamide, bortezomib, and dexamethasone resulted in reduced quality of life and severe adverse effects, leading to early termination of the trial.^461,462

Clarithromycin and Waldenström’s macroglobulinemia: Waldenström’s macroglobulinemia is a rare type of lymphoplasmacytic lymphoma. Several reports suggest clarithromycin may enhance the efficacy of standard treatment for Waldenström’s macroglobulinemia. In a case report, an 84-year-old woman newly diagnosed with Waldenström’s macroglobulinemia responded to treatment with clarithromycin and the anti-inflammatory steroid prednisolone.⁴⁶³ A trial in 12 patients with Waldenström’s macroglobulinemia that had been unable to tolerate high-dose thalidomide therapy found the addition of clarithromycin and dexamethasone to low-dose thalidomide led to a partial treatment response in three patients (25%).⁴⁶⁴ In an uncontrolled trial, treatment with a combination of clarithromycin, dexamethasone, and thalidomide resulted in a significant response in 10 of 12 patients with treatment-resistant Waldenström’s macroglobulinemia after six weeks; however, all of the participants experienced neurological toxicity of varying intensities, which was severe enough to limit treatment in some cases.⁴⁶⁵

Clarithromycin and lymphoma: H. pylori has been implicated as a risk factor for mucosa-associated lymphoid tissue (MALT) lymphoma, a type of B-cell lymphoma that usually arises in the stomach.⁴⁶⁶ H. pylori eradication using triple therapy including clarithromycin has been found to induce long-term remission in a large majority of low- and high-grade MALT lymphoma patients.^467-470

Clarithromycin may have benefits in MALT lymphoma that extend beyond its antibacterial effects. In an uncontrolled clinical trial, 23 H. pylori-negative patients with MALT lymphoma that recurred despite at least two previous treatments were given four 2-week courses of high-dose clarithromycin, with one week between each course. Complete remission occurred in six participants, partial response occurred in six others, and stabilization occurred in five. At a follow-up between 16 and 33 months after treatment, all participants survived and 13 (56%) had no sign of progression.⁴⁷¹ In addition, a number of case reports indicate complete remission occurs in some patients with H. pylori -negative MALT lymphoma after treatment with clarithromycin.⁴⁴⁶

In a controlled trial in 55 patients with untreated, advanced stage, slow-growing, non-Hodgkin lymphoma, clarithromycin plus standard treatment with cyclophosphamide, vincristine (Oncovin), and prednisolone resulted in higher complete and overall response rates than standard treatment alone. The inclusion of clarithromycin also reduced levels of vascular endothelial growth factor, an important promoter of tumor-related blood vessel formation.⁴⁷²

Clarithromycin and lung cancer: In a controlled trial in 49 lung cancer patients who had already received chemotherapy, radiation therapy, or both, long-term treatment with clarithromycin increased survival time among those with non-small cell lung cancer.⁴⁷³ Another controlled trial in conventionally treated non-small cell lung cancer patients found the 33 participants given clarithromycin after chemotherapy and/or radiation therapy had reduced levels of the inflammatory marker interleukin-6 (IL-6), and this reduction was associated with increased survival time.⁴⁷⁴ Several other publications have reported on the effects of clarithromycin use in non-small cell lung cancer treatment.^475-481 However, it is important to note that some evidence suggests clarithromycin may increase bone marrow suppression induced by the chemotherapy drugs docetaxel (Taxotere) and vinorelbine (Navelbine), causing dangerously decreased immune cell numbers, in lung cancer patients.^482,483

Safety Considerations

Clarithromycin use is associated with mostly minor adverse side effects, particularly digestive symptoms, and in rare cases, it has been associated with more serious neurological symptoms. Because clarithromycin alters heart rhythm, it is not safe in patients with cardiac arrhythmias. There is also some evidence long-term clarithromycin use may increase cardiovascular risk. Clarithromycin may have negative interactions with some chemotherapy agents; therefore, care must be taken before combining clarithromycin with other cancer treatments.⁴⁴⁶

Background

Doxycycline is a broad-spectrum, semisynthetic antibiotic from the tetracycline family that works by targeting ribosomal mechanisms for protein synthesis inside the cell.^664-667 It is widely used to treat a host of bacterial infections, and is combined with antiparasitics for certain parasitic infections.⁶⁶⁸ Doxycycline has been proposed for use in cancer due to its antiproliferative effects in multiple cancer cell lines.^664-666 It has also been found to inhibit tumor growth and proliferation in animal models of oral squamous cell carcinoma,⁶⁶⁹ hepatocellular carcinoma, breast cancer,⁶⁷⁰ and others.

A specific modification of mitochondrial transfer RNA (tRNA) (5-methylcytosine) has been identified as an essential requirement for metastasis of cancer cells. Without this modification, cancer cells are severely limited in their ability to spread. Of interest, inhibition of mitochondrial messenger RNA (mRNA) translation to tRNA with doxycycline treatment reduced the invasive metastatic spread of cancer cells in mice, suggesting that doxycycline’s metastasis-inhibiting properties could be due to inhibition of mRNA translation into 5-methylcytosine-containing tRNA.⁶⁷¹

Causal Evidence – Clinical Trial Data

Doxycycline has not been extensively studied for improving cancer outcomes or survival, although several clinical trials are ongoing, using doxycycline alone or in combination with other drugs, including in breast, uterine,^672,673 and pancreatic cancer.⁶⁷⁴

Cancer stem cells, which conventional cancer treatments like chemotherapy and radiation do not effectively eliminate, have been implicated in tumor recurrence, metastasis, and treatment failure in most cancer types.⁶⁷⁵ In one pilot study, 200 mg of doxycycline was administered for 14 days before surgery in nine women with breast cancer, while six served as untreated controls. Tumors from the doxycycline-treated group had significantly decreased “stemness” markers, indicating the targeting of cancer stem cells. However, doxycycline did not appear to affect markers of proliferation.⁶⁷⁶ One of the ongoing clinical trials is testing whether doxycycline can target cancer stem cells in people with pancreatic cancer.⁶⁷⁴

Doxycycline has mainly been studied as a treatment for epidermal growth factor receptor (EGFR) inhibitor-induced skin toxicity. EGFR inhibitors are essential treatments for a variety of cancers, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, and others. However, EGFR inhibitors cause adverse cutaneous reactions, which often makes treatment highly uncomfortable and distressing for patients.⁶⁷⁷ Doxycycline and other tetracyclines have been shown in several—though not all—trials to be effective prophylaxis for this skin toxicity.^677-680 Doxycycline treatment (100 mg) did not affect overall survival time in patients with locally advanced or metastatic non-small cell lung cancer⁶⁸⁰ or metastatic colorectal cancer,⁶⁷⁸ although survival was not a primary outcome in these studies.

Doxycycline has also been studied as a treatment for malignant pleural effusion (buildup of fluid and cancer cells between the chest wall and the lung), although again results have not shown consistent benefit.^681,682 Further studies are necessary to elucidate doxycycline’s role, if any, in cancer therapy.

Safety Considerations

Doxycycline is generally well tolerated, with mild gastrointestinal side effects at typical doses. Digestive, photosensitivity, or skin reactions (sometimes severe) may occur. Systemic toxicity from doxycycline is rare.⁶⁸³

Background

Itraconazole (Sporanox) is classified as a triazole antifungal medication and is widely used to treat fungal infections, including serious lung infections such as aspergillosis, blastomycosis, and histoplasmosis, as well as fungal infections of the fingernails and toenails (onychomycosis). It is also used to prevent fungal infections in immunocompromised patients such as those undergoing cancer therapies.⁴⁸⁴

Itraconazole has been shown to suppress cancer growth by inhibiting a gene signaling pathway called the hedgehog pathway,⁴⁸⁵ which transmits signals between the cell membrane and nucleus, and affects activation and repression of genes, including oncogenes.⁴⁸⁶ The hedgehog pathway serves important functions during development but is mostly inactive in adult cells; abnormal activation of the hedgehog pathway, possibly due to epigenetic alteration, has been implicated in the development of various types of cancer, such as lung, skin, endometrial, cervical, brain, breast, gastric, pancreatic, ovarian, and liver cancers.^485,486 Evidence suggests itraconazole also inhibits other key signaling pathways, including the mTOR pathway.^484,487 By suppressing these cell-signaling pathways, itraconazole arrests cancer cell proliferation, stimulates cancer cell apoptosis, and inhibits tumor-initiated angiogenesis (formation of new blood vessels), and may increase cancer cell sensitivity to chemotherapy agents.^484,485

In laboratory and animal studies, itraconazole has demonstrated anti-cancer effects against brain,⁴⁸⁸ breast,^489,490 cervical,⁴⁹¹ endometrial,^492,493 ovarian,⁴⁹⁴ oral,⁴⁹⁵ esophageal,⁴⁹⁶ pancreatic,⁴⁹⁷ gastric,⁴⁹⁸ and colorectal^39,499 cancers, as well as melanoma.⁵⁰⁰ In an animal model of Barrett’s esophagus, treatment with itraconazole lowered the occurrence of esophageal cancer from 32% to 8%.⁵⁰¹ In gastric cancer cells, itraconazole increased susceptibility to chemotherapy with 5-FU.⁵⁰² A combination of itraconazole plus doxorubicin (Adriamycin) was more effective than either drug alone in a study in acute myeloid leukemia cells.⁵⁰³

Observational (Correlational) Evidence

In a study that included data from 60 gastric cancer patients who underwent treatment that included 5-FU, those who incidentally received itraconazole (200–400 mg per day intravenously for four to five days) had a higher treatment response rate (59%) compared with those who did not (45%). They also had longer progression-free and overall survival.⁵⁰² Another study analyzed survival data collected during a placebo-controlled trial to evaluate the effect of prophylactic itraconazole on fungal infections in patients being treated with chemotherapy for acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). The study found small improvements in outcomes among those treated with itraconazole compared with those treated with placebo, suggesting itraconazole may have increased chemotherapy sensitivity.⁵⁰⁴

One research group examined outcomes in cancer patients who had relapsed or persistent cancer despite initial treatment with chemotherapy, and whose second-line treatment included chemotherapy plus itraconazole to prevent fungal infections:

• In 38 relapsed pancreatic cancer patients, a response rate of 37% was observed: one subject experienced a complete response and 13 experienced partial responses.⁵⁰⁵
• In 28 patients with relapsed metastatic biliary tract cancer, a response rate of 57% was reported: two subjects had complete responses and 14 had partial responses.⁵⁰⁶
• In 13 breast cancer patients whose conditions had worsened during chemotherapy, the response rate was 62%.⁵⁰⁷
• In nine patients with recurrent or persistent ovarian cancer, the response rate was 44%.⁵⁰⁸
• Among 55 patients with ovarian cancer that was unresponsive to chemotherapy, those who received itraconazole had longer overall and progression-free survival.⁵⁰⁹

Although these were retrospective observations, in most cases lacking controls for comparison, they indicate itraconazole has possible benefits in patients with advanced and progressive cancers,⁵¹⁰ and provide data that can be used in the future to evaluate whether the addition of itraconazole to second-line chemotherapy improves treatment responsiveness and lengthens survival.

Causal Evidence - Clinical Trial Data

The following describes the body of clinical evidence as of mid-2020 regarding itraconazole use in cancer therapy. More clinical trials investigating the potential anti-cancer benefits of itraconazole, mainly as an adjuvant to standard cancer therapies, are underway as of the time of this writing.⁴⁸⁷

Cumulatively, this evidence suggests itraconazole has the potential to favorably affect cancer treatment outcomes beyond its ability to prevent treatment-related fungal infections. Nevertheless, more rigorous controlled trials in patients with a range of cancers at various stages of severity are needed to confirm and clarify its usefulness.

Itraconazole and basal cell carcinoma: A randomized controlled trial included 29 patients with basal cell carcinoma (a type of skin cancer), each with one or more tumors greater than 4 mm in diameter. Fifteen of the subjects received 200 mg itraconazole twice daily for one month; four received 100 mg itraconazole twice daily for an average of 2.3 months; and 10 received no itraconazole. In those treated with itraconazole, cancer cell proliferation was reduced by 45% and tumor area by 24%, whereas neither of these parameters changed in the untreated group. Among the eight subjects with multiple tumors, four had a partial response and four had disease stabilization.⁵¹¹ In a study that reported on five cases of metastatic basal cell carcinoma, treatment with itraconazole and arsenic trioxide (another hedgehog-inhibiting agent) led to stabilization of cancer in three subjects.⁵¹² Another report described the case of an 87-year-old man with recurrent metastatic basal cell carcinoma with multiple tumors in the head. After exhausting other treatment options, the patient was given itraconazole plus sonidegib (Odomzo), another hedgehog inhibitor with a slightly different mechanism of action. After eight months on this treatment regime, one tumor resolved completely and the others stabilized.⁵¹³

Itraconazole and prostate cancer: In an open-label trial, 46 men with metastatic prostate cancer were treated with either low-dose (200 mg per day) or high-dose (600 mg per day) itraconazole. Forty-eight percent of the high-dose and 11.8% of the low-dose patients achieved stable PSA levels (rising less than 25% from baseline) at week 24; in addition, high-dose treatment resulted in longer progression-free survival compared with low-dose treatment.⁵¹⁴ Another trial enrolled 21 participants in whom lab tests indicated prostate cancer had become active again after treatment. The participants had PSA doubling times (the time it takes for the PSA level to double) ranging from 1.2 to 13 months. Nineteen of the subjects completed 12 weeks of treatment with itraconazole: PSA doubling time decreased by an average of 25% in nine subjects and did not change significantly in the remaining 10 subjects. Additionally, whereas other treatment options are known to cause adverse side effects related to reduced testosterone levels, itraconazole had no effect on testosterone levels.⁵¹⁵ In a case report describing a 65-year-old man with lab tests indicating recurrence of prostate cancer, 600 mg itraconazole per day led to progressive reductions in PSA levels for five months, at which point adverse side effects required him to discontinue treatment.⁵¹⁶

Itraconazole and stomach cancer: In a pilot trial, 23 patients with advanced or recurrent gastric cancer that was not surgically treatable received a treatment regime with nab-paclitaxel (Abraxane), oxaliplatin (Eloxatin), and itraconazole, administered in six to eight cycles; two patients had a complete response and 14 had partial responses.⁵¹⁷

Itraconazole and pancreatic cancer: A case was reported of a 64-year-old man with advanced pancreatic cancer that was not amenable to surgery. Treatment with chemotherapy and radiation therapy was not successful; however, nine months of itraconazole use for a fungal infection (a result of treatment-related immune suppression) corresponded with tumor regression such that surgery was feasible.⁵¹⁸

Itraconazole and lung cancer: In a controlled trial in 23 patients with non-small cell lung cancer that was progressing despite previous treatment, those treated with the chemotherapy agent pemetrexed (Alimta) plus itraconazole were more likely to have no progression after three months and had longer progression-free and overall survival times than those treated with pemetrexed alone.⁵¹⁹ In another clinical trial, 13 patients with non-small cell lung cancer received 600 mg per day of itraconazole for 10 to 14 days prior to surgery to remove their tumors. This treatment led to reduced tumor volume and tumor blood flow at the time of surgery, and the effects were stronger in those whose tumors had higher concentrations of itraconazole.⁵²⁰

Safety Considerations

Itraconazole has been safely used for decades and is generally well tolerated, but adverse effects can occur, particularly with long-term use. In a minority of short-term itraconazole users, side effects such as nausea and other digestive problems, rashes, fatigue, dizziness, and neuropathy can occur,⁴⁸⁴ whereas protracted itraconazole use may cause liver toxicity, heart failure, low white blood cell count, hair loss, decreased libido, breast tissue enlargement in men, impotence, low sperm count, low levels of potassium or sodium, pancreatitis, and rarely adrenal insufficiency.^484,521 In addition, because itraconazole interacts with a major metabolic pathway in the liver, it can cause numerous drug interactions.⁵²²

Background

Mebendazole (Vermox), a medication used to treat infections caused by helminths (parasitic worms), has been under investigation for possible anti-cancer effects since it was discovered to inhibit tubulin polymerization, an action it shares with some conventional chemotherapy drugs.⁵²³ Tubulin inhibitors interfere with the process of linking tubulin proteins (polymerization) to form important cellular structures called microtubules. Microtubules are components of the intracellular matrix and are needed for maintaining cell shape and function, having roles in cell signaling, movement of molecules within the cell, formation of blood vessels, and cell division. By affecting microtubule formation, tubulin inhibitors can slow or stop cancer cell proliferation and promote apoptosis.⁵²⁴

Laboratory studies have shown mebendazole reduces cancer cell proliferation, invasion, and migration; inhibits critical cancer cell signaling pathways; interrupts tumor-induced formation of new blood vessels; and supports anti-cancer immune cell function.^523,525-527 Through these actions, mebendazole appears to block tumor growth and spread, induce apoptosis, and increase sensitivity to other anti-cancer therapies.^523,528 In particular, mebendazole has demonstrated promising anti-cancer effects in laboratory and animal models of brain cancer.^529-532 A study in tumor cells from brain cancer patients found certain patterns of gene expression were associated with poor response to the standard chemotherapy drug temozolomide, and the addition of mebendazole and another chemotherapy drug enhanced susceptibility.⁵³³ Another study in cancer cells from women with triple-negative breast cancer found mebendazole increased their vulnerability to radiation therapy.⁵³⁴ Mebendazole has also been found to have positive effects in preclinical models of a broad range of cancers, including gastric,^535,536 colorectal,^537,538 prostate,⁵³⁹ breast,⁵⁴⁰ liver,⁵⁴¹ lung,⁵⁴² thyroid,⁵⁴³ head and neck,⁵⁴⁴ gallbladder,⁵⁴⁵ and adrenal cortex⁵⁴⁶ cancers, as well as ALL,^547-549 melanoma,^550,551 myeloma,⁵⁵² and meningioma⁵⁵³; however, one study found it was not effective in a rodent model of fibrosarcoma.⁵⁵⁴

Observational (Correlational) Evidence

While there are no completed clinical trials investigating the potential role of mebendazole in cancer treatment, such trials are underway as of mid-2020.^523,555 Two case reports, however, provide early support for its potential benefits.^556,557

Mebendazole and cancer of the adrenal gland: A case was reported of a 48-year-old man with metastatic cancer of the adrenal cortex, a rare cancer with few treatment options. After finding the cancer was progressing despite treatment attempts with multiple chemotherapy agents, the patient was given 100 mg mebendazole twice daily with no other therapy. He remained stable, with no cancer progression, for two years.⁵⁵⁶

Mebendazole and colorectal cancer: A case was reported in which a 74-year-old patient with metastatic colon cancer was experiencing disease progression despite multiple treatment attempts using chemotherapy protocols. Six weeks after starting 200 mg mebendazole per day as a stand-alone therapy, the patient had complete remission of metastatic tumors in the lungs and lymph nodes and had partial remission in the liver. Treatment was temporarily halted due to lab test abnormalities indicating liver toxicity and then resumed at half dose. The lab tests slowly normalized and the patient and disease remained stable.⁵⁵⁷

Mebendazole and brain cancer: In a preliminary dose-finding trial, patients with relapsed brain cancer were treated with chemotherapy and mebendazole, with or without radiation therapy. This study found mebendazole was tolerable at very high doses, but could not provide useful information about its effects on outcomes.⁵⁵⁸

Safety Considerations

Mebendazole is a well-tolerated drug with mainly gastrointestinal side effects at typical doses. It has also been reported to trigger allergic reactions in rare cases.⁵⁵⁵

Background

All-trans retinoic acid (ATRA) is a member of the retinoid family and the most active metabolite of vitamin A.⁵⁵⁹ Dietary vitamin A, after a series of metabolic changes in the gut and bloodstream, is converted to ATRA inside the body’s cells, where it can be transported into the nucleus and play a role in regulating gene transcription. The rate of its production and breakdown is controlled within the cells.^559-561 The drug version of ATRA, tretinoin (Vesanoid, Retin-A), is best known for its topical and oral use in treating skin conditions such as acne, psoriasis, ichthyosis (a genetic skin disorder characterized by dry, thickened, scaly skin), and skin cancer.⁵⁶² ATRA has demonstrated a number of anti-cancer actions, and research interest in its potential role in cancer therapy has grown over the past decade.^559,561

Humans require 700–900 mcg vitamin A (or retinol equivalents of pro-vitamin A carotenoids such as beta-carotene) from the diet each day in order to support normal cellular function, but therapeutic doses of ATRA are many-fold higher.⁵⁵⁹ Most dietary vitamin A is stored in the liver, from where it is slowly released into circulation.⁵⁶³ Because vitamin A is non-water-soluble, its transport through the blood and uptake by cells are facilitated and regulated by retinol binding proteins and cell membrane receptors; once inside the cell, its conversion to ATRA is enzyme-dependent.^559,561 The capacities of retinol binding proteins, receptors, and enzymes limit the extent to which increasing vitamin A intake can raise intracellular ATRA concentrations. Furthermore, exceeding these capacities can result in toxic damage to cell membranes and disrupt oxidation-reduction balance.⁵⁶⁴ ATRA activity and breakdown is also controlled by specific binding proteins and nuclear membrane receptors.

ATRA is an important inducer of normal cell differentiation, as well as apoptosis.⁵⁶⁰ In vitro experiments have associated deficient levels of intracellular ATRA with cancer initiation and progression, and ATRA exhibits numerous mechanisms that could suppress cancer proliferation and metastasis.^559,562,565 In fact, tumor cells frequently have altered retinoid metabolism and diminished ATRA signaling, and treatment with ATRA has inhibited cancer growth in a number of in vitro models.^559,563 In addition to promoting cell differentiation and apoptosis in tumor cells, ATRA appears to normalize the function of cancer stem cells.^559,566 It is also an important stabilizer of tight junctions (interconnections between neighboring cells), which may reduce the ability of cancer cells to metastasize.⁵⁵⁹ Preclinical research indicates ATRA has potential synergistic effects with other anti-cancer agents.⁵⁶⁷

ATRA is used in combination with other chemotherapeutics as the standard of care for acute promyelocytic leukemia (a blood cancer) and neuroblastoma (a nerve cell cancer that affects children).^559,568 In laboratory research, ATRA has also been shown to have anti-cancer activity against thyroid,^569-572 breast,⁵⁷³ cervical,^574,575 ovarian,^576,577 liver,⁵⁷⁸ colon,^579-581 gastric,⁵⁸² lung,^583,584 pancreatic,^585-587 brain,⁵⁸⁸ and esophageal^589,590 cancers, as well as melanoma,⁵⁹¹ non-melanoma skin cancer,^592-594 acute myeloid leukemia,⁵⁹⁵ lymphoma,^596-598 and chordoma (a type of bone cancer).^599,600

Although ATRA’s performance in clinical trials to date has been mostly disappointing,⁵⁶⁰ more than 20 clinical trials in patients with various types of cancer are actively under way as researchers continue to investigate its best use.⁶⁰¹ A few key challenges to its utility as an anti-cancer agent have been identified: ATRA is a fatty compound with low water solubility, limiting its absorption via the gut; it is rapidly metabolized and inactivated once absorbed; and cancer cells frequently have or develop retinoid resistance.^559,560 Strategies to overcome these challenges are incorporated in a number of new ATRA formulations and delivery methods currently being developed and investigated.⁵⁵⁹ Except where otherwise specified, the clinical evidence described below is based on the use of oral (systemic) ATRA.

ATRA and acute promyelocytic leukemia: Acute promyelocytic leukemia is a severe leukemia which, before the introduction of ATRA, carried a very poor prognosis but is now highly curable. It is characterized by proliferation of immature white blood cell precursors called promyelocytes and rapid deterioration of immune function.⁶⁰² ATRA, alone or in combination with arsenic trioxide, repairs an epigenetic alteration associated with acute promyelocytic leukemia and forces either differentiation or apoptosis of leukemic promyelocytes. ATRA can stimulate complete remission in a large majority of acute promyelocytic leukemia patients, and has been a mainstay of conventional acute promyelocytic leukemia treatment since its approval by the FDA in 1995.^560,603,604

ATRA and neuroblastoma: Neuroblastoma is a group of pediatric cancers that arise from nervous system tissue. ATRA, or another retinoid, cis-retinoic acid, is a standard part of the maintenance phase of chemotherapy for neuroblastoma.^559,605 For this purpose, the retinoid is generally combined with the monoclonal antibody dinutuximab (Unituxin).⁶⁰⁶

ATRA and myelodysplastic syndromes and acute myeloid leukemia: Several mostly older clinical trials have examined the effect of ATRA in patients with myelodysplastic syndromes and acute myeloid leukemia. In a randomized controlled trial in 242 patients with acute myeloid leukemia aged 61 years and older, those given ATRA in conjunction with standard chemotherapy had significantly better treatment response rates and overall survival than those given standard care alone.⁶⁰⁷ In a controlled trial, 45 poor prognosis patients in remission after treatment for myelodysplastic syndromes or acute myeloid leukemia were placed on a maintenance program with an alternating medication schedule, one arm of which included ATRA and the other another retinoid. After a median of 52 months of monitoring, fewer relapses and better disease-free survival were noted in the treated group versus 49 similar patients who received no maintenance therapy.⁶⁰⁸ In an open trial in 53 patients affected by myelodysplastic syndromes or acute myeloid leukemia with poor prognosis, a combination of 5-azacitidine, valproic acid, and ATRA was found to be safe and appeared to have clinical benefits.⁶⁰⁹ In another trial, myelodysplastic syndromes or acute myeloid leukemia patients who responded to initial treatment with valproic acid but later relapsed had an improved second response after the addition of ATRA to treatment, but the addition of ATRA to treatment did not improve outcomes in other myelodysplastic syndromes or acute myeloid leukemia patients.⁶¹⁰ A number of other trials have found no benefit from adding ATRA to myelodysplastic syndromes and acute myeloid leukemia treatments.^337,611-614 A meta-analysis of eight trials that included a combined total of almost 4,000 patients found the addition of ATRA to treatment of acute myeloid leukemia did not alter treatment response or survival outcomes.⁶¹⁵

ATRA and various solid tumors: After ATRA was found to be effective in treatment of acute promyelocytic leukemia, several research teams conducted phase I dose-finding trials in cancer patients with various advanced solid tumors. Unfortunately, no major tumor responses were observed in these trials, and many side effects occurred.^560,561 In addition, in an early pilot trial in pediatric cancer patients, no positive effects were seen in children with solid tumors, and several instances of increased intercranial pressure, which resolved when ATRA therapy was discontinued, were reported.⁶¹⁶

ATRA and specific solid tumors: Despite the lack of clear benefit in small phase I trials in patients with various types of solid tumors, other trials have gone on to investigate the potential usefulness of ATRA in groups of patients with specific types of solid tumors.

ATRA and pancreatic cancer: A phase I clinical trial that included 27 patients with advanced or metastatic pancreatic cancer who received no prior treatment for their cancer published its results in 2020. Patients received ATRA in combination with the chemotherapy agents gemcitabine and nab-paclitaxel. The results of the trial indicated the addition of ATRA to standard chemotherapy did not increase toxicity. Although it was not a controlled trial designed to evaluate outcomes, the results of this trial were considered promising.⁶¹⁷

ATRA and thyroid cancer: One older study reported on the results of ATRA therapy in 11 patients with thyroid cancers. All the subjects had advanced disease that had been unsuccessfully treated with surgery and radioiodine therapy. Lack of sufficient uptake of radioiodine was one reason preventing further standard treatment. After treatment with ATRA, four subjects had increased radioiodine uptake, five had a partial treatment response, and two had stabilization of their condition.⁶¹⁸

ATRA and cervical cancer: Topical ATRA has been a treatment option for decades in women with cervical intraepithelial neoplasia (CIN, a precancerous condition), and was reported in an older trial to increase remission rates in those with stage II and milder CIN.⁶¹⁹ In another older clinical trial in 26 women with metastatic or recurrent cervical cancer, the combination of interferon-alpha (IFN-α) (Intron A) plus oral ATRA, whether on daily or intermittent schedules, resulted in no response. Because blood levels of ATRA were sufficiently elevated in those receiving intermittent treatment, the study authors speculated the lack of response was likely due to cancer cell resistance to the anti-cancer effects of ATRA.⁶²⁰ A more recent placebo-controlled trial in 175 women with CIN II and III found topical ATRA had no effect on outcomes.⁶²⁰

Two other clinical trials examined the effect of ATRA in combination with IFN-α and the chemotherapy agent cisplatin. In both trials, toxicity limited therapy in the majority of participants. However, researchers in these trials concluded that the response rate was reason to consider further trials of retinoids in combination therapy in early disease.^621,622

ATRA and breast cancer: In an open trial, 17 women with previously treated metastatic or recurrent breast cancer were treated with ATRA before and during chemotherapy with paclitaxel. The outcomes were reported to be similar to those expected with paclitaxel alone.⁶²³ In an early open trial, ATRA alone was also found to have no clinical effect in 17 women with metastatic breast cancer that was unresponsive to hormone therapy.⁶²⁴

ATRA may have a role as an adjunct to tamoxifen (Soltamox) in women who have had breast cancer. In another early open trial that included 25 patients with advanced, potentially hormone-sensitive breast cancer who were treated with tamoxifen plus ATRA, some women experienced promising clinical responses, including some who had progressed when treated with tamoxifen alone.⁶²⁵ In a randomized controlled trial in 30 women with locally advanced breast cancer, participants were treated with ATRA, ATRA plus tamoxifen, or tamoxifen alone for 21 days prior to surgery for tumor removal. While tamoxifen use caused increased blood levels of pro-clotting markers, ATRA did not cause this effect and suppressed the rise in clotting markers when used in combination with tamoxifen. An increase in clot risk is an important side effect of tamoxifen, and this research suggests ATRA may mitigate this problem.⁶²⁶

ATRA and lung cancer: Several clinical trials have evaluated the effect of ATRA in advanced or metastatic non-small cell lung cancer. Two early trials found ATRA alone had low toxicity but was not associated with significant improvement in outcomes.^627,628 In two early open trials, combination treatment with ATRA plus cisplatin (20 participants) and ATRA plus IFN-α (29 participants) was reported to have resulted in modest clinical responses.^629,630 In a placebo-controlled trial in 107 participants being treated with paclitaxel and cisplatin for advanced non-small cell lung cancer, adding ATRA to treatment increased response rate and prolonged progression-free survival.⁶³¹ In an early trial in patients with advanced small cell lung cancer, the addition of ATRA to chemotherapy with cisplatin and etoposide (Vepesid, Toposar) was poorly tolerated, resulting in early discontinuation of ATRA in most patients.⁶³²

One placebo-controlled trial evaluated the potential for ATRA to reduce nerve problems related to chemotherapy in lung cancer patients: the trial included 95 patients being treated with cisplatin and paclitaxel for non-small cell lung cancer, and found ATRA reduced chemotherapy-induced nerve damage, as well as the risk of moderate-to-severe neuropathy.⁶³³

ATRA and melanoma: A controlled trial with 10 participants showed ATRA decreased levels of myeloid-derived suppressor cells in advanced melanoma patients being treated with the monoclonal antibody ipilimumab (Yervoy). Myeloid-derived suppressor cells are tumor-induced immune cells that contribute to resistance to immunotherapies; therefore, these findings suggest ATRA may have a role as an adjunct to immunotherapy in melanoma treatment.⁶³⁴ An early open trial found the combination of ATRA plus IFN-α was not more effective than IFN-α alone in 52 patients with metastatic melanoma.⁶³⁵

Several trials have looked at the effect of topical ATRA on dysplastic nevi, which are precursors to melanoma. One research group reported partial or complete resolution of some dysplastic nevi (irregular mole-like skin lesions) with topical ATRA. However, this was an uncontrolled setting and thus the evidence may not be reliable.⁶³⁶ In an early controlled trial, five men with a total of 32 dysplastic nevi received topical ATRA on half of their lesions and the remaining lesions were untreated for six months. At the end of the trial, four of 16 treated nevi and 13 of 16 untreated nevi remained dysplastic, but the use of ATRA also caused significant skin irritation.⁶³⁷ In another early controlled trial with 30 participants with dysplastic nevi, ATRA alone and when combined with topical hydrocortisone (which reduced treatment-related skin irritation) resulted in mild improvement in dysplastic cell characteristics, but not enough to preclude the need for surgical removal.⁶³⁸

ATRA and non-melanoma skin cancers: ATRA and other retinoids have long been used to prevent and treat various types of non-melanoma skin cancers.⁶³⁹ One case report described an 86-year-old Caucasian man with an invasive squamous cell carcinoma for whom treatment consisted of a topical solution containing ATRA, imiquimod (Aldera), and 5-FU (Efudex) on five days per week for a total of 24 treatments, along with intermittent topical cryotherapy (the use of extreme cold to destroy diseased tissue). Fifteen months after the end of treatment, there was no sign of residual cancer.⁶⁴⁰

A research review found the majority of studies indicate retinoid therapy, including topical ATRA, can reduce the number of precancerous actinic keratoses.⁶⁴¹ A placebo-controlled trial examined the potential for topical ATRA to reduce the risk of the two most common skin cancers, squamous cell carcinoma and basal cell carcinoma, in 1,131 individuals with a history of two or more cancerous skin lesions on the face or ears in the previous five years. No difference in risk of new skin cancers was seen after 1.5–5.5 years of monitoring.⁶⁴² Interestingly, the tretinoin group experienced a higher death rate than the placebo group; although the relationship was deemed unlikely to be causal, there was no clear explanation for the difference and the trial was halted six months early.⁶⁴³

ATRA and liver cancer: An early open clinical trial that included 15 patients with inoperable hepatocellular carcinoma reported treatment with ATRA in combination with vitamin E and tamoxifen appeared to prolong survival.⁶⁴⁴ However, another early open trial in 29 hepatocellular carcinoma patients found ATRA alone had no benefit and high-grade toxic side effects were noted in 15 participants.⁶⁴⁵

ATRA and gastric cancer: In a randomized controlled trial in 122 patients with gastric dysplasia (a precancerous condition), those given ATRA plus standard treatment with a proton pump inhibitor (omeprazole) and a protectant (sucralfate [Carafate]) experienced greater reduction in dysplasia compared with those given standard treatment alone.⁶⁴⁶

ATRA and kidney cancer: An early phase I clinical trial showed the combination of ATRA plus IFN-α was reasonably safe in patients with advanced renal cell carcinoma, and outcomes suggested some possible clinical benefit.⁶⁴⁷

Safety Considerations

ATRA is a drug with a serious side effect profile, and thus carries a strong label warning that it should be used in acute promyelocytic leukemia only under the close supervision of health care practitioners experienced in managing acute leukemia in the context of an appropriate facility or clinical setting. Its best recognized possible major severe adverse effects are a dangerous syndrome marked by fever, shortness of breath, and impaired function or failure of multiple organ systems, called acute promyelocytic leukemia differentiation syndrome (APL DS), which occurs in about 25% of patients with acute promyelocytic leukemia treated with ATRA and which can be serious or fatal; severe high white blood cell count, called leukocytosis, which occurs in roughly 40% of ATRA-treated patients, which also can be serious or fatal; and teratogenicity (causing birth defects) at all stages of pregnancy, especially in the first trimester. Individuals using ATRA are warned to initiate treatment within one week of a negative pregnancy test and use two safe contraceptive methods until one month after ATRA is discontinued.⁵⁶⁸

Many chemotherapy drugs target rapidly-dividing cells and frequently cause toxicity by damaging rapidly-dividing non-cancerous cells, such as immune cells and cells that line the intestines; conversely, ATRA reactivates signaling pathways that are suppressed during the development of cancer, forcing cancer cells to resume normal cell cycles or die through apoptosis without damaging non-cancerous cells.⁶⁴⁸

Other common adverse side effects associated with oral ATRA use include increased triglyceride and liver enzyme levels, skin problems, dryness of mucous membranes, nausea, vomiting, and headache. At higher doses and mainly in children, increased intracranial pressure (a condition known as pseudotumor cerebri) has been reported.⁵⁶⁰ Topical ATRA use has been associated with skin burning, itching, and irritation.⁶⁴⁹