Targeting cancer cell metabolism, growth signaling pathways and enhancing anti-cancer immunity are among the hottest topics being explored in oncology, today. It has become increasingly clear that many natural compounds, supplements and FDA-approved medications possess these anticancer properties and look quite promising in both preclinical and clinical studies. In fact, over 200 non-cancer drugs have shown some evidence of anticancer effects. Of these, 50% are supported by relevant human data and 16% are supported by data from at least one positive clinical trial. Some of these drugs include: mebendazole, cimetidine, nitroglycerin, diclofenac, itraconazole, clarithromycin, metformin, aspirin and hydroxychloroquine – all common, generic drugs with excellent safety records and a wide range of data sources showing potent anticancer effects.
An exciting research initiative and collaboration between MIT, Harvard and Dana-Farber Cancer Institute reported a new 2020 study, in which they systematically analyzed thousands of already developed drug compounds and found nearly 50 non-cancer drugs, including those initially developed to lower cholesterol or reduce inflammation, that killed some cancer cells while leaving others alone.
Instead of waiting for years for new drugs that exploit these anticancer mechanisms to be developed, studied for safety and efficacy and approved by the FDA, patients are taking matters into their own hands and treating themselves with thoughtful combinations of these agents to hopefully improve their cancer outcomes. This is often called “repurposing” when existing and well-characterized non-cancer drugs are used as treatments for cancer – either as additions to existing drug protocols or in novel combinations with multiple repurposed drugs.
Drug repurposing of inexpensive generics has been gaining interest over the years for two major reasons: 1) Repurposed, generic cancer drugs have the potential to significantly reduce the financial burden on patients and health care systems from high-cost pharmaceuticals. 2) The time to bring repurposed, non-cancer drugs through the clinical trials and FDA approval process (which typically takes 10+ years) should be much faster than with newer cancer compounds, since these are well-known and well-characterized drugs. Much of the hard work of conducting the preliminary studies (i.e. pharmacodynamics, pharmacokinetics, bioavailability, toxicities, established protocols and dosing) has already been done.
What Are “Off-Label” Drugs?
These are prescription drugs that are approved by the Food and Drug Administration for specific uses to treat specific conditions or diseases. This can mean that the drug is:
- Used for a different disease or medical condition
- Given in a different way (such as by a different route)
- Given in a different dose than in the approved label
Physicians may prescribe a drug for a use that’s not described in the approved labeling if it seems reasonable or appropriate to them. This is what’s called “off-label use.” For example, it is not uncommon for physicians to prescribe low doses of beta blocker drugs to help people overcome jitters before public speaking. Beta blockers are not formally approved for this use. The FDA advises doctors in such circumstances that “they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects.”
Why Are Drugs Used “Off-Label”?
Older, generic (non-brand name) medicines are the ones most often used off label. New uses for these drugs may have been found and there’s often medical evidence from research studies to support the new use. But it’s often too costly for the makers of the drugs to put them through the formal, lengthy, and expensive process required by the FDA to officially approve the drug for new uses. Many patients, especially those with diagnoses of aggressive or advanced malignancies, express that they do not have the luxury of waiting for well-designed clinical trials to prove/disprove the effectiveness of a compound that looks very promising in preclinical, pilot clinical and retrospective studies.
Barriers To “Off-Label” Drug Use:
The biggest problem is getting insurance plans to reimburse for off-label drug use. Many insurance companies will not pay for a drug that’s used in a way that’s not listed in the approved drug label. They do this on the grounds that its use is “experimental” or “investigational.” Another problem is that off-label drug use often does not reflect “standard of care” treatment. This could raise concerns about the legal risk to the health care provider should a patient have an unwanted or bad outcome from the treatment. Finally, there is also a lack of information about how to best use the drug other than for what it was approved. Lack of information on off-label drug use and outcomes may put patients at a higher risk for medication errors, side effects, and unwanted drug reactions. It’s important that the patient and doctor talk about the possible risks of using the drug and weigh them against the possible benefits.
There are thousands of plant-derived and nutrient compounds that have been shown in preclinical and clinical studies to exhibit similar pharmacologic properties with many of the “off-label” non-cancer drugs. Unfortunately, the majority of these compounds have not been studied with similar rigor compared with FDA-approved pharmaceuticals and the lack of standardization in dosing, manufacturing and other quality and safety concerns adds more questions than answers on their potential use in cancer treatment protocols. Regardless, the use of anticancer supplements by patients is prolific.
Use Of Multiple Compounds:
Due to the complexity of cancer metabolism, development of resistance and an individual’s physiology (i.e. immune system, tumor microenvironment, etc.), many conventional oncology treatments employ combination therapies to target these variables. This is the same rationale for the use of multiple “off-label” drugs and supplements, which are thoughtfully selected based on their purported effects on inhibiting important drivers of cancer growth and enhancing anticancer systems in the host.
Blocking Cancer Cell Metabolism:
There has been a tremendous interest by researchers to identify drugs that specifically block important cellular metabolic pathways in cancer cells without significantly impacting the functioning of normal cells. Since cancer cells grow more quickly than normal cells, they require higher amounts of nutrients and building blocks. Therefore, using drugs that impair these metabolic pathways or reduce the availability of these building blocks will have a greater impact on cancer cells. Cancer cells are very adaptable to the availability of these compounds, and they will find other routes of obtaining fuel and building blocks to survive. The following diagram (Metabolic Metro Map) illustrates the complexity of cellular metabolism (aside from plant-specific pathways, such as photosynthesis).
For more fine detail, below is the latest human metabolic “subway map” (Stanford University, School of Medicine, 2018)
The figures, below, (McLelland orginal ‘Metro Map’, from the book: How to Starve Cancer, by Jane McLelland. Used with the author’s permission) serves as a great example of how one might use an evidence-informed approach to combine various “off-label” non-cancer drugs and supplements to simultaneously target key metabolic pathways used by cancer cells for growth and survival. Blocking one metabolic pathway (i.e. glucose metabolism) at a time is not effective, as most cancers are able to use other energy sources for their survival (i.e. fatty acids, ketones, amino acids.) The 2020 Metro Map is from the “How to Starve Cancer” online course
Blocking Cancer Cell Signaling:
As complex (or more) as cancer cell metabolism is, so are the cellular signaling pathways. Manipulation of these pathways enable cancer cells to thrive by taking advantage of any or all of the “hallmarks” of cancer, which include: (1) sustained proliferation, (2) evasion of growth suppressors, (3) death resistance, (4) replicate immortality, (5) angiogenesis, (6) invasion ± metastability, (7) reprogrammed energy metabolism, and (8) immune evasion.
Activating or inhibiting these pathways with targeted drugs is commonly employed in oncology. Patients are also taking matters in their own hands by trying to block these pathways with off-label drugs and supplements.
The Additional Complexity Of Heterogeneity:
To make matters even more complex, your cancer is not the same as someone else’s, even amongst the same cancer types. Furthermore, every one of your cancer cells is slightly different than its neighbor. This is called “heterogeneity,” which means that the targets, metabolic pathways, genetics, epigenetics and the expression of proteins are not all the same…and one more thing…these variables are constantly changing over time as the cancer cells divide. Oy vay!
So, What Are The Most Effective Drugs For Your Cancer?
I wish I could tell you that there is a non-invasive, inexpensive and simple way to figure this out. Unfortunately, there isn’t. What I typically see the vast majority of patients doing is to take different compounds and hope:
- That they don’t develop side effects from the drugs/supplements, and
- That they see a favorable response to treatment on imaging, clinical exam or follow-up.
Eventually, we will have assays (such as the EVA-PCD assay) that will be able to test hundreds of compounds on a sample of your cancer to see which combinations work the best.
So, what does one do if they want to pursue this off-label and supplement approach? First, you need to acknowledge:
- Your cancer is not the same as anyone else’s.
- Response to any treatment will not be same as that of anyone else.
- The signaling targets and metabolic preferences you read about in your cancer are constantly evolving over time and have cell-to-cell heterogeneity.
- You may develop side effects and toxicities that others may not.
- Taking any drug or supplement off-label is an experiment (you are an “n-of-1”, a metaphorical laboratory guinea pig) that may have no effect, improve or worsen cancer-related outcomes.
- As you combine these compounds with each other or other drugs your physicians have prescribed, interactions (known or unknown) are possible. (I always check drug interactions: https://www.webmd.com/interaction-checker/default.htm)
- Many generic drugs and supplements do not contain what is listed on their label.
- While these drugs and supplements may look promising, standard of care (SOC) oncological therapies have higher level evidence supporting their use in peer-reviewed studies. Combining SOC treatments along with these off-label compounds and supplements would be preferred over the latter, alone. Discuss this with your oncologist, first.
- Taking antioxidant supplements may interfere with radiation therapy and chemotherapy: https://integrativeoncology-essentials.com/2019/12/is-it-safe-to-take-antioxidants-during-cancer-treatment/
Once you’ve acknowledged these unknowns, discuss with your oncologist whether they would be open to you trying off-label drugs or supplements. As with any pharmaceutical or supplement, there are concerns about potential side effects, toxicity and harmful interactions between these compounds and other conventional treatments. It is essential that patients understand these issues and discuss their interest in using these compounds with their oncology providers before starting them.
Of course, you can go rogue and do your own thing…many patients do. Thanks to the internet, acquiring off-label drugs (without a doctor’s prescription) and supplements is less of a challenge.
When I counsel patients on using these drugs and supplements, it is based on the understanding of the points I’ve made above. After that, we thoughtfully (based on hypothesis-only, since they are their own experiment) select multiple pathways to address with lifestyle modifications (individualized after functional medicine assay testing) +/- supplements and off-label drugs.
List Of Some Of The More Popular Anticancer Compounds:
TOP TABLE: I have researched dosing information for the metabolic pathway drugs and supplements in the 2021 Updated McLelland Metro Map, and have included these in the table below. BOTTOM TABLE: These compounds are directed at other cell signaling pathways. Dosing information derived from the design and methods sections of published and unpublished clinical studies (main source: ClinicalTrials.Gov)
- Acetazolamide: 250 mg 2 x/day x 1 week, then increase to 500 mg 2 x/day
- Aspirin (low dose, enteric coated aspirin): 81 mg 1 x/day
- Artemisinin or artesunate: (artesunate: 200 mg artesunate 1 x /day, artemisinin: 200-500 mg 1 x/day)
- Berberine: 100-500 mg 2-3x/day (consider a 4-week break every 8-weeks to give the liver a break from this alkaloid compound)
- Beta-Glucan (Beta-1,3/1,6-glucan): 250 mg 3 x/day
- Cannabis oil: no standard dosing (Dr. Lawenda typically recommends using a full spectrum marijuana tincture with a ratio of 1:1 THC:CBD. Sublingual every 3-4 hours or Ingest every 8 hours. Dose the smallest amount that makes you feel slightly relaxed.)
- Chloroquine or hydroxychloroquine (hydroxychloroquine: 200 mg 1-2 x/day)
- Chromium (chelated or niacin-bound): 200-1000 mcg 1 /day
- Cimetidine: 400-800 mg 2 x/day
- Clarithromycin: 500 mg 2 x/day
- Curcumin: 1000-4000 mg 2 x/day
- Dehydroepiandrosterone (DHEA): 100 mg 1 x/day (do not take if you have a testosterone or estrogen sensitive cancer)
- Dichloroacetate “DCA”: 4.0-12.5 mg/kg body weight 2 x/day (more information on dosing: DCA Guide)
- Dipyridamole: 50-100 mg 3 x/day
- **Doxycycline: 100 mg 1 x/day
- Green tea extract “EGCG”: 200 mg 2-3x/day
- Hydroxycitrate: 500-1000 mg 3 x/day (commonly extracted from Garcinia Cambogia)
- Indole-3-carbinol “I3C”: 400-800 mg 1 x/day
- Inositol+IP6: most common dosing is 2-4 grams/day (higher doses used for anxiety and depression: 12-18 grams/day)
- Itraconazole: 200 mg 1-3 x/day
- Loratadine: 10 mg 1 x/day
- **Mebendazole: 100 mg 1 x/day (Fenbendazole is a veterinary version that can be used in humans: 1 gram granules/day, which is 222 mg/day of active ingredient, taken 3 days on and 4 days off; take with an oil for better absorption) https://www.cancertreatmentsresearch.com/fenbendazole/)
- Melatonin: 20 mg 1 x/day
- **Metformin: 500 mg 2-3 x/day (take with high-quality multi-B-vitamin with methyl B12, methyl folate and thiamine, as metformin can reduce B vitamin absorption)
- Mildronate: 500 mg 1 x/day
- Naltrexone (low-dose): 5 mg 1 x/day (LDN Research Trust: start at 1-1.5 mg 1 x/day for 7 days, increase daily dose by 0.5-1.5 mg each week until you reach 4.5-5 mg 1 x/day)
- Niclosamide: 2000 mg 1 x/day (take with oil for better absorption: i.e. omega-3 fish oil, olive oil)
- Non-steroidal anti-inflammatories “NSAIDs” (celecoxib: 200-400 mg 2 x/day; diclofenac: 35 mg 3 x/day; etodolac: 400-800 mg 2 x/day; ibuprofen: 400-800 mg 3 x/day)
- PHY906 (Huang Qin Tang formula: Chinese peony, Chinese jujube, baikal skullcap, and Chinese licorice): 800 mg 2 x/day
- Polydatin (Biotivia Pteromax: 1 pill/day)
- Propranolol: 20-40 mg 2 x/day
- Quercetin: 500 mg 1-2 x/day
- Resveratrol: 20-5000 mg 1 x/day
- Statins (lipophilic statins: simvastatin, lovastatin and atorvastatin; **atorvastatin: 40 mg 2 x/day, or simvastatin: 20 mg 3 x/day; take with vitamins A, D, K resveratrol, olive oil); Bergamot extract appears to have similar statin-like properties and may be an alternative for statin-intolerant patients: 500-1500 mg 1 x /day
- Tamoxifen: 10-20 mg 1 x/day
- Tetrathiomolybdate “TM” (Induction phase: 40 mg 3 x/day with meals and an additional 60 mg at bedtime. Goal of induction phase is to decrease ceruloplasmin level to 5-15 mg/dL. Once this is achieved, the maintenance phase will begin: 40 mg 2 x/day with meals and an additional 20 mg at bedtime.)
- Ursolic acid: 150 mg 1-3 x/day
- Vitamin C (high-dose intravenous): 50-75 grams intravenous 3 x/week; The Riordan Clinic IV vitamin C (IVC) protocol: “In our experience, the majority of cancer patients require 50 gram IVC infusions 2-3x/week to maintain therapeutic IVC plasma levels (350- 400 mg/dL) . All patients reaching therapeutic range should still be monitored monthly with post IVC plasma levels to ensure that these levels are maintained long term. We advise patients to orally supplement with at least 4 grams of vitamin C daily, especially on the days when no infusions are given.”
**4-Drug COC Protocol™ (Care Oncology Clinic):
- Atorvastatin: “Atorvastatin 40mg at night. We typically do not escalate this dose to 80mg whilst a patient receives chemotherapy as there is a risk of causing disruption to liver function enzymes at the higher dose. If no longer receiving chemotherapy, liver function (especially transaminases e.g. AST and ALT) remains stable and there is no significant myalgia/ arthralgia please consider escalating to 80mg every night. An alternative to Atorvastatin is Simvastatin. If not using Atorvastatin we recommend Simvastatin 40mg at night.”
- Metformin: “Metformin at 500mg once a day for two weeks with breakfast, followed by 500mg twice daily after meals thereafter. In three months’ time one might consider escalating the dosing to 500mg three times daily. We advise patients commencing metformin to stop taking berberine. Some patients prefer to continue berberine, in such cases we do not usually recommend prescribing metformin. The optimal dose of berberine for such patients is usually 500mg TDS. There is some evidence for the efficacy of berberine, but the evidence is not as strong as that for metformin.”
- Doxycycline and Mebendazole: “Mebendazole (Vermox) at 100mg once daily with food, alternated on a monthly basis with Doxycycline 100mg once daily Doxycycline should be taken with water at least 1 hour before or two hours after meals. In three months’ time one might consider increasing the Mebendazole dose to 200mg once daily.”
- Clinical trial reference: https://clinicaltrials.gov/ct2/show/NCT02201381
- Additional notes from COC: “Certain side effects can be associated with these medicines; the most common of which are gastrointestinal in nature such as nausea, vomiting, flatulence and diarrhea. Muscle pain/fatigue may also occur, as well as hepatotoxicity and rhabdomyolysis in very rare cases, in patients who are extremely sensitive to statins. Lactic acidosis can arise in patients who suffer from diabetes or renal impairment, and we normally advise patients on Metformin to omit this medication if their renal function deteriorates, they are grossly dehydrated, have an acute infection requiring antibiotics, or before and after a radiological scan that utilizes contrast agent. Usually, however, patients adjust to the medicines quite quickly and side effects, should they occur, are mostly mild and tolerable. Serology to check liver and kidney function, as well as full blood count, should be performed one month after commencing treatment, and then again prior to each follow-up appointment at 3 monthly intervals. We are very happy to advise should the patient experience any toxicities relating to these treatments. Blood results (complete blood count, electrolytes, kidney and liver function panel) should be within acceptable limits to recommend prescribing the medications at the aforementioned doses. The full blood count, liver and kidney profiles should then be rechecked one month after commencing the protocol to ensure there are no biochemical toxicities from treatment.”
Pre- and Post-Cancer Surgery Protocol #1:
Both study medications will be given orally for an intervention phase of 20 days as follows: 5 days prior to surgery, on the day of surgery, and 14 days postoperatively.
- Etodolac: 800 mg 2 x/day for the entire intervention period
- Propranolol: 20 mg 2 x/day for 5 preoperative days, 80 mg 2 x/day on the day of surgery, 40 mg 2 x/day for the first postoperative week, 20 mg 2 x/day for the second postoperative week
- Clinical trial reference: https://clinicaltrials.gov/ct2/show/NCT00888797
Pre- and Post-Cancer Surgery Protocol #2:
Six total days of treatment: starting 3 days before surgery and until 2 days after surgery
- Propranolol: 10 mg 4 x/day
- Etodolac: 400 mg 2 x/day
- Clinical trial reference: https://clinicaltrials.gov/ct2/show/NCT00502684
Helpful References for More Information:
- The Repurposing Drugs in Oncology (ReDO) project
- AntiCancer Fund: Drug Repurposing
- Medscape: Repurposing Drugs in Your Medicine Cabinet
- How to Starve Cancer: Book (by Jane McLelland)…In my opinion, the BEST resource currently available.
- Jane McLelland Off Label Drugs for Cancer Public Group (Facebook)…over 5,400 members.
30 or 60-Minute Phone or Video Consultation Sessions with Dr. Lawenda:
If you are interested in learning more about these drugs and compounds or have questions about your cancer care, I offer 30 or 60 minute counseling sessions for patients, internationally. Learn more here.