by Jacob Schor, ND, FABNO
A rapidly growing subcategory in the chemotherapeutic treatment of cancer is the utilization of prescription drugs originally approved for treating conditions other than cancer. Such off-label use of drugs has taken the world of integrative oncology by storm. This strategy has potential for increasing efficacy of treatment. At the same time, it raises deep questions on how we define naturopathic medicine, natural medicine, and our role as physicians. Will using pharmaceutical drugs to prolong a patient’s life fit into who we claim to be as naturopathic physicians?
One of the earliest non-cancer drugs noted to have anticancer side effect was cimetidine. Cimetidine was an early H-2 agonist approved for treating gastric ulcers in the late 1970s. Reports of an anticancer effect appeared not long afterward; the earliest was likely Armitage and Sidner’s 1979 paper,1 but Burtin’s 1988 trial usually receives the credit. Burtin reported that cimetidine or ranitidine combined with subcutaneous histamine improved survival of gastric cancer patients to the degree that patients survived six times longer than patients receiving palliative treatment alone.2 A double blind, placebo-controlled trial by Tonnesen, published the next year, showed that cimetidine alone at a normal dosage significantly prolonged survival in gastric cancer.3 Cimetidine is now reported helpful against a range of cancers, including renal, melanoma, gastric, and colorectal carcinomas.4 In Ali’s 2018 study, patients starting cimetidine after surgery for colorectal cancer delayed cancer recurrence.5
If cimetidine is the drug longest known for secondary usage in cancer, the best-known drug is likely metformin, the glucose-lowering agent that is first-line treatment for type-2 diabetes. Metformin decreases hepatic gluconeogenesis and improves insulin sensitivity. It was approved for treatment of type-2 diabetes in France in 1957, in the UK in 1958, Canada in 1972, and finally, in the US in 1994.6 During the early 2000s metformin also became the drug of choice for treating hyperinsulinemia and metabolic abnormalities associated with polycystic ovarian syndrome (PCOS). The first major report that associated metformin with lower cancer risk may have been Josie Evan’s 2005 study that examined medical records of over 300,000 people in Scotland. Just under 12,000 of these individuals had type-2 diabetes. Of these individuals, 923 were eventually diagnosed with malignant cancers. Those who had taken metformin had a significantly lower risk of being diagnosed with cancer [OR 0.79 (0.67 to 0.93)].7
Since then numerous papers have been published on metformin’s possible benefit in cancer. Observational studies, systematic reviews, and multiple meta-analyses of case-control and cohort studies suggest metformin use is associated with a 10-40% overall decrease in cancer incidence along with a similar decrease in mortality.6,8
Many of us were first exposed to the idea of using prescription drug cocktails to treat cancer by Ben Williams. Mr. Williams was diagnosed with glioblastoma in March 1995. He availed himself of a drug and supplement protocol that proved to be effective. He chronicled these treatment choices first on a website9 and in his 2002 book, Surviving Terminal Cancer: Clinical Trials, Drug Cocktails, and Other Treatments Your Oncologist Won’t Tell You About. The protocol he followed stood out not just because of the many nutritional supplements but also because he took multiple off-label drugs. When he first posted these protocols, I ignored the drugs, as they were not ‘naturopathic.’ I turn back to his list now with interest. What he did worked. Williams took a range of drugs including Accutane, Actos, and Celebrex that evidence suggested might have an additive or synergistic effect against glioblastoma. His list of supplements became the foundation that we have used with brain tumors.
The phrase ‘repurposing drugs’ first shows up in the medical literature in 2005 with two papers by D. W. Carley.10 In 2009, eight papers were published on the subject. These focused on the prohibitively high cost ($800 million) and long time (20-27 years) that it took to bring a new cancer drug to market and suggested that older, already approved drugs might have new uses and proposed ways to screen for anticancer action.11 In 2011, Vazquez-Martin suggested that metformin might be ‘repositioned’ to utilize its ability to target and eliminate cancer stem cells at preinvasive stages.12 Then in 2012, Michele Holmes and Wendy Chen at Harvard wrote their classic review: “Hiding in plain view: the potential for commonly used drugs to reduce breast cancer mortality.” In this paper, they “… presented and evaluated the evidence for several commonly used over-the-counter and prescription medications—including aspirin (and other non-steroidal anti-inflammatory drugs), beta-blockers, angiotensin-converting enzyme inhibitors, statins, digoxin, and metformin, all of which have been evaluated among breast cancer survivors in prospective studies. Substantial scientific evidence supports the idea that some of these common and relatively safe drugs may reduce breast cancer mortality among those with the disease by an amount that rivals the mortality reduction gained by currently used therapies. In particular, the evidence is strongest for aspirin (approximately 50% reduction), statins (approximately 25% reduction), and metformin (approximately 50% reduction). As these drugs are generic and inexpensive, there is little incentive for the pharmaceutical industry to fund the randomized trials that would show their effectiveness definitively….Because of the multiple potential pathways that can be involved with cancer growth and metastases, tremendous interest remains in whether currently used non-cancer medications may potentially have anti-cancer effects.”13
This paper was the last calm before the storm; thereafter interest in repurposed drugs exploded. While this was an obscure idea in 2009, PubMed lists 247 citations for ‘repurposing drugs’ in 2017 and 312 for the following year. One might argue that this is due to a collective realization by researchers that this is an excellent idea. The excitement is in part due to a man in Belgium named Luc Verelst, whose sister was diagnosed with endometrial cancer in the summer of 2008. Like many of our patients, Verelst searched to find the best and most reliable treatments; and like them, he was overwhelmed, frustrated, and confused by the complex and contradictory information he found. In 2009, Mr. Verelst founded a non-profit organization called Reliable Cancer Therapies (RCT) to publicly share information on cancer treatments and to investigate new treatment options. He founded a second organization in 2013, the Anticancer Fund (ACF), with the ambitious goal of discovering a cure for cancer. As part of their mission, the ACF scientists took on the task of researching this concept of drug repurposing They have cataloged potential repurposed drugs on a website (http://www.redo-project.org), produced summaries on many of these drugs, and are funding research on promising candidates.
