The Care Oncology Protocol and Bladder Cancer
This document is a summary of some of the current scientific evidence which supports the use of the COC Protocol medications alongside standard of care treatments for bladder cancer.
We understand that cancer is a very personal condition, and every patient has a unique set of challenges. For more information regarding your own personal situation please get in touch with the Care Oncology Clinic at 800-392-1353 in the United States, or +44 (0) 20 3855 5939 in the UK or visit the website at https://careoncology.com.
The COC Protocol and bladder cancer: Key points
- The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target bladder cancer and help improve the effectiveness of standard anticancer therapies.
- Research suggests that metabolic-targeted treatments may help to improve bladder cancer outcomes.
- Studies investigating the benefits of COC Protocol medications for bladder cancer are mostly still at the cell and animal level, more patient studies are needed.
- Nevertheless, cell studies carried out in the lab suggest that metformin may help to improve the effectiveness of some chemotherapies in bladder cancer. Several observational studies on groups of patients with diabetes and bladder cancer also report evidence of a potential link between metformin and improved bladder cancer outcomes.
- Lab studies seem to point to a clear mechanism and potential benefit for statin use alongside standard therapy in bladder cancer. However, the patient evidence base is still evolving.
- An innovative screening study which used bladder cancer cells grown in the lab with similar characteristics to patient bladder cancer cells has identified mebendazole as a credible candidate for further investigation as a potential treatment.
- Evidence suggests that doxycycline may help to target harder to treat ‘initiator’ cancer stem cells, which can be more resistant to treatment and responsible for cancer coming back.
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The COC Protocol and bladder cancer: Published evidence
The COC Protocol is a combination regimen of four commonly prescribed medications, each with evidence of metabolically based anticancer activity, and well understood safety profiles. These medications are: metformin, atorvastatin, doxycycline, and mebendazole.
Some of the studies which provide evidence supporting the use of the COC Protocol medications individually as adjunctive therapies alongside current standard treatments for bladder cancer are presented below.
You may notice that the studies we discuss below only focus on individual COC Protocol medications. We are the first to design an adjunct therapy which combines all four. We believe that combining these medications will achieve the greatest results. Our own research program, called METRICS, is already producing some of the evidence needed to show this.
You can read more about why we believe these medications work together so well to help target cancer, and about the METRICS program itself, in the further sections below.
Metformin and bladder cancer
Research increasingly suggests that significant metabolic changes take place in bladder cancer cells, and that targeting these changes may have therapeutic advantages (Pasquale et al., 2020; Woolbright et al., 2018).
Metformin is widely used as a blood glucose-lowering drug for patients with type 2 diabetes. It can also target the glucose-based metabolic molecular processes that cancer cells need to generate energy (called glycolytic metabolism). Consequently, some scientists have begun to investigate the potential effectiveness of using metformin to help control bladder cancer, with encouraging early-stage results.
A number of cell and animal laboratory studies now provide evidence that metformin can directly target and disrupt bladder cancer cell survival and growth through a number of different molecular processes, including via STAT3 and the AMPK/mTOR molecular pathways (Jang et al., 2020; Li et al., 2017; Liu et al., 2016a; Pan et al., 2015; Wu et al., 2019).
A 2016 lab study also provides evidence that metformin may be able to repress bladder cancer progression in part by targeting bladder cancer stem cells (Liu et al., 2016a). These are thought to be an ‘initiator’ type of cancer cell more resistant to treatment, and which may be responsible for cancer coming back in some cases.
Other lab studies provide evidence that metformin could help to sensitize bladder cancer cells to standard chemotherapy treatments, potentially improving the effectiveness of these treatments. For example, Wang & Wu report that combined metformin and cisplatin blocked the growth of bladder cancer (and surrounding blood vessels) to a greater extent than either drug alone in cell and animal studies (Wang and Wu, 2015). Similar findings have also been reported for metformin and gefitinib (Peng et al., 2016), and metformin and the targeted HDAC inhibitor panobinostat (Okubo et al., 2019).
Observational studies investigating the outcomes of patients with diabetes and bladder cancer also provide some generally promising results (Sayyid and Fleshner, 2016).
A ‘meta-analysis’ which looked at the overall results from 9 observational studies totaling more than a million patients with diabetes and bladder cancer reported that taking metformin was linked to improved length of time before a patient’s cancer progressed, improved length of time before it came back, and also improved cancer-specific survival time (Hu et al., 2018).
In further support of this, a more recent study of patients with non-muscle invasive bladder cancer who had been enrolled on a clinical trial for BCG immunotherapy treatment found that those with diabetes and on metformin had the best prognosis for overall survival, compared to those with no diabetes, or with diabetes but not taking metformin (Wang et al., 2020).
Other studies have been less supportive, and the reasons for this are unclear. The presence of other factors may play a part (Ahn et al., 2016). For example, a 2019 cell study suggests that metformin’s anticancer activity on bladder cancer cells may be less effective in a high-glucose, high-insulin environment (Kim et al., 2019).
Promisingly, randomized clinical trials are now taking place to investigate in detail just how metformin may help some patients with bladder cancer (Molenaar et al., 2019).
Statins and bladder cancer
Statins are traditionally prescribed as a long-term treatment to help individuals manage heart and blood vessel-related conditions. The potential anticancer properties of statins have also been studied for many years. Laboratory studies show that statins, particularly fat-soluble ‘lipophilic’ statins like atorvastatin (Kato et al., 2010) can block growth, division, and spread of cancer cells grown in dishes, and slow tumor growth in mice.
In bladder cancer, atorvastatin has been shown to induce a form of preprogrammed cell death called apoptosis and reduce the ability of the cancer cell to grow and divide. This activity has been demonstrated for both bladder cancer cell lines grown in the lab, and also in bladder cancer cells derived directly from patient tumors (Kamat and Nelkin, 2005; Kang et al., 2014; Kettunen et al., 2019).
Emerging cell-based evidence also suggests that atorvastatin may help to maintain effectiveness of standard therapies. A 2015 study investigated the molecular make up of bladder cancer cells that were resistant to the chemotherapy doxorubicin, and found increased activity of a pathway called the mevalonate pathway (Greife et al., 2015). Statins can target and block the mevalonate pathway, and in this same study, application of atorvastatin to cells grown in the lab reduced their resistance to doxorubicin. Doxorubicin resistance is a recognized problem for some patients with bladder cancer, and the authors suggest that statins in combination with doxorubicin may help provide a ‘therapeutic advantage’ for some patients.
Lab studies seem to point to a clear mechanism and potential benefit for statin use alongside standard therapy in bladder cancer, however, patient-based evidence is still evolving.
Various observational studies have investigated outcomes for patients with bladder cancer who happened to also be taking statins vs. those who were not. Some studies now report evidence suggesting an improved outlook for those on statins. For example, a 2020 Canadian study investigated the outcomes of over 3000 patients with bladder cancer, of whom just under half were taking statins prior to and during their diagnosis of cancer. Statin users had improved rates of both survival and relapse, compared to those who had never used statins. For example, the proportion of patients surviving bladder cancer for 5 or more years following diagnosis was 52.8% for statin users vs. 45.5% for never users (Wissing et al., 2020).
And a recent large Italian study which has followed the outcomes of over 1500 patients with bladder cancer also reported evidence that statin use may be linked to longer times before relapse- an average of 53 months for those taking statins vs. 47 months for non-statin users in this group of patients (Ferro et al., 2021). Other patient studies have also reported potentially improved outcomes for patients with bladder cancer (Seppälä, 2019; Tsai et al., 2006).
However, there have also been studies reporting no real difference with statin use in bladder cancer (Crivelli et al., 2013; Lim et al., 2015; da Silva et al., 2013), or even in certain patients a possible disadvantage to taking statins for some outcomes (Pastore et al., 2015).
In an attempt to clarify this mixed evidence, a meta-analysis of 35 separate retrospective studies investigated statin use in patients with urologic cancers (i.e., bladder, renal, or prostate). The analysis reported a link between statin use and improved overall survival for bladder cancer, and no link between statin use or any other bladder cancer outcomes (Luo et al., 2015). Further studies are therefore needed to help build the base of patient evidence, and to better understand which types of patients will benefit most from statins, either alone, or in combination with other treatments.
It is also worth noting that a several studies have specifically investigated outcomes for patients with bladder cancer who were on statins, and who were also treated with BCG immunotherapy. This is because some researchers suggest that the biological activity of statins may interfere with the BCG treatment. However, not one of these studies have found any indication that statin impacts effectiveness of BCG immunotherapy (Berglund et al., 2008; Crivelli et al., 2013; Skolarus et al., 2009). Nevertheless, we always prioritize a patient’s standard therapy above the COC Protocol, and we continue to monitor the research in this area in case modifications are required for patients undergoing BCG immunotherapy.
Mebendazole and bladder cancer
Mebendazole, a member of the benzimidazole drug family, is widely used to treat parasitic infections in both children and adults.
Interest in mebendazole as a potential anticancer treatment is relatively new, and mostly based on promising mechanistic studies and compelling reports from case studies in cancer patients (Bai et al., 2011; Nygren and Larsson, 2014; Pantziarka et al., 2014). Based on this preliminary evidence, a number of clinical trials are now currently investigating mebendazole as an adjunctive treatment for different types of cancer, though not yet for bladder cancer.
A 2020 study published in the journal iScience provides the first compelling cell and animal based evidence that mebendazole may be directly active against a type of bladder cancer called papillary bladder cancer (Shao et al., 2020).
The study took the unusual and effective step of first identifying the most relevant cell model (i.e., cells grown in the lab) to use, by comparing the characteristics of specific cell models with those from tumor cells in the body. They then developed a screening and ranking mechanism to investigate how likely it is that certain compounds which can kill cancer cells grown in the lab may have antitumor activity in the body.
Using their novel screening mechanism, the researchers identified mebendazole as a compound which could potentially be active against papillary bladder cancer. Further tests in a mouse model of papillary bladder cancer confirmed that mebendazole application was able to reduce tumor volume in these animals, and slow tumor growth rate. Tests in patients are now needed.
Doxycycline and bladder cancer
Emerging evidence suggests that the tetracycline antibiotic doxycycline may have real therapeutic potential in targeting cancer (Bahrami et al., 2012). Various lab studies now report that doxycycline can target and suppress cancer cell growth and movement, possibly via several different molecular mechanisms. These include targeting enzymes called MMPs, which can help cancer cells spread (Fife et al., 1998; Ogut et al., 2016), and preventing the cell from repairing DNA damaged by other treatments (Lamb et al., 2015a; Peiris-Pagès et al., 2015).
Doxycycline may also work via preventing activity of an important part of the cell called the ‘mitochondria’ (Lamb et al., 2015b; Tan et al., 2017). Cells use mitochondria to generate the energy they need to survive and grow. Data for doxycycline in bladder cancer is still scarce, but a very early paper from the 1980s which investigated the effect of doxycycline and UVA irradiation on bladder cancer cells grown in the lab, did note that damaged mitochondria occurred in these cells very early, prior to any other type of cell damage (Shea et al., 1986).
More recent work in other types of cancer suggests that, similar to metformin, doxycycline may also be able to target cancer stem cells (Lamb et al., 2015b). Promisingly, a pilot clinical trial in patients with newly diagnosed early-stage breast cancer has reported that short-term oral treatment with doxycycline prior to surgery reduced markers of cancer stem cells in these patients (Scatena et al., 2018).
Our own evidence: The METRICS Study
What is METRICS?
METRICS is our own in-house research study. Although our own experience combined with the level of existing research for the individual COC Protocol medications means we are confident prescribing and managing the Protocol for patients with cancer, more good quality clinical research in this area is needed. METRICS helps us to meet this need. Data from METRICS is helping to ensure that our clinicians understand how these medications work in combination, and how best to prescribe the COC Protocol in the context of cancer.
There is a well acknowledged ‘funding gap’ which currently slows down the repurposing and further clinical development of licensed medications for other conditions. We bridge this gap by using patients’ fees to help fund our research. This means METRICS is essentially ‘patient-funded’. This is a new way of funding clinical research.
METRICS first results
In a first success for METRICS, results from our initial pilot study were recently published in the peer-reviewed scientific journal Frontiers in Pharmacology. The paper can be accessed freely online here.
The METRICS pilot study was an observational retrospective study, which means that our researchers looked back and analyzed patient clinical records to find out what happened. They collected data and recorded the outcomes from 95 patients with an advanced type of brain cancer called glioblastoma who attended the Care Oncology Clinic and who took the full COC Protocol alongside their usual standard treatments. This study did not have a control group, so our researchers compared the results from METRICS with previously published results from earlier studies in patients with the same type of cancer, and who also took standard-of-care treatments.
Initial results suggest that patients who attended our clinic and took the COC Protocol as part of their usual care were much more likely to survive at least 2 years (64.0% of patients in our study survived at least 2 years, compared to 27-29% for patients included in previously published studies), and tended to have longer survival times overall than would usually be expected for patients with this type of cancer (patients survived an average of 27 months in our study, compared to 15-16 months in earlier studies)(Agrawal et al., 2019).
These results are extremely promising, but they are also still preliminary. We do not yet know exactly how the COC Protocol may have impacted survival times for example, or how other factors such as certain patient characteristics may have also influenced these results. But this first, initial evidence is certainly encouraging, and it suggests to us that we are heading in the right direction. Our next planned stage is to conduct a larger, well-designed study. You can find out more about future METRICS plans by looking online or contacting the clinic.
Why do we only prescribe the COC Protocol?
Cancer is a complex disease with complex treatments, and we believe that the potential benefits and risks of adding any further therapies into this mix should be very carefully evaluated. Therefore, our whole approach is based on cautious evaluation of evidence. This is also why we only prescribe the COC Protocol, and do not prescribe any other off-label medications.
Our knowledge of the existing research, plus our own clinical experience means we are confident that we have a good understanding how the protocol medications will behave in patients with differing stages and types of cancer, and in combination with other types of cancer treatments. Although many different medications on the market have at least some published evidence supporting their relatively effective use in cancer, they are not our specialty. Having a solid understanding is extremely important to us. We believe this type and level of evidence is just not there yet for many other off‑label anticancer drug candidates – especially when given in combination.
We chose the four medications included in the COC Protocol from thousands of potential candidates specifically because they fit our predetermined selection criteria. Each medication in the protocol is supported by:
- solid published evidence of effectiveness against cancer. This evidence mainly comes from cell and animal lab studies, observational patient studies, and some small clinical trials (mostly for metformin and statins) and case studies (mebendazole).
- additional evidence of potential ability to work well with the other protocol medications (i.e., a coherent mechanism of action). This evidence is mostly based on cell and animal mechanistic studies, and some observational patient studies (metformin and statins).
- a good overall safety profile in patients. This evidence is mostly based on years of clinical trial and patient study data generated as the medications were originally developed and studied for other conditions. Also, some more recent patient data in the context of cancer, including our own recently published research data.
How does the COC Protocol work?
The COC Protocol is designed to work primarily by restricting the overall ability of cancer cells to take up and use (i.e., ‘metabolize’) energy.
Cancer cells need huge amounts of energy to survive, and the vast majority of cancers use an adaptive process called aerobic glycolysis to generate the excessive energy they need (Kroemer and Pouyssegur, 2008). Each of the medications in the protocol can target the various molecular metabolic processes involved in and surrounding aerobic glycolysis, and this can help lower the overall metabolic rate of the cancer cell (Jang et al., 2013).
We believe the COC Protocol medications can work in combination to consistently restrict energy supply and use, while simultaneously preventing cancer cells from adapting and using other pathways to take up energy (Jagust et al., 2019). As a result, cancer cells become increasingly weaker and less able to take in and use the nutrients (e.g. such as glucose and essential amino acids glutamine and arginine) they need from their surroundings (Andrzejewski et al., 2018; Liu et al., 2016b). This makes it more difficult overall for cancer cells to survive, grow, and spread in the body. Gradually, the weakened cells (including more resilient and previously treatment-resistant cells) become more vulnerable to attack from other cell‑killing cancer therapies such as radiotherapy, chemotherapy, hormonal therapy, and targeted therapies (Bradford and Khan, 2013; Chen et al., 2012; Lacerda et al., 2014; Lamb et al., 2015a; Pantziarka et al., 2014).
By targeting the adapted metabolic mechanisms which are common to most cancers (but not usually healthy cells), we believe that the COC Protocol can be effective and selective for virtually any cancer regardless of specific type, stage, or location of cancer. Published epidemiological and lab studies increasingly support the potentially broad range of this therapy (Chae et al., 2015, 2016; Iliopoulos et al., 2011; Lamb et al., 2015b; Pantziarka et al., 2014).
Why these four medications together?
The true power of the COC Protocol lies in the specific combination of medications we use. We developed the protocol not just as a regimen of four individual treatments each with anticancer activity, but also to work as a single combined treatment (Mokhtari et al., 2017).
Evidence suggests that each medication in the COC Protocol can target cancer cell metabolism in a distinct and complementary way, and we have termed this action ‘mechanistic coherence’. Put simply, mechanistic coherence describes how each medication can attack the cancer cell from a different angle.
For example, cancer stem cells are a particularly resilient type of cancer cell, and each medication targets these cells in a different way: metformin targets the cell’s ‘batteries’ (called mitochondria) by making it very difficult for mitochondria to run the molecular reactions they need to produce energy, doxycycline blocks the cell-DNA machinery that mitochondria need to replicate and repair (Skoda et al., 2019), statins can alter cancer stem cell gene expression, making the cells more sensitive to other cancer therapies (Kodach et al., 2011), and mebendazole can interrupt numerous molecular processes involved in cell division to help block cancer stem cell growth (Hothi et al., 2012; Hou et al., 2015).
By combining all four agents together, the COC Protocol can hit cancer stem cells (and other cancer cells) across multiple ‘weak spots’, and like a one-two punch, this leaves the cells less able to dodge and recover from standard treatments.
Lab studies are beginning to highlight the effectiveness of this approach using COC Protocol medication combinations. In mechanistic studies, combining statin and metformin greatly decreases the growth of prostate and endometrial cancer cells more than either agent alone (Kim et al., 2019b; Wang et al., 2017).
Observational studies have also reported potentially ‘synergistic’ effects of these medications against various cancers (Babcook et al., 2014; Danzig et al., 2015; Lehman et al., 2012; Nimako et al., 2017). A clinical trial investigating metformin and doxycycline in breast cancer is now underway (NCT02874430), and our own research program, METRICS, is now also beginning to produce promising data.
Can I take the COC Protocol long-term?
The COC Protocol is primarily designed to be a long-term ‘adjunctive’ therapy, to help optimize standard treatments. However, as metabolic treatment with the COC Protocol is intended to run long-term, patients may also take the protocol as a maintenance regime after standard treatment has been completed or during breaks from standard treatment and as part of a long-term strategy to mitigate the risk of recurrence or metastases. For this reason, it is also worth noting that each of the COC Protocol medications also has reported beneficial mechanisms of action in cancer which are not dependent on the co-administration of standard therapies, and which may independently help to reduce the risk of relapse and metastatic spread.
The Care Oncology model
Active medical supervision of each patient
Although the COC Protocol medications have been used safely in the general population for many years, they are not without side-effects. In addition, every patient’s situation is both complex and unique, and requires careful personalized assessment. This is why every patient who attends the Care Oncology Clinic is placed under the direct care of clinicians with specialist knowledge of prescribing the COC Protocol medications in the context of cancer. Our clinicians individually assess the potential benefits and risks involved in taking the COC Protocol with each patient. We will only recommend the COC Protocol to patients when we believe it will be safe and beneficial to do so. Each COC Protocol prescription is tailored to the needs of the patient, and doses and regimens are carefully reviewed and adjusted based on how the patient progresses.
It is therefore essential that patients are carefully monitored at our clinic throughout the course of their treatment.
Purpose of this article
This article is an overview of some of the scientific and medical published literature concerning the medications which comprise the patented Care Oncology protocol. Care has been taken to select relevant articles supporting the off-label use of these medicines in a clinical setting for the adjunct treatment of cancer. This article does not purport to be a comprehensive review of all the evidence, nor does it capture all the potential side-effects of such treatment.
This article is for information purposes only and it does NOT constitute medical advice. The medicines discussed herein are available on prescription-only and should not be taken without consultation with your doctor or other professional healthcare provider. Care Oncology doctors will discuss the suitability of these medicines with you and will liaise with your doctor or oncologist to discuss their suitability for you.
You must NOT rely on the information in this article as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare provider. If you think you may be suffering from any medical condition you should seek immediate medical attention. You should never delay seeking medical advice, disregard medical advice, or discontinue medical treatment because of information contained in this article.
The copyright in this article is owned by Health Clinics USA Corp and its licensors.
The Care Oncology (“COC”) Protocol is protected by United States patent US9622982B2 and by various additional international patents.
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