The Care Oncology Protocol and Pancreatic 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 pancreatic 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 +44 20 3855 5939 in the UK or 800-392-1353 in the United States, or visit the website at https://careoncology.com.
If you are new to Care Oncology please note the following:
- You do not need to travel. You can meet with our team of oncologists and oncology nurses through secure video for ongoing support.
- The Care Oncology adjunct protocol medications are shipped directly to your home from our US Partner Pharmacies and can be used alongside your standard of care treatment.
- We are incredibly proud to announce that we have passed the Validation Institute’s extremely rigorous validation process of data analysis, outcome claims, and value calculation. We have worked hard to get to this point. Early on, we recognized the tremendous value a responsibly delivered program of repurposed drugs offered to cancer patients, yet, it was not being offered at scale. Four years ago, we set out to change this knowing it was a marathon, not a sprint.
The COC Protocol and pancreatic cancer: Key points
- The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target pancreatic cancer and help improve the effectiveness of standard anticancer therapies.
- Some researchers suggest that metabolic-targeted treatments may help to improve pancreatic cancer outcomes.
- A number of observational studies have linked metformin or statin use to improved survival outcomes in patients with pancreatic cancer.
- An observational study which followed patients with advanced pancreatic cancer undergoing standard treatment found that statin use either prior to or at the time of cancer diagnosis was associated with much better rates of survival at 2 years (84.1%, compared to 55.0% for those without statin use (Iarrobino et al., 2018)).
- Lab studies report that metformin may also target pancreatic cancer stem cells- these are a rare type of cancer cell which have the capacity to initiate tumors, and which tend to be more resistant to standard cancer treatments.
- Two recent lab studies also suggest doxycycline could effectively target pancreatic cancer stem cells by restricting the assembly and activity of important cell components called mitochondria.
- Mebendazole also has potential in pancreatic cancer. A 2019 cell-based study investigated the potency of four different types of benzimidazole, including mebendazole, on pancreatic cancer cells grown in the lab. All four types of benzimidazole were found to effectively suppress the viability of the pancreatic cancer cells at concentrations reached in the blood following administration of normal therapeutic doses.
- Safety is our top priority. Care Oncology doctors supervise your treatment to minimize risk of polypharmacy.
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The COC Protocol and pancreatic cancer: Published evidence
The COC Protocol is a combination regime 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 support the use of the COC Protocol as an adjunctive therapy alongside current standard treatments for pancreatic cancer are presented below. This evidence mainly comes from laboratory studies and large epidemiological studies (which investigate links between taking medications and pancreatic cancer outcomes in groups of individuals).
You may notice that the studies 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 more 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 further sections below.
Metformin and pancreatic cancer
Metformin is widely used to lower blood glucose levels in patients with type 2 diabetes. The drug can also target the glucose-based molecular processes cancer cells use to generate energy (glycolytic metabolism).
Studies show that metformin can directly act to slow pancreatic cancer cell growth in the lab, and also pancreatic tumor growth in mouse models of the disease (Chen et al., 2017). Cell-based studies have identified several metabolism-related molecular mechanisms which may be involved in pancreatic cancer cell growth and survival, and which are known targets of metformin (Bhaw-Luximon and Jhurry, 2016). mTOR is a key protein used by cancer cells to generate energy and grow. mTOR is also a well-known metformin target, and a number of studies suggest that mTOR is (along with other related factors) an especially important molecular target for metformin in pancreatic cancer cells (Ming et al., 2014; Mohammed et al., 2013; Soliman, 2016).
Other possible mechanisms of metformin activity in pancreatic cancer have also been identified. For example, one study showed that metformin decreased the activity of Sp transcription factor genes in pancreatic cancer cells, as well as other pro-cancer genes (Nair et al., 2013).
Studies also find that metformin may be able to help target pancreatic cancer stem cells (Mohammed et al., 2013; Shibuya et al., 2014). These are a rare type of cancer cell which have the capacity to initiate tumors. They are also often more resilient to treatments and harder to eradicate with standard cancer therapies. At least one lab study reports that metformin treatment is able to help increase the sensitivity of pancreatic cancer cells grown in the lab to other standard pancreatic cancer chemotherapy treatments, such as gemcitabine, cisplatin, and 5-fluorouracil (Candido et al., 2018).
Finally, tumor infiltrating immune cells, which are known to help facilitate pancreatic cancer cell spread, have also been reported to rely excessively on metformin-sensitive glycolytic metabolism (Penny et al., 2016)
In addition to lab work, several observational studies in diabetic patients with pancreatic cancer have also reported that those who took metformin may have had better outcomes and longer survival times (see (Li et al., 2017; Zhou et al., 2017) for two recent overviews of this work).
For example, a US study which followed 302 patients with diabetes and pancreatic cancer found that the 2‑year survival rate was 30.1% for patients in the metformin group, compared to 15.4% for the patients in the non-metformin group. Average (median) survival time was 15.2 months for the metformin group, compared to 11.1 months for the non-metformin group (Sadeghi et al., 2012).
Some researchers question whether the extended survival noted with metformin in these studies is more due to inherent biases in the study, and is perhaps not ‘real’ (Wei et al., 2019). However, other researchers have suggested that perhaps better stratification of patients and improved use of cancer biomarkers are needed. These data could then help define which patients are likely to gain the most benefit from metformin, and how useful metformin could be as part of a combination metabolic treatment (Bhaw-Luximon and Jhurry, 2016; Elmaci and Altinoz, 2016).
Statins and pancreatic cancer
Statins have been around for decades, and are still in regular use as a long-term treatment to help manage chronic cardiovascular 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.
Observational studies in patients taking statins for other conditions and who develop pancreatic cancer repeatedly link statin use to better pancreatic cancer outcomes.
One study which followed patients with advanced-stage pancreatic adenocarcinoma found that statin use either prior to or at the time of cancer diagnosis was associated with much better rates of survival at 2 years. The patient group who had an active or prior history of statin use alongside surgery and chemoradiation treatment had an average 2-year survival rate of 84.1%, compared to 55.0% for those without statin use (p<0.001)(Iarrobino et al., 2018).
A different study followed patients with pancreatic cancer who were being treated with a standard chemotherapy combination of gemcitabine-erlotinib, and looked at numerous factors to see if any might influence long-term response to treatment. This study found that a history of statin use in patients was linked to better long-term response to treatment and improved patient survival (Moon et al., 2016).
An observational study by Lee et al looked at different statin types. This group found that specifically simvastatin or atorvastatin use after diagnosis of pancreatic cancer was associated with longer survival for patients with pancreatic cancer that had not yet spread (Lee et al., 2016).
And a recent analysis of the outcomes of patients with pancreatic cancer taking part in clinical trials for standard treatments found that those with metastatic pancreatic cancer seemed to have better rates of survival if they were also taking statins (Abdel-Rahman, 2019).
Other studies with have also reported similar positive results (Huang et al., 2017; Kozak et al., 2016).
Scientists don’t yet know exactly how, why, or when statin use may help to improve outcomes for patients with pancreatic cancer. But cell and animal studies show that statins can directly target numerous molecular processes involved in pancreatic cancer cell growth, division, survival, and spread. These studies suggest statins can target pancreatic cancer cells via a number of different mechanisms, including blocking cholesterol uptake and synthesis, preventing protein ‘prenylation’ (the proper formation of proteins in cells), and modulating expression of genes involved in tumor blood vessel formation and inflammation (Gbelcová et al., 2017; Gong et al., 2017; Guillaumond et al., 2015). In addition, statins reduce blood cholesterol levels. High levels of blood fats and obesity-related conditions are known possible risk factors for pancreatic cancer (Dai and Jiang, 2020; Gong et al., 2017).
Mebendazole and pancreatic cancer
Mebendazole, a member of the benzimidazole drug family, is widely and safely 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 cancer.
Emerging laboratory evidence supports the potential of benzimidazoles to target pancreatic cancer cells.
A 2019 cell-based study investigated the potency of four different types of benzimidazole, including mebendazole, on pancreatic cancer cells grown in the lab. All four types of benzimidazole were found to effectively suppress the viability of the pancreatic cancer cells at concentrations reached in the blood following administration of normal therapeutic doses. Further experiments also showed that combined application of the benzimidazole parbendazole with the standard pancreatic cancer chemotherapy drug gemcitabine reduced pancreatic cell viability to an even greater extent (Florio et al., 2019). And in a very recent study, the benzimidazole albendazole was also shown to reduce pancreatic cell growth and spread activity in laboratory cell experiments, and slow tumor growth in mouse studies (Chen et al., 2020).
Doxycycline and pancreatic cancer
Apart from being an effective antibiotic, doxycycline, a type of tetracycline, may also have real therapeutic potential in targeting cancer (Bahrami et al., 2012). Data reported from cell studies also hint at the potential for doxycycline activity against pancreatic cancer. For example, a 2009 study showed that doxy application induced programmed cell death in pancreatic cells grown in the lab, and suppressed tumor growth by up to 80% in mouse models of the disease (admittedly this was at extremely high and fairly unfeasible treatment concentrations)(Son et al., 2009).
But real promise is emerging through more recent research illuminating the antibiotic’s potential to target a harder-to-treat type of cancer cell, called a cancer stem cell. Two recent studies suggest doxy could effectively target pancreatic cancer stem cells by restricting the assembly and activity of important cell components called mitochondria (Lamb et al., 2015a; Sotgia et al., 2018). Mitochondria work like ‘batteries’ in cancer cells, generating the energy they need to survive. Restricting mitochondrial activity in cancer cells can severely deplete the cell’s ability to thrive, and particularly to withstand attack by other standard anticancer therapies.
Finally, a very small early-stage Phase 1 clinical trial has investigated the anticancer potential of COL-3, a synthetic tetracycline derivative, which is designed to block molecules called MMPs. High MMP activity is linked to cancer spread (metastases). This trial reported that one patient who had metastatic pancreatic cancer and who had progressed during treatment with gemcitabine experienced ‘stable disease’ (i.e. little or no progression) for 7 months during COL-3 treatment (Syed et al., 2004). Several previous pre-clinical studies have highlighted the potential of existing licensed Doxycycline as MMP inhibitor (e.g. Wang et al., 2017)
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 don’t 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. This is why 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 also 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., 2016). 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., 2015b; 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., 2015a; 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., 2019; 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 of 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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