CANNABIS CULTURE – Patients with various diagnoses of cancer were offered the opportunity to supplement the standard treatments prescribed by their physicians with bioRenovate. In all cases, we found patients responded better with bioRenovate than without it. Based on these results, we now consider bioRenovate an important complementary treatment to chemotherapy.
Cannabidiol
The cannabis plant (Cannabis sativa L.) con- tains a large number of pharmacologically ac- tive compounds called phytocannabinoids. The two most abundant of these compounds are ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD), although the amounts and proportions of the various phytocannabinoids in each plant vary by strain and can be adjusted by breeding.
Many cannabinoids, including CBD, have been shown to be non-toxic and to possess anti-tumor activity in multiple cancer types (Massi, Solinas et al. 2013). Numerous mechanisms have been proposed to explain these anti-tu- mor effects, including producing free radicals (Massi, Vaccani et al. 2004, Massi, Vaccani et al. 2006), promoting cell death (Shrivastava, Kuzontkoski et al. 2011), reducing inflammation (Nagarkatti, Pandey et al. 2009), inhibiting drug transport (Zhu, Wang et al. 2006) and tumor formation (Aguado, Carracedo et al. 2007), and making certain forms of chemotherapy work better (Fisher, Katta et al. 2019).
With respect to toxicity, the safety and tolerability of CBD have been investigated in single and multiple ascending dose studies up to 3,000 mg without any concern (Wall, Brine et al. 1976, Harvey, Martin et al. 1979, Benowitz, Nguyen et al. 1980, Agurell, Carlsson et al.
1981, Agurell, Halldin et al. 1986, Ohlsson, Lindgren et al. 1986, Harvey and Mechoulam 1990, Consroe, Kennedy et al. 1991, Consroe, Laguna et al. 1991, Harvey 1991, Zuardi, Morais et al. 1995, McArdle, Mackie et al. 2001, Hawksworth and McArdle 2004, Nadulski, Sporkert et al. 2005, Huestis 2007, Bergamaschi, Queiroz et al. 2011, Huestis and Smith 2014, Taylor, Gidal et al. 2018). Our selected daily dose of 100 mg of CBD was therefore well below the limit of concern.
Given the tantalizing evidence that CBD is both safe and effective in multiple cancer models, we developed a proprietary formulation of CBD, bioRenovate. We conducted a small observational study, comprised of 24 patients diagnosed with cancer, to assess how CBD affected clinical responses to treatment.
Cancer and Study Results
bioRenovate was used in conjunction with standard care to treat patients. (All patients on bioRenovate received 50 mg doses of CBD twice daily.) These patient responses were then compared to diagnosis-matched treatment control patients who were treated at the same facility and who opted not to take bioRenovate. All patient responses are summarized in Figure 1. (Additional information is available upon request.)
Standard treatment Standard treatment + bioRenovate
Breast cancer (Stage IV)
*Cholangiocarcinoma *Colon cancer (Stage IV)
Lung cancer (Stage iII)
Multiple myeloma (Stage III)
Pancreatic cancer (Stage III)
Rectal cancer (Stage III)
-120% -80% -40% 0% 40% 80% 120% 160%
Change in tumor size
Figure 1. Clinical responses to standard treatment ± bioRenovate. Patient responses to standard chemotherapy supplemented with bioRenovate (green bars) were compared to responses in stage and treatment-matched control patients on standard chemotherapy alone (blue bars). Positive values indicate increases in tumor growth; negative values, decreases in tumor growth. The asterisks indicate no data were available on responses to standard treatment.
Breast cancer. Breast cancer is the most frequently diagnosed cancer in the world and the leading cause of mortality in women. The American Cancer Society estimates 249,260 women will be diagnosed with invasive breast cancer and 40,890 women will die in the United States. Since 1991, breast cancer mortality has been decreasing suggesting a benefit from the combination of early detection and treatment.
Two patients with stage IV breast cancer were treated with the chemotherapy regimen of pal- bociclib plus fulvestrant. One of these patients agreed to take bioRenovate throughout the course of treatment.
At the initiation of treatment, the patient who received standard therapy only had a non-tar- get lesion 2.4 cm in size. At the time of re-assessment, a second radiographic image could not be acquired due to pleural effusion, a dangerous consequence of metastatic lesions to the lung and a marker of progressive disease (by RECIST). A randomized phase III study of 521 advanced breast cancer patients found that 10% of patients had an overall objective
response, with a clinical benefit rate of 34% (Turner, Ro et al. 2015). (The clinical benefit rate is defined as the percentage of patients with advanced or metastatic cancer who respond to treatment with a complete response, partial response, or stable disease.) The addition of bio- Renovate to this treatment regimen resulted in a 14% overall decrease in the size of two different non-target lesions. These results classified the patient’s response as non-complete or non-progressive disease (by RECIST), a better outcome for the patient.
Cholangiocarcinoma. Cholangiocarcinoma is a cancer of the gallbladder and is the most common biliary tract cancer. The vast majority of gallbladder cancers are adenocarcinomas. The incidence increases with age.
One patient with metastatic cholangiocarcino- ma was treated with FOLFIRINOX (folinic acid [leucovorin], fluorouracil [5-FU], irinotecan, ox- aliplatin), to which bioRenovate was added as companion therapy throughout the course of treatment.
At the initiation of treatment, the patient had multiple measurable lesions. Historically, a ret- rospective study of 92 patients with advanced biliary tract cancers (including cholangiocarcinoma) found that FOLFIRNOX treatment had a clinical benefit rate of 42% (Kus, Aktas et al. 2017). Following treatment with FOLFIRINOX supplemented with bioRenovate, the patient responded with a 95% overall reduction in lesion size (non-complete response / non-pro- gressive disease).
Colon cancer. Colorectal cancer is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the Unit- ed States. In 2018, an estimated 95,270 new cases of colon cancer and 43,030 cases of rectal cancer will occur. During the same year, an estimated 50,630 people will die of colon and rectal cancer combined.
Seven patients with stage IV colon cancer were treated with FOLFOX (folinic acid [leucovorin], fluorouracil [5-FU], oxaliplatin) plus bevacizum- ab. Three of these patients agreed to take bioRenovate as companion therapy throughout the course of treatment.
At the initiation of treatment, each of the four patients who received standard therapy only (FOLFOX plus bevacizumab) had multiple le- sions. Following treatment, two of the patients had their tumors reduced by 18% (one patient, with measurable non-target lesions only, had a non-complete response / non-progressive dis- ease by RECIST; the other patient, who had an initial target lesion, had progressive disease); the other two patients saw increases of 41% and 88% in the size of their lesions (progressive disease). A randomized study of 829 metastatic colon cancer patients found that 21% of patients had a partial response to treatment with FOLFOX plus bevacizumab (Giantonio, Catalano et al. 2007). By contrast, all three patients who added bioRenovate to this treatment regimen exhibited decreases in the sizes of their lesions, of 96% (partial response), 33% (non-complete response / non-progressive disease), and 12% (stable disease).
Rectal cancer. Two patients with stage III rectal cancer were treated with 5-FU plus radiotherapy. One of these patients agreed to take bioRenovate as companion therapy throughout the course of treatment. At the conclusion of the study, one patient on 5-FU plus radiotherapy only (i.e., without bioRenovate) switched to FOLFOX plus bevacizumab.
At the initiation of treatment, all patients had measurable lesions. Following treatment, the patient on standard chemoradiotherapy only responded with an increase in target lesion size of 150% (progressive disease by RECIST). Historically, a meta-analysis of 71 trials, comprising 4,732 patients with advanced rectal cancer, found that 5-FU-based chemoradiotherapy resulted in a complete response rate of 20% (Sanghera, Wong et al. 2008). The patient who added bioRenovate to the treatment regimen had a partial response, with a reduction in target lesion size of 72%.
Lung cancer. Lung cancer is the leading cause of cancer death in the United States. In 2019, an estimated 228,150 cases will be diagnosed, with 142,670 deaths.
Four patients with stage III lung cancer were treated with standard chemotherapy regimens: two with erlotinib, and two with carboplatin plus taxol. One patient on each standard regimen agreed to take bioRenovate as companion therapy throughout the course of treatment.
At the initiation of treatment, all patients had measurable lesions. Following treatment, the patient on erlotinib only showed a decrease of 8% in the size of the target lesion (stable disease by RECIST); the patient on carboplatin plus taxol had a 167% increase in the size of the target lesion (progressive disease). A randomized study of 731 patients with advanced lung cancer found a response rate to treatment with erlotinib of 8.9% (Shepherd, Rodrigues Pereira et al. 2005); for carboplatin plus taxol, a randomized study of 618 patients reported a response rate of 25% (Rosell, Gatzemeier et al. 2002). Patients who supplemented their therapy with bioRenovate fared better, both exhibiting partial responses: with erlotinib plus bioRenovate, target lesions were reduced by 23%; with carboplatin plus taxol plus bioRenovate, the target lesion was reduced by 31%.
Multiple myeloma. Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in the bone marrow. It compromises 1.8% of all cancers and more than 17% of hematologic malignancies. Newly diagnosed multiple myeloma is sensitive to a variety of cytotoxic drugs. Although responses are typically durable, relapse is expected.
Five patients with stage III multiple myeloma were treated with the chemotherapy regimen of RVD (lenalidomide, bortezomib, dexametha- sone). Three of these patients agreed to take bioRenovate as companion therapy throughout the course of treatment. At the conclusion of the study, one patient on RVD only (i.e., without bioRenovate) switched to pomolidamide plus dexamethasone.
At the initiation of treatment, baseline assessments of markers of multiple myeloma were acquired for all patients. (Not all markers were assessed for all patients; supplementary information available upon request.) Following treatment, the two patients on RVD only were classified as having progressive disease and minimal response (by IMWG criteria). In a combined phase I/II study of RVD as a frontline treatment in 66 multiple myeloma patients, a partial response rate of 100% (Richardson, Weller et al. 2010). All three patients who added bioRenovate to this treatment regimen had partial responses, with 100% reduction in plasma-cytomas, and 98% and 75% reductions in the percentage of plasma cells.
Pancreatic cancer. Pancreatic cancer is the third most common cause of death due to cancer in the United States. The incidence of pancreatic cancer has likely increased because of the increased prevalence of obesity, diabetes, and the aging population.
Four patients with stage III pancreatic cancer were treated with gemcitabine-based chemotherapy regimens: one with gemcitabine only, three with gemcitabine plus nab-paclitaxel. Two of the patients treated with gemcitabine plus nab-paclitaxel agreed to take bioRenovate as companion therapy throughout the course of treatment. At the conclusion of the study, one patient on gemcitabine and nab-paclitaxel only
(i.e., without bioRenovate) switched to FOLFOX plus bevacizumab.
At the initiation of treatment, all patients had measurable lesions. Following treatment, the two patients on standard therapy only showed progressive disease (by RECIST), with an 11% reduction and 63% increase in the size of the lesions. A randomized phase III study of 861 advanced pancreatic cancer patients treated with gemcitabine plus nabpaclitaxel reported a 23% response rate and 48% disease control rate (complete response, partial response, or stable disease) (Von Hoff, Ervin et al. 2013). The patients who added bioRenovate to their treatment regimens exhibited large decreases in the sizes of their lesions, of 73% and 75% (both partial responses).
In summary, patients who supplemented their standard therapy regimens with bioRenovate had better clinical responses than treatment controls (Figure 1). These responses included greater reductions in the size of tumor lesions and number of cancerous cells (for multiple myeloma patients). We did not observe any “average” responses to standard treatment for cholangiocarcinoma and multiple myeloma, and the breast cancer patient comparison had missing data; hence the missing histogram bars.
Notes from an oncologist . . .
For many people, a diagnosis of cancer can feel like a death sentence. This, despite all the advances science has made, such as better education, better methods to diagnose the disease, better treatments, better support systems, and better ways to manage pain. Yet, even with these advancements, cancer remains one of the worst health issues most of us will ever face.
Sadly, one of the deadliest diagnoses to confront is pancreatic cancer. For every 10 people newly diagnosed with the disease in a given year, eight previously diagnosed patients will die. It is often diagnosed late, due to the fact its symptoms are subtle and easily ignored. Imagine have back pain that lasts for several weeks, finally going to the doctor because Advil or Tylenol isn’t working, and being told you have pancreatic cancer. That news alone is terrifying. But then comes the treatment.
A Google search for “pancreatic cancer testimonial” yields far too many results, most with sad endings. For example, imagine a 51 year old man who never smoked, never drank, worked out regularly, and was a cycling enthusiast. Symptoms appeared suddenly feeling full quickly after eating meals, pain in his ribs and back – none of which were picked up by doctors as anything out of the ordinary. Finally, a liver panel revealed elevated enzymes, which prompted an ultrasound and discovery of many lesions on his liver, having originated in the pancreas. By this point, surgery was not an option, and treatment was ineffective. Within two weeks of his diagnosis, he was dead, leaving his loved ones to cope with this sudden and all too tragic loss.
Catching the disease early and immediately initiating treatment remains the best hope for patients. It is impossible to know if there would have been a way to alter the trajectory of this man’s illness. Perhaps no treatment would have worked regardless of when the diagnosis was made. Perhaps, however, at the very first signs of distress – when the back pain started – our patient decided to take cannabidiol, appears to help make other medicines, such as chemotherapy, work better. In this case, perhaps it would have improved his response to therapy. We’ll never know if it would have saved him, but we do know that this outcome is all too common. If CBD could make the difference between living or dying in response to treatment, isn’t it worth trying?
Conclusions
Cannabinoids, and CBD in particular, have been proposed as therapeutic agents for a wide variety of diseases. Although precisely how cannabinoids exert their effects remains unknown, it has been suggested that a natural part of the human body, the endocannabinoid system, renders us all capable of responding to these molecules.
When taken together with standard therapy, our proprietary formulation of CBD, bioRenovate, was found to have significant positive impact on patients. Clinical responses were assessed using RECIST (for solid tumors) and IMWG (for multiple myeloma) criteria. In all cases observed, patients had greater reductions in tumor burden, of both target and non-target lesions, than control patients, both historical and diagnosis matched at the same clinic.
In conclusion, we found that bioRenovate is a safe and effective adjunct to chemotherapy. Our findings indicate patients diagnosed with many different types of cancer can benefit from this treatment. Moreover, these results strongly suggest CBD can help potentiate the anti-tumor effects of chemotherapy itself, opening up new avenues of potential research.
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