 May 31, 2010 MEDICOR's Comments - Latest DCA Research Shows Favourable Results in GlioblastomaSince the first paper on DCA as a potential cancer treatment was published in Cancer Cell in January 2007, there has been a great interest in further DCA research in humans. However, because DCA cannot be patented, there were no financial incentives for pharmaceutical companies to fund the research. It was left up to academic institutions to raise money to conduct trials. Due to generous donations from the public, the first human trial of DCA in 50 brain cancer patients was funded and approved in October 2007. The results of this eagerly awaited trial were published on May 12, 2010 in the journal Science Translational Medicine titled “Metabolic Modulation of Glioblastoma with Dicholoacetate”. Medicor has been using DCA in a clinical setting from early 2007, giving us first hand experience with DCA in over 560 patients. However, since we have not conducted a clinical trial, this paper is a very exciting and encouraging step towards more widespread application of DCA in cancer treatment. Based on the large number to enquiries we have received, we are providing our detailed comments on the study below. Since our focus is clinical application, most of the comments deal with the clinical aspects of the study. Summary of Study Methodology According to the paper, 49 patients with the aggressive brain cancer glioblastoma multiforme (GBM) were enrolled in the study over a 2 year period. These patients had surgery and the freshly excised tumors were tested in the lab with DCA to determine its effectiveness. Based on the favorable results, it was felt that DCA could subsequently be given to patients with GBM. According to the paper, DCA was then administered to five consecutive patients with GBM. Tumour samples from these patients were available because they all had prior neurosurgery. All five patients were given oral DCA 25mg/kg/day (divided into 2 doses) for one month. This was followed by 50mg/kg/day (divided into 2 doses) for an unspecified period after which the dose was reduced if side effects developed. Details of the dose reduction protocol are not clear, however the paper states that the dose was reduced by 50% after toxicity developed. The lowest dose used was 12.5mg/kg/day. The patients were followed clinically for up to 15 months. Summary of Clinical Findings The pertinent clinical history and progression of the five patients given oral DCA as published in this paper is summarized in Table 1. Table 1. Summary of patients’ history and progress during DCA treatment*
* Dose of DCA was 25 mg/kg/day for first month followed by 50mg/kg/day for unspecified period. A dose reduction protocol was then used where the dose was reduced by 50% when dose limiting toxicity developed. Minimum dose was 12.5mg/kg/day ** Temozolomide Discussion/ Comments: This paper confirms the in vitro mitochondrial and metabolic effects of DCA on the glioblastoma samples isolated from 49 patients. This is very exciting and promising news and confirms the hypothesis of the researchers that DCA can reverse cancer-specific metabolic and mitochondrial remodeling. Looking at the description of the original study protocol, this was one of the secondary objectives of the trial. An additional goal of this trial was also to correlate these in vitro effects of DCA with clinical data. Oddly, no clinical data on the 49 patients was provided to support this correlation (because it appears that none of the 49 patients received DCA treatment). Looking at the clinical data provided for the other five patients, it is unclear whether this correlation was proven. The only post-treatment DCA samples available for analysis from patients 2, 3 and 4 were obtained after disease deterioration requiring de-bulking surgery in patients 2 and 4, and after the death of patient 3. While all these samples show a positive response to DCA in vitro, no information about correlation with their clinical progress was provided. In fact, since the tissues samples were obtained due to (and at the time of) clinical deterioration, the positive in vitro effects of DCA does not seem to correlate with clinical response. There were three primary objectives of the study (ClinicalTrials.gov Identifier: NCT00540176 - click to view PDF)
It is disappointing that the research paper did not shed light on any of these objectives, and no explanation is given for this. The therapeutic response to oral DCA was only evaluated in five patients. Only 2 of the five patients showed a favourable response that was clearly attributable to DCA (see Table 1). Concurrent treatment with surgery, radiation or chemotherapy confounded the results for 2 patients making it difficult to assess how much of their response was actually due to DCA itself. In spite of this confounding, our experience with over 500 patients leads us to believe that the researchers were correct in their conclusion that DCA is more effective in combination therapy than by itself. The published study did not objectively shed light on the safety and tolerability to oral DCA in glioma patients. The experience with the 5 patients led the researchers to conclude that peripheral neuropathy was the only apparent side effect. This conclusion is seriously limited by the small number of patients, confounding with other treatments as well as symptoms of the disease itself making it hard to concur with this assessment. From our experience, we can also state with confidence that DCA does in fact have other side effects such as sedation, fatigue, confusion, stomach upset, and a rise in liver enzymes. Fortunately, not every patient gets side effects, and they are generally easily managed by the treating physician. Given the very small number of patients treated, perhaps a more complete picture would be obtained if all possible side effects were listed and compared to a control group. The study also does not shed light on the dose of this “dose dependent” toxicity or the time it took to reverse it in these patients. Based on our experience, we believe the dose of 50mg/kg/day would be high enough to produce toxicity in a majority of adult patients leading to discontinuation or interruption of DCA treatment. Further, without the addition of neuro-protective supplements like alpha lipoic acid, benfotaimine, acetyl L-carnitine etc. peripheral neuropathy is more likely to appear quickly, be more severe and take longer to resolve. The researchers did not comment on the overall progression-free survival and overall survival with oral DCA, likely due to the very small number of patients. It is however encouraging to note that 4 patients were clinically stable at month 15 and alive at month 18 of the study. This paper did not give many details about the dose of DCA used. According to the paper, 25mg/kg/day (12.5 mg/kg twice a day) was given for one month followed by 50mg/kg/day. It is not clear how long the higher dose was given, and when the dose de-escalation protocol was started. There are other aspects of the study which raise questions. One is the study timeline. According to the authors, tissue samples were obtained from the 49 patients over a period of two years (24 months) and DCA was “subsequently” administered to five patients. These patients (other than patient 3) were followed up over an 18 month period. This would require a total time of 24+18, or 42 months. Since the study was approved in October 2007 and concluded around November 2009 (a time span of about 24 months), the timelines do not correspond. Based on this, it would appear that in vitro study of DCA in human glioblastoma tumour samples had to start in 2005 or the 5 patients with clinical data must have been taken from the original 49 patients. The paper however, explicitly states that the 5 patients were enrolled subsequent to the in vitro part of the study. It is also confusing why only 5 instead of the original 50 patients approved for the study were given oral DCA. This maybe explained by either under-enrollment or a high patient drop-out/attrition. These questions cannot be adequately answered based on the published results. We acknowledge that in research, sometimes the questions we originally set out to answer may not get answered fully. Having said that, all answers - whether positive or negative - serve a very useful purpose. The positive answers give us hope and pave the way for clinical application and further research. The negative answers allow us to learn from our mistakes, change our hypotheses and protocols and improve upon our research for the future. We hope that the original research done here will lead to another paper where some of these unanswered questions may be elucidated. The second confusing issue is the dose of DCA in patient 4 and its correlation with the authors’ conclusions. According to the paper, patient 4 who required surgery after the first three months of DCA had not achieved therapeutic levels of DCA. This however does not correlate with the tissue analysis where response to DCA was observed. Further, it is not clear why this patient was not simply put on a higher dose of DCA after the surgery if the researchers felt that the disease progression was attributable to a sub-therapeutic dose of DCA. Instead this patient was put on a combination of DCA with chemo and radiation. The authors later state that DCA at 12.5 mg/kg/day has minimal side effects and that “this dose showed biologic and clinical efficacy and achieved plasma concentration of values required for PDK inhibition.” Looking at the DCA dose protocol (25 mg/kg/day for the first month, followed by 50mg/kg/day), it seems surprising that patient 4 did not achieve this level in the first three months. Overall we believe the doses being used in the study were high, and might have resulted in an unacceptable patient dropout rate due to drug side effects (such as neuropathy). However, researchers have gained valuable new insights into the biochemical mechanism of DCA’s action on cancer cells, and we believe this will assist in future in vitro and in vivo research and development of treatment strategies. The patient case reports are further evidence for DCA’s effectiveness in humans as a cancer treatment, in addition to our own case studies presented at http://www.medicorcancer.com/dca-reports.html. We conclude that this new research supports the relative safety of DCA as a cancer treatment. On the other hand, it also demonstrates that the rate of severe nerve side effects (“peripheral neuropathy”) can be very high if DCA is not given at the appropriate dose, and no nerve-protecting supplements are used. Our belief in Medicor’s unique DCA treatment regimen is strengthened, since the rate of severe neuropathy in our patients is very low. It is clear to us that treatment strategies such as
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