New DCA Publication!

CASE REPORT

Metastatic melanoma long-term stabilization with sodium dichloroacetate

Akbar Khan, Doug Andrews, Jill Shainhouse, Anneke C Blackburn

Akbar Khan and Doug Andrews are with the Medicor Cancer Centers in Toronto, Ontario, Canada, M2N 6N4.

Insight Naturopathic Clinic, Toronto, Ontario, M4P 1N9, Canada, Jill Shainhouse

Australian National University’s John Curtin School of Medical Research, Canberra, ACT 2601, Anneke C. Blackburn

Khan A. treated the patient and penned the majority of the case report; Andrews D. contributed to the formulation of the natural pharmaceutical protocol for minimizing the side effects of DCA and penned a piece of the case report. Shainhouse J administered natural therapy to the patient; Blackburn AC wrote portions of the introduction and discussion, examined the whole article, and provided an interpretation of the case report within the context of the literature on in vitro and in vivo DCA research.

Contact information is as follows: Akbar Khan, MD, Medical Director, Medicor Cancer Centres Inc., 4576 Yonge St., Suite 301, Toronto, ON M2N 6N4, Canada.

Phone number: (416) 2270037 Fax number: (416) 2271915

30 January 2017 Date Received May 5, 2017 revision 30 May 2017 – Accepted

Online since: 10 August 2017.

Abstract

Based on a publication from Bonnet et al showing that DCA can cause apoptosis (programmed cell death) in human breast, lung, and brain cancer cells, DCA has being explored as a metabolic cancer therapy since 2007. The Response Evaluation Criteria for Solid Tumours definitions, which define “response” by the degree of tumor reduction or tumour disappearance on imaging, are traditionally used to measure the response of cancer to a medical therapy in human research. However, disease stabilization is also a beneficial clinical outcome. In vitro and in vivo studies have demonstrated that DCA can act as a cytostatic agent without inducing apoptosis. In a 32-year-old male patient, DCA therapy without concomitant conventional therapy led to the metastatic melanoma’s recurrence and stabilization for more than 4 years with just minor adverse effects. This instance highlights how DCA can be utilized to manage long-term stability and disease volume in patients with advanced melanoma.

Key words: BRAF, cancer, melanoma, dichloroacetate, and cytostatic

Blackburn AC, Shainhouse J, Khan A, Andrews D sodium dichloroacetate’s long-term stabilization of metastatic melanoma. 2017; 8(4): 371-377. World J Clin Oncol. Accessible at: URL: https://www.wjgnet.com/2218-4333/full/v8/i4/371.html The following DOI is available: 10.5306/wjco.v8.i4.371

Core advice: Since 2007, sodium dichloroacetate (DCA) has been investigated as a treatment for metabolic cancer. It has been demonstrated that DCA therapy can provide a typical response, as indicated by a decrease in tumor size or disappearance on imaging. However, DCA can also inhibit the development of cancer cells without inducing apoptosis (cytostatic effect). Metastatic cancer may eventually stabilize as a result of this. We provide a case of oral DCA therapy successfully treating a 32-year-old man’s metastatic melanoma for more than 4 years while only experiencing minor side effects.

INTRODUCTION

When Bonnet et al.[1] published the first in vitro and in vivo study demonstrating the efficacy of sodium dichloroacetate (DCA) as a metabolic cancer therapy, through its inhibitory impact on the mitochondrial enzyme pyruvate dehydrogenase kinase, DCA attracted the attention of the medical world. Earlier investigations on DCA for the treatment of congenital lactic acidosis in mitochondrial diseases[2-5] have been published by Stacpoole et al[2-4]. These investigations proved that DCA used orally is a safe medication for people. The absence of renal, pulmonary, bone marrow, and cardiac damage was seen with DCA[4]. The majority of DCA adverse effects were mild, with reversible peripheral neuropathy being the most severe one[6]. There have also been reports of reversible delirium[7]. A small number of patients have elevated liver enzymes that are reversible and asymptomatic[3]. Prior human studies on mitochondrial diseases have sped up the adoption of DCA as an off-label cancer treatment in humans. Now that several reports of clinical trials with DCA as a cancer therapy have been published, confirming its safety profile, it is clear that DCA’s potential use in the treatment of cancer is becoming more widely acknowledged[8–11]. The fact that these studies only covered a portion of the course of treatment for late stage patients is one of their limitations.

DCA treatment was demonstrated to decrease mitochondrial membrane potential, which increased apoptosis specifically in human cancer cells, in Bonnet’s 2007 publication[1]. The Warburg effect and stimulation of mitochondrial potassium ion channels were found to be the mechanisms by which DCA works. Additional in vitro studies of DCA have demonstrated its anti-cancer effectiveness against a variety of cancer types, which have recently been reviewed by Kankotia and Stacpoole[12]. When used in conjunction with other treatments, DCA can potentially increase apoptosis[13–15]. Inhibition of angiogenesis[16], altered HIF1-a expression[17], altered V-ATPase and MCT1 cell pH regulators, and other cell survival regulators including p53 and PUMA[18] have all been proposed as additional anticancer effects of DCA. However, in order to demonstrate cytotoxic effect, many in vitro experiments employ too high doses of DCA that are not practicable[12]. Other investigations showed that DCA could be cytostatic when taken at lower DCA doses. In a metastatic model of breast cancer, DCA alone was found to be cytostatic in the second report on its in vivo anti-cancer efficacy published in 2010[19], reducing proliferation without inducing apoptosis. This shows that DCA may have a similar function to angiogenesis inhibitors in stabilizing cancer.

Khan started utilizing DCA for the treatment of cancer patients with a poor prognosis or who had ceased responding to traditional cancer therapies in reaction to the 2007 publication on the anti-cancer effects of DCA. For the purpose of treating the dose-limiting neurologic toxicity of DCA, a natural treatment plan was created in partnership with a naturopathic doctor (Andrews). This included three medications for the prevention of encephalopathy and neuropathy: benfotiamine[26–28], R-alpha lipoic acid[23–25], and acetyl L-carnitine[20–22]. Observational data on more than 300 patients with advanced cancer showed that 60%–70% of cases benefited after DCA therapy. When natural neuroprotective drugs were coupled with DCA, the risk of neuropathy was about 20%, utilizing a 20–25 mg/kg per day dosage on a 2 wk on/1 wk off cycle (clinic observational data published online at www.medicorcancer.com). Here, a patient case report that shows how persistent DCA treatment for more than four years had both apoptotic and anti-proliferative effects is given.

TRIAL REPORT

A 32-year-old fair-skinned man who had previously been in good health noticed that a mole on his left calf started to change in 2006. After seeing a doctor, the mole was removed. Melanoma was identified on a pathological basis. An examination of the sentinel nodes revealed no evidence of metastatic illness. In addition to minor melanocytic lesions on his left leg’s skin, the patient noticed enlargement of his left inguinal lymph nodes in 2007. He received interferon alpha therapy as part of a clinical trial at a local cancer hospital, and the nodes and skin metastases were reduced. Due to negative effects, interferon was discontinued after 9 months.

Up until 2010, when a fresh left leg skin metastasis surfaced, the patient was in good health. This was removed surgically. In the area of the original melanoma surgery scar on the left leg, another new cutaneous meta­stasis was discovered in late 2011. After a biopsy, it was determined that this was recurrent melanoma. Then, a large resection and a skin transplant were used to treat him.

The patient was identified as having a recurrence within the left leg skin transplant in March 2012. This was removed, and fresh skin grafting was done. A second excision was conducted, and this time the margins of the removed metastasis were positive. The diagnosis of metastatic BRAF-positive melanoma was also verified by needle biopsy of a left inguinal lymph node. In March 2012, a CT scan was performed, but it found no signs of distant metastases. 8mm in diameter was the largest left inguinal node, which was described as “insignificant by size criterion” (Figure 1).

The patient sought the advice of a naturopathic physician (Shainhouse) in April 2012 and started treatment with the oral natural anti-cancer medications Active hexose correlated compound, also known as AHCC (mushroom extract), dandelion root, curcumin, and astragalus root. Additionally, parenteral therapy was commenced, which included subcutaneous European mistletoe extract[34] and twice-weekly intravenous vitamin C injections[33]. Additionally, the patient adopted a vegan diet.

The patient visited the author’s (Khan) clinic in May 2012 with the intention of pursuing additional alternative treatments. Although DCA therapy was discussed, the patient chose to first give the natural anti-cancer treatments (recommended by Shainhouse) a thorough trial. After only one month of natural therapy, a second CT scan was done in May 2012, and the results showed modest increase in a number of inguinal and external iliac nodes with sizes ranging from 10 mm to 14 mm to 15 mm.

A second CT scan was performed in July 2012 to evaluate the patient’s use of natural anti-cancer treatments. The left inguinal and external iliac nodes had grown once again at that point, and their sizes ranged from 13 mm to 16 mm to 22 mm to 20 mm (Figure 2). In Boston, Massachusetts (United States), a PET scan was also carried out in order to prepare for enrollment in a clinical trial. This scan indicated enhanced glucose uptake in the left inguinal nodes. A new, dull (2/10) painful ache appeared in the left inguinal area. Upon examination, it was discovered that the left calf skin transplant included two minor skin metastases as well as a 20 mm non-tender left inguinal lymph node.

This led to the diagnosis of illness progression in the patient. He made the decision to start DCA therapy at that point. In addition to continuing the other natural treatments, he started taking oral DCA 500 mg three times each day, which was the equivalent of 17 mg/kg per day (manufacturer: Tokyo Chemical Industry, United States). A two-week on and one-week off DCA treatment cycle was used. Benfotiamine 80 mg twice daily, R-alpha lipoic acid 150 mg three times daily, and oral acetyl L-carnitine 500 mg three times daily were recommended as additional natural remedies to reduce the likelihood of DCA side effects. These vitamins were consumed every day (no cycle). Standard baseline blood tests were conducted (Table 1). With the exception of a low creatinine, which was thought to be unimportant, these were all normal.

The patient was reevaluated in November 2012, 4 months after adding DCA to his initial natural anti-cancer therapy. He was feeling good overall. Two new symptoms were noted to have appeared only after starting DCA therapy: a minor decrease in the sensation in his fingers and toes, as well as a slight decline in his ability to focus for the two weeks that he was taking DCA. The moderate sensory loss was thought to be mild DCA-related neuropathy because it wasn’t getting worse. During the weeks that the patient was off DCA, it was reported that both the numbness and the difficulty concentrating disappeared. A blood test from October 2012 revealed no appreciable alterations (Table 1). CT scans performed in August 2012 and November 2012 showed that all previously swollen lymph nodes had significantly shrunk. There were no signs of intra-thoracic or intra-abdominal illness or bone metastases, and the biggest node measured 10 mm (Figure 3).

On DCA medication, the patient felt healthy and did not develop any new skin metastases or inguinal node enlargements. He continued to get yearly follow-up care from his primary care physician and routine clinical monitoring from his naturopathic physician (Shainhouse) (Khan). Shainhouse’s recommended natural anti-cancer treatments and DCA therapy were kept in place through 2016. In June 2016, blood panel findings remained consistent with normal (Table 1). After a full 4 years of continued DCA medication together with natural anti-cancer therapy, the CT scan was redone in August 2016 and revealed no evidence of metastatic melanoma (Figure 4). The patient reported a decline in medication compliance by December 2016 and an increase in work-related stress. He saw a fresh left inguinal mass at the time. A new aggregation of swollen lymph nodes measuring 40 mm by 25 mm by 23 mm was discovered by ultrasound imaging, which also indicated blood flow within the mass using color Doppler. This was diagnosed as melanoma regrowth after receiving ongoing DCA therapy for around four and a half years. A PET/CT scan was part of the further workup, and it revealed disease recurrence in 3 of the left inguinal nodes (SUVmax ranging from 13 to 17.8).

In conclusion, during the course of six years, the patient underwent standard treatment for recurrent stage 3 melanoma, which included primary surgical excision with lymph node dissection, interferon alpha, and five surgical excisions for recurrent cutaneous metastases. After three months of natural anti-cancer therapy (as suggested by Shainhouse), the patient showed no improvement, as seen by the constant advancement of the disease on subsequent CT scans. Finally, the patient combined oral DCA medication with the natural anti-cancer therapy, while also taking three neuroprotective drugs at the same time (lipoic acid, acetyl L-carnitine, and benfotiamine), but no concurrent conventional cancer treatments. A complete radiological remission that lasted for more than 4 years was the end result, followed by recurrence. The patient encountered insignificant adverse effects including mild neuropathy and a little decrease in concentration during the course of DCA medication. The patient was still functioning at ECOG level 0 and was able to hold down a full-time job.

DISCUSSION

According to clinical status and CT imaging, the oral DCA treatment in the metastatic melanoma patient presented here shows tumor shrinkage and long-term disease stability. In the absence of any concomitant conventional therapy, disease stability was maintained while using DCA for more than 4 years, with a 10-year survival period since the first diagnosis. The survival of this patient, who had no sign of distant metastases, is not exceptional, according to SEER cancer statistics from the National Cancer Institute (62.9% 5-year survival rate for melanoma with dissemination to regional lymph nodes, https://seer.cancer.gov/statfacts/html/melan.html). What is surprising is that oral DCA medication was effective in decreasing the growing nodes in a case where implicated lymph nodes were plainly enlarging (Figures 2 and 3), and in obtaining a remission lasting more than 4 years. It’s possible that the patient’s natural anti-cancer treatments worked in concert with DCA, but it’s also obvious that they couldn’t have prevented the disease from regressing on their own. This patient’s clinical course of regression (apoptotic) and extended remission is consistent with DCA’s known apoptotic and cytostatic effects[14,17,19,35,36] (cytostatic). The 4 year recurrence was accompanied by decreased compliance, indicating that this form of cancer care with DCA necessitates ongoing maintenance of the metabolic pressure. Despite the recurrence, the patient was clinically stable and had plans to begin using fresh immunotherapy drugs. If a change in therapy results in disease regression or stability once more, it remains to be seen.

This example demonstrates that DCA can be well-tolerated in a cancer patient for an extended time period, as compared to all published DCA cancer clinical trials, in addition to the maintenance of remission for more than 4 years. It is noteworthy that this patient tolerated 17 mg/kg per day in a schedule of 2 weeks on and 1 week off for 4 years with few adverse effects. This contrasts with the clinical trial recommendations for DCA, which call for a lower dose of 10-12.5 mg/kg per day given continuously[9,11], which are similar to our earlier case report of chronic DCA usage in colon cancer[37], where the patient was able to tolerate 16 mg/kg per day (but not 25 mg/kg per day) in the same regime. The patients in the case reports may have been able to handle the increased dose thanks to the 1-week respite or the neuroprotective supplements. The amount of DCA that can be tolerated may also depend on genetic variations in GSTZ1, the liver enzyme that metabolizes DCA[9,38]. The trials have reported varying drug levels, but not all of them have taken into account this pharmacogenetic element of DCA therapy[9,11], and more research is required to determine whether this is a significant factor in DCA tolerance. As of the time of writing, a DCA multiple myeloma human trial (Australia New Zealand Clinical Trials Register #ACTRN12615000226505, https://www.anzctr.org.au) is investigating GSTZ1 genotypes and drug levels to advance our understanding of these problems.

Comparing this case report to more traditional melanoma treatments like interferon, it is clear that persistent DCA therapy can be utilized without degrading quality of life. Human trials are required to establish the best regimen for the most acceptable acute or chronic DCA treatment. But more significantly, it is still unclear what dose is necessary to provide on-target effects that are effective against cancer. Before funding more extensive, long-term investigations on patient outcomes, this information is required. Due to its affordable price and low toxicity, DCA merits additional study in clinical trials as a non-toxic cancer therapy and deserves consideration as an off-label cancer treatment.

ACKNOWLEDGMENTS

The patient’s support and permission to publish his case are also appreciated by the authors, who also thank Dr. Humaira Khan for her assistance.

COMMENTS

Case characteristics

The 32-year-old male patient presented with a pigmented lesion on his leg.

Clinical diagnosis

The patient was diagnosed with a melanoma.

Laboratory diagnosis

Melanoma confirmed by excisional biopsy.

Imaging diagnosis

Enlarged inguinal node confirmed to be involved with melanoma (needle biopsy).

Pathological diagnosis

Melanoma, BRAF positive.

Treatment

Multiple excisions of recurrent cutaneous metastases, sentinel node dissection, and excision of the primary lesion with a skin graft. Natural anti-cancer medicines began when traditional treatment was discontinued (AHCC, dandelion root, curcumin, astragalus root, i.v. vitamin C, s.c. European mistletoe). progression with dichloroacetate (DCA) added after three months. Following the use of DCA, there was a long-lasting regression and remission.

Related reports

Reports from computed tomography scans show how the disease has progressed and how treatments have worked..

Term explanation

ECOG is for Eastern Cooperative Oncology Group. DCA stands for Dichloroacetate Sodium. RECIST stands for Response Evaluation Criteria for Solid Tumors.

Experiences and lessons

As demonstrated by this melanoma example, DCA can serve as a pro-apoptotic and cytostatic medication, resulting in regression as well as long-term stabilization of metastatic cancer without major side effects.

Peer-review

According to Dr. Khan, a 32-year-old man with metastatic melanoma was treated with DCA therapy for over 4 years while also receiving other medications from natural healers. It is a case worth exploring.

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FIGURE LEGENDS

Figure 1: CT scan taken in March 2012, before natural treatments and before dichloroacetate therapy. The largest node had a diameter of 8 mm.

Figure 2 CT scan taken in July 2012, three months after starting only natural treatment, just before beginning dichloroacetate treatment. The largest node was 22 mm by 20 mm in size.

Figure 3: CT scan taken in November 2012, 4 months after dichloroacetate treatment. The biggest node was 10 mm large.

Figure 4 shows a CT scan that was performed four years after starting dichloroacetate therapy in the absence of any additional conventional cancer treatments. The scan shows no evidence of cancer regrowth. Each node is smaller than 10 mm in length.

FOOTNOTES

Patient’s informed consent to publication of his case anonymously was obtained before publication of the manuscript.

Conflict of interest disclosure: Khan, one of the authors, provides cancer patients with dichloroacetate therapy through Medicor Cancer Centres at a cost and without profit. A member of this author’s family owns the clinic. There is nothing to disclose from the other authors.

Open-Access: This paper is open-access and was completely peer-reviewed by outside reviewers before being chosen by an internal editor. It is distributed under the terms of the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which enables others to distribute, remix, adapt, and build upon this work without incurring any financial gain, as long as proper attribution is made to the original author and the use is for noncommercial purposes. View this license: https://creativecommons.org/licenses/by-nc/4.0

Source of manuscript: Invited manuscript

Beginning of peer review: February 12, 2017

Initial ruling: March 28, 2017

Press release date: May 31, 2017

Su CC served as the P- reviewer, Ji FF as the S- editor, and Lu YJ as the E- editor.

TRIAL REPORT

Metastatic melanoma long-term stabilization with sodium dichloroacetate

Doug Andrews, Jill Shainhouse, Anneke C. Blackburn, Akbar Khan

Akbar Khan and Doug Andrews are with the Medicor Cancer Centers in Toronto, Ontario, Canada, M2N 6N4.

Insight Naturopathic Clinic, Toronto, Ontario, M4P 1N9, Canada, Jill Shainhouse

Australian National University’s John Curtin School of Medical Research, Canberra, ACT 2601, Anneke C. Blackburn

Khan A. treated the patient and penned the majority of the case report; Andrews D. contributed to the formulation of the natural pharmaceutical protocol for minimizing the side effects of DCA and penned a piece of the case report. Shainhouse J administered natural therapy to the patient; Blackburn AC wrote portions of the introduction and discussion, examined the whole article, and provided an interpretation of the case report within the context of the literature on in vitro and in vivo DCA research.

Contact information is as follows: Akbar Khan, MD, Medical Director, Medicor Cancer Centres Inc., 4576 Yonge St., Suite 301, Toronto, ON M2N 6N4, Canada.

Phone number: (416) 2270037 Fax number: (416) 2271915

30 January 2017 Date Received May 5, 2017 revision 30 May 2017 – Accepted

Online since: 10 August 2017.

Abstract

Based on a publication from Bonnet et al showing that DCA can cause apoptosis (programmed cell death) in human breast, lung, and brain cancer cells, DCA has being explored as a metabolic cancer therapy since 2007. The Response Evaluation Criteria for Solid Tumours definitions, which define “response” by the degree of tumor reduction or tumour disappearance on imaging, are traditionally used to measure the response of cancer to a medical therapy in human research. However, disease stabilization is also a beneficial clinical outcome. In vitro and in vivo studies have demonstrated that DCA can act as a cytostatic agent without inducing apoptosis. In a 32-year-old male patient, DCA therapy without concurrent conventional therapy led to the metastatic melanoma’s recurrence and stabilization for more than 4 years with only minor side effects. This instance demonstrates how DCA can be used to manage long-term stability and disease volume in patients with advanced melanoma.

Key words: BRAF, cancer, melanoma, dichloroacetate, and cytostatic

Blackburn AC, Shainhouse J, Khan A, Andrews D sodium dichloroacetate’s long-term stabilization of metastatic melanoma. 2017; 8(4): 371-377. World J Clin Oncol. Accessible at: URL: https://www.wjgnet.com/2218-4333/full/v8/i4/371.html The following DOI is available: 10.5306/wjco.v8.i4.371

Core advice: Since 2007, sodium dichloroacetate (DCA) has been investigated as a treatment for metabolic cancer. It has been demonstrated that DCA therapy can produce a typical response, as indicated by a decrease in tumor size or disappearance on imaging. However, DCA can also inhibit the growth of cancer cells without inducing apoptosis. Metastatic cancer may eventually stabilize as a result of this. We present a case of oral DCA therapy successfully treating a 32-year-old man’s metastatic melanoma for more than 4 years while only experiencing minor side effects.

INTRODUCTION

When Bonnet et al.[1] published the first in vitro and in vivo study demonstrating the efficacy of sodium dichloroacetate (DCA) as a metabolic cancer therapy, through its inhibitory impact on the mitochondrial enzyme pyruvate dehydrogenase kinase, DCA attracted the attention of the medical world. Earlier investigations on DCA for the treatment of congenital lactic acidosis in mitochondrial diseases[2-5] have been published by Stacpoole et al[2-4]. These investigations proved that DCA used orally is a safe medication for people. The absence of renal, pulmonary, bone marrow, and cardiac damage was seen with DCA[4]. The majority of DCA adverse effects were mild, with reversible peripheral neuropathy being the most severe one[6]. There have also been reports of reversible delirium[7]. A small number of patients have elevated liver enzymes that are reversible and asymptomatic[3]. Prior human studies on mitochondrial diseases have sped up the adoption of DCA as an off-label cancer treatment in humans. Now that several reports of clinical trials with DCA as a cancer therapy have been published, confirming its safety profile, it is clear that DCA’s potential use in the treatment of cancer is becoming more widely acknowledged[8–11]. The fact that these studies only covered a portion of the course of treatment for late stage patients is one of their limitations.

DCA treatment was demonstrated to decrease mitochondrial membrane potential, which increased apoptosis specifically in human cancer cells, in Bonnet’s 2007 publication[1]. The Warburg effect and stimulation of mitochondrial potassium ion channels were found to be the mechanisms by which DCA works. Additional in vitro studies of DCA have demonstrated its anti-cancer effectiveness against a variety of cancer types, which have recently been reviewed by Kankotia and Stacpoole[12]. When used in conjunction with other treatments, DCA can potentially increase apoptosis[13–15]. Inhibition of angiogenesis[16], altered HIF1-a expression[17], altered V-ATPase and MCT1 cell pH regulators, and other cell survival regulators including p53 and PUMA[18] have all been proposed as additional anticancer effects of DCA. However, in order to demonstrate cytotoxic effect, many in vitro experiments employ too high doses of DCA that are not practicable[12]. Other investigations showed that DCA could be cytostatic when taken at lower DCA doses. In a metastatic model of breast cancer, DCA alone was found to be cytostatic in the second report on its in vivo anti-cancer efficacy published in 2010[19], reducing proliferation without inducing apoptosis. This shows that DCA may have a similar function to angiogenesis inhibitors in stabilizing cancer.

Khan started utilizing DCA for the treatment of cancer patients with a poor prognosis or who had ceased responding to traditional cancer therapies in reaction to the 2007 publication on the anti-cancer effects of DCA. For the purpose of treating the dose-limiting neurologic toxicity of DCA, a natural treatment plan was created in partnership with a naturopathic doctor (Andrews). This included three medications for the prevention of encephalopathy and neuropathy: benfotiamine[26–28], R-alpha lipoic acid[23–25], and acetyl L-carnitine[20–22]. Observational data on more than 300 patients with advanced cancer showed that 60%–70% of cases benefited after DCA therapy. When natural neuroprotective drugs were coupled with DCA, the risk of neuropathy was about 20%, utilizing a 20–25 mg/kg per day dosage on a 2 wk on/1 wk off cycle (clinic observational data published online at www.medicorcancer.com). Here, a patient case report that shows how persistent DCA treatment for more than four years had both apoptotic and anti-proliferative effects is given.

CASE REPORT

A 32-year-old fair-skinned man who had previously been in good health noticed that a mole on his left calf started to change in 2006. After seeing a doctor, the mole was removed. Melanoma was identified on a pathological basis. An examination of the sentinel nodes revealed no evidence of metastatic illness. In addition to minor melanocytic lesions on his left leg’s skin, the patient noticed enlargement of his left inguinal lymph nodes in 2007. He received interferon alpha therapy as part of a clinical trial at a local cancer hospital, and the nodes and skin metastases were reduced. Due to negative effects, interferon was discontinued after 9 months.

Up until 2010, when a fresh left leg skin metastasis surfaced, the patient was in good health. This was removed surgically. In the area of the original melanoma surgery scar on the left leg, another new cutaneous meta­stasis was discovered in late 2011. After a biopsy, it was determined that this was recurrent melanoma. Then, a large resection and a skin transplant were used to treat him.

The patient was identified as having a recurrence within the left leg skin transplant in March 2012. This was removed, and fresh skin grafting was done. A second excision was conducted, and this time the margins of the removed metastasis were positive. The diagnosis of metastatic BRAF-positive melanoma was also verified by needle biopsy of a left inguinal lymph node. In March 2012, a CT scan was performed, but it found no signs of distant metastases. 8mm in diameter was the largest left inguinal node, which was described as “insignificant by size criterion” (Figure 1).

The patient sought the advice of a naturopathic physician (Shainhouse) in April 2012 and started treatment with the oral natural anti-cancer medications Active hexose correlated compound, also known as AHCC (mushroom extract), dandelion root, curcumin, and astragalus root. Additionally, parenteral therapy was commenced, which included subcutaneous European mistletoe extract[34] and twice-weekly intravenous vitamin C injections[33]. Additionally, the patient adopted a vegan diet.

The patient visited the author’s (Khan) clinic in May 2012 with the intention of pursuing additional alternative treatments. Although DCA therapy was discussed, the patient chose to first give the natural anti-cancer treatments (recommended by Shainhouse) a thorough trial. After only one month of natural therapy, a second CT scan was done in May 2012, and the results showed modest increase in a number of inguinal and external iliac nodes with sizes ranging from 10 mm to 14 mm to 15 mm.

A second CT scan was performed in July 2012 to evaluate the patient’s use of natural anti-cancer treatments. The left inguinal and external iliac nodes had grown once again at that point, and their sizes ranged from 13 mm to 16 mm to 22 mm to 20 mm (Figure 2). In Boston, Massachusetts (United States), a PET scan was also carried out in order to prepare for enrollment in a clinical trial. This scan indicated enhanced glucose uptake in the left inguinal nodes. A new, dull (2/10) painful ache appeared in the left inguinal area. Upon examination, it was discovered that the left calf skin transplant included two minor skin metastases as well as a 20 mm non-tender left inguinal lymph node.

This led to the diagnosis of illness progression in the patient. He made the decision to start DCA therapy at that point. In addition to continuing the other natural treatments, he started taking oral DCA 500 mg three times each day, which was the equivalent of 17 mg/kg per day (manufacturer: Tokyo Chemical Industry, United States). A two-week on and one-week off DCA treatment cycle was used. Benfotiamine 80 mg twice daily, R-alpha lipoic acid 150 mg three times daily, and oral acetyl L-carnitine 500 mg three times daily were recommended as additional natural remedies to reduce the likelihood of DCA side effects. These vitamins were consumed every day (no cycle). Standard baseline blood tests were conducted (Table 1). With the exception of a low creatinine, which was thought to be unimportant, these were all normal.

The patient was reevaluated in November 2012, 4 months after adding DCA to his initial natural anti-cancer therapy. He was feeling good overall. Two new symptoms were noted to have appeared only after starting DCA therapy: a minor decrease in the sensation in his fingers and toes, as well as a slight decline in his ability to focus for the two weeks that he was taking DCA. The moderate sensory loss was thought to be mild DCA-related neuropathy because it wasn’t getting worse. During the weeks that the patient was off DCA, it was reported that both the numbness and the difficulty concentrating disappeared. A blood test from October 2012 revealed no appreciable alterations (Table 1). CT scans performed in August 2012 and November 2012 showed that all previously swollen lymph nodes had significantly shrunk. There were no signs of intra-thoracic or intra-abdominal illness or bone metastases, and the biggest node measured 10 mm (Figure 3).

On DCA medication, the patient felt healthy and did not develop any new skin metastases or inguinal node enlargements. He continued to get yearly follow-up care from his primary care physician and routine clinical monitoring from his naturopathic physician (Shainhouse) (Khan). Shainhouse’s recommended natural anti-cancer treatments and DCA therapy were kept in place through 2016. In June 2016, blood panel findings remained consistent with normal (Table 1). After a full 4 years of continued DCA medication together with natural anti-cancer therapy, the CT scan was redone in August 2016 and revealed no evidence of metastatic melanoma (Figure 4). The patient reported a decline in medication compliance by December 2016 and an increase in work-related stress. He saw a fresh left inguinal mass at the time. A new aggregation of swollen lymph nodes measuring 40 mm by 25 mm by 23 mm was discovered by ultrasound imaging, which also indicated blood flow within the mass using color Doppler. This was diagnosed as melanoma regrowth after receiving ongoing DCA therapy for around four and a half years. A PET/CT scan was part of the further workup, and it revealed disease recurrence in 3 of the left inguinal nodes (SUVmax ranging from 13 to 17.8).

In conclusion, during the course of six years, the patient underwent standard treatment for recurrent stage 3 melanoma, which included primary surgical excision with lymph node dissection, interferon alpha, and five surgical excisions for recurrent cutaneous metastases. After three months of natural anti-cancer therapy (as suggested by Shainhouse), the patient showed no improvement, as seen by the constant advancement of the disease on subsequent CT scans. Finally, the patient combined oral DCA medication with the natural anti-cancer therapy, while also taking three neuroprotective drugs at the same time (lipoic acid, acetyl L-carnitine, and benfotiamine), but no concurrent conventional cancer treatments. A complete radiological remission that lasted for more than 4 years was the end result, followed by recurrence. The patient encountered insignificant adverse effects including mild neuropathy and a little decrease in concentration during the course of DCA medication. The patient was still functioning at ECOG level 0 and was able to hold down a full-time job.

DISCUSSION

According to clinical status and CT imaging, the oral DCA treatment in the metastatic melanoma patient presented here shows tumor shrinkage and long-term disease stability. In the absence of any concomitant conventional therapy, disease stability was maintained while using DCA for more than 4 years, with a 10-year survival period since the first diagnosis. The survival of this patient, who had no sign of distant metastases, is not exceptional, according to SEER cancer statistics from the National Cancer Institute (62.9% 5-year survival rate for melanoma with dissemination to regional lymph nodes, https://seer.cancer.gov/statfacts/html/melan.html). What is surprising is that oral DCA medication was effective in decreasing the growing nodes in a case where implicated lymph nodes were plainly enlarging (Figures 2 and 3), and in obtaining a remission lasting more than 4 years. It’s possible that the patient’s natural anti-cancer treatments worked in concert with DCA, but it’s also obvious that they couldn’t have prevented the disease from regressing on their own. This patient’s clinical course of regression (apoptotic) and extended remission is consistent with DCA’s known apoptotic and cytostatic effects[14,17,19,35,36] (cytostatic). The 4 year recurrence was accompanied by decreased compliance, indicating that this form of cancer care with DCA necessitates ongoing maintenance of the metabolic pressure. Despite the recurrence, the patient was clinically stable and had plans to begin using fresh immunotherapy drugs. If a change in therapy results in disease regression or stability once more, it remains to be seen.

This example demonstrates that DCA can be well-tolerated in a cancer patient for an extended time period, as compared to all published DCA cancer clinical trials, in addition to the maintenance of remission for more than 4 years. It is noteworthy that this patient tolerated 17 mg/kg per day in a schedule of 2 weeks on and 1 week off for 4 years with few adverse effects. This contrasts with the clinical trial recommendations for DCA, which call for a lower dose of 10-12.5 mg/kg per day given continuously[9,11], which are similar to our earlier case report of chronic DCA usage in colon cancer[37], where the patient was able to tolerate 16 mg/kg per day (but not 25 mg/kg per day) in the same regime. The patients in the case reports may have been able to handle the increased dose thanks to the 1-week respite or the neuroprotective supplements. The amount of DCA that can be tolerated may also depend on genetic variations in GSTZ1, the liver enzyme that metabolizes DCA[9,38]. The trials have reported varying drug levels, but not all of them have taken into account this pharmacogenetic element of DCA therapy[9,11], and more research is required to determine whether this is a significant factor in DCA tolerance. As of the time of writing, a DCA multiple myeloma human trial (Australia New Zealand Clinical Trials Register #ACTRN12615000226505, https://www.anzctr.org.au) is investigating GSTZ1 genotypes and drug levels to advance our understanding of these problems.

Comparing this case report to more traditional melanoma treatments like interferon, it is clear that persistent DCA therapy can be utilized without degrading quality of life. Human trials are required to establish the best regimen for the most acceptable acute or chronic DCA treatment. But more significantly, it is still unclear what dose is necessary to provide on-target effects that are effective against cancer. Before funding more extensive, long-term investigations on patient outcomes, this information is required. Due to its affordable price and low toxicity, DCA merits additional study in clinical trials as a non-toxic cancer therapy and deserves consideration as an off-label cancer treatment.

ACKNOWLEDGMENTS

The patient’s support and permission to publish his case are also appreciated by the authors, who also thank Dr. Humaira Khan for her assistance.

COMMENTS

Case-specific features

The 32-year-old patient was a male who had a pigmented lesion on his leg when he was seen.

Clinical evaluation

Melanoma was identified as the patient’s condition.

experimental diagnosis

Excisional biopsy results showed melanoma.

diagnostic imaging

Melanoma involvement of the enlarged inguinal node has been verified (needle biopsy).

pathological determination

Melanoma, positive for BRAF.

Treatment

Multiple excisions of recurring cutaneous metastases, sentinel node dissection, and excision of the initial lesion with a skin transplant. Natural anti-cancer medicines began when traditional treatment was discontinued (AHCC, dandelion root, curcumin, astragalus root, i.v. vitamin C, s.c. European mistletoe). progression with dichloroacetate (DCA) added after three months. Following the use of DCA, there was a long-lasting regression and remission.

comparable reports

Reports from computed tomography scans show how the disease develops and how treatments work.

Term definition

ECOG is for Eastern Cooperative Oncology Group. DCA stands for Dichloroacetate Sodium. RECIST stands for Response Evaluation Criteria for Solid Tumors.

Lessons and experiences

As demonstrated by this melanoma example, DCA can serve as a pro-apoptotic and cytostatic medication, resulting in regression as well as long-term stabilization of metastatic cancer without major side effects.

Peer-review

According to Dr. Khan, a 32-year-old man with metastatic melanoma was treated with DCA therapy for almost 4 years while also receiving additional medications from natural healers. It is a case worth exploring.

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FIGURE LEGENDS

Figure 1: CT scan taken in March 2012, before natural treatments and before dichloroacetate therapy. The largest node had a diameter of 8 mm.

Figure 2 CT scan taken in July 2012, three months after starting only natural treatment, right before beginning dichloroacetate treatment. The largest node was 22 mm by 20 mm in size.

Figure 3: CT scan taken in November 2012, 4 months following dichloroacetate treatment. The biggest node was 10 mm large.

Figure 4 shows a CT scan that was performed four years after starting dichloroacetate therapy in the absence of any additional conventional cancer treatments. The scan shows no evidence of cancer regrowth. Each node is smaller than 10 mm in length.

FOOTNOTES

Patient’s informed consent to publication of his case anonymously was obtained before publication of the manuscript.

Conflict of interest disclosure: Khan, one of the authors, provides cancer patients with dichloroacetate therapy through Medicor Cancer Centres at a cost and without profit. A member of this author’s family owns the clinic. There is nothing to disclose from the other authors.

Open-Access: This paper is open-access and was completely peer-reviewed by outside reviewers before being chosen by an internal editor. It is distributed under the terms of the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which enables others to distribute, remix, adapt, and build upon this work without incurring any financial gain, as long as proper attribution is made to the original author and the use is for noncommercial purposes. View this license: https://creativecommons.org/licenses/by-nc/4.0F

Manuscript source: Invited manuscript

Peer-review started: February 12, 2017

First decision: March 28, 2017

Article in press: May 31, 2017

P- Reviewer: Su CC    S- Editor: Ji FF    L- Editor: A    E- Editor: Lu YJ