Long-term stabilization of metastatic melanoma with sodium dichloroacetate 用二氯乙酸鈉長期穩定轉移性黑色素瘤

World J Clin Oncol. 2017 Aug 10; 8(4): 371–377. Published online 2017 Aug 10. doi: 10.5306/wjco.v8.i4.371PMCID: PMC5554882PMID: 28848705

More reports on dichloroacetate treatment

Akbar Khan, Doug Andrews, Jill Shainhouse, and Anneke C BlackburnAuthor informationArticle notesCopyright and License informationDisclaimerThis article has been cited by other articles in PMC.Go to:

Abstract

Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007, based on a publication from Bonnet et al demonstrating that DCA can induce apoptosis (programmed cell death) in human breast, lung and brain cancer cells. Classically, the response of cancer to a medical therapy in human research is measured by Response Evaluation Criterial for Solid Tumours definitions, which define “response” by the degree of tumour reduction, or tumour disappearance on imaging, however disease stabilization is also a beneficial clinical outcome. It has been shown that DCA can function as a cytostatic agent in vitro and in vivo, without causing apoptosis. A case of a 32-year-old male is presented in which DCA therapy, with no concurrent conventional therapy, resulted in regression and stabilization of recurrent metastatic melanoma for over 4 years’ duration, with trivial side effects. This case demonstrates that DCA can be used to reduce disease volume and maintain long-term stability in patients with advanced melanoma.Keywords: Dichloroacetate, Cancer, BRAF, Melanoma, Cytostatic

Core tip: Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007. It has been shown that DCA therapy can result in a classic response which is measured by reduction or disappearance of tumours on imaging. However, DCA can also halt cancer cell growth without causing apoptosis (cytostatic effect). This can result in long-term stabilization of metastatic cancer. We present a case of oral DCA therapy resulting in reduction and stabilization of metastatic melanoma in a 32-year-old male for over 4 years, with only minor side effects.Go to:

INTRODUCTION

Sodium dichloroacetate (DCA) caught the attention of the medical community in 2007, when Bonnet et al[1] published the first in vitro and in vivo study illustrating the value of DCA as a metabolic cancer therapy, through its inhibitory action on the mitochondrial enzyme pyruvate dehydrogenase kinase. Previously, Stacpoole et al[24] had published several studies of DCA for the treatment of congenital lactic acidosis in mitochondrial diseases[25]. These studies demonstrated that oral DCA is a safe drug for human use. DCA was noted to have an absence of renal, pulmonary, bone marrow and cardiac toxicity[4]. Most DCA side effects were modest, with the most serious one being reversible peripheral neuropathy[6]. Reversible delirium has also been reported[7]. Elevation of liver enzymes (asymptomatic and reversible) has been noted in a small percentage of patients[3]. The prior human research in mitochondrial disorders has enabled the rapid translation of DCA into human use as an off-label cancer therapy. Several reports of clinical trials using DCA as cancer therapy have now been published, confirming its safety profile, and indicating an increasing recognition of the potential usefulness of DCA in the cancer clinic[811]. One limitation of these studies involving late stage patients is that they have only reported on treatment for short periods of time.

In Bonnet’s 2007 publication[1], DCA treatment was shown to reduce mitochondrial membrane potential which promoted apoptosis selectively in human cancer cells. Aerobic glycolysis inhibition (the Warburg effect) and mitochondrial potassium ion channel activation were identified as the mechanisms of action of DCA. Further investigations of DCA in vitro have confirmed the anti-cancer activity against a wide range of cancer types, which have been reviewed recently by Kankotia and Stacpoole[12]. In addition, DCA is also able to enhance apoptosis when combined with other agents[1315]. Other anticancer actions of DCA have also been suggested, including angiogenesis inhibition[16], alteration of HIF1-α expression[17], alteration of cell pH regulators V-ATPase and MCT1, and other cell survival regulators such as p53 and PUMA[18]. However, many in vitro studies use unreasonably high concentrations of DCA that are not clinically achievable, in an effort to show cytotoxic activity[12]. In other studies, more modest DCA concentrations were used, demonstrating that DCA could be cytostatic. The second report in 2010 of its in vivo anti-cancer activity found DCA alone to be cytostatic in a metastatic model of breast cancer[19], inhibiting proliferation without triggering apoptosis. This suggests a role for DCA as a cancer stabilizer, similar to angiogenesis inhibitors.

In response to the 2007 report of the anti-cancer actions of DCA, Khan began using DCA for the treatment of cancer patients with short prognosis or who had stopped responding to conventional cancer therapies. A natural medication protocol was developed in collaboration with a naturopathic physician (Andrews) to address the dose-limiting neurologic toxicity of DCA. This consisted of 3 medicines: Acetyl L-carnitine[2022], R-alpha lipoic acid[2325] and benfotiamine[2628], for neuropathy and encephalopathy prevention. In over 300 advanced stage cancer patients, observational data revealed that DCA therapy benefitted 60%-70% of cases. The neuropathy risk when natural neuroprotective medicines were combined with DCA was approximately 20% using 20-25 mg/kg per day dosing on a 2 wk on/1 wk off cycle (clinic observational data published online at www.medicorcancer.com). Here, a patient case report illustrating both the apoptotic and anti-proliferative effects of chronic DCA treatment over a period of over four years is presented.Go to:

CASE REPORT

A 32 years old previously healthy fair-skinned male originally noted that a mole on his left calf began to change in 2006. He consulted a doctor and the mole was excised. A pathologic diagnosis of melanoma was made. A sentinel node dissection was carried out, and was negative for metastatic disease. In 2007, the patient noted enlargement of left inguinal lymph nodes, and small melanocytic lesions on the skin of his left leg. He was treated with interferon alpha under a clinical trial at a regional cancer hospital, with reduction of the nodes and resolution of the skin metastases. Interferon was stopped after 9 mo due to side effects.

The patient remained well until 2010, when a new left leg skin metastasis appeared. This was surgically excised. In late 2011, another new cutaneous metastasis was identified on the left leg, within the scar from the original melanoma surgery. This was biopsied and a diagnosis of recurrent melanoma was confirmed. He was then treated with wide excision and skin graft.

In March 2012, the patient was diagnosed with a recurrence within the left leg skin graft. This was excised and a new skin graft procedure was performed. Pathology revealed positive margins of the excised metastasis, so a re-excision was performed, again with positive margins. At the same time, needle biopsy of a left inguinal lymph node confirmed the presence of BRAF-positive metastatic melanoma. A Computed tomography (CT) scan performed in Mar 2012 revealed no evidence of distant metastases. The largest left inguinal node was 8mm in diameter, which was reported as “insignificant by size criteria” (Figure ​(Figure11).Figure 1

Computed tomography scan from March 2012 prior to natural therapies and prior to dichloroacetate therapy. Largest node measured 8 mm in diameter.

In April 2012, the patient consulted a naturopathic doctor (Shainhouse) and began therapy with the following oral natural anti-cancer agents: Active hexose correlated compound or AHCC (mushroom extract)[29], dandelion root[30], curcumin[31], and astragalus root[32]. Parenteral therapy was also started, which consisted of intravenous vitamin C twice weekly[33] and subcutaneous European mistletoe extract[34]. The patient also changed to a vegan diet.

In May 2012, the patient attended the author’s clinic (Khan) looking to pursue additional non-traditional therapies. DCA therapy was discussed, but the patient decided to give the natural anti-cancer therapies (prescribed by Shainhouse) an adequate trial first. CT scan was performed again in May 2012 (after only 1 mo of natural therapy) and indicated mild growth of multiple inguinal and external iliac nodes, with sizes ranging from 10 mm × 11 mm to 14 mm × 15 mm.

In July 2012, CT scan was repeated to assess the patient’s natural anti-cancer therapies. At that time, the left inguinal and external iliac nodes had enlarged again, and ranged in size from 13 mm × 16 mm to 22 mm × 20 mm (Figure ​(Figure2).2). PET scan was also performed in preparation for entering a clinical trial in Boston, MA (United States), and confirmed increased glucose uptake in the left inguinal nodes. There was new low intensity (2/10) aching pain in the left inguinal region. Examination revealed a 20 mm non-tender left inguinal lymph node, and two small skin metastases within the left calf skin graft.Figure 2

Computed tomography scan from July 2012 after 3 mo of natural therapy alone, just prior to the start of dichloroacetate therapy. Largest node measured 22 mm × 20 mm.

The patient was thus diagnosed with disease progression. At that point he decided to initiate DCA therapy. He began oral DCA 500 mg 3 times per day, which was equivalent to 17 mg/kg per day (manufacturer: Tokyo Chemical Industry, United States) in addition to maintaining the other natural therapies. The DCA treatment cycle was 2 wk on and 1 wk off. To minimize the occurrence of DCA side effects, 3 additional natural medications were prescribed: Oral acetyl L-carnitine 500 mg 3 times a day, oral benfotiamine 80 mg twice a day and oral R-alpha lipoic acid 150 mg 3 times a day. These supplements were taken daily (no cycle). Routine baseline blood tests were performed (Table ​(Table1).1). These were all normal, except for low creatinine which was felt to be insignificant.

Table 1

Blood panel prior to and during dichloroacetate therapy

Blood testJuly 12 pre-DCAOctober 12 3 mo DCAJune 16 4 yr DCAUnitsNormal range
Hemoglobin154150157g/L135-175
White cell count4.54.15× 109/L4.0-11.0
Platelets220214229× 109/L150-400
Glucose4.64.9mmol/L3.6-7.7
Urea3.93.23.9mmol/L2.5-8.0
Creatinine491501551µmol/L62-115
Calcium2.472.412.47mmol/L2.15-2.60
Albumin484547g/L35-50
Bilirubin81013µmol/L< 22
Sodium139141140mmol/L135-147
Potassium44.33.9mmol/L3.5-5.5
Chloride106107105mmol/L100-110
Alkaline Phosphatase776971U/L45-129
LDH139135144U/L120-246
GGT181920U/L15-73
AST182521U/L7-37
ALT182819U/L12-49

Open in a separate window1Indicates abnormal value. DCA: Dichloroacetate; LDH: Lactate dehydrogenase; GGT: Gamma-glutamyltransferase; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

In November 2012, 4 mo after the addition of DCA to his original natural anti-cancer therapies, the patient was re-assessed. He felt generally well. Two new symptoms were reported to have begun only after initiation of DCA therapy: Slightly reduced sensation of the finger tips and toes, and slightly reduced ability to concentrate during the 2 wk periods in which he was taking DCA. The mild sensory loss was not worsening and was felt to be mild DCA-related neuropathy. Both the numbness and reduced concentration were reported to resolve during the weeks when the patient was off DCA. Blood panel from October 2012 showed no significant changes (Table ​(Table1).1). August 2012 and November 2012 CT scans revealed significant regression of all previously enlarged lymph nodes. The largest node was 10 mm, and there was no evidence of intra-thoracic or intra-abdominal disease, and no bone metastases (Figure ​(Figure33).Figure 3

Computed tomography scan from November 2012 after 4 mo of dichloroacetate therapy. Largest node measured 10 mm.

The patient continued to feel well on DCA therapy, and did not notice any new skin metastases or new enlargement of inguinal nodes. He continued to have frequent clinical monitoring with his naturopathic doctor (Shainhouse), and annual follow-up with his medical doctor (Khan). The listed natural anti-cancer therapies (prescribed by Shainhouse) and DCA therapy were maintained into 2016. Blood panel results in June 2016 continued to be normal (Table ​(Table1).1). CT scan was repeated in August 2016, showing no evidence of metastatic melanoma, after a full 4 years of ongoing DCA therapy, combined with natural anti-cancer therapy (Figure ​(Figure4).4). By December 2016, the patient reported an increase in work-related stress and a reduction in compliance with his medications. At the time, he noted a new left inguinal mass. Ultrasound imaging was obtained, which revealed a new conglomerate of enlarged lymph nodes measuring 40 mm × 25 mm × 23 mm, with colour Doppler showing blood flow within the mass. This was interpreted as re-growth of melanoma, after approximately four and a half years of continuous DCA therapy. Further workup was performed including a PET/CT scan, which confirmed disease recurrence in 3 left inguinal nodes (SUVmax ranging from 13 to 17.8).Figure 4

Computed tomography scan after 4 years of dichloroacetate therapy without any concurrent conventional cancer therapies. Scan demonstrates absence of cancer re-growth. All nodes measure less than 10 mm.

In summary, the patient received conventional therapy for recurrent stage 3 melanoma over a period of 6 years, consisting of primary surgical excision with lymph node dissection, interferon alpha and surgical excisions for recurrent cutaneous metastases on 5 occasions. The patient then received natural anti-cancer therapy alone (prescribed by Shainhouse) for 3 mo with no response, evidenced by steady disease progression on serial CT scans. Finally the patient added oral DCA therapy to the natural anti-cancer therapy, with 3 concurrent neuroprotective medicines (lipoic acid, acetyl L-carnitine and benfotiamine) and no concurrent conventional cancer therapies. The result was a complete radiological remission lasting for over 4 years, followed by recurrence. During the course of DCA therapy, the patient experienced trivial side effects consisting of slight neuropathy and slight reduction of concentration. The patient maintained ECOG level 0 function, and he was able to work full time.Go to:

DISCUSSION

The use of oral DCA in the metastatic melanoma patient described herein demonstrates tumour shrinkage and long-term disease stability according to clinical status and CT imaging. Disease stability was maintained for over 4 years while taking DCA in the absence of any concurrent conventional therapy, with a survival time since the initial diagnosis of 10 years. According to the National Cancer Institute’s SEER cancer statistics, the survival of this patient who showed no evidence of distant metastases is not remarkable (62.9% 5-year survival rate for melanoma with spread to regional lymph nodes, https://seer.cancer.gov/statfacts/html/melan.html). What is remarkable is that in a situation where involved lymph nodes were clearly enlarging, the addition of oral DCA therapy was efficacious in shrinking the enlarging nodes (Figures ​(Figures22 and ​and3),3), and in achieving a remission lasting over 4 years. It is possible that the natural anti-cancer therapies the patient received synergized with DCA, but it is also clear that these natural therapies alone cannot account for the disease regression. DCA has been reported to have both apoptotic and cytostatic effects[14,17,19,35,36], which is consistent with this patient’s clinical course of regression (apoptotic) and prolonged remission (cytostatic). The recurrence after 4 years coincided with reduced compliance, suggesting that this method of cancer management with DCA requires the metabolic pressure to be maintained continuously. Despite recurrence, the patient remained clinically well and planned to start new immunotherapy medications. It remains to be seen if a change in therapy can once again achieve disease regression or stability.

In addition to the maintenance of remission for over 4 years, this case illustrates that DCA can be well-tolerated in a cancer patient for a prolonged time period, as compared to all published DCA cancer clinical trials. Notably, this patient was able to tolerate 17 mg/kg per day in a regime of 2 wk on/1 wk off for 4 years with minimal side effects. This is similar to our previous 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, but contrasts with the clinical trials for DCA, which recommend a lower dose of 10-12.5 mg/kg per day given continuously[9,11]. The 1 wk break or the neuroprotective supplements may both contribute to the ability of the patients in the case reports to tolerate the higher dose. Genetic polymorphisms in GSTZ1, the liver enzyme that metabolises DCA, may also contribute to the dose of DCA that can be tolerated[9,38]. Variable drug levels have been reported in the trials, but not all of them have considered this pharmacogenetic aspect of DCA therapy[9,11], and further studies are needed to clarify if this is a significant contributor to DCA tolerance. As of this writing, a DCA multiple myeloma human trial is ongoing, which is examining both GSTZ1 genotypes and drug levels to contribute to our understanding of these issues (Australia New Zealand Clinical Trials Register #ACTRN12615000226505, http://www.anzctr.org.au).

This case report shows that chronic DCA therapy can be used without reducing quality of life, as compared to conventional melanoma therapies such as interferon. To determine the optimal protocol for maximum tolerable acute or chronic treatment with DCA, human trials are needed. But more importantly, it still remains to be clarified what dose is required for on-target effects that will be efficacious against cancer. This information is necessary before investing in larger, long term studies on patient outcomes. DCA deserves further investigation in clinical trials as a non-toxic cancer therapy due to its modest cost and low toxicity, and deserves consideration as an off-label cancer therapy.Go to:

ACKNOWLEDGMENTS

The authors wish to thank Dr. Humaira Khan for her assistance, and also the patient for his support and consent to publish his case.Go to:

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

Excision of primary lesion with skin graft, sentinel node dissection, multiple excisions of recurrent cutaneous metastases. Traditional therapy stopped and natural anti-cancer therapies started (AHCC, dandelion root, curcumin, astragalus root, i.v. vitamin C, s.c. European mistletoe). Progression after 3 mo, dichloroacetate (DCA) added. Regression and remission following addition of DCA lasting for over 4 years.

Related reports

Computed tomography scan reports demonstrate the course of the disease and response to therapies.

Term explanation

DCA: Dichloroacetate sodium; RECIST: Response Evaluation Criteria for Solid Tumours; ECOG: Eastern Cooperative Oncology Group.

Experiences and lessons

DCA can act as a pro-apoptotic and cytostatic drug, and can thus achieve regression as well as long-term stabilization of metastatic cancer without serious side effects, as illustrated by this melanoma case.

Peer-review

Dr. Khan described a 32-year-old man received DCA therapy, with other medications from natural therapists and maintained in a stabilization state (metastatic melanoma) for over 4 years. It is an interesting case.Go to:

Footnotes

Informed consent statement: The patient described in this manuscript has given consent to publish his case anonymously.

Conflict-of-interest statement: One of the authors (Khan) administers dichloroacetate therapy for cancer patients through Medicor Cancer Centres at a cost, and without profit. The clinic is owned by a family member of this author. The other authors have nothing to disclose.

Manuscript source: Invited manuscript

Specialty type: Oncology

Country of origin: Canada

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

Peer-review started: February 12, 2017

First decision: March 28, 2017

Article in press: May 31, 2017

P- Reviewer: Peters GJ, Su CC S- Editor: Ji FF L- Editor: A E- Editor: Lu YJGo to:

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世界 J 臨床病例。2016 年 10 月 16 日;4(10):336-343。 2016 年 10 月 16 日在線發布 。doi:  10.12998/wjcc.v4.i10.336 PMCID: PMC5067498 PMID: 27803917

使用二氯乙酸鈉療法長期穩定 4 期結腸癌

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抽象的

自 2007 年以來,根據 Bonnet 等人的數據,口服二氯乙酸鈉 (DCA) 已被研究作為各種癌症的新型代謝療法,DCA 可以引發人肺癌、乳腺癌和腦癌細胞的凋亡。人體研究中對治療的反應是通過標準的 RECIST 定義來衡量的,該定義通過腫瘤縮小的程度或影像學上的腫瘤消失來定義“反應”。然而,Blackburn 等人已經證明 DCA 也可以作為體外體內細胞生長抑製劑,不會引起細胞凋亡(程序性細胞死亡)。介紹了一個案例,其中口服 DCA 治療導致 57 歲女性的 4 期結腸癌的腫瘤穩定近 4 年,沒有嚴重的毒性。由於 4 期結腸癌的自然病程包括導致殘疾和死亡的穩定進展,因此該病例突出了 DCA 作為細胞抑製劑的新用途,具有維持晚期癌症長期穩定性的潛力。關鍵詞: 二氯乙酸鹽,癌症,結腸,結腸直腸,細胞抑制,穩定,生長抑制,靜脈注射

核心提示:口服二氯乙酸鈉 (DCA) 已被研究作為治療各種癌症的新型代謝療法。人體研究中對治療的反應是通過標準的 RECIST 定義來衡量的,該定義通過腫瘤縮小的程度或影像學上的腫瘤消失來定義“反應”。然而,DCA 也可以作為細胞抑製劑,而不會引起細胞凋亡(程序性細胞死亡)。介紹了一個案例,其中口服 DCA 治療導致 57 歲女性的 4 期結腸癌的腫瘤穩定近 4 年,沒有嚴重的毒性。去:

介紹

自 2007 年 Bonnet 等人 [ 1 ] 發表了一項體外/體內聯合大鼠研究證明 DCA 治療人類肺、乳腺和腦的功效以來,藥物二氯乙酸鈉 (DCA) 已被研究作為各種癌症的新型代謝療法通過抑制線粒體丙酮酸脫氫酶激酶來抑制癌症。 Stacpoole等人[ 24 ] DCA涉及先天性乳酸性酸中毒,這是由遺傳線粒體疾病[集合的治療以前發表的多個研究5 ]。這些研究確定了口服 DCA 在人類中的安全性。 DCA 被發現是一種安全的藥物,沒有心臟、肺、腎臟或骨髓毒性[ 4]]。最嚴重的常見副作用是周圍神經病變,這是可逆的[ 6 ]。譫妄已有報導,在停用 DCA 後可逆轉 [ 7 ]。據報導,一小部分患者出現無症狀且可逆的肝酶升高[ 3 ]。先天性乳酸性酸中毒的先前工作使 DCA 迅速發展到癌症診所。現在四份報告已經發表使用DCA癌症的臨床試驗,表明人們日益認識到DCA [的潛在有用的811 ]。然而,這些治療晚期患者的試驗只能報告相對較短的治療時間。

在 Bonnet 等人在 2007 年的最初論文中 [ 1 ],據報導 DCA 降低線粒體膜電位,導致癌細胞選擇性凋亡。確定的機制是抑制有氧糖酵解(Warburg 效應)和激活線粒體鉀離子通道 [ 1 ]。 DCA 的進一步研究證實了幾種癌症類型的抗癌活性,包括結腸癌[ 12 ]、前列腺癌 [ 13 ]、卵巢癌 [ 14 ]、神經母細胞瘤 [ 15 ]、肺癌類癌 [ 16 ]、宮頸癌 [ 17 ]、子宮內膜癌[ 18 ]、膽管癌[ 19 ],肉瘤[ 20 ]] 和 T 細胞淋巴瘤 [ 21 ]。還提出了 DCA 的其他抗腫瘤作用。這些包括血管生成阻斷 [ 22 ]、HIF1-α[ 23 ]表達的變化、pH 調節因子 V-ATPase 和 MCT1 的改變,以及其他細胞存活調節因子,如 PUMA、GLUT1、Bcl2 和 p53[ 24 ]。然而,在尋求細胞毒活性的過程中,許多體外報告使用了臨床上不太可能達到的 DCA 濃度[ 25 ]。一些研究使用限制濃度,發現DCA是抑制細胞生長的,而非細胞毒性,但能增強細胞凋亡與其他藥物[ 2628 ]。在體內成功的報告中DCA治療乳腺癌,Sun等[ 26 ]發現DCA具有細胞抑製作用,抑制增殖而不增加細胞凋亡。乳腺癌的高轉移性體內模型中,DCA 能夠顯著降低大鼠肺部的轉移負擔。這表明 DCA 作為癌症穩定劑的新作用,類似於抗血管生成療法。然而,據作者所知,尚未發表支持使用 DCA 長期維持穩定疾病的人類數據。

由於 Bonnet 開創性的 DCA 出版物,在 2007 年初,Khan 開始臨床使用 DCA 來治療預後不良或對批准的癌症療法沒有反應的癌症患者。與自然療法醫師 (Andrews) 合作開發了一項天然藥物方案,以解決劑量限制性神經毒性。開發的口服 DCA 方案包括三種天然藥物乙酰左旋肉鹼 [ 2931 ]、R-α 硫辛酸 [ 3234 ] 和苯磷硫胺 [ 3537]],主要目的是預防神經病變。從 300 多名晚期癌症患者收集的觀察數據顯示,DCA 治療在 60%-70% 的病例中具有可衡量的益處。包含天然神經保護劑的神經病變風險約為 20%,每天給藥 20-25 mg/kg,2 週開/1 週停藥週期。在該患者組中,約有 2% 的患者出現可逆性肝酶升高(臨床觀察數據在線發佈於www.medicorcancer.com)。

展示了一個患者案例,說明了維持數年的口服 DCA 治療的細胞抑製作用。該患者預後不良(使用積極的常規姑息性化療的 4 期結直腸癌的中位生存期為 9-12 個月)[ 38 ]。Khan 與自然療法醫師 Andrews 合作治療了該患者,他制定了一種由天然神經保護劑組成的方案。去:

案例報告

一名 57 歲女性於 2012 年 3 月到提交人的診所 (Khan) 就診,尋求治療轉移性結直腸癌。該患者最初在 2010 年年中被診斷出患有直腸癌,當時她因新出現的便秘和腰痛而去看醫生。嘗試了結腸鏡檢查,但由於存在部分阻塞的直腸腫瘤,結腸鏡無法推進。活檢證實為中分化結直腸腺癌。當時的計算機斷層掃描 (CT) 掃描顯示 4 期疾病,多發性肝轉移直徑達 3 厘米,可能有微小的肺轉移和難以測量的環狀直腸癌(癌症的邊緣難以與周圍的腫瘤區分開來) CT 掃描上的組織)。患者接受了環迴腸造口術以繞過阻塞,並且直腸腫瘤沒有被切除。手術後進行化療,包括 5-氟尿嘧啶、伊立替康、亞葉酸和貝伐單抗(FOLFIRI + 貝伐單抗)。最初,患者對化療有反應,肝轉移減少,原發直腸病變減少,血癌胚抗原 (CEA) 標誌物從化療前的 260.9 ng/mL 降至 DCA 治療開始前的 3.5 ng/mL .然後對化療的反應開始趨於平穩。當患者出現在作者的診所時,化療已使疾病的減少微乎其微,並且基本上只是保持穩定。最初,患者對化療有反應,肝轉移減少,原發直腸病變減少,血癌胚抗原 (CEA) 標誌物從化療前的 260.9 ng/mL 降至 DCA 治療開始前的 3.5 ng/mL .然後對化療的反應開始趨於平穩。當患者出現在作者的診所時,化療已使疾病的減少微乎其微,並且基本上只是保持穩定。最初,患者對化療有反應,肝轉移減少,原發直腸病變減少,血癌胚抗原 (CEA) 標誌物從化療前的 260.9 ng/mL 降至 DCA 治療開始前的 3.5 ng/mL .然後對化療的反應開始趨於平穩。當患者出現在作者的診所時,化療已使疾病的減少微乎其微,並且基本上只是保持穩定。並且本質上只是保持穩定。並且本質上只是保持穩定。

患者既往健康,有 20 年吸煙史。她偶爾喝酒。有結腸癌和胃癌的陽性家族史。藥物包括上述持續化療、過氧化氫灌腸劑、口服維生素 C、偶爾口服維生素 D、緩釋氫嗎啡酮 32 毫克,每天兩次,以及根據“突破性”疼痛的需要口服短效氫嗎啡酮 2-4 毫克。沒有過敏。功能檢查顯示一些與正在進行的化療相關的輕度口腔潰瘍、輕度腹瀉(預計進行迴腸造口術)和輕度間歇性直腸出血。下背部和骶骨疼痛/燒灼感高達 10 分之 6 的強度,輕度右肩尖疼痛因化療而加劇(感覺是與肝轉移相關的牽涉痛)。

由於化療仍然有效,並且患者沒有出現任何嚴重的副作用,最初的方法是支持患者現有的治療,而不是取代它。與自然療法醫師 (Andrews) 合作制定了綜合計劃。該計劃包括除了高劑量口服維生素d中的每一天萬國際單位,口服維生素C維生素C50克靜脈內(的變化IV)每週和加成二氯乙酸鈉(DCA)3000毫克IV。 (49 mg/kg) 每週(製造商:Tokyo Chemical Industry,美國)。為了降低 DCA 副作用的風險,開了 3 種天然補充劑:α-硫辛酸(外消旋)500 毫克iv.對於每個 DCA 劑量,口服 R-α 硫辛酸 150 毫克,每天 3 次,口服乙酰左旋肉鹼 500 毫克,每天 3 次,以及口服苯磷硫胺 80 毫克,每天兩次。計劃在化療輸注前後進行輸注(與化療至少相隔 2 天),以避免任何潛在的干擾或藥物相互作用。硫辛酸不在化療日或化療前後 1 d 內給藥,因為它是一種強大的抗氧化劑,有可能降低化療療效。綜合治療於 2012 年 3 月開始。沒有註意到副作用,因此 DCA 增加到 4000 毫克iv。 (66 毫克/公斤) 每週。在較高 DCA 劑量下注意到的唯一副作用是輸注後輕度鎮靜。

添加口服二甲雙胍以幫助提高癌症對化療的敏感性,從每天口服 500 毫克開始,每天 3 次滴定至 500 毫克[ 39 ]。添加普瑞巴林以幫助控制神經性骶骨疼痛(開始每天 50 毫克,每天 3 次滴定至 50 毫克)。化療的副作用包括噁心和嘔吐(在開始使用二甲雙胍之前),如果患者脫水,在患者感到不適的幾天內不使用二甲雙胍以防止潛在的毒性。

獲得了常規基線血液測試,包括完整的細胞計數、標準代謝組、肝酶和膽紅素(表 ​(表格1)。1)。在開始 DCA 綜合治療前 2 個月進行了基線 CT 掃描。

表格1

二氯乙酸鈉治療前的血檢

驗血價值單位普通範圍
血紅蛋白131克/升115-155
白細胞計數6.5× 10 9 /升4.0-11.0
血小板202× 10 9 /升145-400
葡萄糖5.9毫摩爾/升2.6-7.0
尿素6.5毫摩爾/升2.5-8.1
肌酐64微摩爾/升50-100
2.38毫摩爾/升2.20-2.65
白蛋白43克/升35-52
膽紅素15微摩爾/升< 23
140毫摩爾/升136-146
4.2毫摩爾/升3.7-5.4
氯化物102毫摩爾/升95-108
鹼性磷酸酶186 1升/升35-122
乳酸脫氫酶167升/升110-215
GGT364 1升/升< 36
AST33 1升/升< 31
ALT31升/升< 36

在單獨的窗口中打開1表示異常值。LDH:乳酸脫氫酶;GGT:γ-谷氨酰轉移酶;AST:天冬氨酸氨基轉移酶;ALT:丙氨酸氨基轉移酶。

按照所述的綜合治療 4 個月後,進行了新的 CT 掃描(圖 ​(圖1),1),被報告為“穩定和不變”,但沒有給出測量結果。注意到偶然發現的膽結石(也從先前的掃描中穩定下來)。患者對沒有註意到改善感到沮喪,並且 CT 報告中沒有顯示詳細的測量結果。曾嘗試進行正電子發射斷層掃描以明確活腫瘤壞死腫瘤,但無法獲得政府資助,患者拒絕為掃描支付私人費用。 圖1

使用二氯乙酸鈉、5-氟尿嘧啶和天然藥物進行綜合治療 4 個月後進行腹部計算機斷層掃描。顯示了具有各種可測量肝轉移灶的三個切片。A:23 mm × 33 mm 肝轉移;B:直徑15mm的肝轉移;C:11.2 mm × 25 mm 肝轉移。

經過一番討論,患者選擇繼續治療,並在不同的醫院獲得未來的 CT 掃描。到 2012 年 9 月,注意到化療副作用增加,包括疲勞、噁心和嘔吐。一項新的 CT 掃描顯示,所有肝髒病變“要么變小,要么不再被識別”。然而,最大的腫瘤縮小僅為 2 毫米(肝段 4a 中的 2.5 厘米標記病變縮小至 2.3 厘米)。沒有發現新的病變。

複查CT掃描後,患者決定停止所有化療,以及貝伐單抗和二甲雙胍。DCA。繼續,劑量增加到 4500 毫克iv。每週。噁心和嘔吐解決了。疼痛仍在控制之中。3 個月後進行了新的 CT 掃描,顯示殘留的直腸腫瘤狹窄,近端糞便負荷(未改變),以及“肝轉移,未顯著改變”。患者報告手指和腳趾輕度麻木。無症狀肝酶升高進一步增加(表​(表2)。2)。這兩個都被診斷為 DCA 副作用。在截至目前的治療期間,CEA 表現出輕微波動,但總體上被認為是穩定的(圖​(圖22)。

表 2

二氯乙酸鈉治療期間的血檢,2013 年 1 月

驗血價值單位普通範圍
血紅蛋白134克/升115-155
白細胞計數5.1× 10 9 /升4.0-11.0
血小板142 1× 10 9 /升145-400
葡萄糖5.5毫摩爾/升2.6-7.0
尿素4.1毫摩爾/升2.5-8.1
肌酐57微摩爾/升50-100
2.24毫摩爾/升2.20-2.65
白蛋白39克/升35-52
膽紅素11微摩爾/升< 23
140毫摩爾/升136-146
4.2毫摩爾/升3.7-5.4
氯化物106毫摩爾/升95-108
鹼性磷酸酶267 1升/升35-122
乳酸脫氫酶183升/升110-215
GGT837 1升/升< 36
AST104 1升/升< 31
ALT100升/升< 36

在單獨的窗口中打開1表示異常值。LDH:乳酸脫氫酶;GGT:γ-谷氨酰轉移酶;AST:天冬氨酸氨基轉移酶;ALT:丙氨酸氨基轉移酶。 圖2

整個治療過程中的癌胚抗原圖。CEA:癌胚抗原。

DCA 治療中斷 3 個月以解決 DCA 副作用。在此期間,僅給予自然療法(由安德魯斯開處方)。乙酰左旋肉鹼、苯磷硫胺和硫辛酸繼續加速 DCA 神經病變的恢復。口服薑黃素[ 40 ]和和厚朴酚(玉蘭樹提取物)被添加到試圖保持癌症控制[ 41 ]。在 DCA 停止期間,CEA 從 4.1 增加到 5.1 ng/mL(圖​(圖2)。2)。輕度 DCA 神經病變已消退,肝酶開始改善。

到2013年3月,由於擔心輸液治療的費用,決定開始口服DCA治療。新的基線 CT 掃描顯示肝段 7 標誌物病變增加 1 毫米,標誌物主動脈腔淋巴結增加 1 毫米,但報告為“結腸外觀穩定”和“穩定的肝轉移”。

開始口服 DCA,劑量為 500 毫克(8.2 毫克/千克),每天兩次,並繼續服用由口服乙酰左旋肉鹼、苯磷硫胺和 R-α 硫辛酸組成的神經保護補充劑。連續給予補充劑,並以 2 週開/1 週關的周期給予 DCA。

2013 年 12 月,止痛藥從氫嗎啡酮過渡到每天 3 次 10 毫克的美沙酮,為簡單起見,改善疼痛控制並節省成本。

患者繼續採用這種方案,每 3 至 6 個月定期進行一次 CT 掃描。由於工作繁忙,患者對定期血液檢測的依從性降低。她保持高度功能性(ECOG 1 級),輕度慢性 DCA 神經病變得到控制,不影響她的日常功能。曾嘗試將 DCA 增加至 500 mg,每天 3 次,但這導致顯著的無症狀肝酶升高和神經病變的增加。因此,在短暫的治療中斷後,又恢復了每天兩次 500 毫克的 DCA 劑量。

持續的 CT 掃描繼續顯示病情穩定(圖 ​(圖3),3),沒有出現新的病灶。從開始 DCA 治療開始,總體 CEA 沒有顯著變化(DCA 治療開始時 CEA 為 3.5,近 4 年治療後 CEA 為 3.7)。一般血液檢測在 3 年時也表現良好(表​(表3)3) 和 4 年之後 (表 ​(表44)。

表3

二氯乙酸鈉治療期間的血檢,2015 年 5 月

驗血價值單位普通範圍
血紅蛋白134克/升115-155
白細胞計數7.7× 10 9 /升4.0-11.0
血小板173× 10 9 /升145-400
葡萄糖5.3毫摩爾/升2.6-7.0
尿素5.1毫摩爾/升2.5-8.1
肌酐70微摩爾/升50-100
2.37毫摩爾/升2.20-2.65
白蛋白——克/升35-52
膽紅素8微摩爾/升< 23
144毫摩爾/升136-146
4.1毫摩爾/升3.7-5.4
氯化物104毫摩爾/升95-108
鹼性磷酸酶——升/升35-122
乳酸脫氫酶174升/升110-215
GGT156 1升/升< 36
AST30升/升< 31
ALT25升/升< 36

在單獨的窗口中打開1表示異常值。LDH:乳酸脫氫酶;GGT:γ-谷氨酰轉移酶;AST:天冬氨酸氨基轉移酶;ALT:丙氨酸氨基轉移酶。 圖 3

綜合治療(二氯乙酸鈉 + 5-氟尿嘧啶 + 天然藥物)3 個月後進行腹部計算機斷層掃描,隨後是近 4 年的二氯乙酸鈉,沒有任何並發的常規癌症治療。掃描顯示沒有癌症再生長和新的肝轉移。與圖相同的切片​圖11顯示。A:11.3 mm × 27.5 mm 肝轉移;B:無可見轉移;C:沒有可見的轉移。

表 4

二氯乙酸鈉治療期間的血檢,2016 年 4 月

驗血價值單位普通範圍
血紅蛋白133克/升115-155
白細胞計數5.2× 10 9 /升4.0-11.0
血小板155× 10 9 /升145-400
葡萄糖——毫摩爾/升2.6-7.0
尿素4.9毫摩爾/升2.5-8.1
肌酐——微摩爾/升50-100
2.39毫摩爾/升2.20-2.65
白蛋白42克/升35-52
膽紅素9微摩爾/升< 23
142毫摩爾/升136-146
4毫摩爾/升3.7-5.4
氯化物102毫摩爾/升95-108
鹼性磷酸酶101升/升35-122
乳酸脫氫酶156升/升110-215
GGT149 1升/升< 36
AST30升/升< 31
ALT28升/升< 36

在單獨的窗口中打開1表示異常值。LDH:乳酸脫氫酶;GGT:γ-谷氨酰轉移酶;AST:天冬氨酸氨基轉移酶;ALT:丙氨酸氨基轉移酶。

綜上所述,患者接受常規化療約18個月後,接受靜脈DCA治療並同步化療約6個月,隨後靜脈和口服DCA治療,近4年未同步常規癌症治療。在口服 DCA 治療期間,患者通過 CT 掃描病情穩定,通過 CEA 腫瘤標誌物測量病情穩定。她的臨床情況也很穩定,沒有增加美沙酮劑量、維持 ECOG 1 級功能、穩定的輕度 DCA 神經病變,並且她能夠成功地經營自己的事業。去:

討論

根據臨床、生化和放射學標準,這例晚期 4 期結腸癌患者的 DCA 治療表明疾病長期穩定。在沒有其他積極化療的情況下使用 DCA 時的穩定性持續時間目前為 46 個月(近 4 年),自最初診斷出 4 期結直腸癌以來的生存時間為 6 年。根據美國國家癌症研究所 1975-2011 年的 SEER 癌症統計回顧,診斷為 IV 期結腸/直腸癌的女性的 5 年相對存活率為 14.4% ( http://seer.cancer.gov/csr/1975_2013/)。雖然不能明確斷定 DCA 是否有效,但在沒有正在進行的化療的情況下,在這段時間內存活的可能性相對較低。抑制細胞生長的,而非DCA對大腸和其它癌細胞的細胞毒性作用已報導並支持這一臨床發現[ 23274244 ]。迄今為止,該患者臨床狀況良好,仍在接受 DCA 治療。

除了維持穩定的疾病外,該病例還證明了癌症患者口服 DCA 的耐受性比目前已發表的癌症患者臨床試驗報告的耐受時間長得多。 Chu 等人 [ 11 ] 報告了 24 名患者在不使用神經保護補充劑的情況下連續口服 DCA,以 6.25 或 12.5 mg/kg BID 治療中位時間為 2 個月。他們得出的結論是,推薦的 2 期劑量為 6.25 mg/kg BID(每天 12.5 mg/kg),需要仔細監測神經病變。鄧巴等人[ 9] 推薦 5 mg/kg BID 作為大多數患者的起始劑量,他們的試驗連續給藥 4、8 或 12.5 mg/kg BID(DCA 34 天的中位時間),也沒有神經保護補充劑。本報告中的患者服用 500 mg BID,相當於 8.2 mg/kg BID,2 wk on/1 wk off,但不能耐受該劑量,每天 3 次(總共 25 mg/kg 每天)。 Dunbar 等[ 9 ] 建議對GSTZ1 中的多態性進行基因分型,GSTZ1是肝臟中的 DCA 代謝酶,隨著 DCA 的持續使用而失活 [ 45],在確定患者的起始劑量時應予以考慮。然而,還需要進一步的工作來收集令人信服的基因型數量和劑量耐受性數據。DCA 在多發性骨髓瘤患者中的臨床試驗目前正在進行中,以促進這一數據池(澳大利亞新西蘭臨床試驗註冊 #ACTRN12615000226505,http: //www.anzctr.org.au )。需要進一步的研究來確定 DCA 最大可耐受急性或慢性治療的最佳劑量方案,以及確實需要多大劑量才能達到療效。

所呈現的案例表明 DCA 作為一種癌症療法具有廣闊的前景。患者從她的治療中獲得了顯著的益處,副作用輕微,沒有血液、心臟、肺或腎毒性。觀察到一些肝毒性(表​(表2),2),這很容易通過 DCA 治療中斷然後調整劑量來管理。據報導,輕度可逆的外周神經毒性。與 DCA(乙酰左旋肉鹼、α-硫辛酸和苯磷硫胺)相結合的自然療法有助於患者減少副作用,但不知道其可作為癌症療法。

在撰寫本文時,尚無研究 DCA 作為細胞生長抑製劑的人體使用的積極臨床試驗。由於 DCA 未獲得專利,因此籌集足夠的資金來支持大規模人體試驗是一項嚴峻的挑戰。希望這個例子說明口服 DCA 的好處將刺激進一步的臨床研究。

根據我們的臨床經驗,結合現有的出版物,一旦他們了解並接受治療的風險和益處,那麼標籤外 DCA 治療是可用常規治療有限的患者的一種選擇。該病例報告表明,即使在晚期疾病中,與化療相比,DCA 也有可能在不影響患者生活質量的情況下延長生命,而化療會頻繁出現使人衰弱的副作用或生理功能受損。鑑於其合理的成本和適度的毒性,DCA 值得進一步研究。去:

致謝

作者要感謝 Humaira Khan 博士的幫助,也感謝患者的支持和同意發表她的病例。去:

註釋

案例特點

這位 57 歲的女性患者出現便秘和腰痛。

臨床診斷

該患者被診斷出患有部分梗阻性直腸癌。

實驗室診斷

癌胚抗原腫瘤標誌物升高。

影像診斷

結腸鏡檢查可見直腸腫塊。

病理診斷

中分化結直腸腺癌。

治療

環狀迴腸造口術,然後是由 5-氟尿嘧啶、伊立替康、亞葉酸和貝伐珠單抗組成的化療,然後加入二氯乙酸鈉 (DCA),然後是近 4 年沒有化療的 DCA。

相關報導

計算機斷層掃描報告顯示,聯合化療 + DCA 可減少癌症,然後在 DCA 和不化療的情況下疾病穩定近 4 年。

術語解釋

DCA:二氯乙酸鈉;RECIST:實體瘤療效評價標準;ECOG:東方合作腫瘤學組;SEER:監測、流行病學和最終結果。

經驗教訓

DCA 不僅是一種促凋亡藥物,而且還可以作為細胞抑製劑,因此可以實現晚期癌症的長期穩定,而不會產生嚴重的副作用,如該直腸癌病例所示。

同行評審

DCA 是二氯乙酸的鈉鹽,是一種廉價的化合物,已顯示出作為替代癌症治療的一些明顯潛力,已在許多腦癌或膠質母細胞瘤患者的試驗中使用。這是一份寫得很好的病例報告,其中口服 DCA 治療使 57 歲女性的 4 期結腸癌的腫瘤穩定了 3 年多,沒有嚴重的毒性。這份報告涵蓋了它的承諾。作者在解釋 DCA 治療的基礎知識及其在不同腫瘤類型中的作用方面做得很好。除了增加對癌細胞的作用機制和 DCA 的治療潛力外,作者還為不熟悉 DCA 治療的讀者提供了很好的資源,但也提供了詳細信息。去:

腳註

機構審查委員會聲明:不適用。

知情同意聲明:本手稿中描述的患者同意匿名發表她的病例。

利益衝突聲明:作者之一 (Khan) 通過 Medicor 癌症中心為癌症患者提供二氯乙酸鹽治療,但不收取任何費用。該診所歸作者的一位家庭成員所有。其他作者沒有什麼可透露的。

稿件來源:特邀稿件

專業類型:醫學、研究和實驗

原產國:澳大利亞

同行評審報告分類

A級(優秀):0

B級(很好):B,B

C級(好):0

D級(一般):D

E級(差):0

同行評審開始時間:2016 年 5 月 3 日

第一次決定:2016 年 6 月 17 日

發表文章:2016 年 8 月 8 日

P- 審稿人:Lakatos PL, Song J, Zhu YL S- 編輯:Ji FF L- 編輯:A E- 編輯:Wu HL

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