Journal of Pain & Palliative Care Pharmacotherapy. 2014;28:206–211. Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 1536-0288 print / 1536-0539 online DOI: 10.3109/15360288.2014.938882
ARTICLE
Palliative Treatment for Advanced Biliary Adenocarcinomas With Combination Dimethyl Sulfoxide–Sodium Bicarbonate Infusion and S-Adenosyl-L-Methionine Ba X. Hoang, Hung Q. Tran, Ut V. Vu, Quynh T. Pham, and D. Graeme Shaw AB STRACT Adenocarcinoma of the gallbladder and cholangiocarcinoma account for 4% and 3%, respectively, of all gastrointestinal cancers. Advanced biliary tract carcinoma has a very poor prognosis with all current available modalities of treatment. In this pilot open-label study, the authors investigated the efficacy and safety of a combination of dimethyl sulfoxide–sodium bicarbonate (DMSO-SB) infusion and S-adenosyl-L-methionine (ademetionine) oral supplementation as palliative pharmacotherapy in nine patients with advanced nonresectable biliary tract carcinomas (ABTCs). Patients with evidence of biliary obstruction with a total serum bilirubin ≤300 μmol/L were allowed to join the study. The results of this 6-month study and follow-up of all nine patients with ABTC indicated that the investigated combination treatment improved pain control, blood biochemical parameters, and quality of life for the patients. Moreover, this method of treatment has led to a 6-month progression-free survival for all investigated patients. The treatment was well tolerated for all patients without major adverse reactions. Given that ABTC is a highly fatal malignancy with poor response to chemotherapy and targeted drugs, the authors consider that the combination of DMSO-SB and ademetionine deserves further research and application as a palliative care and survival-enhancing treatment for this group of patients. KEYWORDS adenosylmethionine, biliary tract carcinoma, cholangiocarcinoma, dimethyl sulfoxide, sodium bicarbonate
group of cancers is 1 to 2 per 100,000 persons per year in the United States and Europe, and the rate increases to 87 per 100,000 in Southeast Asia.1 These highly fatal malignancies have 1- and 2-year survival rates of 25% and 13%, respectively.2 Because there are no specific symptoms in early malignant lesions, patients with this type of carcinoma mostly present in the advanced stages of the disease, which contributes to its poor prognosis. Patients with nonresectable disease receive palliative chemotherapy. Many agents, including fluoropyrimidines, gemcitabine, cisplatin/oxaliplatin, mitomycin C, doxorubicin, docetaxel, and irinotecan, have been tested and have shown very poor response rates and significant toxicities.3 Targeted therapy with sorafenib as a single agent has a low activity against advanced nonresectable
INTRODUCTION Biliary adenocarcinoma is the second most common primary hepatic malignancy worldwide. It arises either within the liver (intrahepatic cholangiocarcinoma) or in the extrahepatic bile ducts (extrahepatic cholangiocarcinoma). The rate of occurrence of this
Ba X. Hoang, MD, PhD, is a medical consultant with the Department of Oncology, and Hung Q. Tran, MD, PhD, is head of the Oncology Center, 198 Hospital, Hanoi, Vietnam. Quynh T. Pham, MD, is with the Departments of Internal Medicine and Palliative Care, Labor Medical Center, Hanoi, Vietnam. Ut V. Vu, MD, is with the Departments of Surgery and Oncology, Hospital of Traditional Medicine, Hanoi, Vietnam. D. Graeme Shaw, MD, is an internist in private practice in Los Altos, California, USA. Address correspondence to: Dr. Ba X. Hoang, Oncology Department, 198 Hospital, Tran Binh Street, Hanoi, Vietnam (E-mail: [email protected]).
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biliary tract carcinomas (ABTCs). Sorafenib is indicated for treatment of hepatocellular carcinoma and treatment of patients with advanced renal cell carcinoma who have failed prior interferon-α– or interleukin-2–based therapy or are considered unsuitable for such therapy. Recent trials suggest a median survival of 4.4 months and a progression-free survival of 2.3 months.4 Patients with ABTC usually present with obstructive jaundice and abdominal pain. Other common complaints include pruritus, weight loss, fever, and symptoms related to biliary obstruction such as claycolored stools and dark urine. Physical signs include jaundice, hepatomegaly, and a right upper quadrant mass. Despite the implementation of new techniques such as neoadjuvant chemoradiation, chemotherapy, radiotherapy, and palliative biliary drainage, these therapies have not been demonstrated to prolong survival significantly.5 For those diagnosed at an early stage, surgery remains the only possibility for cure and yet still only provides patients with a 20% 5-year survival. Treatment options for advanced disease are limited. Systemic chemotherapy is increasingly being used; however, many studies report a dismal median survival of approximately 6 months.6 In this study, we investigated the efficacy and safety of dimethyl sulfoxide–sodium bicarbonate (DMSOSB) infusion in combination with ademetionine in the palliative care and anticancer treatment for ABTC. Our prior clinical observations indicated that DMSOSB infusions in patients with metastatic prostate cancer showed significant improvement in a 90-day follow-up in clinical symptoms, blood and biochemistry tests, and quality of life.7 The same treatment may be a viable, effective, and safe treatment for refractory pain in patients with different types of advanced cancer.8 S-Adenosyl-L-methionine (also called S-adenosyl methionine, S-adenosylmethionine, SAMe, or SAMe in the United States or ademetionine in Europe, and also often abbreviated as AdoMet) is a chemical that is found naturally in the body. SAMe is sold in the United States as a dietary supplement. Ademetionine plays a critical role in the synthesis of polyamines and provides cysteine for the production of glutathione, the major endogenous hepatoprotective agent. We therefore decided to combine the supplementation of ademetionine in the treatment protocol for ABTC, considering our prior clinical experiences and results of published clinical trials that showed this agent was effective and well tolerated for patients with chronic diffuse liver disease with intrahepatic cholestasis syndrome.9–11
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PATIENTS AND METHODS Study Design This was an open-label, single-arm, nonrandomized trial conducted as both inpatient and outpatient. Written informed consent was obtained from all patients. We used a verbal descriptor scale (VDS) to measure the level of pain: “no pain” = 0; “mild pain” = 1; “moderate pain” = 2; “severe pain” = 3; “extreme pain” = 4. To evaluate the pain control effectiveness of the investigated protocol, the analgesic intake scale (AIS) according to the World Health Organization (WHO) (0 = no analgesics; 1 = NSAIDs [nonsteroidal anti-inflammatory drugs]; 2 = weak opioids; 3 = morphine) was used. To evaluate the performance status of the patients, we used a public-domain scoring system, the Eastern Cooperative Oncology Group (ECOG) performance status, that is widely used in the United States to assess how patients’ disease is progressing, to assess how the disease affects the daily living abilities of the patient, and to help determine appropriate treatment and prognosis. That scale is given in Box 1. Eligibility Criteria
Patients with ABTC were newly diagnosed by a complex of clinical symptoms and other standard biochemistry/imaging methods at special oncology hospitals or departments. Oncologists determined the patients’ tumors to be nonresectable or metastatic ABTC, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder adenocarcinoma.
BOX 1. ECOG Performance Status 0 Fully active, able to carry on all predisease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 5 Dead
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These patients were recommended by their oncologists to receive palliative and symptomatic treatments. The patients had refused to undergo standard treatment because of concern about cost, possible side effects, and the low rate of improvement and survival. All the patients were informed about the cost, possible toxicities, and potential rate of successes with the offered specific treatment. Included patients were required to have a ECOG ≤2, a hemoglobin level of ≥100 g/L, platelet count ≥100 × 109 g/L, bilirubin (serum) ≤300 μmol/L, albumin concentrations in serum ≥30 g/L, total serum proteins ≥60 g/L, creatinine ≤160 μmol/L, glutamicoxaloacetic transaminase (GOT) and glutamicpyruvic transaminase (GPT) ≤300 U/L, and γ glutamyltransferase (GGT) ≤300 U/L. Patient with uncontrollable hypertension and stage II heart failure were not accepted to the treatment protocol.
TABLE 1.
Clinical Endpoints
The patients decided to take part in our study by their own will after receiving a thorough explanation regarding the proposed treatment and other therapeutic options available. The main reasons for these patients choosing the studied therapy were the side effects of conventional treatments and the positive experience of other patients who had been successfully treated with the investigated therapeutic approach. The characteristics of patients and their current disease are shown in Tables 1 and 2.
The primary clinical endpoint was defined in the protocol as a ≥50% reduction in the pain score from baseline, or a reduction of ≥50% analgesic drug use. Improvement in ECOG scores was considered the second important clinical endpoint. Besides pain reduction and ECOG score reduction, any reduction in the symptoms and paraclinical measurement of the patients was considered as an important clinical endpoint of our study. Disease control as an objective was defined as the percentage of patients without disease progression by ECOG score, pain score, and total serum bilirubin. Secondary objectives included progression-free survival (PFS) and tolerability. Progression-free survival was defined as the time from the first day of administration of the study medications to disease progression. The primary endpoint was an improvement in 6 months (PFS6) from the historical 57.1% with current standard systemic therapy using gemcitabine and cisplatin for advanced biliary adenocarcinomas.12 Treatment continued until there was evidence of positive disease control rate progression by monitoring pain score, ECOG, and serum total bilirubin, development of side effects, or consent withdrawal.
Patients Nine patients with nonresectable ABTC with symptoms of obstructive jaundice with no prior specific treatment were enrolled in the study over a period of 6 months. The diagnosis of ABTC was made at specialized oncology departments based on the findings of computed tomography (CT), biopsy with cytomorphologic examination and a combination of clinical and biochemistry parameters.
Characteristics of the Patients N=9
Number of patients Median age Gender Female Male Median weight Site Intrahepatic Gallbladder Extrahepatic Major associated disorders Diabetes Chronic hepatitis B Liver cirrhosis Hypertension Gastritis Ulcerative colitis
61 (range: 48–73) 4 5 54 kg (range: 44–65) 3 2 4 3 1 2 4 4 2
Treatment All nine patients were treated with infusion of 25 mL of 99.9% DMSO solution mixed with 500 mL of sodium bicarbonate (SB) 1.4% solution and the equivalent of 1000 mg of potassium chloride and 1500 mg of magnesium sulfate. The infusions of DMSO-SB were performed by giving a continuous 5day infusion with a 2-day break for a total of three cycles of 20 treatments. Thereafter, the patients continued with two infusions in 5 days with a 2-day break for 24 more treatments. The mean speed of drip was 60 drops per minute. Despite the design of total 84 infusions for the 6-month treatment period, there were no patients who received the full treatment program due to different reasons. The maximal number of infusions was 80, the minimal was 74. The median number of infusion was 78. Besides the DMSO-SB infusion, the patients received 200 mg of ademetionine in enteric coated capsules, three times daily with food for the first week; 300 mg three times daily in the second week; and 400 mg and then three times daily after 2 weeks until the end of 6-month treatment period. Patients with edema were treated with appropriate Journal of Pain & Palliative Care Pharmacotherapy
Report TABLE 2 Patients’ Major Clinical Symptoms Related to ABTC Number of patients having symptoms Abdominal pain VDS 0 VDS 1 VDS 2 VDS 3 Total VDS Analgesic intake scale AIS = 0 AIS = 1 AIS = 2 AIS = 3 Total AIS Jaundice Pruritis Paraneoplastic fever Fatigue Low appetite Weight loss Hyperbilirubinemia
Elevated GOT
Elevated GPT
Elevated GGT
Clay-colored stool Dark urine Blood sugar elevation Anemia with a hemoglobin level of ≥100 g/L and ≤ 120 g/L Thrombocytopenia with platelet count ≥100 × 109 /L and ≤140 × 109 /L Hepatomegaly Right upper quadrant mass Splenomegaly ECOG 0 ECOG 1 ECOG 2
N=9 2 2 3 2 14 2 5 1 1 10 7 5 3 9 6 5 9 (maximal: 278 μmol/L, minimal: 38 μmol/L; mean: 186 μmol/L) 9 (maximal: 266 U/L, minimal: 122 U/L; mean: 191 U/L) 9 (maximal: 259 U/L; minimal: 116 U/L; mean: 185 U/L) 9 (maximal: 297 U/L; minimal: 252 U/L; mean: 276 U/L) 3 4 3 5 3
6 3 2 2 4 3
diuretics. All patients were allowed to take any medication for their symptoms and associated diseases, nutritional supplements, vitamins, and herbal medicines. Patients were advised to avoid red meats and dairy products in their diet. The patients were advised to take a dose of digestive enzymes before each meal if they experienced indigestion problems.
RESULTS Palliative Care and Quality of Life Outcome Two weeks after the treatment of DMSO-SB and ademetionine, abdominal pain decreased more than C
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50% from the baseline: VAS = 4 and AIS = 4. All patients reported a significant improvement; the ECOG total was reduced to 6 points. After 1 month, the VAS score was further reduced to 2, the AIS score was equal to 2, and the ECOG total for all patients was 4. By the end of 3-month treatment, the VAS was reduced to 0, the AIS was reduced to 0, and the ECOG was 1 total. Pain intensity and quality of life scores remained at these levels until the end of the 6-month treatment period. Pain control and quality of life progress in the 6 months of treatment are shown in Table 3.
Disease Control Rate and Progression-Free Survival (PSF) Besides the improvement in pain control and quality of life measured by VAS, AIS, and ECOG scores, the treatment of DMSO-SB and Ademetionine showed a positive disease control rate by the continually decreasing serum levels of total bilirubin and key liver functional enzymes, as shown in Table 4. The positive progress in the level of total serum bilirubin and liver enzymes shown in Table 4 indicates that treatment with DMSO-SB infusion plus ademetionine oral supplementation is effective in the improvement of the disease control rate and possible tumor reduction, since it reversed the bile obstructive syndrome and liver damage caused mainly by tumors in the biliary system metastases to the liver. The clinical symptoms of the patients with ABTC also improved throughout the 6-month period of treatment, as shown in Table 5. The surprising findings in monitoring the clinical symptoms such as abdominal pain, weight loss, weight gain, jaundice, hepatomegaly, total serum albumin, and liver enzyme elevations showed that all the subjects achieved stabilization of their disease. The clinical endpoints were achieved in all nine investigated patients. The treatment with DMSO-SB infusion and ademetionine oral supplementation not only showed that this combination effectively controlled pain, but also released the bile obstructive symptoms that enhanced quality of life for the patients. The PFS6 showed improvement to 100% compared with the historical PFS6 of 57.1%
Tolerability The treatment was well tolerated by all patients. There were a few cases of diarrhea and nausea during the initial 2 weeks of treatment. These were controlled by appropriate medication or resolved without any specific treatment. There was no toxicity observed clinically and in monthly monitoring of
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TABLE 3.
Pain Control and Quality of Life Outcome
Measure
Baseline
2 Weeks
1 Month
2 Months
3 Months
4 Months
5 Months
6 Months
4 4 6
2 2 4
1 0 2
0 0 1
0 0 1
0 0 1
0 0 1
0 0 1
Pain score VAS Pain score AIS ECOG
blood analysis and biochemistry parameters. The pH of blood remained within normal levels with maximum of 7.6 and minimum of 7.45 during the 6-month treatment.
DISCUSSION Most ABTCs are locally or metastatic disease at the time of diagnosis. Even if the tumors are resectable, long-time survival rates are low. For nonresectable ABTCs, chemotherapy combining gemcitabine with a platinum agent is the recommended first-line treatment regimen for advanced biliary tract cancer, with very poor results for an overall survival rate of more than 1 year. The addition of sorafenib to gemcitabine and cisplatin in advanced biliary tract cancers failed to show any improvement in outcome and proved to have significant toxicity at standard cytotoxic dosing.13 Due to their late diagnosis, the vast majority of the patients with ABTC are candidates for palliative management. The primary aim is to provide biliary drainage for relief from pain, jaundice, pruritus, and cholangitis. Endoscopically placed self-expanding metallic biliary stents is the modality of choice for patients with nonresectable ABTC. There are now multiple options to achieve this goal; however, they are still under investigation and are expensive, complicated, and associated with side effects that sometime contribute to a worsening of the disease outcome. DNA methylation plays a critical role in gene expression and other phenotypes, and DNA hypomethylation leads to gene instability and an increase in mutation frequency. The consequences of methylation abnormalities may activate oncogene transcription, increasing carcinogenesis and metasta-
TABLE 4.
sis. Ademetionine is a DNA hypermethylating agent that has been shown to inhibit carcinogenesis by controlling the activation of oncogenes. It also appears to be tumor specific, being both anti-apoptotic in normal liver cells and pro-apoptotic in liver cancer cells. Gastric and colon cancers also have benefited from similar treatments.14 Based on this research, we may speculate that other gastrointestinal tumors may respond to Ademetionine therapy. In our previous publications, we proposed the concept of cell membrane hyperexcitability through sodium channel activation and glutamate-induced N-methyl-D-aspartate (NMDA) receptor stimulation as a significant causal factor in carcinogenesis.15 We have published research regarding the role of dimethyl sulfoxide as a dual-inhibitory agent, which inhibits both voltage-gated sodium channels and glutamate receptors.16 In addition to its other properties, Ademetionine has been shown to be a NMDA receptor antagonist that inhibits glutamate cytotoxicity.17 Further research has documented S-adenosyl-Lmethionine’s ability to suppress neuronal excitability. This inhibitory property may have neuromodulatory effects on the physiological functions of the central nervous system (CNS) and peripheral organs.18 Not only do ademetionine and DMSO have complementary functions, but because of its ability to enhance membrane transport, DMSO also may have a synergistic effect on ademetionine by increasing its cellular levels. There is a possibility of synergic and potentiating therapeutic action of the three major components of the treatment—DMSO, sodium bicarbonate, and ademetionine—that would be of interest for future exploratory research and advancements for the management of hepatobiliary cancers among other possible cancers.
Dynamic of Total Serum Bilirubin (mmol/L) and Liver Enzymes During 6 Months of Treatment
Parameter
Baseline
2 Weeks
1 Month
2 Months
3 Months
4 Months
5 Months
6 Months
Median total Median GOT Median GPT Median GGT
186 191 U/L 185 U/L 276 U/L
124 117 U/L 108 U/L 129 U/L
102 93 U/L 96 U/L 104 U/L
85 82 U/L 85 U/L 91 U/L
68 74 U/L 79 U/L 86 U/L
52 66 U/L 71 U/L 82 U/L
36 64 U/L 66 U/L 79 U/L
32 63 U/L 62 U/L 74 U/L
Journal of Pain & Palliative Care Pharmacotherapy
Report TABLE 5.
Number of Patients With ABTC Symptoms During the 6-Month Treatment
Symptom Abdominal pain Jaundice Pruritus Paraneoplastic fever Fatigue Low appetite Weight loss Weight gain Hepatomegaly Splenomegaly Right upper quadrant
Baseline
2 Weeks
1 Month
2 Months
3 Months
4 Months
5 Months
6 Months
7 7 5 3 9 7 5 0 6 2 3
3 6 3 0 5 4 3 0 6 2 3
1 5 1 0 5 2 0 2 5 2 3
1 3 1 0 3 0 0 4 3 1 2
0 2 0 0 3 0 0 5 2 1 2
0 0 0 0 2 0 0 5 2 1 1
0 0 0 0 2 1 0 6 1 1 1
0 0 0 0 2 1 0 6 1 1 1
CONCLUSION Although this study represents only a small patient trial, we suggest that further research with the DMSO-SB infusion and ademetionine supplementation is indicated to determine the value of this therapy as a palliative and survival-enhancing treatment for patients with ABTC. Although this preliminary work is promising, a larger patient study with longer follow-up is needed to determine the potential benefit and overall survival of cancer patients using this nontoxic, noncomplicated, and inexpensive method of treatment. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES [1] de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med. 1999;341:1368–1378. [2] Fong Y, Blumgart LH, Lin E, Fortner JG, Brennan MF. Outcome of treatment for distal bile duct cancer. Br J Surg. 1996;83:1712–1715. [3] Hezel AF, Zhu AX. Systemic therapy for biliary tract cancers. Oncologist. 2008;13:415–423. [4] Bengala C, Bertolini F, Malavasi N, et al. Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial. Br J Cancer. 2010;102:68–72. [5] Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51(Suppl 6):VI1–VI9. [6] Grove MK, Hermann RE, Vogt DP, Broughan TA. Role of radiation after operative palliation in cancer of the proximal bile ducts. Am J Surg. 1991;161:454–458. [7] Hoang BX, Le BT, Tran HD, et al. Dimethyl sulfoxide-sodium bicarbonate infusion for palliative care and pain relief in patients with metastatic prostate cancer. J Pain Palliat Care Pharmacother. 2011;25:350–355.
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[8] Hoang BX, Tran DM, Tran HQ, et al. Dimethyl sulfoxide and sodium bicarbonate in the treatment of refractory cancer pain. J Pain Palliat Care Pharmacother. 2011;25:19–24. [9] Bottiglieri, T. S-adenosyl-L-methionine (SAMe): from the bench to the bedside—molecular basis of a pleiotrophic molecule. Am J Clin Nutr. 2002;76:1151S–1157S. [10] Lineva OI, Osadchenko, E, Nesterenko SA. [Clinical trial of heptral in patients with chronic diffuse liver disease with intrahepatic cholestasis syndrome]. Klin Med (Mosk). 1998;76:45–48. [11] Frezza M, Centini G, Cammareri G, Le Grazie, C, Di Padova, C. S-adenosylmethionine for the treatment of intrahepatic cholestasis of pregnancy. Results of a controlled clinical trial. Hepatogastroenterology. 1990;37(Suppl 2):122–125. [12] Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–1281. [13] Lee JK, Capanu M, O’Reilly EM, et al. A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas. Br J Cancer. 2013;109:915–919. [14] Luo J, Li YN, Wang F, Zhang WM, Geng, X. Sadenosylmethionine inhibits the growth of cancer cells by reversing the hypomethylation status of c-myc and H-ras in human gastric cancer and colon cancer. Int J Biol Sci. 2010;6:784–795. [15] Hoang BX, Graeme Shaw D, Pham, P, Levine SA. Neurobioenergetic concepts in cancer prevention and treatment. Med Hypotheses. 2007;68:832–843. [16] Hoang BX, Levine SA, Shaw DG, et al. Dimethyl sulfoxide as an excitatory modulator and its possible role in cancer pain management. Inflamm Allergy Drug Targets. Nov. 4, 2010;9: 306–12. [17] Akaike A, Tamura Y, Sato, Y, Yokota, T. Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons. Eur J Pharmacol. 1993;241:1–6. [18] Travagli RA, Gillis RA, Kellar KJ. S-adenosyl-L-methionine modulates firing rate of dorsal motor nucleus of the vagus neurones in vitro. Eur J Pharmacol. 1994;264:385–390.
RECEIVED: 15 March 2014 REVISED: 23 April 2014 ACCEPTED: 2 May 2014
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ARTICLE
Palliative Treatment for Advanced Biliary Adenocarcinomas With Combination Dimethyl Sulfoxide–Sodium Bicarbonate Infusion and S-Adenosyl-L-Methionine Ba X. Hoang, Hung Q. Tran, Ut V. Vu, Quynh T. Pham, and D. Graeme Shaw AB STRACT Adenocarcinoma of the gallbladder and cholangiocarcinoma account for 4% and 3%, respectively, of all gastrointestinal cancers. Advanced biliary tract carcinoma has a very poor prognosis with all current available modalities of treatment. In this pilot open-label study, the authors investigated the efficacy and safety of a combination of dimethyl sulfoxide–sodium bicarbonate (DMSO-SB) infusion and S-adenosyl-L-methionine (ademetionine) oral supplementation as palliative pharmacotherapy in nine patients with advanced nonresectable biliary tract carcinomas (ABTCs). Patients with evidence of biliary obstruction with a total serum bilirubin ≤300 μmol/L were allowed to join the study. The results of this 6-month study and follow-up of all nine patients with ABTC indicated that the investigated combination treatment improved pain control, blood biochemical parameters, and quality of life for the patients. Moreover, this method of treatment has led to a 6-month progression-free survival for all investigated patients. The treatment was well tolerated for all patients without major adverse reactions. Given that ABTC is a highly fatal malignancy with poor response to chemotherapy and targeted drugs, the authors consider that the combination of DMSO-SB and ademetionine deserves further research and application as a palliative care and survival-enhancing treatment for this group of patients. KEYWORDS adenosylmethionine, biliary tract carcinoma, cholangiocarcinoma, dimethyl sulfoxide, sodium bicarbonate
group of cancers is 1 to 2 per 100,000 persons per year in the United States and Europe, and the rate increases to 87 per 100,000 in Southeast Asia.1 These highly fatal malignancies have 1- and 2-year survival rates of 25% and 13%, respectively.2 Because there are no specific symptoms in early malignant lesions, patients with this type of carcinoma mostly present in the advanced stages of the disease, which contributes to its poor prognosis. Patients with nonresectable disease receive palliative chemotherapy. Many agents, including fluoropyrimidines, gemcitabine, cisplatin/oxaliplatin, mitomycin C, doxorubicin, docetaxel, and irinotecan, have been tested and have shown very poor response rates and significant toxicities.3 Targeted therapy with sorafenib as a single agent has a low activity against advanced nonresectable
INTRODUCTION Biliary adenocarcinoma is the second most common primary hepatic malignancy worldwide. It arises either within the liver (intrahepatic cholangiocarcinoma) or in the extrahepatic bile ducts (extrahepatic cholangiocarcinoma). The rate of occurrence of this
Ba X. Hoang, MD, PhD, is a medical consultant with the Department of Oncology, and Hung Q. Tran, MD, PhD, is head of the Oncology Center, 198 Hospital, Hanoi, Vietnam. Quynh T. Pham, MD, is with the Departments of Internal Medicine and Palliative Care, Labor Medical Center, Hanoi, Vietnam. Ut V. Vu, MD, is with the Departments of Surgery and Oncology, Hospital of Traditional Medicine, Hanoi, Vietnam. D. Graeme Shaw, MD, is an internist in private practice in Los Altos, California, USA. Address correspondence to: Dr. Ba X. Hoang, Oncology Department, 198 Hospital, Tran Binh Street, Hanoi, Vietnam (E-mail: [email protected]).
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biliary tract carcinomas (ABTCs). Sorafenib is indicated for treatment of hepatocellular carcinoma and treatment of patients with advanced renal cell carcinoma who have failed prior interferon-α– or interleukin-2–based therapy or are considered unsuitable for such therapy. Recent trials suggest a median survival of 4.4 months and a progression-free survival of 2.3 months.4 Patients with ABTC usually present with obstructive jaundice and abdominal pain. Other common complaints include pruritus, weight loss, fever, and symptoms related to biliary obstruction such as claycolored stools and dark urine. Physical signs include jaundice, hepatomegaly, and a right upper quadrant mass. Despite the implementation of new techniques such as neoadjuvant chemoradiation, chemotherapy, radiotherapy, and palliative biliary drainage, these therapies have not been demonstrated to prolong survival significantly.5 For those diagnosed at an early stage, surgery remains the only possibility for cure and yet still only provides patients with a 20% 5-year survival. Treatment options for advanced disease are limited. Systemic chemotherapy is increasingly being used; however, many studies report a dismal median survival of approximately 6 months.6 In this study, we investigated the efficacy and safety of dimethyl sulfoxide–sodium bicarbonate (DMSOSB) infusion in combination with ademetionine in the palliative care and anticancer treatment for ABTC. Our prior clinical observations indicated that DMSOSB infusions in patients with metastatic prostate cancer showed significant improvement in a 90-day follow-up in clinical symptoms, blood and biochemistry tests, and quality of life.7 The same treatment may be a viable, effective, and safe treatment for refractory pain in patients with different types of advanced cancer.8 S-Adenosyl-L-methionine (also called S-adenosyl methionine, S-adenosylmethionine, SAMe, or SAMe in the United States or ademetionine in Europe, and also often abbreviated as AdoMet) is a chemical that is found naturally in the body. SAMe is sold in the United States as a dietary supplement. Ademetionine plays a critical role in the synthesis of polyamines and provides cysteine for the production of glutathione, the major endogenous hepatoprotective agent. We therefore decided to combine the supplementation of ademetionine in the treatment protocol for ABTC, considering our prior clinical experiences and results of published clinical trials that showed this agent was effective and well tolerated for patients with chronic diffuse liver disease with intrahepatic cholestasis syndrome.9–11
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PATIENTS AND METHODS Study Design This was an open-label, single-arm, nonrandomized trial conducted as both inpatient and outpatient. Written informed consent was obtained from all patients. We used a verbal descriptor scale (VDS) to measure the level of pain: “no pain” = 0; “mild pain” = 1; “moderate pain” = 2; “severe pain” = 3; “extreme pain” = 4. To evaluate the pain control effectiveness of the investigated protocol, the analgesic intake scale (AIS) according to the World Health Organization (WHO) (0 = no analgesics; 1 = NSAIDs [nonsteroidal anti-inflammatory drugs]; 2 = weak opioids; 3 = morphine) was used. To evaluate the performance status of the patients, we used a public-domain scoring system, the Eastern Cooperative Oncology Group (ECOG) performance status, that is widely used in the United States to assess how patients’ disease is progressing, to assess how the disease affects the daily living abilities of the patient, and to help determine appropriate treatment and prognosis. That scale is given in Box 1. Eligibility Criteria
Patients with ABTC were newly diagnosed by a complex of clinical symptoms and other standard biochemistry/imaging methods at special oncology hospitals or departments. Oncologists determined the patients’ tumors to be nonresectable or metastatic ABTC, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder adenocarcinoma.
BOX 1. ECOG Performance Status 0 Fully active, able to carry on all predisease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 5 Dead
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These patients were recommended by their oncologists to receive palliative and symptomatic treatments. The patients had refused to undergo standard treatment because of concern about cost, possible side effects, and the low rate of improvement and survival. All the patients were informed about the cost, possible toxicities, and potential rate of successes with the offered specific treatment. Included patients were required to have a ECOG ≤2, a hemoglobin level of ≥100 g/L, platelet count ≥100 × 109 g/L, bilirubin (serum) ≤300 μmol/L, albumin concentrations in serum ≥30 g/L, total serum proteins ≥60 g/L, creatinine ≤160 μmol/L, glutamicoxaloacetic transaminase (GOT) and glutamicpyruvic transaminase (GPT) ≤300 U/L, and γ glutamyltransferase (GGT) ≤300 U/L. Patient with uncontrollable hypertension and stage II heart failure were not accepted to the treatment protocol.
TABLE 1.
Clinical Endpoints
The patients decided to take part in our study by their own will after receiving a thorough explanation regarding the proposed treatment and other therapeutic options available. The main reasons for these patients choosing the studied therapy were the side effects of conventional treatments and the positive experience of other patients who had been successfully treated with the investigated therapeutic approach. The characteristics of patients and their current disease are shown in Tables 1 and 2.
The primary clinical endpoint was defined in the protocol as a ≥50% reduction in the pain score from baseline, or a reduction of ≥50% analgesic drug use. Improvement in ECOG scores was considered the second important clinical endpoint. Besides pain reduction and ECOG score reduction, any reduction in the symptoms and paraclinical measurement of the patients was considered as an important clinical endpoint of our study. Disease control as an objective was defined as the percentage of patients without disease progression by ECOG score, pain score, and total serum bilirubin. Secondary objectives included progression-free survival (PFS) and tolerability. Progression-free survival was defined as the time from the first day of administration of the study medications to disease progression. The primary endpoint was an improvement in 6 months (PFS6) from the historical 57.1% with current standard systemic therapy using gemcitabine and cisplatin for advanced biliary adenocarcinomas.12 Treatment continued until there was evidence of positive disease control rate progression by monitoring pain score, ECOG, and serum total bilirubin, development of side effects, or consent withdrawal.
Patients Nine patients with nonresectable ABTC with symptoms of obstructive jaundice with no prior specific treatment were enrolled in the study over a period of 6 months. The diagnosis of ABTC was made at specialized oncology departments based on the findings of computed tomography (CT), biopsy with cytomorphologic examination and a combination of clinical and biochemistry parameters.
Characteristics of the Patients N=9
Number of patients Median age Gender Female Male Median weight Site Intrahepatic Gallbladder Extrahepatic Major associated disorders Diabetes Chronic hepatitis B Liver cirrhosis Hypertension Gastritis Ulcerative colitis
61 (range: 48–73) 4 5 54 kg (range: 44–65) 3 2 4 3 1 2 4 4 2
Treatment All nine patients were treated with infusion of 25 mL of 99.9% DMSO solution mixed with 500 mL of sodium bicarbonate (SB) 1.4% solution and the equivalent of 1000 mg of potassium chloride and 1500 mg of magnesium sulfate. The infusions of DMSO-SB were performed by giving a continuous 5day infusion with a 2-day break for a total of three cycles of 20 treatments. Thereafter, the patients continued with two infusions in 5 days with a 2-day break for 24 more treatments. The mean speed of drip was 60 drops per minute. Despite the design of total 84 infusions for the 6-month treatment period, there were no patients who received the full treatment program due to different reasons. The maximal number of infusions was 80, the minimal was 74. The median number of infusion was 78. Besides the DMSO-SB infusion, the patients received 200 mg of ademetionine in enteric coated capsules, three times daily with food for the first week; 300 mg three times daily in the second week; and 400 mg and then three times daily after 2 weeks until the end of 6-month treatment period. Patients with edema were treated with appropriate Journal of Pain & Palliative Care Pharmacotherapy
Report TABLE 2 Patients’ Major Clinical Symptoms Related to ABTC Number of patients having symptoms Abdominal pain VDS 0 VDS 1 VDS 2 VDS 3 Total VDS Analgesic intake scale AIS = 0 AIS = 1 AIS = 2 AIS = 3 Total AIS Jaundice Pruritis Paraneoplastic fever Fatigue Low appetite Weight loss Hyperbilirubinemia
Elevated GOT
Elevated GPT
Elevated GGT
Clay-colored stool Dark urine Blood sugar elevation Anemia with a hemoglobin level of ≥100 g/L and ≤ 120 g/L Thrombocytopenia with platelet count ≥100 × 109 /L and ≤140 × 109 /L Hepatomegaly Right upper quadrant mass Splenomegaly ECOG 0 ECOG 1 ECOG 2
N=9 2 2 3 2 14 2 5 1 1 10 7 5 3 9 6 5 9 (maximal: 278 μmol/L, minimal: 38 μmol/L; mean: 186 μmol/L) 9 (maximal: 266 U/L, minimal: 122 U/L; mean: 191 U/L) 9 (maximal: 259 U/L; minimal: 116 U/L; mean: 185 U/L) 9 (maximal: 297 U/L; minimal: 252 U/L; mean: 276 U/L) 3 4 3 5 3
6 3 2 2 4 3
diuretics. All patients were allowed to take any medication for their symptoms and associated diseases, nutritional supplements, vitamins, and herbal medicines. Patients were advised to avoid red meats and dairy products in their diet. The patients were advised to take a dose of digestive enzymes before each meal if they experienced indigestion problems.
RESULTS Palliative Care and Quality of Life Outcome Two weeks after the treatment of DMSO-SB and ademetionine, abdominal pain decreased more than C
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50% from the baseline: VAS = 4 and AIS = 4. All patients reported a significant improvement; the ECOG total was reduced to 6 points. After 1 month, the VAS score was further reduced to 2, the AIS score was equal to 2, and the ECOG total for all patients was 4. By the end of 3-month treatment, the VAS was reduced to 0, the AIS was reduced to 0, and the ECOG was 1 total. Pain intensity and quality of life scores remained at these levels until the end of the 6-month treatment period. Pain control and quality of life progress in the 6 months of treatment are shown in Table 3.
Disease Control Rate and Progression-Free Survival (PSF) Besides the improvement in pain control and quality of life measured by VAS, AIS, and ECOG scores, the treatment of DMSO-SB and Ademetionine showed a positive disease control rate by the continually decreasing serum levels of total bilirubin and key liver functional enzymes, as shown in Table 4. The positive progress in the level of total serum bilirubin and liver enzymes shown in Table 4 indicates that treatment with DMSO-SB infusion plus ademetionine oral supplementation is effective in the improvement of the disease control rate and possible tumor reduction, since it reversed the bile obstructive syndrome and liver damage caused mainly by tumors in the biliary system metastases to the liver. The clinical symptoms of the patients with ABTC also improved throughout the 6-month period of treatment, as shown in Table 5. The surprising findings in monitoring the clinical symptoms such as abdominal pain, weight loss, weight gain, jaundice, hepatomegaly, total serum albumin, and liver enzyme elevations showed that all the subjects achieved stabilization of their disease. The clinical endpoints were achieved in all nine investigated patients. The treatment with DMSO-SB infusion and ademetionine oral supplementation not only showed that this combination effectively controlled pain, but also released the bile obstructive symptoms that enhanced quality of life for the patients. The PFS6 showed improvement to 100% compared with the historical PFS6 of 57.1%
Tolerability The treatment was well tolerated by all patients. There were a few cases of diarrhea and nausea during the initial 2 weeks of treatment. These were controlled by appropriate medication or resolved without any specific treatment. There was no toxicity observed clinically and in monthly monitoring of
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TABLE 3.
Pain Control and Quality of Life Outcome
Measure
Baseline
2 Weeks
1 Month
2 Months
3 Months
4 Months
5 Months
6 Months
4 4 6
2 2 4
1 0 2
0 0 1
0 0 1
0 0 1
0 0 1
0 0 1
Pain score VAS Pain score AIS ECOG
blood analysis and biochemistry parameters. The pH of blood remained within normal levels with maximum of 7.6 and minimum of 7.45 during the 6-month treatment.
DISCUSSION Most ABTCs are locally or metastatic disease at the time of diagnosis. Even if the tumors are resectable, long-time survival rates are low. For nonresectable ABTCs, chemotherapy combining gemcitabine with a platinum agent is the recommended first-line treatment regimen for advanced biliary tract cancer, with very poor results for an overall survival rate of more than 1 year. The addition of sorafenib to gemcitabine and cisplatin in advanced biliary tract cancers failed to show any improvement in outcome and proved to have significant toxicity at standard cytotoxic dosing.13 Due to their late diagnosis, the vast majority of the patients with ABTC are candidates for palliative management. The primary aim is to provide biliary drainage for relief from pain, jaundice, pruritus, and cholangitis. Endoscopically placed self-expanding metallic biliary stents is the modality of choice for patients with nonresectable ABTC. There are now multiple options to achieve this goal; however, they are still under investigation and are expensive, complicated, and associated with side effects that sometime contribute to a worsening of the disease outcome. DNA methylation plays a critical role in gene expression and other phenotypes, and DNA hypomethylation leads to gene instability and an increase in mutation frequency. The consequences of methylation abnormalities may activate oncogene transcription, increasing carcinogenesis and metasta-
TABLE 4.
sis. Ademetionine is a DNA hypermethylating agent that has been shown to inhibit carcinogenesis by controlling the activation of oncogenes. It also appears to be tumor specific, being both anti-apoptotic in normal liver cells and pro-apoptotic in liver cancer cells. Gastric and colon cancers also have benefited from similar treatments.14 Based on this research, we may speculate that other gastrointestinal tumors may respond to Ademetionine therapy. In our previous publications, we proposed the concept of cell membrane hyperexcitability through sodium channel activation and glutamate-induced N-methyl-D-aspartate (NMDA) receptor stimulation as a significant causal factor in carcinogenesis.15 We have published research regarding the role of dimethyl sulfoxide as a dual-inhibitory agent, which inhibits both voltage-gated sodium channels and glutamate receptors.16 In addition to its other properties, Ademetionine has been shown to be a NMDA receptor antagonist that inhibits glutamate cytotoxicity.17 Further research has documented S-adenosyl-Lmethionine’s ability to suppress neuronal excitability. This inhibitory property may have neuromodulatory effects on the physiological functions of the central nervous system (CNS) and peripheral organs.18 Not only do ademetionine and DMSO have complementary functions, but because of its ability to enhance membrane transport, DMSO also may have a synergistic effect on ademetionine by increasing its cellular levels. There is a possibility of synergic and potentiating therapeutic action of the three major components of the treatment—DMSO, sodium bicarbonate, and ademetionine—that would be of interest for future exploratory research and advancements for the management of hepatobiliary cancers among other possible cancers.
Dynamic of Total Serum Bilirubin (mmol/L) and Liver Enzymes During 6 Months of Treatment
Parameter
Baseline
2 Weeks
1 Month
2 Months
3 Months
4 Months
5 Months
6 Months
Median total Median GOT Median GPT Median GGT
186 191 U/L 185 U/L 276 U/L
124 117 U/L 108 U/L 129 U/L
102 93 U/L 96 U/L 104 U/L
85 82 U/L 85 U/L 91 U/L
68 74 U/L 79 U/L 86 U/L
52 66 U/L 71 U/L 82 U/L
36 64 U/L 66 U/L 79 U/L
32 63 U/L 62 U/L 74 U/L
Journal of Pain & Palliative Care Pharmacotherapy
Report TABLE 5.
Number of Patients With ABTC Symptoms During the 6-Month Treatment
Symptom Abdominal pain Jaundice Pruritus Paraneoplastic fever Fatigue Low appetite Weight loss Weight gain Hepatomegaly Splenomegaly Right upper quadrant
Baseline
2 Weeks
1 Month
2 Months
3 Months
4 Months
5 Months
6 Months
7 7 5 3 9 7 5 0 6 2 3
3 6 3 0 5 4 3 0 6 2 3
1 5 1 0 5 2 0 2 5 2 3
1 3 1 0 3 0 0 4 3 1 2
0 2 0 0 3 0 0 5 2 1 2
0 0 0 0 2 0 0 5 2 1 1
0 0 0 0 2 1 0 6 1 1 1
0 0 0 0 2 1 0 6 1 1 1
CONCLUSION Although this study represents only a small patient trial, we suggest that further research with the DMSO-SB infusion and ademetionine supplementation is indicated to determine the value of this therapy as a palliative and survival-enhancing treatment for patients with ABTC. Although this preliminary work is promising, a larger patient study with longer follow-up is needed to determine the potential benefit and overall survival of cancer patients using this nontoxic, noncomplicated, and inexpensive method of treatment. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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RECEIVED: 15 March 2014 REVISED: 23 April 2014 ACCEPTED: 2 May 2014
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