| | Advanced Cancer Cases Treated With Cultivated Wild Ginseng PhamacopunctureReceived 24 March 2010; accepted 15 April 2010. Abstract After administering cultivated wild ginseng pharmacopuncture (CWGP) to advanced cancer patients, the response and survival rate were evaluated. This prospective observational pilot study of CWGP was conducted at the East-West Cancer Center of Daejeon University, Dunsan Oriental Hospital from August 2007 to June 2008. Seven patients were recruited for this study. One cycle of treatment consisted of intravenous infusion of CWGP (20 mL/day) for 2 weeks with an expected treatment duration of four cycles (60 days, 2 months). Blood tests were conducted every cycle and computed tomography was performed every second cycle as follow-up. Overall survival was measured from initial administration of CWGP to death. We used the international standards provided by the Response Evaluation Criteria in Solid Tumors for measuring response rate and Kaplan-Meier analysis to determine statistical significance. Seven patients received a total of 55 cycles (1 with 1 cycle, 2 with 2 cycles, 1 with 3 cycles, 2 with 13 cycles, 1 with 20 cycles). One-year survival rate was 57.1%, and the median survival time was 544 days. Among these patients, two non-small cell lung carcinoma patients and one advanced gastric adenocarcinoma patient showed stable disease. Two patients dropped out after the first and second cycles of treatment without receiving a new computed tomography scan. Two patients showed progressive disease. Although a further large scale study is necessary, CWGP showed potential as an effective treatment for two non-small cell lung carcinoma patients and one advanced gastric carcinoma patient.
1. Introduction  Cancer patients receive not only modern Western medical care but also other treatments, commonly known as complementary and alternative medicine (CAM) [1]. CAM is more prevalent in Asia due to the unique use of traditional medical care. Within traditional medicine, oriental medicine is one of the most widely used in many countries for various diseases. Traditional medicine has not been able to develop methods of cancer treatment on the same scale as Western medicine because most of the traditional medical theories were developed during times when the idea of cancer was not definitively formulated. Recently, with the advancement of CAM around the world, there have been many clinical trials and developments in cancer therapy using traditional medical. Pharmacopuncture therapy is a new form of therapy derived from a combination of herbal medicine and acupuncture therapy. Minute amounts of herbal extract are injected in affected areas (acupoints or intravenous) to induce a therapeutic response by maximizing the efficacies of acupuncture and herbal medicine [2]. In Korean medicine, ginseng (Panax ginseng C.A. Meyer) has long been used as a general tonic or an adaptogen to promote longevity and enhance bodily functions. It has also been claimed to be effective in combating stress, fatigue, oxidants, diabetes mellitus and cancer [3]. The literature on Cultivated Wild Ginseng Pharmacopuncture (CWGP) comprises anecdotal evidence, case reports of cancer treatment, phase I clinical trials for healthy volunteers, cell culture experiments, animal experiments and mechanism studies [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]. Evidence of dosage, treatment period and cancer type are not sufficient to support its anti-cancer efficacy even though some Korean oriental medical doctors believe that intravenous infusion or point injection of CWGP is effective for terminally ill cancer patients. We decided to conduct a descriptive pilot study for heterogeneous cancer patients in advanced stages to collect clinical evidence for the effects of CWGP on advanced cancer. 2. Materials and Methods 2.1. Patients Seven patients were recruited between August, 2007 and June, 2008. We explained treatment to these patients and obtained their informed consent. This study proceeded at East-West Cancer Center. Eligibility criteria included the following:
(1)Histological or radiological diagnosis of progressive malignant tumor. The patient also was not subject to conventional therapies including surgery, anticancer drugs, radiation, embolization, hormone therapy, immunotherapy and traditional oriental medicine;
(2)Eastern Cooperative Oncology Group (ECOG) score ≤ 3;
(3)Measurable malignant disease using the international standard provided by the Response Evaluation Criteria in Solid Tumors (RECIST), including complete/partial response, progressive/stable disease);
(4)Completed anti-cancer drugs and/or radiation treatment 4 weeks prior to participation;
(5)Recovered from any side-effects of anti-cancer drugs and/or radiation treatment;
(6)Possess proper bone marrow function (peripheral absolute granulocyte count > 150×109/L, platelet count > 100×109/L);
(7)Proper liver function (bilirubin ≤ 1.5 mg/dL, serum glutamic pyruvic transaminase or serum glutamic oxaloacetic transaminase < 3×normal) and kidney function (creatinine ≤ 1.5 mg/dL).
2.2. Treatment Patients received CWGP 20 mL/day by intravenous infusion. One cycle was composed of 2 weeks (14 days). 2.3. Endpoints Two endpoints were set to evaluate the result: (1) survival rate, including overall survival (from initial administration of CWGP to death), survival or discontinued follow-up (from initial administration of CWGP to final check or discontinued follow-up), and Kaplan-Meier analysis; (2) response rate, as measured by the International standard provided by RECIST as complete response, partial response, progressive disease and stable disease. 2.4. Tumor measurement for response rate Computed tomography (CT) scan was performed in patients at the start of the study and initial tumor size was recorded. After every two cycles (4 weeks), another CT scan was performed. RECIST criteria for solid tumors were used in our study. Compared with initial tumor size, a decrease of 30% or greater in size was confirmed as partial response, an increase of 20% or greater was confirmed as progressive disease, and neither was confirmed as stable disease. 3. Results 3.2. Overall survival In Figure 1, the median for 20 mL CWGP total survival period was 544 days. Minimum survival was 26 days and the maximum survival was 898 days. One year survival rate was 57.1% (4/7). Figure 2 is a comparison of survival times between patients with ECOG ≤ 2 versus patients with ECOG=3. This observation demonstrated that patients with ECOG ≤ 2 all survived the trial duration (4/4), but patients with ECOG=3 all died during this period (3/3). Median survival days were 657 vs. 56, respectively. 3.3. Response rate The data of each patient is shown in Table 2, Table 3. Two patients were not evaluated due to drop out after the first and second cycles of treatment and no follow up CT scans were obtained. In the remaining five patients, two patients showed progressive disease and three patients experienced stable disease. 3.4. Cases of stable disease Case 1 (No.7) was a 67-year-old woman diagnosed with non-small cell lung carcinoma (NSCLC; adenocarcinoma) on June 25, 2007. Tumor stage was IIIB (T2N3M0) with a mass (5 cm×4 cm) in the left lower lobe of the lung and accompanying lymph node enlargements. Because of her old age, she refused conventional therapy. Instead, she initiated CWGP treatment as a CAM from July 6, 2007. Administration of CWGP was 20 mL daily (21 cycles). Cancer growth was halted for 29 weeks (7 months). But positron emission tomography-computed tomography on January 31, 2008 revealed a metastatic lesion of the adrenal gland. Subsequent PET-CT on May 7, 2008 also showed an increase in the size of the metastatic lesion in the adrenal gland. Case 2 (No.6) was a 63-year-old man diagnosed with non-small cell lung carcinoma on October 31, 2007. Tumor stage was IIIA (T1N2). He refused conventional therapy as he wished to be treated with CAM even though health providers recommended surgical therapy for him. CWGP treatment was initiated from November 26, 2007. Administration of CWGP was 20 mL daily (13 cycles). Cancer growth was halted for 33 weeks (8 months), but chest CT on July 6, 2008 showed progression of the disease. Case 3 (No. 4) was a 55-year-old man diagnosed by CT as having stomach cancer metastasized to the liver on October 9, 2007. Tumor stage was IV. CWGP treatment was initiated from December 12, 2007. Administration of CWGP was 20 mL daily (13 cycles). Cancer growth was halted for 26 weeks (6.5 months), but abdominal CT on June 4, 2008 showed progression of the disease. 4. Discussion Cultivated wild Ginseng (Panax ginseng C.A. Meyer), a Korean traditional medicinal herb, has been used clinically in Korea and other Asian countries for thousands of years [3]. Recently, there have been controversies concerning the usefulness of ginseng in cancer therapy. Most studies claimed that the pharmacological effects of ginseng are attributed to its bioactive constituents such as ginsenosides, saponins, phytosterols, peptides, polysaccharides, fatty acids, polyacetylenes, vitamins and minerals [12]. However, in a previous study, wild ginseng pharmacopuncture was experimentally shown to have anti-tumor effects, while its intravenous safety showed no difference from that of saline [4, 8, 15]. Produced by a distillation process, CWGP is composed of over 99% water and less than 1% wild ginseng. However, the present study did not verify its effective compounds. In the production process, less than 1% was found to contain flavonoids by gas chromatography-mass spectrometry. There are many types of flavonoids, such as quercetin, hesperidin and anthocyanidins (cyanidins, delphinidin, malvidin, pelargonidin, peonidin and petunidin). Flavonoids, as a group of compounds, interfere with inflammation and carcinogenesis in various ways. Several flavonoids quench reactive oxygen species. Other flavonoids suppress the pro-inflammatory and growth promoting gene mediated by nuclear factor kappa B. Flavonoids also interfere with signal transduction pathways, which reduce tumor initiation and promotion [16]. Delphinidin, an anthocyanidin flavonoid, interferes with signal transduction pathways. Low concentrations of delphinidin in vitro have been shown to inhibit vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of VEGFR-2, leading to the inhibition of downstream signaling and VEGF-induced activation of ERK-1/2 signaling [17]. In the present study, it is not clear whether the effect of CWGP treatment came via flavonoid activity; however, a connection with some flavonoid components may be a possibility. Six previous studies have investigated the anti-cancer effect of CWGP. The first study [6] concluded that CWGP did not show a significant anti-cancer effect in B16/F10 melanoma, but inhibited the damage to epithelial cells seen with doxorubicin. The second study [7] concluded that cultivated wild ginseng herbal acupuncture caused negligible toxicity. All experimental groups showed significant increase in survival rate following the anti-cancer effects on a sarcoma-180 cancer cell line [7]. In the third study [8], inhibitory effects of ginseng against cancer growth in a case of hepatic metastasis were also observed when colon 26-L5 carcinoma cells were injected via the hepatic portal vein. The level of cytokine IL-4, which stimulates Th2, showed a significant increase [8]. The fourth study [9] described a clinical case which concluded that CWGP could be an effective measure for multiple metastatic cancer patients with hepatocellular carcinoma. The fifth study [10] was conducted in apoptosis induced A549 human lung cancer cell lines which showed that the cell destruction efficacy of CWGP improved when pH and electrolytes were adjusted. Additionally, various concentrations of CWGP have been experimentally demonstrated to induce apoptosis in lung cancer cells [11]. Some findings pertaining to CWGP treatment were observed preceding this trial. Intravenous infusion of CWGP 20 mL/day was shown not to be useful in prolonging the survival rate of poor ECOG patients. By contrast, a possibility of increased survival was seen in good ECOG patients. For our small number of participants, differences in cancer type, stage and ECOG score made it difficult to make any conclusions about the efficacy of CWGP on the response rate, but given that three of seven participants showed stable disease, future studies into CWGP may be warranted. In this study, three advanced cancer patients (two NSCLC, one advanced gastric cancer) showed stable disease that even when it became progressive, were with few complications. These patients lived well over 1 year in spite of their poor prognosis, and maintained good quality of life. This observation suggests that dosage and treatment periods should be over 20 mL/day and 13 cycles long, respectively. The efficacy of CWGP in NSCLC would be interesting to investigate in the next stage of studies, given the accumulated evidence of CWGP use for the treatment of this cancer to date. Although further large scale study are needed, CWGP was found to be an effective treatment intervention for two NSCLC patients and one advanced gastric carcinoma patient in this study. Acknowledgments This work was supported by a Korea Pharmacopuncture Institute grant. The authors thank Ms. Hyo-Min Park for English proofreading. References 1.
1
Liu YS
, Lee JH
, Lee YW
, et al.
Integrative oncology practice guidelines
.
J Kor Orient Oncol
. 2007;12:37–65
.
2.
2
Korean Institute of Pharmacopuncture
.
In:
Pharmacopuncturology
. Seoul: Elsevier Korea LLC; 2008;p. 2–4
.
3.
3
Yue PYK
, Mak NK
, Cheng YK
, Leung KW
, Ng TB
, Fan DTP
, et al.
Pharmacogenomics and the Yin/Yang actions of ginseng: anti-tumor, angiomodulating and steroid-like activities of ginsenosides
.
Chin Med
. 2007;2:1–21
.
4.
4
Kwon KR
.
Clinical study on the effects of intravenous wild ginseng herbal acupuncture on the human body
.
J Korean Pharmacopuncture Inst
. 2004;7:15–26
.
5.
5
Bang SH
, Kwon KR
, Yoo HS
.
Two cases of non-small cell lung cancer treated with intravenous cultivated wild ginseng pharmacopuncture
.
J Korean Pharmacopuncture Inst
. 2008;11:13–19
.
6.
6
Kwon KR
, Park CW
, Ra MS
, Cho CK
.
Clinical observation of multiple metastatic cancer patients with hepatocellular carcinoma treated with cultivated wild ginseng herbal acupuncture therapy
.
J Korean Acupunct Moxibustion
. 2005;22:211–217
.
7.
7
Kwon KK
, Cho AL
, Lee SG
.
The study on acute and subacute toxicity and sarcoma-180 anti-cancer effects of cultivated wild ginseng herbal acupuncture
.
J Korean Herb Acupunct
. 2003;6:7–27
.
8.
8
Kwon KK
, Yoon HC
, Kim HH
.
Anti-cancer effects of cultivated wild ginseng herbal acupuncture in C57BL/6 mice injected with B16
.
J Korean Herb Mox
. 2006;23:105–120
.
9.
9
Lim SY
, Lee SJ
, Kwon KK
.
Anti-cancer and immune promoting effects of cultivated wild ginseng herbal acupuncture on hepatic metastatic model using colon 26-L5 carcinoma cells
.
J Korean Acupunct Mox
. 2006;23:121–134
.
10.
10
Gok KS
, Lee SG
, Kwon KR
.
An experimental study on apoptosis of cultivated wild ginseng distilled herbal acupuncture by controlled pH and electrolytes
.
J Korean Acupunct Moxibustion
. 2004;21:1–17
.
11.
11
Cho HC
, Lee SG
, Kwon KR
.
An experimental study on apoptosis of cultivated wild ginseng distilled herbal acupuncture by concentration level
.
J Korean Pharmacopuncture Inst
. 2004;7:1–15
.
12.
12
Chang YS
, Seo EK
, Gyllenhaal C
, Block KI
.
Panax ginseng: a role in cancer therapy?
.
Integr Cancer Ther
. 2003;2:13–33
.
MEDLINE |
CrossRef
13.
13
Kim JS
, Shin SS
, Seo BI
, Jee SY
.
Effect of mountain grown ginseng radix, mountain cultivated ginseng radix, and cultivated ginseng radix on apoptosis of HL-60 cells
.
Korean J Herbology
. 2004;19:41–50
.
14.
14
Chung DK
, Kwon SJ
.
The immune-enhancing effect of mountain gown ginseng, mountain cultivated ginseng, and Panax ginseng
.
J Orient Neuropsychiatry
. 2004;15:89–101
.
15.
15
Kwon KR
, Lee SG
, Cho AL
.
The study on acute and subacute toxicity and anti-cancer effects of cultivated wild ginseng herbal acupuncture
.
J Korean Pharmacopuncture Inst
. 2003;6:7–27
.
16.
16
Donald IA
, Andrew TW
.
In:
Integrative Oncology
. Oxford University Press; 2009;p. 124–125
.
17.
17
Lamy S
, Blanchette M
, Michaud-Levesque J
, Lafleur R
, Yves Durocher Y
, Albert Moghrabi A
, et al.
Delphinidin, a dietary anthocyanidin, inhibits vascular endothelial growth factor receptor-2 phosphorylation
.
Carcinogenesis
. 2006;27:989–996
.
MEDLINE |
CrossRef
a East-West Cancer Center, Dunsan Korean Medical Hospital, Daejeon University, Daejeon, Korea b Departments of Acupuncture and Moxibustion, College of Korean Medicine, Sangji University, Wonju, Korea  Corresponding author. East-West Cancer Center, Dunsan Korean Medical Hospital, Daejeon University, 1136 Dunsan-dong, Seo-gu, Daejeon 302-122, Korea
PII: S2005-2901(10)60022-2 doi:10.1016/S2005-2901(10)60022-2 © 2010 Korean Pharmacopuncture Institute. Published by Elsevier Inc. All rights reserved. | |
|
FULL TEXT
