Research Highlights

A Mixed Bag When it Comes to Acupuncture Randomized Control Trials Reporting

Acupuncture is a relatively safe complementary and alternative medicine modality and has been used for centuries. Acupuncture, as a part of cancer care, is increasing in availability at cancer centers. A recent systematic review* by M. Kay Garcia Dr.P.H., M.S.N., LAc of the University of Texas MD Anderson Cancer Center, and colleagues, identified prospective randomized clinical trials (RCT) investigating the use of acupuncture for symptom management among patients with cancer, along with evaluating each study's inherent risk of bias. The authors also provided recommendations for physicians and researchers regarding the use and study of acupuncture. This research was supported in part by a cooperative agreement and grant from the National Cancer Institute**.

Prospective RCTs using acupuncture with needle insertion for symptom management in patients with cancer were screened for inclusion in the systematic review. Studies using therapies similar to acupuncture, but that did not involve needle insertion (such as acupressure or laser acupuncture) or trials that compared only two types of acupuncture to each other were excluded. Forty-one studies were deemed acceptable for inclusion; four of the studies were written in Chinese and were read by study authors fluent in the language. Some studies included treatment for more than one symptom.

Risk of bias (ROB) in the studies was determined according to the Cochrane ROB criteria, which included criterion relating to missing data, lack of blinding of participants, and small study sample size, among others. Meeting the criterion for high risk in any of these categories caused a study to be rated as having high ROB, and alternatively, meeting criterion for low risk in all categories allowed studies to be rated as low ROB. Issues with ROB appeared throughout most of the studies. Of the 41 studies included in the review, only one trial was categorized as having low ROB (positive trial). Of the remaining trials, eight had unclear ROB (four positive, three negative, one unclear), and 33 had high ROB (19 positive, 11 negative, 3 both positive and negative outcomes). Issues with small sample size were also found throughout, with 39% of trials having had fewer than 60 participants.

The analysis of studies showed that the majority of symptoms treated with acupuncture included pain, nausea, postoperative ileus, and xerostomia (dry mouth). Other symptoms studied included hot flashes, fatigue, mood disturbances, and sleep disturbance. Pain was the most common symptom treated, and was represented by 11 RCTs. Problems with high ROB included lack of blinding of patients and small sample size. One trial tested acupuncture in a small group for the management of aromatase-inhibitor-associated joint pain, with initial positive results of reduced joint symptoms and improved functional ability. The subsequent blinded, sham- control trials showed that worst pain scores were significantly lower in the true acupuncture group.

Nausea and vomiting are common side effects associated with cancer treatment. A three- arm study (n=104) to help control myeloablative chemotherapy-induced emesis (vomiting) among women with breast cancer was assessed by the authors. All patients were receiving the same chemotherapy regimen and antiemetic drugs. The three arms of the study included: electroacupuncture at sites indicated for nausea and emesis control; minimal needling away from emesis acupuncture sites; and antiemetic medication only. This trial had low ROB, and showed that at the end of the 5-day study period, the electroacupuncture group had significantly fewer episodes of emesis versus minimal needling. Also the minimal needling group had significantly fewer episodes of emesis than the medication- alone group.

Postoperative ileus, or the inhibition of muscular contractions in the wall of the intestine responsible for pushing along the gastrointestinal (GI) tract contents, which can cause abdominal distention, nausea, vomiting, and diet intolerance, can be a common side effect of many surgical operations. Eight RCTs investigating acupuncture and postoperative ileus met inclusion criteria, though six had high ROB. One study in patients with intestinal tumors, randomizing 35 participants to acupuncture and 35 to usual care, did show a positive effect. No studies of acupuncture to treat diarrhea, constipation, or loss of appetite met the inclusion criteria.

According to the authors, the strongest evidence for use of acupuncture was for the control of nausea and vomiting. At least two studies provided positive results with low or unclear ROB.

High ROB due to a lack of complete reporting was an issue across studies, and given the strong placebo effect associated with acupuncture, the authors noted it is important to know more about the therapeutic ritual, who provided the treatments, and if different practitioners were used in different groups. These details would lead to a better understanding of any placebo component in the patient-practitioner relationship. Authors noted that “studies in which a single unblinded acupuncturist provides all treatments may be at risk of introducing bias, especially if one individual provides treatment to both active and inactive groups in a sham-controlled trial.” The authors continued that “regardless of the specific molecular basis of the effects, acupuncture for nausea/vomiting is a safe and inexpensive treatment that can relieve considerable suffering and may be an especially important option for patients who do not get good symptom control with pharmaceuticals.”

However, the authors cautioned that “for other symptoms such as pain, hot flashes, xerostomia, anxiety, or fatigue, efficacy is undetermined largely owing to high ROB among studies.”

According to this review, future acupuncture trials should focus on standardizing comparison groups and treatment methods, ensuring that at least single blinding is used, use multiple acupuncturists, identify biologic mechanisms, and conduct trials with adequate statistical power.

NCI researchers presented in vitro and in vivo research
at the American Association of Cancer Research
2013 annual meeting

As part of an intramural research collaboration with Guang An Men Hospital, China Academy of Chinese Medical Sciences in Beijing, China, the NCI Laboratory of Cancer Prevention within the Center for Cancer Research is currently hosting Guang An Men visiting fellow, Weidong Li, M.D., Ph.D. Dr. Li, supported in part by OCCAM, is working with NCI staff scientist Matthew R. Young, Ph.D. and scientist emeritus and former Laboratory Chief, Nancy H. Colburn, Ph.D. on research designed to explore the potential for certain compounds used in Traditional Chinese Medicine (TCM) to prevent colon cancer and investigate their related mechanisms.

“OCCAM is interested in traditional medical systems, especially understanding and verifying drug efficacy against cancer,” said Libin Jia, M.D., scientific program manager at OCCAM managing this project. “This study is the fourth collaboration project between Guang An Men Hospital and NCI on the research of Chinese medicine and cancer. The other projects looked at several TCM products such as Sheng Qi Formula and Kushen Injection, but this is the first one on cancer prevention.”

Dr. Li’s work, which was accepted for a poster presentation at the 2013 AACR annual meeting, consisted of both in vitro colorectal cancer cell lines and in vivo mouse studies testing berberine. Berberine is an isoquinoline alkaloid isolated from plants. It can be found in plants such as the Oregon grape, barberry, goldenseal, Chinese goldthread and others. It has been used for many purposes from traditionally dying fabric to use as an antibiotic. It has also shown anti-diabetic, anti-inflammatory, and anti-tumor effects. Berberine is often used clinically in China as one of the traditional drug components for cancer patients for symptom management, such as diarrhea control.

Three human colorectal cancer cell lines were treated with berberine to evaluate inhibitory effects on cell growth. Dr. Li and colleagues tested berberine on the AMP-activated protein kinase, or AMPK. AMPK is a cellular energy sensor that is a potential therapeutic target for cancer. Previous research by others has shown that berberine displays beneficial effects in the treatment of diabetes and obesity in part by stimulating AMPK activity. Dr. Li’s work tested whether berberine, when used to treat colon cancer, is also linked to the activation of the AMPK pathway.

The three human colorectal cancer cell lines were treated with escalating doses of berberine and cell growth was monitored. It was found that berberine inhibited the growth of the three cell lines and activated AMPK in a dose-dependent manner. The experiment also showed that berberine down-regulated other colorectal cancer targets related to cell growth, such as mTOR (mammalian target of rapamycin, which regulates cell growth, proliferation, and other processes).

An in vivo mouse model of colitis-induced colon cancer was used to explore the effects of berberine against colon cancer. Mice were divided into two groups and treated with either berberine or water for 10 weeks. Results showed that berberine-treated mice experienced a significant reduction in the number of tumors present compared to control mice (60%). The researchers also compared the sizes of tumors that were present in the animals at the end of the experiment. Berberine-treated mice did not have any tumors that were larger than 4mm. Compared to control animals, berberine-treated mice had 94% less tumors between 2-4mm and 49% less tumors that were smaller than 2mm.

Dr. Li and colleagues noted that their data suggests that berberine suppresses colon cancer cell proliferation via inhibition of the mTOR protein through activation of AMPK. Interestingly, the antidiabetic drug Metformin has shown anticancer activity via similar mechanisms.

“To elucidate the berberine mechanism of action on the molecular level is important. We are very impressed to see the progress within a short time from this collaborative research project by Drs. Li, Young, and Colburn on TCM cancer prevention,” praised Dr. Jia.

Dr. Li and colleagues noted that berberine may become a promising candidate for chemoprevention, and possibly treatment, of colon cancer but further studies in humans are needed. “Clinical studies in humans would most likely include using berberine in combination with another conventional cancer therapy, like chemotherapy. This may be a possibility for the future,” noted Dr. Li.