Goshajinkigan

Goshajinkigan

PEP Topic 
Peripheral Neuropathy
Description 

Goshajinkigan is a Japanese herbal medicine composed of 10 ingredients that is reported to affect sensory nerves. This preparation was studied for its effectiveness in preventing and managing chemotherapy-induced peripheral neuropathy.

Effectiveness Not Established

Research Evidence Summaries

Abe, H., Kawai, Y., Mori, T., Tomida, K., Kubota, Y., Umeda, T., & Tani, T. (2013). The Kampo medicine Goshajinkigan prevents neuropathy in breast cancer patients treated with docetaxel. Asian Pacific Journal of Cancer Prevention, 14, 6351–6356.

doi: 10.7314/APJCP.2013.14.11.6351
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Study Purpose:

To evaluate the effects of ​goshajinkigan (GJG) compared to vitamin B12 on the incidence of docetaxel (DOC)-associated peripheral neuropathy (PN) in chemotherapy-naïve patients with breast cancer

Intervention Characteristics/Basic Study Process:

Patients were stratified by type of chemotherapy and age for randomization by dynamic allocation (balanced marginal distribution of stratification factors) then randomly assigned to receive either GJG (7.5 g per day orally divided into two to three doses before or between meals during DOC therapy) or B12 (1,500 mcg per day orally after meals daily during DOC therapy). A baseline evaluation of adverse effects was completed on days 1 and 8 by nurses. using the Neurotoxicity Criteria of Debiopharm (DEB-NTC), the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), and a Visual Analog Scale (VAS) for pain. The VAS for pain was completed again after DOC chemotherapy. The study continued as long as DOC treatment or for six cycles. Patients were premedicated with 5-HT receptor antagonists and corticosteroids. A granulocyte-colony stimulating factor (filgrastim or lenograstim) was administered if a patient's neutrophil was less than 500/mcL or if febrile neutropenia occurred. Chemotherapy regimens included TC (DOC 75 mg/m2 and cyclophosphamide 600 mg/m2 for three weeks for four cycles), single-agent DOC (DOC 100 mg/m2 for three weeks for four cycles), and XT (capecitabine 900 mg/m2 PO BID on days 1–14 and DOC 60 mg/m2 for three weeks for six cycles). Patients receiving HER-2 therapy received trastuzumab before chemotherapy.

Sample Characteristics:

  • N = 57
  • MEDIAN AGE = 58 years (range = 33–70 years)
  • FEMALES: 100%
  • KEY DISEASE CHARACTERISTICS: Breast cancer stages I, IIa, IIb, and III

Setting:

  • SITE: Single-site
  • SETTING TYPE: Outpatient
  • LOCATION: Shiga University of Medical Science Hospital, Shiga, Japan

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Study Design:

Prospective, randomized, parallel-group trial

Measurement Instruments/Methods:

  • Neurotoxicity Criteria of Debiopharm (DEB-NTC)
  • National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE v3.0)
  • Visual Analog Scale (VAS) for pain

Results:

The incidence of PN was significantly lower in the group receiving GJG (39.3%) compared to the group receiving B12 (88.9% [p < 0.01]). The incidence of grades 2 and 3 PN were significantly lower in the group receiving GJG compared to the group receiving B12 (DEB-NTC = p < 0.01 and NCI-CTCAE p < 0.01). The mean VAS score was significantly lower in the group receiving GJG (2.7 + 2.2) versus B12 (4.9 + 2.4 [p = < 0.01]). There were no significant differences in characteristics between the groups. The completion rate and recommended dietary intake percent were similar for the GJG and B12 treatment groups. The total dose of DOC was 338.5 mg/m2 in the GJG group versus 340 mg/m2 in the B12 group.

Conclusions:

The findings of this study suggest that GJG might be helpful in the prevention of PN in patients receiving chemotherapy regimens that include DOC. However, additional research to develop strong evidence in this area is needed.

Limitations:

  • Small sample (< 100)
  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Measurement/methods not well described
  • Findings not generalizable
  • Other limitations/explanation: There was a reporting discrepancy in which N = 57 patients enrolled in results, but the data report n = 33 in the GJG group and n= 27 in the B12 group, totaling 60 patients. There is no explanation for drop-outs or missing data. There was no placebo control group receiving only chemotherapy. There was no explanation of the study's timeframe. The VAS was completed at baseline and after DOC chemotherapy, but the methods of assessment not well described. The study included conflicting reports of patient characteristics, stating that 16% of patients received neoadjuvant chemotherapy even though this was stated as an exclusion criterion. It was unclear whether the total DOC dose between groups was significant. It was reported that there was no difference between groups regarding other toxicities, but the data displayed frequencies not of significance with the chi square P value. There was no report regarding the timeframe of PN onset or occurrences during treatment between groups. The use of B12 was reported as increasing the incidence of neurotoxicity, yet no control group existed as a frame of reference to make this assumption. A break-down of the data differences in the PN scales used (NCI-CTCAE and DEB-NTC, sensory severity/impairment and duration) was not provided. The definitions of grades are different between the two scales.

Nursing Implications:

GJG at 7.5 g per day orally divided into two to three doses before or between meals may be beneficial to reduce incidence and severity of PN in patients with breast cancer receiving first-time DOC regimens. The safety and efficacy of this treatment need to be validated in larger randomized, controlled trials that compare GJC to placebos and use other assessment instruments.

Kono, T., Hata, T., Morita, S., Munemoto, Y., Matsui, T., Kojima, H., . . . Mishima, H. (2013). Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): A phase 2, multicenter, randomized, double-blind, placebo-controlled trial of goshajinkigan to prevent oxaliplatin-induced neuropathy. Cancer Chemotherapy and Pharmacology, 72, 1283–1290.

doi: 10.1007/s00280-013-2306-7
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Study Purpose:

To evaluate the efficacy of a Japanese medicine called goshajinkigan (TJ-107) for preventing oxaliplatin-induced neuropathy, compared to placebo controls, and also to evaluate its safety

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive goshajinkigan ( TJ-107) 7.5 mg per day day, a mix of extracts of 10 crude herbs, or placebo for 26 weeks starting on the first day of chemotherapy. Neuropathy was measured before each chemotherapy cycle every two weeks until the eighth chemotherapy cycle and every four weeks thereafter until 26 weeks. Patients randomly were assigned to the intervention or control group.

Sample Characteristics:

  • N = 89
  • MEDIAN AGE = 64 years
  • AGE RANGE = 36–88 years
  • MALES: 53.9%, FEMALES: 41.6%
  • KEY DISEASE CHARACTERISTICS: To be included in the study, patients had to be undergoing oxaliplatin-based chemotherapy for colorectal cancer.
  • OTHER KEY SAMPLE CHARACTERISTICS: Primarily Eastern Cooperative Oncology Group score of 0 upon enrollment

Setting:

  • SITE: Multi-site   
  • SETTING TYPE: Outpatient    
  • LOCATION: Japan

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active treatment
  • APPLICATIONS: Palliative and supportive care

Study Design:

  • Double-blinded, randomized, placebo-controlled trial

Measurement Instruments/Methods:

  • Neuropathy was measured by National Cancer Institute Common Terminology Criteria for Adverse Events (version 3) sensory items at baseline and every two weeks until the eighth cycle of chemotherapy and monthly until the 26th week.
  • The FACT/GOG-NTX-12 also was completed by patients at baseline and before every chemotherapy cycle.

Results:

Although there was a trend toward lower neuropathy scores as measured by the FACT/GOG-NTX in the intervention group at eight weeks (p = .421) and 26 weeks (p = .151), the differences were not statistically significant. The incidence of grade 2 peripheral neuropathy or greater until the eighth cycle was 39% in the experimental group and 51% in the control group (RR = 0.76, 95% CI 0.47–1.21), and the incidence of grade 3 or greater neurotoxicity was 7% in the treatment group and 13% in the placebo group (RR = 0.51, 95% CI 0.14–1.92). The time to development of grade 2 or greater toxicity was 5.5 months in the experimental group and 3.9 months in the placebo group (RR = 0.65, 95% CI 0.36–1.17). No differences were observed between those getting the different FOLFOX regimens. The goshajinkigan was tolerated well. Adverse effects were similar between study groups and most likely caused by the chemotherapy, but vomiting was significantly less prevalent in the treatment group (p = .029).

Conclusions:

Goshajinkigan may delay development of grade 2 or greater oxaliplatin-induced peripheral neuropathy, and there was a trend toward less severe chemotherapy-induced peripheral neuropathy in the intervention group at 8 and 26 weeks as compared to the control group.

Limitations:

  • Small sample (less than 100)
  • Findings not generalizable
  • Other limitations/explanation: Not generalizable to people with neuropathy caused by any other drug than oxaliplatin

Nursing Implications:

This study showed that administration of goshajinkigan, a traditional Japanese kampo medicine, was associated with reduced prevalence and severity of neurotoxicity among patients receiving oxaliplatin and was tolerated well by patients. Further study is needed to support the use of goshajinkigan for oxaliplatin-induced peripheral neuropathy. Goshajinkigan may not be widely available in the United States or outside of Japan.

Nishioka, M., Shimada, M., Kurita, N., Iwata, T., Morimoto, S., Yoshikawa, K., . . . Kono, T. (2011). The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen. International Journal of Clinical Oncology, 16, 322-327.

doi: 10.1007/s10147-010-0183-1
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Study Purpose:

To clarify the efficacy of Goshajinkigan (GJG) for peripheral neuropathy associated with oxaliplatin

Intervention Characteristics/Basic Study Process:

Intervention Studies: From January 2007 through December 2009, 45 patients with advanced or recurrent colorectal cancer who were being treated with 5-fluorouracil, oxaliplatin, and leucovorin (FOLFOX) every two weeks participated in the study. Patients were randomized to receive either oral GJG (7.5 g/daily) or no drug. The median number of cycles was 13 for the patients in the GJG group and 12 for the control group. Neuropathy was evaluated during every course according to the Neurotoxicity Criteria of Debiopharm. Other neuromodulatory agents such as calcium and magnesium infusions were not allowed during the study. Oxaliplatin dose was reduced in the event of grade 3 neuropathy.

Sample Characteristics:

  • N = 21      
  • MEDIAN AGE = 67 years
  • MALES = 51%,  FEMALES = 49%
  • KEY DISEASE CHARACTERISTICS: The GJG group included 15 patients with colon cancer and 7 patients with rectal cancer. The control group included 16 patients with colon cancer and 7 patients with rectal cancer.
  • OTHER KEY SAMPLE CHARACTERISTICS: 82% had received no previous treatment. The median cumulative dose of oxaliplatin was 1112.5 mg/m2, with a range of 340–2720.

Setting:

  • SITE: Single site
  • SETTING TYPE: Outpatient
  • LOCATION: Tokushima University Hospital in Tokushima, Japan

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active treatment
  • APPLICATIONS: Late effects and survivorship

Study Design:

Prospective, randomized, controlled trial

Measurement Instruments/Methods:

Patients were evaluated at baseline and during their every-two-weeks treatment course according to the Neurotoxicity Criteria of Debiopharm.

Results:

The incidence of grade 3 peripheral neuropathy in the GJG group was significantly lower than in the control group (p < 0.01, log-rank test). The incidence of grade 3 peripheral neuropathy after 10 courses was 0% in the GJG group and 12% in the control group. After 20 courses, it was 33% in the GJG group and 75% in the control group. The only differences in adverse effects between the two groups were peripheral neuropathy and influence on tumor response.

Conclusions:

A randomized, double-blind, placebo-controlled trial would be needed to determine efficacy of this oriental herbal medication. No trials with GJG have been conducted in the United States, so no history exists of it being used as an intervention for chemotherapy-induced peripheral neuropathy. These preliminary findings suggest that further research in use of GJG may be warranted.

Limitations:

  • Small sample < 30
  • Not placebo-controlled
  • Not double-blind
  • The Neurotoxicity Criteria of Debiopharm was not described. Several other neurotoxicity scales, even a specific oxaliplatin scale, exist. No explanation was provided for why this scale was chosen.
  • Sample characteristics of those randomized are provided; however, characteristics of only those who actually completed the study are not described.
  • GJG is an oriental herb and would need further testing to be used in the United States in a clinical trial.

Nursing Implications:

Although it has shown some positive results in reducing neuropathy in a clinical trial in Japan, GJG can not be recommended for treating chemotherapy-induced peripheral neuropathy in the United States until further testing occurs in a large, randomized, double-blind study.

Ohno, T., Mine, T., Yoshioka, H., Kosaka, M., Matsuda, S., De Kerckhove, M., . . . Izumida, R. (2014). Management of peripheral neuropathy induced by nab-paclitaxel treatment for breast cancer. Anticancer Research, 34, 4213–4216.

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Study Purpose:

To evaluate the effects of prophylactic compression therapy using stockings and sleeves combined with oral goshajinkigan, mecobalamin, and lafutidine on the prevention of nab-paclitaxel-induced peripheral neuropathy (PN)

Intervention Characteristics/Basic Study Process:

The control and treatment groups received 260 mg/m2 one time every three weeks from June 2012 to April 2013. Patients in the prophylactic treatment group wore stockings and sleeves from the beginning of nab-paclitaxel infusion, continuing for total of 24 hours. The treatment group also received prophylactic goshajinkigan (7.5 g per day), mecobalamin (1,500 mcg per day), and lafutidine (20 mg day) over the course of treatment. Assessments for side effects, including PN grade, were first conducted by a pharmacist then by a physician. If a subject proceeded to chemotherapy, a third set of tests were conducted by a nurse. For the treatment group, the nurse confirmed use of compression stockings and sleeves prior to chemotherapy.

Sample Characteristics:

  • N = 14 
  • AGE RANGE = 42–76 years
  • MALES: Not provided, FEMALES: Not provided
  • KEY DISEASE CHARACTERISTICS: Recurrent breast cancer; metastatic or locally advanced
  • OTHER KEY SAMPLE CHARACTERISTICS: Previous treatment with taxanes; prior treatment lines; no other data provided

Setting:

  • SITE: Single-site
  • SETTING TYPE: Outpatient
  • LOCATION: Nagasaki Harbor Medical Center, Nagasaki, Japan

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment
  • APPLICATIONS: Elder care, palliative care

Study Design:

Parallel-group trial

Measurement Instruments/Methods:

  • National Cancer Institute'sCommon Terminology Criteria for Adverse Events (NCI-CTCAE)
  • Various assessments for side effects including PN (not well described)

Results:

After the first cycle of chemotherapy, there was a significant difference in presence of PN (all grades) between groups. PN occurred in five out of seven subjects in the control group versus one out of seven subjects in the treatment group. The average grade of PN improved over cycles one through four in the treatment group.

Conclusions:

In this small, nonrandomized trial, the grade of PN during one to four cycles of nab-paclitaxel therapy at 260 mg/m2 was lower in the treatment group receiving compression therapy and prophylactic medications than the control group.

Limitations:

  • Small sample (< 30)
  • Baseline sample/group differences of import
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Risk of bias (no appropriate attentional control condition)
  • Risk of bias (sample characteristics)
  • Unintended interventions or applicable interventions not described that would influence results
  • Selective outcomes reporting
  • Measurement/methods not well described
  • Measurement validity/reliability questionable
  • Findings not generalizable
  • Questionable protocol fidelity
  • Other limitations/explanation: This study had a small sample size, and sample characteristics were not well described. The design also was not well described, and there was no explanation of randomization techniques, inclusion and exclusion criteria, or measurements and methods. There was no explanation of baseline PN or the presence of other neurologic symptoms, and other medications previously or currently taken by participants were not reported. The total dose of ​nab-paclitaxel for both groups was not reported, and the mean dose of nab-paclitaxel was significantly greater in the treatment group with no explanation for this difference between samples. The total number of cycles completed for each group was not reported. There was no explanation of the method of administration for the prophylactic medication regimen. Compliance and tolerance rates were not reported. There was no report of any adverse side effects for the sample. The results reported appear incomplete and selectively done for the time period of collected data. Figure 1 depicting grade of neuropathy and number of cycles includes only four cycles for study period June 2012 to April 2013. Assumptions for statistical analysis not reported as met. There is a suggestion that this treatment supports the protection of peripheral nerves, but this assumption cannot be made based on this study as there is no discussion on the main effect on PN and the interaction of the combination of treatments in the treatment group. Citations are missing for the data reported in many places.
 

 

Nursing Implications:

Combination prophylaxis with compression sleeves and stockings and medication (goshajinkigan 7.5 mg day, mecobalamin 1,500 mcg per day, and lafutidine 20 mg per day) needs additional investigation of its use for the treatment for nab-paclitaxel-induced PN. The safety, efficacy, benefit, and generalizability for appropriate target populations of this regimen also requires additional study in large, randomized, controlled trials. This study report had numerous flaws and limitations.


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