Goshajinkigan

STUDY PURPOSE: To evaluate the efficacy and safety of Goshajinkigan for prevention of CIPN

TYPE OF STUDY: Meta analysis and systematic review

DATABASES USED: SCOPUS, Ovid, Medline, Cochrane Central Register of Controlled Trials, ICHUSHI, Google Scholar 

YEARS INCLUDED: Not specified

INCLUSION CRITERIA: Randomized controlled trials, cluster-randomized, crossover, and quasi-randomized trials evaluating goshajinigan for CIPN; studies needed to include adult patients (aged 18 years or older) receiving hospital-based chemotherapy

EXCLUSION CRITERIA: Articles that did not meet this criteria

TOTAL REFERENCES RETRIEVED: 1,345 originally; 9 selected for full-text review; 5 included in the final analysis

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Potential biases were evaluated for each study using methods described in the Cochrane Handbook for Systematic Reviews of Interventions

FINAL NUMBER STUDIES INCLUDED: 5

TOTAL PATIENTS INCLUDED IN REVIEW: 386

SAMPLE RANGE ACROSS STUDIES: 10-182

KEY SAMPLE CHARACTERISTICS: Three of the studies were in colorectal cancer and two in breast cancer; three focused on oxaliplatin, one on paclitaxel, and one on docetaxel; two studies did not include a comparison, two compared goshajinigan to placebo, and one compared goshajinigan to Vitamin B12

PHASE OF CARE: Active anti-tumor treatment

Goshajinkigan did not reduce the incidence of grade 2 or 3 CIPN in studies that reported CTCAE results.

The article reports trends toward decreased risk of developing grade 2 or 3 CIPN in studies using neurotoxicity criteria of debiopharm; however, these findings were not statistically significant. 

No severe adverse events seen with Goshajinkigan.

Goshajinkigan did not influence the response to chemotherapy.

This article does not provide evidence to support the use of Goshajinkigan for prevention of CIPN

• Limited number of studies included
• Mostly low quality/high risk of bias studies   
• High heterogeneity
• Low sample sizes

Based on this meta-analysis, Goshajinkigan should not be recommended to patients. Further study, using rigorous, randomized, double blinded methods and large sample sizes are needed.

STUDY PURPOSE: Examine whether goshajinkagin prevents CIPN in patients receiving neurotoxic chemotherapy.

TYPE OF STUDY: Meta analysis and systematic review

DATABASES USED: PubMed, EMBASE, Ichushi, Cochrane Central Register of Controlled Trials

YEARS INCLUDED: (Overall for all databases) inception through August, 2017

INCLUSION CRITERIA: Randomized controlled trials that assessed efficacy and safety of goshajinkagin in preventing CIPN; patients had to be undergoing neurotoxic chemotherapy (taxanes, vinca alkaloids, platinum agents); adult patients older than age 18 years ; prophylactic doses of goshajinkagin (7.5 g per day)

EXCLUSION CRITERIA: Patients that had already developed CIPN; dosing of goshajinkagin that was given as treatment for CIPN rather than prophylaxis

TOTAL REFERENCES RETRIEVED: 234 articles retrieved; five articles evaluable after inclusion/exclusion applied

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Five trials with 397 total patients; 3 colon cancer, 2 breast cancer

FINAL NUMBER STUDIES INCLUDED: 5 

TOTAL PATIENTS INCLUDED IN REVIEW: 397

SAMPLE RANGE ACROSS STUDIES: Included patients with breast cancer or colon cancer, receiving FOLFOX 4 or FOLFOX 6, and weekly paclitaxel- or docetaxel-based chemotherapy. Studies ranged from 18-186 patients; studies ranged from 12-26 weeks in duration. Two trials with placebo comparator; two trials with no interventions for control; one trial administered mecobalamin for comparison; one trial terminated early due to incidence of increased CIPN. Two different definitions of CIPN used, those from NCI-CTCAE in four studies (measuring severity) and that from the Neurotoxicity Criteria of Debiopharm (DEB-NTC) in one study (measuring duration)

KEY SAMPLE CHARACTERISTICS: 35-88 years old; breast cancer and colon cancer

PHASE OF CARE: Active anti-tumor treatment

Overall, the use of goshajinkagin was not related to a decreased incidence of CIPN; though in the one study there was reduced incidence of grade 1 and grade 3 CIPN, but no difference in grade 2 CIPN. One study with increased incidence of CIPN (stopped early).

No evidence to support the use of goshajinkagin for prevention of CIPN.

• Limited number of studies included
• High heterogeneity
• Different criteria for grading of CIPN

Further research on use of the medication may be warranted. Education of patients about the inconsistent results.

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

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.

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

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

• PHASE OF CARE: Active antitumor treatment

Prospective, randomized, parallel-group trial

• 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

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.

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.

• 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.

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.

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

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.

• 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

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

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

• Double-blinded, randomized, placebo-controlled trial

• 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.

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).

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.

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

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.

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

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.

• 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.

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

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

Prospective, randomized, controlled trial

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

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.

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.

• 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.

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.

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)

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.

• 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

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

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

Parallel-group trial

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

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.

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.

• 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.

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.

To evaluate the effectiveness of goshajinkigan (GJG) in reducing peripheral neurotoxicity in patients receiving FOLFOX for colorectal cancer

Patients with colorectal cancer were randomized to receive either GJG 7.5 mg three times daily or placebo in a double-blind manner. The time to grade 2 or higher neuropathy was the primary endpoint.

• N = 155 (of planned 310)   
• MEAN AGE = 62.4 years (GJG), 60.4 years (placebo)
• MALES: 53.9% (GLG), 54.8% (placebo); FEMALES: 46.1% (GLG), 45.2% (placebo)
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: All patients had stage III colorectal cancer. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Most patients had no comorbidities.
• OTHER KEY SAMPLE CHARACTERISTICS: Creatinine clearance greater than 60 in 86.5% of patients receiving GJG; 90.3% of patients receiving placebo

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

PHASE OF CARE: Active antitumor treatment

Double-blind, placebo-controlled, randomized study

Time to grade 2 or higher neuropathy as described by Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, and the DEB-NTC. Standardized questions regarding symptoms of neurotoxicity and examples of answers were used to facilitate accurate classification and grading of symptoms. Grades were determined by physicians and were documented in patient records.

A total of 142 patients were evaluable. Incidence of grade 1 peripheral neuropathy was 43.8% in the GJG group and 62.4% in the placebo group; incidence of grade 2 or higher was 50.6% in the GJG group and 31.2% in the placebo group. Time to development of neuropathy was also significantly less in the GJG group (p = 0.007). GJG did not reduce time to neuropathy even for grade 1. Adverse events other than neuropathy showed no difference between the two groups. Secondary endpoints of dose intensity and treatment cycle were higher in the GJG group (not significant).

GJG did not decrease the time to grade 2 neuropathy; in fact, it seems to have hastened development. There was some effect on the dose intensity and treatment cycle given, but this was not a significant difference.

• Key sample group differences that could influence results
• The study stopped early because of findings that it was not effective in the manner theorized.

A total of 155 patients in each arm were planned, but after a total of 155 patient enrolled, an interim analysis was performed and the study was stopped at that time because of findings that GJG was not as effective as hoped. Nurses must ask patients medications, including all supplements, to educate patients on potential interactions and potential harm from supplemental medications. This is marketed in Japan for treatment for diabetic neuropathy but does not seem to be effective for chemotherapy-induced neuropathy, and education of patients is key.