Glutathione

STUDY PURPOSE: To examine the efficacy of chemoprotective agents to prevent or limit neurotoxic side effects of cisplatin and related chemotherapy agents

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 20 
• TOTAL PATIENTS INCLUDED IN REVIEW = 2459
• SAMPLE RANGE ACROSS STUDIES: 18–755
• KEY SAMPLE CHARACTERISTICS: Varied tumor types receiving platinum-based chemotherapy

PHASE OF CARE: Active antitumor treatment

There is insufficient high quality evidence to show that any agent is protective against platinum-induced neuropathy. There is some suggestion that amifostine, glutathione, and calcium and magnesium may have some effect.

• Limited number of studies included
• Low sample sizes
• There were few studies per intervention, and very few studies with small sample were included in the meta-analyses.

There is insufficient evidence to show that any agent is truly effective in protecting against neurotoxic effects of platinum-based chemotherapy. There is a continued need for well designed research using appropriate objective as well as subjective measures of neuropathy.

STUDY PURPOSE: To evaluate status of research on pharmacologic interventions for CIPN

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: Medline, Embase, and China National Knowledge Internet

YEARS INCLUDED: (Overall for all databases) Information for dates of search not provided, articles included were from 1995 to 2014

INCLUSION CRITERIA: The study (a) assessed CIPN in patients with cancer, (b) compared two or more drugs or placebo, (c) provided sufficient data to assess differences, and (c) assessed incidence or severity of CIPN

EXCLUSION CRITERIA: None listed

TOTAL REFERENCES RETRIEVED: 1,839

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: No description of quality evaluation

FINAL NUMBER STUDIES INCLUDED: 23

TOTAL PATIENTS INCLUDED IN REVIEW: 2,298

SAMPLE RANGE ACROSS STUDIES: 20-732

KEY SAMPLE CHARACTERISTICS: All but one of the studies focused on patients getting platinum-based chemotherapy and 12 of 23 only included people with colorectal cancer.

PHASE OF CARE: Active antitumor treatment

Contrary to the title, this article does not include any commonly prescribed prescription drugs, including gabapentin, pregabalin, or duloxetine. This review included studies of amifostine, Vitamin E, calcium and magnesium infusions, and glutathione. Eighteen studies had a placebo control group and had no control group. Neither blinding nor control were needed for inclusion. Findings indicate that Vitamin E and amifostine reduce incidence of CIPN, while glutathione and amifostine reduced severity of CIPN. There was one study (n = 20) included that had patients getting amifostine who all had cervical cancer and were receiving cisplatin with radiation therapy. The authors of this original study (Gallardo et al., 1999) found no statistically significant difference in neurotoxicity between those getting amifostine and those who did not. It is therefore unclear how the authors of the meta-analysis found otherwise. There was also only a single study of glutathione versus placebo versus calcium/magnesium (n = 93, 33 of whom received glutathione) included. The original study (Dong et al., 2010) showed no significant differences in CIPN incidence or severity between the three groups. Four studies of Vitamin E, two which were placebo controlled and two with no control group.

The limitations, including lack of quality control, small sample sizes, focus on platinum use, and GI malignancies, limit the generalizability of the findings from this meta-analysis.

• Limited search
• Limited number of studies included
• No quality evaluation
• Low sample sizes

Findings from this study suggest that amifostine, glutathione, and Vitamin E may be helpful for CIPN but no recommendations for practice can be made at this time due to limitations of this meta-analysis.

Fifty-two patients with advanced colorectal cancer who were treated with a bimonthly oxaliplatin-based regimen were randomized to receive glutathione (GSH) (1,500 mg/m² over a 15-minute infusion period before oxaliplatin) or normal saline solution. Chemotherapy regimen was given as follows: oxaliplatin 100 mg/m² on day 1 concurrent with leucovorin 250 mg/m² followed by 5-FU 1,500 mg/m² per day for two consecutive days every two weeks. GSH was administered at a dose of 1,500 mg/m² in 100 ml of normal saline over 15 minutes immediately before each oxaliplatin administration. The placebo-randomized patients received normal saline. Disease response was assessed after four cycles of therapy. Those with responsive or stable disease received four additional cycles of treatment.

• Fifty-two patients with histologically verified advanced colorectal carcinoma were randomized to receive combination chemotherapy; 26 with and 26 without GSH.
• Patients were excluded if they had established clinical neuropathy, diabetes, alcoholic disease, other neurologic disease or brain involvement.
• Those who received vitamin B1, B6, or B12 supplements also were excluded.

The study had a randomized, double-blind, placebo-controlled trial design.

• A neurologic examination, including measures of strength and reflexes, assessment of neurologic symptoms, position and vibratory sensation, and neurophysiologic evaluations of sural nerves were conducted at baseline, 4, 8, and 12 cycles of chemotherapy.
• The presence of signs and symptoms of peripheral nervous system involvement and the assessment of position and vibratory sensations also was performed.
• Neurotoxicity was expressed according to National Cancer Institute Common Terminology Criteria for Adverse Events.
• Neurophysiologic evaluation of sensory nerve conduction in the sural nerves was performed by the same examiners who were blinded to the group affiliation.

At baseline, no patients suffered from clinical neuropathy in either arm. At the time of second the neurologic exam (four cycles) seven patients had clinical neuropathy in the GSH arm and 11 in the placebo arm. After eight cycles of chemotherapy, nine patients had clinical neuropathy in the GSH arm compared with 15 patients in the placebo arm with an incidence of moderate to severe (grade 2–4) clinical neurotoxicity present in 11 of 19 assessable patients in the placebo arm, as compared to 2 of 21 assessable patients in GSH arm. No grade 3–4 neurotoxicity was present in GSH arm while grade 3–4 neurotoxicity was reported in five patients in placebo arm. Only 18 patients received 12 cycles of chemotherapy, 10 in the GSH arm and 8 in the placebo arm. Grade 2–3 neurotoxicity was observed in three patients in GSH arm and eight patients in the placebo arm.

The study was performed on patients who had received preliminary date on a small number of patients with no true control group.

Fifty patients with advanced gastric cancer were randomized to receive either 1.5 g/m² GSH in 1 L of normal saline or normal saline 1 L as a placebo infusion given over 15 minutes before cisplatin-based chemotherapy. GSH also was given by intramuscular injection on days 2 and 5. One cycle consisted of nine weekly treatments. Patients who showed responsive or stable disease received an additional six weeks of therapy.

• Fifty patients with advanced gastric cancer; 25 received GSH treatment and 25 received placebo infusions of normal saline.
• Sample size was determined to detect a 40% difference in the occurrence of grade 1–4 (World Health Organization [WHO] scale) neurotoxicity between the two treatment arms.
• Exclusion criteria includes previous chemotherapy, established clinical neuropathy, diabetes, alcoholic disease, brain involvement, or use of vitamins B1, B6, or B12.

The study had a randomized, placebo-controlled clinical trial design.

• Complete neurologic examination (strength, deep tendon reflexes, symptoms of peripheral nervous system involvement, position, and vibratory sensation); neurophysiologic assessment of the medial, ulnar; and sural nerves also were performed.
• Toxicity scores (using the WHO criteria) were evaluated weekly by the same examiner who was blinded to treatment group assignment.

Seven patients in the placebo group were unable to complete the study (six with progressive disease and one from grade 3 neurotoxicity). Only one patient in the GSH group was not able to complete the study. At nine weeks, no patients who received GSH had clinical evidence of neuropathy, compared to16 patients (66%) in the placebo-control group. After 15 weeks, 4 of 24 (17%) patients in the GSH arm showed clinical evidence of neurotoxicity compared to 16 (88%) in the placebo-control group. Most common symptoms included distal parasthesias and numbness in legs, decreased sense of vibration, and reduced or absent deep reflexes. No changes in mean latency and sensory amplitude potentials were noted in the group that received GSH but were significantly affected at 9 and 15 weeks in the control group. No patients reported ototoxicity.

• The study is almost 20 years old.
• Well-described methods and measures recorded higher than expected levels of neurotoxicity in the control arm, but could be from specific attention to the symptom.
• This study did not examine potential delayed toxicity. This could lead to an inaccurate conclusion about the benefits of GSH if it delays rather than prevents toxicity.

To determine the effectiveness of glutathione for the prevention of taxol/carboplatin-induced peripheral neuropathy

One hundred eighty-five patients were randomized to receive either placebo or glutathione 1.5 mgm/m² while receiving paclitaxel and carboplatin therapy over 15 minutes immediately before chemotherapy.

• N = 185  
• MEDIAN AGE = 63 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Patients with ovarian cancer, lung cancer, or other
• OTHER KEY SAMPLE CHARACTERISTICS: Some patients received weekly taxol, whereas others received taxol every three to four weeks. Patients with diabetes were also included.

• SITE: Multi-site    
• SETTING TYPE: Outpatient    
• LOCATION: U.S. 

PHASE OF CARE: Active antitumor treatment

Placebo-controlled, randomized, controlled trial

• European Organization for Research and Treatment of Cancer (EORTC) Quality of Life
• Chemotherapy-induced peripheral neuropathy–specific sensory subscale
• National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE)
• Functional Assessment of Cancer Therapy-Ovarian (FACT-O)

No differences were reported in neurotoxic symptoms between the groups the week following taxol infusion. In addition, no differences were reported between the groups receiving taxol every three to four weeks. Time to development of at least grade 2 neurotoxicity was higher in the placebo group (p = 0.039).

The results indicated that this was a negative trial and do not support the use of glutathione for neurotoxic symptoms from taxol/carboplatin therapy.

The results of this negative trial showed that glutathione was not effective in patients receiving taxol/carboplatin. Very limited evidence supports effective interventions for preventing or minimizing chemotherapy-induced peripheral neuropathy. Ongoing research is needed in this area.

GSH has high affinity for heavy metals, so the researchers postulated that it may reduce the toxic effects of cisplatin. Early clinical studies suggest that GSH provides neuroprotection.

151 women with advanced ovarian cancer were randomized to receive cisplatin with or without GSH 3 g/m² in 200 cc of normal saline or cisplatin and a placebo-infusion of 200 cc of normal saline administered over 20 minutes immediately before cisplatin administration. Randomized in double-blind fashion to cisplatin 100 mg/m² plus 3 g/m² GSH in 200 cc normal saline or a placebo infusion of 200 cc normal saline every three weeks for six cycles. Seventy-seven women received the placebo infusion and 74 received GSH.

151 women with ovarian cancer

Multicenter

The study had a randomized, placebo-controlled, clinical trial with parallel group design.

• Audiograms and neurologic examinations were conducted at baseline and after three and six cycles of chemotherapy.
• Four of 10 centers measured quality of life with the Hospital Anxiety and Depression Scale.
• Anemia, leukopenia, thrombocytopenia, neurohearing, nephrotoxicity, peripheral neuropathy, and nausea and vomiting were assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events and World Health Organization toxicity scales.

The addition of GSH to cisplatin chemotherapy allowed the full six cycles to be administered to more patients (58%) as compared to those who received cisplatin alone (39%). Women in the GSH arm had a statistically significant rise in weight of 2 kg over the study period (p = 0.01). Women in the study who received GSH reported an improvement in quality of life during cisplatin chemotherapy. Significant difference in the reduction of creatinine clearance for GSH treated group as compared to the control group (74% versus 62%). Significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath, and difficulty concentrating as measured by the Hospital Anxiety and Depression scale. Those who received GSH were significantly more able to undertake housekeeping and shopping. The trend was toward a better outcome in GSH-treated group (p = 0.25).

• The study did not clearly identify what the neurologic examination involved.
• The study has substantial between-center differences which may make findings less interpretable.