What are the benefits of L-glutathione (glutathione) in patients with cancer?

L-Glutathione in Cancer Patients: Benefits and Limitations

L-glutathione demonstrates significant benefit for preventing chemotherapy-induced peripheral neuropathy (CIPN) specifically with platinum-based chemotherapy (cisplatin and oxaliplatin), but should NOT be used with taxane-based regimens or for preventing oral mucositis. 1

Primary Indication: Prevention of Platinum-Induced Neuropathy

Evidence for Neuroprotection

The most robust evidence supports glutathione at 1,500 mg/m² IV over 15 minutes immediately before each platinum-based chemotherapy infusion. 2 This recommendation is based on multiple randomized controlled trials showing:

• Reduction in severe neurotoxicity with oxaliplatin: Grade 3-4 neuropathy decreased from 26% to 0% (P=0.01) 1, 2
• Dramatic reduction with cisplatin: Neuropathy incidence decreased from 88% to 17% after 15 weeks of treatment (P<0.001) 1, 3
• Clinical neuropathy prevention: After 9 weeks, 0% of glutathione-treated patients versus 66% of placebo patients developed neuropathy (P=0.001) 1, 3

Dosing Protocol

The standard evidence-based regimen consists of: 2

• 1,500 mg/m² IV over 15 minutes immediately before each chemotherapy infusion 1, 2
• Alternative studied doses include 2.5 g IV over 15 minutes for cisplatin regimens 1, 2
• Some protocols add 600 mg intramuscular on days 2-5 after chemotherapy 3

Neurophysiologic Benefits

Beyond clinical symptoms, glutathione preserves nerve function: 1, 3

• Maintains sensory nerve conduction velocities (median, ulnar, and sural nerves) 3
• Prevents decline in sensory nerve action potential amplitudes 1
• Reduces both incidence and severity of neuropathy across multiple measurement scales 1

Critical Limitation: Ineffective with Taxanes

Glutathione showed NO significant advantage for paclitaxel-induced neuropathy (P=0.449), and weekly paclitaxel schedules actually favored placebo over glutathione (P=0.002). 1, 2 This represents a crucial clinical distinction—the neuroprotective effect is specific to platinum agents, not taxanes. 1

NOT Recommended for Oral Mucositis Prevention

Major guidelines explicitly recommend AGAINST glutathione for preventing oral mucositis: 4, 5

• The Multinational Association of Supportive Care in Cancer (MASCC) and International Society of Oral Oncology (ISOO) recommend against intravenous glutamine for mucositis prevention 4, 5
• The European Society for Clinical Nutrition and Metabolism (ESPEN) states insufficient data to recommend glutathione during conventional cytotoxic therapy 4, 5
• Evidence is contradictory, with larger studies showing no benefit 4

Safety Concerns Regarding Tumor Biology

A major unresolved safety issue is that glutathione is metabolized at high rates by cancer cells, raising theoretical concerns about tumor protection: 4, 5, 6

• Glutathione may stabilize cancer cells against intracellular acidification 4
• Elevated glutathione levels in tumor cells confer resistance to chemotherapeutic drugs in bone marrow, breast, colon, larynx, and lung cancers 6
• Higher tumor relapse rates have been associated with glutamine (a related compound) in hematopoietic stem cell transplantation 5

Reassuring Data on Tumor Response

Despite theoretical concerns, clinical trials have not shown reduced chemotherapy efficacy: 3

• Response rates were actually higher in glutathione groups (76% vs 52%) in gastric cancer trials 3
• Studies confirm lack of reduction in cytotoxic drug activity 3
• No interference with platinum-based chemotherapy effectiveness has been documented 1

Additional Clinical Benefits

Beyond neuroprotection, glutathione may provide: 3

• Reduced hemotransfusion requirements (32 vs 62 transfusions in one trial) 3
• Decreased treatment delays (55 vs 94 weeks) 3
• Improved quality of life scores in some studies 1

Monitoring Requirements

Baseline and serial neuropathy assessments using validated scales are essential: 2

• National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC) 1, 2
• EORTC-QLQ-CIPN20 questionnaire 1, 2
• Neurophysiologic testing when available 1, 3

Clinical Algorithm for Use

Use glutathione when:

• Patient is receiving cisplatin or oxaliplatin-based chemotherapy 1, 2
• Neuropathy prevention is a priority 2
• No contraindications exist 2

Do NOT use glutathione when:

• Patient is receiving taxane-based chemotherapy (paclitaxel, docetaxel) 1, 2
• Goal is preventing oral mucositis 4, 5
• Patient has severe kidney failure (applies to glutamine, not glutathione) 2

Common Pitfalls to Avoid

• Confusing glutathione with glutamine: These are different compounds with different evidence profiles 4, 5, 2
• Using with taxanes: This is ineffective and may worsen outcomes with weekly paclitaxel schedules 1, 2
• Expecting mucositis prevention: Guidelines explicitly recommend against this indication 4, 5
• Delaying administration: Must be given immediately before chemotherapy (within 15-20 minutes) for maximum benefit 2, 3