Abstract
Oxaliplatin and infusional fluorouracil/leucovorin or capecitabine has emerged as important options in the adjuvant and palliative treatment of colorectal cancer. Severe Oxaliplatin induced neurotoxicity may require chemotherapy dose reduction or cessation. The incidence of oxaliplatin-induced neurotoxicity has varied from 12% - 18%. Several attempts have been proposed to prevent or treat oxaliplatin-induced neurotoxicity, but treatment of established chronic Oxaliplatin induced neurotoxicity is limited. Purpose: To assess the efficacy of parenteral Glutamine dipeptide (N2-L-Alanyl-L-Glutamine Dipeptide, 20 g·m/100ml, IV) for preventing of oxaliplatin induced neurotoxicity. Patients and Methods: A pilot study was performed. 120 patients with metastatic colorectal cancer (mCRC) entered into the study. 60 patients randomly assigned to receive IV glutamine dipeptide (20 g·m IV) day 1-2 with FOLFOX-4 to be repeated every 15 days as a first line of treatment of metastatic colorectal cancer and 60 patients assigned to receive only FOLFOX-4 (control group). Neurotoxicity symptoms and signs were evaluated before each cycle. Results: There were significantly fewer neurological symptoms in patients receiving glutamine dipeptide than in those who did not. A decreased percentage of grade 1-2 peripheral neuropathy was observed in the glutamine dipeptide group after two cycles (8.3% versus 20%; P = 0.04) and 4 cycles (13.3% vs 26.7%; P = 0.02). A significantly lower incidence of grade 3-4 neuropathy was noted in the glutamine dipeptide group after four and six cycles (6.7% versus 15%, P = 0.02 and 13.3% versus 33.3%. P = 0.04, respectively). The need for oxaliplatin dose reduction was significantly lower in the glutamine dipeptide (Dipeptiven) group (10% vs 26.7%; P = 0.02) and there were no significant differences between two groups in response to chemotherapy among patient with mCRC (48.3% vs 50%). Conclusion: These data concluded that IV dipeptide glutamine significantly decreases the incidence and severity of oxaliplatin induced neurotoxicity of mCRC without any attendant side effects.
Highlights
Oxaliplatin from the diaminocyclohexane platinum family, is a cytotoxic agent exerting its cytotoxic effects through the formation of DNA adducts which block both DNA replication and transcription in actively dividing cells
A decreased percentage of grade 1-2 peripheral neuropathy was observed in the glutamine dipeptide group after two cycles (8.3% versus 20%; P = 0.04) and 4 cycles (13.3% vs 26.7%; P = 0.02)
A 100 ml vial which corresponds to 20 g of L-alanyl L-glutamine dipeptide (8.2 g of alanine + 13.46 g of L-glutamine, this is added to the standard amino acid solution)
Summary
Oxaliplatin from the diaminocyclohexane platinum family, is a cytotoxic agent exerting its cytotoxic effects through the formation of DNA adducts which block both DNA replication and transcription in actively dividing cells. Temporary interruption of oxaliplatin before limiting neurotoxicity that develops during therapy has been seen as a potential approach to avoid the problem of neuropathy associated with oxaliplatin in patients with metastatic colorectal cancer. Many neuromodulator agents such as antiepileptic drugs like carbamazepine and gabapentin, calcium-magnesium infusions, mifostine, and glutathione [14]-[17] have demonstrated some activity in the treatment and prophylaxis of oxaliplatin-induced acute neuropathy. In patients with malignant diseases, marked glutamine depletion develops with time, and cachexia development is accompanied by massive depletion of glutamine in skeletal muscle This leads to a negative impact on the function of host tissues that are dependent upon adequate stores of glutamine for optimal functioning [21]. All were treated with the same oxaliplatin-based regimen and were randomized to receive or not to receive glutamine dipeptide (Dipeptiven, by Fresenius Laboratories, Germany)
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