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ARTICLES: A. A. Argyriou, E. Chroni, A. Koutras, J. Ellul, S. Papapetropoulos, G. Katsoulas, G. Iconomou, and H. P. Kalofonos Vitamin E for prophylaxis against chemotherapy-induced neuropathy: A randomized controlled trial Neurology 2005; 64: 26-31 [Abstract] [Full text] [PDF]

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Reply to Pace et al

Andreas A. Argyriou, E. Chroni, A. Koutras,J . Ellul, S. Papapetropoulos, G. Katsoulas, G. Iconomou and H.P. Kalofonos   (16 March 2005)

Vitamin E for prophylaxis against chemotherapy-induced neuropathy: A randomized controlled trial

Andrea Pace, Loredana Bove, Bruno Jandolo   (16 March 2005)

Reply to Pace et al 16 March 2005
Andreas A. Argyriou, University of Patras Medical School P.O. Box 1045, Rion-Patras, Greece, E. Chroni, A. Koutras,J . Ellul, S. Papapetropoulos, G. Katsoulas, G. Iconomou and H.P. Kalofonos Send Correspondence to journal: Re: Reply to Pace et al andargyriou{at}yahoo.gr Andreas A. Argyriou, et al.	Our article presented a pilot study with a small sample size which prevented us from subgroup analysis. It was also considered unnecessary to stratify patients treated with cisplatin and carboplatin. Although both drugs are platinum- compounds, carboplatin does not share the same toxic effect of cisplatin and is not expected to relate to occurrence of neurotoxicity. Our decision was supported by the results of a previously published trial where carboplatin administration even at an AUC dose of 12 (we used AUC 6) was found as almost unrelated (only 2% of patients) to occurrence of grade 3-4 neurotoxicity[1]. The “dying back” process starting for distal nerve endings followed by neuronal body or axonal transport changes is the most widely accepted type of paclitaxel neurotoxicity. [2] However, others support the possibility of paclitaxel neuronopathy.[3] Even in the case of the nerve axon as the primary target of paclitaxel toxicity, secondary structural damage or metabolic dysfunction of the cell body could benefit from vitamin E supplementation. [2] Paclitaxel administration also changes the peripheral nerves and, to a lesser extent, the spinal rootlets and posterior columns of the spinal cord. [4] Central extensions of sensory ganglion cells in the posterior white matter are also structures particularly sensitive to vitamin E deficiency. [5] Sensory neurons and their corresponding central and peripheral paths are the sites of action of both the drugs (cisplatin and paclitaxel) and vitamin E. This could explain the similar beneficial effect of vitamin E supplementation for two cytotoxic drugs that induce neurotoxicity by different modes. Despite the unclear underlying mechanisms, vitamin E could have an important role in CIPN protection. References 1. Gore M, Mainwaring P, A'Hern R, et al. Randomized trial of dose- intensity with single-agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological Oncology Group. J Clin Oncol 1998; 16(7): 2426-2434 2. Rowinsky EK, Donehower RC. Paclitaxel (Taxol). NEJM 1995; 332: 1004- 1014 3. Roytta M, Horwitz SB, Raine CS. Taxol-induced neuropathy: short-term effects of local injection. J Neurocytol 1984;13(5):685-701. 4. Cavaletti G, Tredici G, Braga M, et al. Experimental peripheral neuropathy induced in adult rats by repeated intraperitoneal administration of taxol. Exp Neurology 1995; 133: 64-72 5. Satya-Murti S, Howard L, Krohel G, Wolf B. The spectrum of neurological disorder from vitamin E deficiency. Neurology 1986; 36: 917-921.
Vitamin E for prophylaxis against chemotherapy-induced neuropathy: A randomized controlled trial 16 March 2005
Andrea Pace, Regina Elena National Cancer Institute Via Chianesi 53, 00144, Rome, Italy, Loredana Bove, Bruno Jandolo Send Correspondence to journal: Re: Vitamin E for prophylaxis against chemotherapy-induced neuropathy: A randomized controlled trial pace{at}ifo.it Andrea Pace, et al.	Argyriou et al report the result of a pilot study on vitamin E prophylaxis against chemotherapy-induced neuropathy in patients treated with cisplatin and paclitaxel. [1] There is growing data regarding neuroprotective strategies for the control of peripheral neurotoxicity of anticancer drugs. The possible neuroprotective effect of vitamin E against cisplatin-induced neurotoxicity and ototoxicity has been investigated in many experimental studies. [2] Recent data indicate that vitamin E and other antioxidants seem to protect against cisplatin oxidative stress on the dorsal root ganglia, the target of cisplatin neurotoxicity. [3,4] Cisplatin neuropathy is defined as a late-onset, dose-dependent, pure sensory neuronopathy with selective involvement of large myelinated fibers. [5] Clinical and neuropathological features observed in cisplatin-induced neuropathy are similar to those observed in vitamin E deficiency neuropathy with involvement of dorsal root ganglia. [1] However, the mechanism of action of paclitaxel-induced neuropathy is completely different: the inhibition of tubulin polymerization induced by paclitaxel leads to an acute distal axonal sensory-motor polyneuropathy that is reversible after the end of chemotherapy. There is no evidence of a possible neuroprotective role for vitamin E or other antioxidants in paclitaxel-induced neurotoxicity. Unfortunately, in Argyriou’s study, both group I (Vitamin E) and group II (control) included patients treated with cisplatin or paclitaxel or both and, in some cases, as stated in the results, with carboplatin as well, a platinum compound less neurotoxic than cisplatin. Moreover, patients were treated with different schedules, different combinations of drugs and different doses (and the cumulative dose was not reported). The study of Argyriou et al raises a number of questions: were the two groups of patients stratified for different schedules and dose intensities? Were patients treated with carboplatin evaluated separately from patients treated with cisplatin? And more generally: what is the rationale for neuroprotection with antioxidants in paclitaxel-induced neurotoxicity? Considering the different neurotoxicity mechanisms of the two drugs and the specific effects of antioxidants in preventing cisplatin toxicity, we disagree entirely with the study’s conclusion on the effectiveness of vitamin E supplementation for neuroprotection in patients treated with paclitaxel. Large randomized and controlled trials are needed to provide a more thorough understanding of the role of vitamin E in cisplatin neuroprotection, but neuroprotective strategies should be tailored to the different mechanism of action of neurotoxic drugs. References 1.) Argyriou AA, Chroni E, Koutras A et al. Vitamin E for prophylaxis against chemotherapy-induced neuropathy: A randomized controlled trial Neurology 2005; 64: 26-31. 2.) Kalkanis JG, Withworth C, Rybak LP:Vitamin E reduces cisplatin ototoxicity. Laryngoscope 114: 538-542, 2004. 3.) Leonetti C, Biroccio A, Gabellini C, et al. Alpha- tocopherol protects against cisplatin-induced toxicity without interfering with antitumor efficacy. Int J Cancer. 2003 Mar 20;104:243-50. 4.) Bove L, Picardo M, Maresca V, Jandolo B, Pace A. A Pilot study on the relationship between cisplatin neuropathy and Vitamin. E. J Exp Clin Cancer Res 20: 277-280, 2001. 5.) Krarup-Hansen A, Rietz B, Krarup C, et al. Histology and platinum content of sensory ganglia and sural nerves in patients treated with cisplatin and carboplatin: an autopsy study. Neuropathol Appl Neurobiol 25:29-40, 1999. The authors report no conflicts of interest.