Neuroprotective Effect of Reduced Glutathione on Oxaliplatin-Based Chemotherapy in Advanced Colorectal Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

Cascinu, Stefano; Catalano, Vincenzo; Cordella, L; Labianca, Roberto; Giordani, Paolo; Baldelli, Anna Maria; Beretta, Giordano Domenico; Ubiali, E; Catalano, Giuseppina

doi:10.1200/jco.2002.07.061

Cited by 324 publications

(210 citation statements)

References 17 publications

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“…They also mention that, although sensory nerve conduction may be affected significantly after oxaliplatin-based treatment, the severity of clinical sensory neuropathy does not always correlate with findings of nerve conduction studies. Cascinu et al [2] reached the same conclusion, demonstrating that sensory nerve conduction was significantly affected by oxaliplatin only in patients receiving placebo, but not in those receiving glutathione.…”

supporting

confidence: 61%

The Usefulness of Nerve Conduction Studies in Objectively Assessing Oxaliplatin-Induced Peripheral Neuropathy

Polychronopoulos

Chroni

2007

The Oncologist

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supporting

confidence: 61%

The Usefulness of Nerve Conduction Studies in Objectively Assessing Oxaliplatin-Induced Peripheral Neuropathy

Polychronopoulos

Chroni

2007

The Oncologist

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“…7,29,38 It remains to be seen if their therapeutic limited effectiveness is due to the scarce activity of the presently available substances or to the complexity of oxaliplatin neurotoxicity where oxidative stress could be only an epiphenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, glutathione, N-acetylcysteine, and vitamin E (a-tocopherol) may have a clinical role in patient neuroprotection. 4,6,7,25,29,35 However, the major bias of these clinical trials resides in their small size and/ or in their short term follow-up. 2 An important limit in this field is the insufficient information on the molecular basis of the neuropathy.…”

mentioning

confidence: 99%

Oxaliplatin-Induced Neuropathy: Oxidative Stress as Pathological Mechanism. Protective Effect of Silibinin

Mannelli

Zanardelli

Failli

et al. 2012

The Journal of Pain

156

120

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Oxaliplatin is the standard treatment for advanced colorectal cancer. Its dose-limiting toxicity is the development of a painful neuropathic syndrome sustained by unclear mechanisms. Although the oxidative hypothesis is a matter of debate, direct data about oxidative damage induced in vivo by anticancer agents are lacking and the efficacy of the available antioxidant compounds are unsatisfactory. In a rat model of painful oxaliplatin-induced neuropathy (2.4 mgkg À1 i.p., daily for 21 days), we described an important component of oxidative stress. In the plasma of oxaliplatin-treated rats, the increases in carbonylated protein and thiobarbituric acid reactive substances were the index of the resultant protein oxidation and lipoperoxidation, respectively. The same pattern of oxidation was revealed also in the sciatic nerve, and in the spinal cord where the damage reached the DNA level. The antioxidant compound silibinin (100 mgkg À1 per os), administered once a day, starting from the first day of oxaliplatin injection until the 20th, prevented oxidative damage as did a-tocopherol. Repetitive administration of silibinin, as well as a-tocopherol, reduced oxaliplatin-dependent pain induced by mechanical and thermal stimuli. Antioxidants were also able to improve motor coordination. The antineuropathic effect of both molecules improved by about 50% oxaliplatin-induced behavioral alterations.Perspective: This study characterizes oxidative stress parameters in a rat model of oxaliplatininduced neuropathy. A relationship between the improvement of oxidative alterations and pain relief is established in rats treated with natural antioxidant compounds like a-tocopherol and silibinin. Silibinin could be a valid therapeutic option for chemotherapy-induced neuropathy.

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“…The bulk of evidence is negative for both scenarios [12], [14], [19], [20], with rare exceptions [17], [21]. Importantly, the large majority of studies have not used validated pain measurement tools [10], [11], [13], [14], [16], [19], [22], [23], while most have used the common terminology criteria (CTC) adverse events grading system as the primary outcome measurement. While this choice is sound and supported by robust evidence [24], it must be kept in mind that most patients with OXAIPN have small‐fiber‐predominant polyneuropathy [1], which has as its main symptom neuropathic pain.…”

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confidence: 99%

Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial

et al. 2017

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Lessons Learned. Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin‐related neuropathic pain, compared with placebo.Background.Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin‐induced peripheral neuropathy (OXAIPN). Acute and chronic OXA‐related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti‐hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN.Methods.Pain‐free, chemotherapy‐naïve CRC patients receiving at least one cycle of modified‐FLOX [5‐FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1‐3‐5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow‐up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0–10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique‐4 (DN‐4), pain dimensions (short‐ form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile.Results.One hundred ninety‐nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79–1.26), and 0.85 (95% CI = 0.64–1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN‐4, NPSI, and NCS and side‐effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1–11.2]; pregabalin 6.8 [5.6–8.0]).Conclusion.The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.

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Neuroprotective Effect of Reduced Glutathione on Oxaliplatin-Based Chemotherapy in Advanced Colorectal Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract: This study provides evidence that GSH is a promising drug for the prevention of oxaliplatin-induced neuropathy, and that it does not reduce the clinical activity of oxaliplatin.

Cited by 324 publications

References 17 publications

The Usefulness of Nerve Conduction Studies in Objectively Assessing Oxaliplatin-Induced Peripheral Neuropathy

The Usefulness of Nerve Conduction Studies in Objectively Assessing Oxaliplatin-Induced Peripheral Neuropathy

Oxaliplatin-Induced Neuropathy: Oxidative Stress as Pathological Mechanism. Protective Effect of Silibinin

Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial

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