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      Oxaliplatin-Induced Neuropathy in Colorectal Cancer

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      Journal of Oncology
      Hindawi Publishing Corporation

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          Abstract

          Oxaliplatin use in palliative and adjuvant treatment of colon cancer is frequently limited by cumulative neurotoxicity, leading to reduced quality of life and decreased dose. The mechanism of this neurotoxicity is unclear, but may relate to neuronal voltage-gated sodium channels involving calcium chelation by a metabolite of the drug. Various preventative measures have been tested to reduce the incidence of neurotoxicity, including calcium and magnesium infusions, dose interruption of the drug, and prophylactic neuromodulatory agents. Despite the promising efficacy of these measures, they are not universally accepted. Less is known about the best way to treat established neurotoxicity, which is permanent in some patients, although venlafaxine has shown promise in small clinical trials. This paper analyzes the extent, cause and risk factors for neuropathy, and the potential preventative and therapeutic treatments for oxaliplatin-induced neuropathy.

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          Most cited references62

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          Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.

          The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI). Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR). A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032). The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.
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            Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer.

            To evaluate whether capecitabine plus oxaliplatin (XELOX) is noninferior to fluorouracil. folinic acid, and oxaliplatin (FOLFOX-4) as first-line therapy in metastatic colorectal cancer (MCRC). The initial design of this trial was a randomized, two-arm, noninferiority, phase III comparison of XELOX versus FOLFOX-4. After patient accrual had begun, the trial design was amended in 2003 after bevacizumab phase III data became available. The resulting 2 x 2 factorial design randomly assigned patients to XELOX versus FOLFOX-4, and then to also receive either bevacizumab or placebo. We report here the results of the analysis of the XELOX versus FOLFOX-4 arms. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately. The prespecified primary end point for the noninferiority analysis was progression-free survival. The intent-to-treat population comprised 634 patients from the original two-arm portion of the study, plus an additional 1,400 patients after the start of the amended 2 x 2 design, for a total of 2,034 patients. The median PFS was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4-containing arms (hazard ratio [HR], 1.04; 97.5% CI, 0.93 to 1.16). The median overall survival was 19.8 months with XELOX versus 19.6 months with FOLFOX-4 (HR, 0.99; 97.5% CI, 0.88 to 1.12). FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhea and grade 3 hand-foot syndrome than FOLFOX-4. XELOX is noninferior to FOLFOX-4 as a first-line treatment for MCRC, and may be considered as a routine treatment option for appropriate patients.
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              OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study.

              In metastatic colorectal cancer, a combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) 4 is a standard first-line regimen. The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX7, a simplified leucovorin and fluorouracil regimen with high-dose oxaliplatin. Previously untreated patients were randomly assigned to either FOLFOX4 administered every 2 weeks until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). Six hundred twenty patients were enrolled, including an exploratory cohort of 95 elderly or poor prognosis patients. Median progression-free survival and survival times were 9.0 and 19.3 months, respectively, in patients allocated to arm A compared with 8.7 and 21.2 months, respectively, in patients allocated to arm B (P = not significant). Response rates were 58.5% with arm A and 59.2% with arm B. National Cancer Institute Common Toxicity Criteria grade 3 or 4 toxicity was observed in 54.4% of the patients in arm A v 48.7% of patients in arm B. From cycle 7, fewer patients experienced grade 3 or 4 toxicity in arm B. Grade 3 sensory neuropathy was observed in 17.9% of the patients in arm A v 13.3% of patients in arm B (P = .12). In arm B, oxaliplatin was reintroduced in only 40.1% of the patients but achieved responses or stabilizations in 69.4% of these patients. Oxaliplatin can be safely stopped after six cycles in a FOLFOX regimen. Further study is needed to fully evaluate oxaliplatin reintroduction.
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                Author and article information

                Journal
                J Oncol
                JO
                Journal of Oncology
                Hindawi Publishing Corporation
                1687-8450
                1687-8469
                2011
                12 December 2011
                : 2011
                : 201593
                Affiliations
                Division of Medical Oncology, University of Colorado Cancer Center, Aurora, CO 80045, USA
                Author notes

                Academic Editor: Andrea Bonetti

                Article
                10.1155/2011/201593
                3238400
                22203844
                bee3ff40-5b7d-4d7a-914d-12294b91c377
                Copyright © 2011 Andrew Weickhardt et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 2 September 2011
                : 24 October 2011
                Categories
                Review Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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