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      Observational Study of Prevalence of Long-term Raynaud-Like Phenomena and Neurological Side Effects in Testicular Cancer Survivors

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          Abstract

          Background

          Sensory neuropathy (paresthesias), tinnitus, hearing impairment, and Raynaud phenomena are side effects of cisplatin-based chemotherapy used to treat testicular cancer patients. We assessed the long-term occurrence of these side effects among testicular cancer survivors according to the treatment they received.

          Methods

          A total of 1814 men who were treated for unilateral testicular cancer in Norway during 1980–1994 were invited to participate in a national multicenter follow-up survey conducted during 1998–2002. The men were allocated to six groups according to the treatment they had received. Self-reported symptoms were assessed by a mailed questionnaire that included the Scale for Chemotherapy-Induced Neurotoxicity. A total of 1409 participants who responded to the questionnaire and/or underwent audiometry were assessable in this study. Respondents to the questionnaire (n = 1402) scored the relevant symptoms according to how troubled they were by each (not at all, a little, quite a bit, or very much). Hearing impairment was objectively assessed by audiometry at 4000 Hz in 755 men (seven of whom did not respond to the questionnaire). Group comparisons of symptom assessments were performed with χ 2 or Kruskal–Wallis tests. Associations between relevant factors and self-reported symptoms or hearing impairment measured by audiometry were assessed using proportional odds ordinal logistic regression models and linear regression models, respectively. All statistical tests were two-sided.

          Results

          The median follow-up for the 1409 assessable men was 10.7 years (range = 4–21 years). All chemotherapy groups had statistically significantly higher odds for increasing severity of all assessed symptoms and inferior audiometric results compared with men who did not receive chemotherapy. Among chemotherapy-treated men, 39% (95% confidence interval [CI] = 35% to 43%) reported Raynaud-like phenomena (defined as white or cold hands or fingers [or feet or toes] on cold exposure), 29% (95% CI = 25% to 33%) reported paresthesias in the hands or feet, 21% (95% CI = 18% to 25%) reported hearing impairment, and 22% (95% CI = 19% to 26%) reported tinnitus as major symptoms troubling them quite a bit or very much. Hearing impairment (odds ratio [OR] = 5.3, 95% CI = 3.0 to 9.2) and tinnitus (OR = 7.1, 95% CI = 4.1 to 12.4) were particularly common in the dose-intensive chemotherapy group compared with the no chemotherapy group. Men who were treated with radiotherapy had higher odds of self-reported paresthesias in feet compared with those not treated with radiotherapy (OR = 1.5, 95% CI = 1.01 to 2.1, P = .04).

          Conclusion

          Long-term survivors of testicular cancer who were treated with cisplatin-based chemotherapy were more often troubled by dose-dependent neurological side effects and Raynaud-like phenomena compared with those who were not treated with chemotherapy.

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          Most cited references71

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          International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group.

          Cisplatin-containing chemotherapy has dramatically improved the outlook for patients with metastatic germ cell tumors (GCT), and overall cure rates now exceed 80%. To make appropriate risk-based decisions about therapy and to facilitate collaborative trials, a simple prognostic factor-based staging classification is required. Collaborative groups from 10 countries provided clinical data on patients with metastatic GCT treated with cisplatin-containing chemotherapy. Multivariate analyses of prognostic factors for progression and survival were performed and models were validated on an independent data set. Data were available on 5,202 patients with nonseminomatous GCT (NSGCT) and 660 patients with seminoma. Median follow-up time was 5 years. For NSGCT the following independent adverse factors were identified: mediastinal primary site; degree of elevation of alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactic dehydrogenase (LDH); and presence of nonpulmonary visceral metastases (NPVM), such as liver, bone, and brain. For seminoma, the predominant adverse feature was the presence of NPVM. Integration of these factors produced the following groupings: good prognosis, comprising 60% of GCT with a 91% (89% to 93%) 5-year survival rate; intermediate prognosis, comprising 26% of GCT with a 79% (75% to 83%) 5-year survival rate; and poor prognosis, comprising 14% of GCT (all with NSGCT) with a 48% (42% to 54%) 5-year survival rate. An easily applicable, clinically based, prognostic classification for GCT has been agreed on between all the major clinical trial groups who are presently active worldwide. This should be used in clinical practice and in the design and reporting of clinical trials to aid international collaboration and understanding.
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            Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies.

            Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side effect of many commonly used chemotherapeutic agents, including platinum drugs, taxanes, epothilones and vinca alkaloids, and also newer agents such as bortezomib and lenolidamide. Symptom control studies have been conducted looking at ways to prevent or alleviate established CIPN. This manuscript provides a review of studies directed at both of these areas. New evidence strongly suggests that intravenous calcium and magnesium therapy can attenuate the development of oxaliplatin-induced CIPN, without reducing treatment response. Accumulating data suggest that vitamin E may also attenuate the development of CIPN, but more data regarding its efficacy and safety should be obtained prior to its general use in patients. Other agents that look promising in preliminary studies, but need substantiation, include glutamine, glutathione, N-acetylcysteine, oxcarbazepine, and xaliproden. Effective treatment of established CIPN, however, has yet to be found. Lastly, paclitaxel causes a unique acute pain syndrome which has been hypothesised to be caused by neurologic injury. No drugs, to date, have been proven to prevent this toxicity.
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              Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy.

              Peripheral neuropathy induced by cancer chemotherapy represents a large unmet need for patients due to the absence of treatment that can prevent or mitigate this common clinical problem. Chemotherapy-induced peripheral neuropathy (CIPN) diagnosis and management is further compounded by the lack of reliable and standardized means to diagnose and monitor patients who are at risk for, or who are symptomatic from, this complication of treatment. The pathogenesis and pathophysiology of CIPN are not fully elucidated, but there is increasing evidence of damage or interference with tubulin function. The diagnosis of CIPN may present a diagnostic dilemma due to the large number of potential toxic etiologies and conditions, which may mimic some of the clinical features; the diagnosis must be approached with care in such patients. The incidence and severity of CIPN is commonly under-reported by physicians as compared with patients. The development of new and reliable methods for the assessment of CIPN as well as safe and effective treatments to prevent this complication of treatment would represent important medical advancements for cancer patients.
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                Author and article information

                Journal
                J Natl Cancer Inst
                jnci
                jnci
                JNCI Journal of the National Cancer Institute
                Oxford University Press
                0027-8874
                1460-2105
                16 December 2009
                16 December 2009
                16 December 2009
                16 December 2009
                : 101
                : 24
                : 1682-1695
                Affiliations
                Affiliations of authors: Department of Oncology, Haukeland University Hospital, Bergen, Norway (MB, OD); Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway (MB, OD); Cancer Clinic, Department of Clinical Cancer Research, Rikshospitalet-Radiumhospitalet Medical Centre, Oslo, Norway (JO, SDF); Institute of Health, Buskerud University College, Drammen, Norway (JO); Department of Oncology, St Olavs University Hospital, Trondheim, Norway (OK); Department of Oncology, University Hospital of North Norway, Tromsø, Norway (RMB); Department of Oncology, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway (RMB); The Cancer Center, Ullevål University Hospital, Oslo, Norway (EAW); Medical Faculty, Faculty Division the Norwegian Radium Hospital, University of Oslo, Oslo, Norway (SDF); Medical Faculty, Faculty Division Ullevål University Hospital, University of Oslo, Oslo, Norway (EAW); Centre for Clinical Research, Research and Development Department, Haukeland University Hospital, Bergen, Norway (TW-L); NKS Olaviken, Hospital for Old Age Psychiatry, Bergen, Norway (ERH)
                Author notes
                Correspondence to: Marianne Brydøy, MD, Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway (e-mail: marianne.brydoy@ 123456helse-bergen.no ).
                Article
                10.1093/jnci/djp413
                2794301
                19940282
                6eacaf0c-832f-424f-a2f3-aa4199c23d73
                © The Author 2009. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5/uk/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 February 2009
                : 25 September 2009
                : 13 October 2009
                Categories
                Articles

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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