The induction of peripheral neuropathy is a common factor in limiting therapy with chemotherapeutic drugs. Little is known about the mechanisms responsible for the development of neuropathy. Depending on the substance used, a pure sensory and painful neuropathy (with cisplatin, oxaliplatin, carboplatin) or a mixed sensorimotor neuropathy with or without involvement of the autonomic nervous system (with vincristine, taxol, suramin) can ensue. Neurotoxicity depends on the total cumulative dose and the type of drug used. In individual cases neuropathy can evolve even after a single drug application. A general predisposition for developing a chemotherapy-induced neuropathy has been observed in nerves previously damaged by diabetes mellitus, alcohol or inherited neuropathy. The recovery from symptoms is often incomplete and a long period of regeneration is required to restore function. Up to now, no drug is available to reliably prevent or cure chemotherapy-induced neuropathy.

Chemotherapy-induced peripheral neuropathy.

PURPOSE: To review the pharmacodynamics, pharmacokinetics, toxicities, and relative clinical activities of cisplatin and carboplatin. Through a search of the MEDLINE database, we identified phase III clinical trials and pharmacologic studies comparing cisplatin and carboplatin published in the English language medical literature from January 1966 to December 1997. RESULTS: Prospective randomized trials comparing cisplatin to carboplatin were identified for ovarian (n = 12), germ cell (n = 4), non–small-cell lung (n = 1), small-cell lung (n = 3), and head and neck (n = 4) cancers. Carboplatin and cisplatin were equally effective in suboptimally debulked ovarian cancer and extensive-stage small-cell lung cancer. One study each showed a trend toward better survival in favor of cisplatin for patients with optimally debulked ovarian and limited-stage small-cell lung cancers. These results were, however, based on subset analyses. In germ cell tumors, carboplatin was inferior because of lower relapse-free surviv...

Review of the Comparative Pharmacology and Clinical Activity of Cisplatin and Carboplatin

With a 3-fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long-term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy-induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy-induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies. CA Cancer J Clin 2013;63:419-437. ©2013 American Cancer Society, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21204

Chemotherapy-induced peripheral neurotoxicity: a critical analysis.

While cisplatin and carboplatin are active versus most common cancers, epithelial malignancies are incurable when metastatic. Even if an initial response occurs, acquired resistance due to mutations and epigenetic events limits efficacy. Resistance may be due to excess of a resistance factor, to saturation of factors required for tumor cell killing, or to mutation or alteration of a factor required for tumor cell killing. Platinum resistance could arise from decreased tumor blood flow, extracellular conditions, reduced platinum uptake, increased efflux, intracellular detoxification by glutathione, etc., decreased binding (e.g., due to high intracellular pH), DNA repair, decreased mismatch repair, defective apoptosis, antiapoptotic factors, effects of several signaling pathways, or presence of quiescent non-cycling cells. In lung cancer, flattening of dose-response curves at higher doses suggests that efficacy is limited by exhaustion of something required for cell killing, and several clinical observations suggest epigenetic events may play a major role in resistance.

Mechanisms of resistance to cisplatin and carboplatin

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating this syndrome are very limited. There are six main substance groups that cause damage to peripheral sensory, motor and autonomic neurons, which result in the development of CIPN: platinum-based antineoplastic agents, vinca alkaloids, epothilones (ixabepilone), taxanes, proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). Among them, the most neurotoxic are platinum-based agents, taxanes, ixabepilone and thalidomide; other less neurotoxic but also commonly used drugs are bortezomib and vinca alkaloids. This paper reviews the clinical picture of CIPN and the neurotoxicity mechanisms of the most common antineoplastic agents. A better understanding of the risk factors and underlying mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.

Mechanisms of Chemotherapy-Induced Peripheral Neuropathy.

PURPOSETo identify the major sites of platinum accumulation within neural tissues after treatment with cisplatin and to determine the relationship between cumulative dosage, time, and the development of histopathological and clinical neurotoxicity.PATIENTS AND METHODSTwenty-one patients treated antemortem with cisplatin had neural tissue harvested at autopsy. Neural tissues were assayed for platinum and examined for histopathologic evidence of neurotoxicity. The relationship between histopathologic neurotoxicity and various pharmacologic parameters was analyzed.RESULTSTissue platinum levels were found to be highest in the dorsal root ganglia and lowest in tissue protected by the blood-brain barrier. For peripheral nerve, dorsal root, and dorsal root ganglia, a linear relationship was observed between platinum levels and cumulative dose. Platinum levels in neural tissue were not observed to decrease with time. Histopathologic toxicity closely matched an index of exposure to platinum (cumulative dose and lo...

Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity.

We assessed factors which affect cisplatin concentrations in human surgical tumour specimens. Cisplatin 10 mg m-2 was given i.v. to 45 consenting patients undergoing surgical resection of neoplasms, and platinum was assayed in resected tumour and in deproteinated plasma by flameless atomic absorption spectrophotometry. By multiple stepwise regression analysis of normalised data, patient characteristics that emerged as being most closely associated (P 'others' > lung cancer > head/neck cancer > gliomas) or tumour 'type' (LMM > brain metastases > extracerebral tumours > gliomas), serum calcium and chloride (positive correlations) and bilirubin (negative). Tumour location (intracranial vs extracranial) did not correlate with platinum concentrations. If values for a single outlier were omitted, high-grade gliomas had significantly higher platinum concentrations (P < 0.003) than low-grade gliomas. For intracranial tumours, the computerised tomographic scan feature that correlated most closely with platinum concentrations in multivariate analysis was the darkness of peritumoral oedema. Tumour source or type is a much more important correlate of human tumour cisplatin concentrations than is intracranial vs extracranial location. Serum calcium, chloride and bilirubin levels may affect tumour cisplatin uptake or retention. CT scan characteristics may help predict cisplatin concentrations in intracranial tumours.

Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin

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Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity.

Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin