More About: Irinotecan-Related Cholinergic Syndrome Induced by Coadministration of Oxaliplatin

JNCI Journal of the National Cancer Institute (Impact Factor: 12.58). 02/1999; 91(1):91-2. DOI: 10.1093/jnci/91.1.91a
Source: PubMed
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    ABSTRACT: – Although progress in cancer research is paralleled by the discovery and development of novel chemotherapeutic agents, the benefits of these agents are offset by their side-effect profiles. Of the numerous adverse effects associated with antineoplastic drugs, peripheral neuropathy is the most frequent and is often debilitating. This article reviews the treatment options—both primary and secondary—for neuropathic complications of cancer therapy. – Before a potentially neurotoxic chemotherapeutic regimen is started, patients should undergo 1) a baseline neurologic history for possible coexisting risk factors for neuropathy; 2) physical evaluation; and 3) if indicated, electrophysiologic testing, including nerve conduction studies and electromyography. Patients should be followed closely for the development of neuropathic signs and symptoms. When symptoms (eg, paresthesias or pain) or deficits (eg, weakness) develop, their severity and their effect on quality of life will determine whether the neurotoxic chemotherapy should be continued at a lower dose or discontinued. Neuropathic pain should be treated aggressively with a stepwise approach. The decision to initiate therapy should be guided first by the severity of pain and second by the convenience of dosing and the side-effect profile of the medication. – Specific antineuropathic pain therapy may begin with a tricyclic antidepressant (TCA), titrated to 100 to 150 mg/d, unless anticholinergic side effects appear before this dosage is reached. The TCA may be replaced by or supplemented with antiepileptic agents, such as gabapentin, which is attractive because of its rapid dose titration (maximum, 3600 mg/d) and minimal interaction with other medications. – In addition to pharmacologic therapies targeting symptom management, new therapies directed at preventing the onset or progression of neurotoxicity are desperately needed.
    Current Treatment Options in Neurology 12/1999; 1(5):428-437. DOI:10.1007/s11940-996-0006-x · 1.94 Impact Factor
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    ABSTRACT: Camptothecins represent an established class of effective agents that selectively target topoisomerase I by trapping the catalytic intermediate of the topoisomerase I-DNA reaction, the cleavage complex. The water-soluble salt camptothecin-sodium — introduced in early trials in the 1960s — was highly toxic in animals, whereas the semisynthetic derivatives irinotecan and topotecan did not cause haemorrhagic cystitis because of their higher physicochemical stability and solubility at lower pH values. Myelosuppression, neutropenia and, to a lesser extent, thrombocytopenia are dose-limiting toxic effects of topotecan. In contrast to the structurally-related topotecan, irinotecan is a prodrug which has to be converted to SN-38, its active form. SN-38 is inactivated by conjugation, thus patients with Gilbert’s syndrome and other forms of genetic glucuronidation deficiency are at an increased risk of irinotecan-induced adverse effects, such as neutropenia and diarrhoea. The cytotoxic mechanism of podophyllotoxin is the inhibition of topoisomerase II. Common adverse effects of etoposide include dose-limiting myelosuppression. Hypersensitivity reactions are more common with etoposide and teniposide than with etoposide phosphate because the formulations of the former contain sensitising solubilisers. Leukopenia and thrombocytopenia occur in 65% and 80%, respectively, of patients after administration of conventional doses of teniposide. Anorexia, vomiting and diarrhoea are generally of mild severity after administration of conventional doses of topoisomerase II inhibitors. Clinical pharmacokinetic studies have revealed substantial interindividual variabilities regarding the area under the concentration-time curve values and steady-state concentrations for all drugs reviewed in this article. Irinotecan, etoposide and teniposide are degraded via complex metabolic pathways. In contrast, topotecan primarily undergoes renal excretion. Regarding etoposide and teniposide, the extent of catechol formation over time during drug metabolism may be associated with a higher risk for secondary malignancies.
    Drug Safety 01/2006; 29(3). DOI:10.2165/00002018-200629030-00005 · 2.82 Impact Factor
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    ABSTRACT: Oxaliplatin is a platinum compound that inhibits DNA synthesis, primarily by causing intrastrand cross-links in DNA. Oxaliplatin has a broad spectrum of antineoplastic activity and has demonstrated a lack of cross-resistance with other platinum compounds. In patients with metastatic colorectal cancer, intravenous oxaliplatin has been trialled as a monotherapy and in combination with other agents. The highest response rates were achieved when oxaliplatin was used in combination with fluorouracil/folinic acid (leucovorin; calcium folinate), typically > or = 50% in the first-line setting and 13 to 45% as a second-line therapy. First-line triple therapy with oxaliplatin and fuorouracil/folinic acid achieved significantly higher response rates and longer median progression-free survival than fluorouracil/folinic acid therapy alone. However, no significant difference in the median duration of overall survival was found. This may be a consequence of the subsequent use of oxaliplatin and/or surgery after disease progression in patients who relapsed after fluorouracil/folinic acid therapy alone. Neoadjuvant therapy with oxaliplatin/fluorouracil/folinic acid has proven beneficial in enabling surgical removal of previously unresectable liver metastases. In 2 studies, surgery with curative intent was performed in 16 and 51% of patients with initially unresectable liver metastases following oxaliplatin/fluorouracil/folinic acid therapy; the 5-year survival rates were 40 and 50%, respectively. In patients with advanced ovarian cancer, first-line therapy with oxaliplatin/cyclophosphamide achieved an objective response rate which did not differ significantly from that of cisplatin/cyclophosphamide (33 vs 42%). In addition, oxaliplatin has shown efficacy in patients with platinum-pretreated ovarian cancer and achieved objective response rates similar to paclitaxel in this setting (16 vs 17%). Promising results have also been found with oxaliplatin in patients with non-Hodgkin's lymphoma, breast cancer, mesothelioma and non-small cell lung cancer. Reversible, cumulative, peripheral sensory neuropathy is the principle dose-limiting factor of oxaliplatin therapy. Haematological and gastrointestinal toxicities occur frequently but are generally mild to moderate in intensity. CONCLUSION: Oxaliplatin in combination with fluorouracil/folinic acid is an effective treatment option for patients with metastatic colorectal cancer, both as a first-line therapy and in patients refractory to previous chemotherapy. Although preliminary results failed to show any overall survival advantage of this regimen over fluorouracil/folinic acid alone, this may be a consequence of trial design and requires further examination. Additional clinical investigation of oxaliplatin in patients with other cancers is warranted given the promising results achieved in early trials, most notably in patients with platinum-pretreated ovarian cancer.
    Drugs 10/2000; 60(4):895-924. · 4.34 Impact Factor
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