Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The treatment for advanced gastroesophageal tumors is still largely based on 5-fluorouracil and cisplatin combinations, and the treatment for advanced pancreatic tumors principally relies on gemcitabine. The need for more active agents is evident in light of the poor outcomes for patients with these tumors. Oxaliplatin is an important chemotherapeutic agent currently being investigated in the treatment of gastrointestinal carcinomas. This diaminocyclohexane-platinum compound has significant differences from cisplatin and carboplatin with respect to its activity and toxicity. It appears to have activity in tumors believed to be marginally sensitive to the other platinum agents, and it is neither ototoxic nor nephrotoxic. The main side effect of oxaliplatin is a sensory neuropathy exacerbated by cold exposure. After extensive clinical development, oxaliplatin has become an important option in the treatment of colorectal cancer. Its role in the treatment of upper gastrointestinal cancers is less well established, but is the focus of intense investigation. Much of what we currently know is based on small phase I and II studies, but knowledge is rapidly accumulating. The fact that cisplatin remains an important drug in the treatment of several upper gastrointestinal cancers raises the hope that oxaliplatin will contribute significantly to the treatment of those malignancies as well. Larger randomized phase III trials are being designed and conducted to fully define the role of oxaliplatin in the treatment of upper gastrointestinal tumors in the relatively near future.
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PMID:The experience with oxaliplatin in the treatment of upper gastrointestinal carcinomas. 1452 96

The effectiveness and toxicity of many drugs can vary depending on the time of administration in relation to 24-hour rhythms of biochemical, physiological and behavioural processes under the control of the circadian clock. Such chronopharmacological phenomena are influenced by not only the pharmacokinetics but also pharmacodynamics of medications. Chronotherapy is especially relevant when the risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke and peptic ulcer disease. Morning, once-daily administration of corticosteroids results in little adrenocortical suppression, while the same daily dose split into four equal doses to coincide with daily meals and bedtime results in significant hypothalamus-pituitary-adrenal axis suppression. In a randomised, multicentre trial involving patients with previously untreated metastases from colorectal cancer, the chronomodulated infusion of oxaliplatin, fluorouracil and folinic acid was compared with a constant-rate infusion method. Adverse effects such as stomatitis and peripheral sensory neuropathy were lower and objective response was higher with chronotherapy as compared with the fixed-rate infusion. The merit of chronomodulated infusion is supported by the 24-hour rhythm of DNA synthesis and the activity of dehydropyrimidine dehydrogenase, which brings about the intracellular catabolism of fluorouracil. On the other hand, haloperidol and selective serotonin reuptake inhibitors have diverse effects on sleep continuity and nocturnal arousals. Although interferon also alters the clock function, this disruptive effect can be overcome by devising an administration regimen that minimises adverse drug effects on clock function. Thus, one approach to increasing the efficiency of pharmacotherapy is the administration of drugs at times at which they are most effective and/or best tolerated.
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PMID:Changes in toxicity and effectiveness with timing of drug administration: implications for drug safety. 1458 62

Oxaliplatin-based combination chemotherapy is an option for first-line therapy of metastatic colorectal cancer. It is associated with acute hyperexcitability of motor and sensory nerves, and a cumulative sensory axonal neuropathy. We describe a 56-year-old male with metastatic colorectal cancer treated with oxaliplatin and capecitabine who developed a rapidly ascending motor and sensory neuropathy, which rendered him wheelchair-bound. Heightened clinical suspicion for possible oxaliplatin-induced motor neuropathies may be warranted.
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PMID:Severe disabling sensory-motor polyneuropathy during oxaliplatin-based chemotherapy. 1526 7

The purpose of this study was to evaluate the efficacy, assessed as response rate, and toxicity of UFT (Tegafur-Uracil) in combination with oxaliplatin as first-line treatment of advanced colorectal cancer (CRC). In all, 84 patients with recurrent or metastatic CRC with measurable disease were included. Treatment consisted of oxaliplatin 85 mg m(-2) in 120-min intravenous (i.v.) infusion on days 1 and 15; i.v. l,leucovorin (l,LV) 250 mg m(-2) given in 2 h on day 1, followed by oral UFT 390 mg m(-2) on days 1-14, and oral l,LV 7.5 mg/12 h on days 2-14. Cycles were repeated every 28 days. A total of 492 cycles of chemotherapy were delivered with a median of six per patient (range 1-12). There was one complete response (1%) and 28 partial responses (34%) for an overall response rate of 35% (95% confidence interval (CI): 24-46%). A total of 36 patients (44%) had stable disease, whereas 17 (21%) had a progression. The median time to progression was 7.3 months and the median overall survival was 16.8 months. A prescheduled preliminary analysis was performed after inclusion of 16 patients who detected a high gastrointestinal toxicity, which led to a reduction of the UFT dose to 300 mg m(-2). With this new dosage, grade 3-4 diarrhoea and grade 3-4 nausea/vomiting dropped to 21 and 14% of patients, respectively. Other grade 3-4 toxicities were stomatitis in one (1%), anaemia in three (5%), neutropenia in two (3%), thrombocytopenia in one(1%), fatigue in six (9%), peripheral sensory neuropathy in nine (14%) and laryngopharyngeal dysesthesia in two patients (2%). The combination of oxaliplatin and UFT-l,LV is an active, easy-to-administer regimen with moderate toxicity. Hence, this regimen is worthy of further investigation.
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PMID:Phase II study of UFT and oxaliplatin in first-line treatment of advanced colorectal cancer. 1550 21

Oxaliplatin is a relatively new platinum analogue that is currently used in pharmacotherapy of metastatic colorectal cancer. Its dose-limiting toxicity is sensory neuropathy, which can be modulated by infusion of calcium and magnesium. Oxaliplatin exerts its anti-tumour effects by platinum-adduct formation, binding to cellular proteins and possibly interfering with RNA synthesis as well. If they are not removed from DNA, oxaliplatin adducts are lethal. Cellular defense mechanisms prevent adduct formation (e.g., glutathione-S-transferase) or remove DNA adducts (e.g., nucleotide excision repair). Depending on the activity of necessary enzymes in these cellular defense pathways, oxaliplatin induced damage varies from one individual to another. There is growing evidence that polymorphisms in genes coding for DNA repair enzymes and metabolic inactivation routes contribute to the interindividual differences in anti-tumour efficacy and toxicity of oxaliplatin. Single nucleotide polymorphisms (SNPs) may yield inactive enzymes, or increased gene transcription and hence increased enzyme production. This review covers findings of recent investigations on the associations of SNPs and clinical outcome after oxaliplatin chemotherapy in metastatic colorectal cancer.
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PMID:Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy. 1584 79

In recent years, oxaliplatin-based chemotherapy protocols, particularly oxaliplatin in combination with infusional 5-fluorouracil/leucovorin (FOLFOX or FUFOX), have emerged as the standard of care in first- and second-line therapy of advanced-stage colorectal cancer. Although oxaliplatin by itself has only mild hematologic and gastrointestinal side effects, its clinically dominating toxicity affects the peripheral sensory nervous system in the form of 2 distinct types of neurotoxicity: (1) a unique, frequent, acute sensory neuropathy that is triggered or aggravated by exposure to cold but at the same time is rapidly reversible without persistent impairment of sensory functions; (2) the dose-limiting toxicity of oxaliplatin, a cumulative, chronic sensory neurotoxicity that resembles that of cisplatin with the important difference of its being more rapidly and completely reversible. This chronic sensory neurotoxicity is highly predictable, being closely associated with the cumulative dose of oxaliplatin that is administered. Various strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity. The stop-and-go concept uses the predictability and reversibility of neurologic symptoms to allow patients to stay on an oxaliplatin-containing first-line therapy for a prolonged period. Several neuromodulatory agents such as calcium-magnesium infusions; antiepileptic drugs like carbamazepine, gabapentin, and venlafaxine; amifostine; a-lipoic acid; and glutathione have demonstrated some activity in the prophylaxis and treatment of oxaliplatin-induced acute neuropathy. However, randomized trials demonstrating a prophylactic or therapeutic effect on oxaliplatin's cumulative neurotoxicity are still lacking. The predictability of neurotoxicity associated with oxaliplatin-based therapy should allow patients and doctors to develop strategies to manage this side effect in view of the individual patient's clinical situation. This is of increasing importance, because the addition of bevacizumab to FOLFOX will conceivably further prolong the progression-free survival achieved with FOLFOX so that neurotoxicity and not tumor progression could become the dominating treatment-limiting issue in the first-line therapy of advanced colorectal cancer.
Clin Colorectal Cancer 2005 Apr
PMID:Clinical management of oxaliplatin-associated neurotoxicity. 1587 65

Oxaliplatin in combination with 5-fluorouracil/leucovorin (LV5FU) improves the response rate and survival of patients with metastatic colorectal cancer. The objective of the Mosaic study was to evaluate the efficacy of this association in the adjuvant treatment of stage II and III colon cancer. This international study, including 2,246 patients, compared the efficacy of standard treatment with LV5FU2 alone to that of oxaliplatin-LV5FU (Folfox4 regimen) following R0 resection of the primary tumour. Both treatments were administered every two weeks for six months. At 3-year follow-up, the risk of relapse was decreased by 23% in the Folfox4 group (p = 0.002). The protocol was well tolerated, with an identical overall mortality during treatment (0.5%) in both groups. The main specific complication, peripheral sensory neuropathy was reversible in the great majority of cases. A new analysis at 4-year follow-up (median 48.6 months) confirmed the superior efficacy of the Folfox4 regimen compared to the standard treatment, the reduction in relapse risk being 24% (p = 0.0008). On the strength of these results, oxaliplatin was granted a marketing authorization for the indication adjuvant treatment of stage III colon cancer. Based on the data currently available, physicians should consider adjuvant treatment for stage II patients, making each individual decision for treatment on a case-by-case basis.
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PMID:[Adjuvant treatment of colon cancer MOSAIC study's main results]. 1648 40

In early clinical trials, oxaliplatin has demonstrated significant activity against colorectal cancer in combination with 5-fluorouracil (5-FU) and folinic acid (FA), both in metastatic as in radically resected disease. The drug differs from the other two most important platinum compounds (cisplatin and carboplatin) for the absence of nephrotoxicity or for the reduced drug-induced ototoxicity. During its administration, two different types of neurological symptoms can be experienced: the first one occurs during or immediately after the end of the infusion and it appears as a transient peripheral sensory neuropathy manifesting as paresthesias and dysesthesia in the extremities sometimes accompanied by muscular contractions of the extremities or the jaw (triggered or enhanced by exposure to cold). The second one occurs after long-term administration of oxaliplatin presenting with deep sensory loss, sensory ataxia and functional impairment (similar to those observed with cisplatin). This type of neurotoxicity is usually late-onset and correlated with the cumulative-dose of oxaliplatin. The aim of this review is to analyse the mechanism underlying induction of neurotoxicity and the possible treatments to prevent and to treat it.
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PMID:Oxaliplatin-related neurotoxicity: how and why? 1680 62

Oxaliplatin (L-OHP) has become a standard treatment for advanced colorectal cancer and a valid option for patients in the adjuvant setting. Compared with cisplatin, L-OHP has no renal toxicity, only mild hematological and gastrointestinal toxicity, while neurotoxicity is the limiting toxicity. This side effect has been described as a transient distal dysesthesia, enhanced by exposure to cold, and as a dose-related cumulative mild sensitive neuropathy. We studied two groups of patients (18 and 13) with advanced colorectal cancer, treated with median cumulative doses of L-OHP 862 mg/m2 and 1,033.5 mg/m2. All the patients had been evaluated previously, during treatment, after discontinuation and after a long follow-up of 5 years to verify the incidence and the characteristics of the neuropathy induced by this antineoplastic agent. The clinical and neurophysiological examinations showed an acute and transient neurotoxicity and a cumulative dose-related sensory neuropathy in nearly all the patients. The reversibility of these effects was studied. Five patients continue to manifest symptoms and signs of neurotoxicity after a long follow-up, indicating persistence of this peculiar type of neuropathy.
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PMID:Persistence of high-dose oxaliplatin-induced neuropathy at long-term follow-up. 1682 73

In metastatic colorectal cancer, a combination of Leucovorin (LV) and fluorouraci (l FU) with oxaliplatin (FOLFOX) is a standard first-line regimen. The two limiting toxicities of FOLFOX are neutropenia and the specific reversible sensory neuropathy of oxaliplatin. The cumulative neurotoxicity often requires therapy to be stopped. Immediate hypersensitive reactions (anaphylaxis) have been noted as often as to 0.6 percent. We should pay sufficient attention to side effects of FOLFOX.
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PMID:[FOLFOX]. 1683 79


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