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)

A significant increase in the dose intensity of chemotherapy with fluoropyrimidines and platinum complexes has resulted from selective circadian timing and/or circadian modulation of the infusion rate. The relevance of such chronopharmacologic strategy for improving the outcome of metastatic colorectal cancer was evaluated in an extended Phase II clinical trial involving 93 patients. Of these, 49% previously had received chemotherapy and/or radiation therapy. The drugs 5-fluorouracil (5-FU, 700 mg/m2/d) and folinic acid (FA, 300 mg/m2/d) combined with oxaliplatin (l-OHP, a nonnephrotoxic platinum complex, 25 mg/m2/d) were infused continuously for 5 days every 3 weeks. In a pilot randomized study, the infusion of all three drugs at a constant rate resulted in World Health Organization (WHO) Grade 3 or 4 toxicity in all four patients compared with no such toxicity in four patients if the infusion rate was modulated according to circadian rhythms. In this Phase II trial, drug delivery was modulated sinusoidally over the 24-hour day with peak flow rates at 4 AM for 5-FU and FA and at 4 PM for l-OHP, using an ambulatory programmable-in-time pump. All patients and 784 of 839 courses (93%) were evaluable for toxicity. Dose-limiting toxicities (WHO Grade 2 to 4) included diarrhea (19% of courses) and vomiting (35% of courses). In addition, WHO Grade 2 to 4 hematologic or mucosal toxicity, respectively, occurred in 2.5% and 7% of courses. Two toxic deaths were encountered. Peripheral sensory neuropathy led to discontinuation of l-OHP in 14 patients after 7 to 12 courses; it completely disappeared within 3 months. Fifty-four of the 93 patients had an objective response (58%; 95% confidence limits, 48% to 68%), irrespective of previous treatment or prior documented progression while receiving standard chemotherapy with 5-FU and FA or continuous 5-FU. Complete responses (CR) were seen in 6 patients (4 of which were proved histologically) and, after surgery, in 12 additional patients (overall CR rate, 18 of 93 [19%]; 95% confidence limits, 11% to 27%). Median progression-free survival (PFS) and overall survival were, respectively, 10 and 15 months, irrespective of prior therapy. Both PFS and survival were significantly longer in patients with a good performance status (PS, 0 or 1, by WHO criteria; respectively, 12 and 21 months) than in patients with poor PS (respectively, 8 and 10 months; P less than 0.01, by log-rank test). This chronopharmacologic protocol may have circumvented, to some extent, both the natural and acquired resistance of colorectal cancer to chemotherapy.
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PMID:A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer. 173 81

Oxaliplatin (trans-/-diaminocyclohexane oxalatoplatinum; L-OHP) is a new platinum derivative for the treatment of advanced colorectal cancer. Preclinical data have shown that oxaliplatin is active in a wide range of human and murine tumour cell lines, and has been found to be non-cross-resistant with cisplatin in various cisplatin-resistant cell lines and tumours. Oxaliplatin in combination with 5-fluorouracil (5-FU) leads to synergistic antiproliferative activity both in vivo and in vitro. Clinical data have shown that oxaliplatin is active and well tolerated both as monotherapy and in combination with 5-FU/folinic acid in first- or second-line treatment of patients with metastatic colorectal cancer. Oxaliplatin has a very good safety profile, and studies have confirmed that peripheral sensory neuropathy is related to the cumulative dose of oxaliplatin administered and that this neuropathy is generally reversible after discontinuation of treatment. High response rates and prolonged survival have been achieved in metastatic colorectal cancer patients, even after 5-FU failure.
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PMID:Oxaliplatin (L-OHP): a new reality in colorectal cancer. 964 11

Oxaliplatin, a new third-generation platinum complex, is active in the treatment of colorectal and advanced ovarian cancers, both as monotherapy and in combination therapy. It has demonstrated a very good safety profile, characterized by low haematotoxicity, and moderate and manageable gastrointestinal toxicity. No significant renal or ototoxicities have been observed. Oxaliplatin induces a peripheral sensory neuropathy which is characterized by distal and perioral dysaesthesia, and is induced or exacerbated by the cold; in general, it is regressive between cycles of treatment. This dose-limiting toxicity is cumulative, but reversible within a few months of discontinuation of treatment in the majority of cases. In a cohort study of 490 patients with advanced colorectal cancer included in an extended access programme, more than 2700 cycles of oxaliplatin plus 5-fluorouracil (5-FU) were administered. The overall safety profile of oxaliplatin was shown to be very favourable. Oxaliplatin and cisplatin, each in combination with cyclophosphamide, have a similar efficacy in the treatment of advanced ovarian cancer, but oxaliplatin was better tolerated than cisplatin in terms of haematological, gastrointestinal, neurosensory and renal toxicities. The safety profile of oxaliplatin makes it an ideal candidate for combination therapy.
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PMID:Oxaliplatin in practice. 964 12

Oxaliplatin is a new platinum derivative. A multicentric phase I study was conducted with a monotherapy of Oxaliplatin. A total of 20 patients were enrolled who had histologically proven 6 ovarian cancers, 5 uterine cervix cancers, 3 lung cancers, 3 breast cancers, 1 endometrial cancer, 1 gastric cancer, and 1 colorectal cancer. Oxaliplatin was administered as a 2-hour infusion at doses of 20, 40, 80, 130, and 180 mg/m2 every 3 weeks, for a total of 30 cycles. A dose-related and reversible peripheral sensory neuropathy was the dose-limiting toxicity with minimal hematotoxicity and no nephrotoxicity. No hydration was needed. The plasma platinum concentration was biphasically decreased. Cmax and AUC were dose-dependent. T1/2 beta was 31.3 hours. The recommended dose for further studies was 130 mg/m2. A partial response was observed in endometrial cancer.
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PMID:[Phase I clinical study of oxaliplatin]. 979 12

Oxaliplatin is the first clinically available diaminocyclohexane platinum coordination complex. The drug is non-cross-resistant with cisplatin or carboplatin and is one of the few active drugs against human colorectal cancer. Its cytotoxicity is synergistic with fluorouracil and folinic acid (leucovorin), the reference treatment for this disease. The main cumulative dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy. The drug can also produce diarrhoea, vomiting and haematological suppression. Unlike cisplatin, no renal failure or peripheral motor neuropathy have been reported and the sensory neuropathy is partly reversible. Unlike carboplatin, oxaliplatin produces only mild to moderate haematological toxicity. Oxaliplatin undergoes biotransformation into aquated forms in the blood, where 3 species can be found: total platinum, ultrafilterable or 'free' platinum and erythrocyte platinum. Flameless atomic absorption (FAAS) is used for assaying platinum concentration in various tissues. Inductively-coupled plasma mass spectrometry (ICP-MS), with a >10-fold lower sensitivity threshold than FAAS, was also used for the determination of oxaliplatin pharmacokinetics. The pharmacokinetics of oxaliplatin are described by a 3-compartment model. The drug rapidly crosses the cellular membrane as a result of its lipophilicity. Hence, at the end of a 2-hour infusion, approximately 40% of the blood platinum is found in erythrocytes. The distribution half-life of ultrafiltrated plasma platinum ranges from 10 to 25 minutes and its terminal elimination half-life is 26 hours (determined with FAAS) or 270 hours (ICP-MS). The elimination half-life of erythrocytic platinum is 12 to 50 days, close to that of erythrocytes. 30 to 50% of the platinum is recovered in the urine within 2 to 5 days, with renal clearance accounting for half of the total clearance of ultrafiltrated platinum. The total clearance of this species is correlated with the glomerular filtration rate. No pharmacokinetic-pharmacodynamic relationship has been established for oxaliplatin. Pharmacokinetic alterations produced by fluorouracil + folinic acid or irinotecan were minimal if any. The prolonged stability of oxaliplatin makes it suitable for continuous infusions over 4 to 5 days, with a delivery rate which can be either constant or chronomodulated (peak rate at 1600h), using programmable ambulatory pumps. Chronomodulation significantly reduces toxicity and improves antitumour activity as compared with constant rate infusion. These differences in pharmacodynamic properties were paralleled by differences in plasma concentration time courses. The different drug concentration profiles achieved with different infusional modalities may be useful tools for understanding the relationship between the pharmacokinetics and pharmacodynamics of oxaliplatin and may lead to further optimisation of its administration schedule and its combination with other drugs.
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PMID:Oxaliplatin: pharmacokinetics and chronopharmacological aspects. 1066 56

When treating patients for metastatic cancer, there is always a balance between the benefits of treatment and resulting side-effects. Peripheral sensory neuropathy (PSN) is a side-effect of many anticancer agents used in routine practice. Oxaliplatin is a relatively new agent currently licensed in over 50 countries including France, Germany and the UK for the treatment of metastatic colorectal cancer. Although it is a new agent, it is from the same family of drugs as cisplatin, an agent that has been used for many years. PSN is the most commonly discussed side-effect associated with oxaliplatin. Oxaliplatin-induced PSN is characterized by two distinct syndromes: a transient acute dysaesthesia and a cumulative distal neurotoxicity. Importantly, both are generally reversible after stopping treatment. Oxaliplatin-induced acute PSN is triggered and exacerbated by cold and can be greatly reduced in affected patients simply by avoiding cold conditions. Oxaliplatin-induced cumulative PSN may also be managed by temporary cessation of treatment.
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PMID:An overview of chemotherapy-induced peripheral sensory neuropathy, focusing on oxaliplatin. 1195 4

A phase II study was performed to evaluate the clinical efficacy and toxicity of oxaliplatin combined with uracil and tegafur (UFT) in patients with advanced colorectal cancer previously treated with a fluoropyrimidine-based regimen. From January to December 1999, 34 patients were enrolled in this study. Patients received intravenous oxaliplatin 130 mg/m2 on day 1 and daily oral UFT 350 mg/m2 in 3 divided doses for 21 days and repeated every 21 days. Thirty-one of 34 patients were assessable for response and 32 patients for toxicity. Partial response was observed in four patients and stable disease in six patients. The response rate was 12.9% (95% CI, 3.6-29.8%) and median duration of response was 17 weeks. The median overall survival and progression-free survival of all patients were 26 weeks (range, 3-90+ weeks) and 9 weeks (range, 3-56 weeks), respectively. Sensory neuropathy was the most common toxicity, but there was no severe toxicity (>grade II) except for a case of grade III neutropenia. We conclude that oxaliplatin and UFT combination chemotherapy was well tolerated without significant toxicities. The results of this trial will serve as the basis for designing new clinical trials with a different dose or schedule.
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PMID:Oxaliplatin and UFT combination chemotherapy in patients with metastatic colorectal cancer. 1215 64

Oxaliplatin, a platinum compound characterized by a diaminocyclohexane (DACH) platinum carrier ligand, has proven its efficacy in first- and second-line advanced colorectal cancer (CRC) treatment. Acute reversible and cumulative peripheral sensory neuropathy has been observed frequently with oxaliplatin treatment and limits its use. Its synergism with other drugs, as well as its different mechanism of action and toxicity profile make it an attractive candidate for combination studies in CRC. It can be combined safely with 5-fluorouracil (5-FU)+/-folinic acid (LV), irinotecan, raltitrexed, multitarget antifolate LY231514 (MTA), and oral 5-FU prodrugs. These combinations confer both an increased response rate compared to that of any single agent and an increased secondary surgical resection of initially unresectable metastases, possibly leading to prolonged survival. In three prospective randomized phase III studies in advanced CRC, oxaliplatin plus 5-FU/LV improved significantly progression-free survival without a significant increase in median survival time and without affecting quality of life, compared to treatment with 5-FU/LV. Ongoing clinical trials will define its role in the adjuvant setting.
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PMID:Oxaliplatin: results in colorectal carcinoma. 1239 98

Oxaliplatin is the only third-generation platinum derivative to have found a place in routine cancer therapy. It is particularly useful therapy for advanced colorectal cancer and has shown scheduling flexibility in combination with 5-fluorouracil/folinic acid. Oxaliplatin has a unique pattern of side effects unrelated to those observed with other therapeutic platinum derivatives. During the course of oxaliplatin clinical trials, the adverse events most often cited were hematologic toxicity, gastrointestinal tract toxicity, and a neurolopathy unlike that observed with other platinum derivatives. Grade 3/4 neutropenia occurred in 41.7% of patients in the phase III clinical trial that used the FOLFOX-4 regimen, and thrombocytopenia is a rare event sometimes observed after multiple cycles of therapy. Nausea and vomiting is usually mild to moderate and readily controlled with standard antiemetics. Grade 1/2 diarrhea may occur but studies have shown that 5-fluorouracil contributes significantly more to gastrointestinal toxicity than does single-agent oxaliplatin. Nephrotoxicity has not been reported in any of the oxaliplatin trials, allowing administration of oxaliplatin without hydration. Oxaliplatin-induced neurotoxicity consists of a rapid-onset acute sensory neuropathy and a late-onset cumulative sensory neuropathy that occurs after several cycles of therapy. In about three fourths of patients, neurotoxicity is reversible with a median time to recovery of 13 weeks after treatment discontinuation. To date, oxaliplatin has proven to be a safe and effective therapy for colorectal cancer and side effects have been easy to manage with appropriate awareness from patients and care providers.
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PMID:Oxaliplatin-related side effects: characteristics and management. 1242 4

Oxaliplatin has become an integral part of various chemotherapy protocols, and in advanced colorectal cancer in particular. While oxaliplatin has only mild hematologic and gastrointestinal side effects, its dose-limiting toxicity is a cumulative sensory neurotoxicity that resembles that of cisplatin with the important difference of a more rapid and complete reversibility. The reversibility of neurotoxicity has been assured in long-term follow-up of patients who have received adjuvant oxaliplatin-based chemotherapy. In addition, oxaliplatin causes a very unique, but frequent, acute sensory neuropathy that is triggered or aggravated by exposure to cold but is rapidly reversible, without persistent impairment of sensory function. Various strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity. The "Stop-and-Go" concept uses the reversibility of neurologic symptoms to aim at delivering higher cumulative oxaliplatin doses as long as the therapy is still effective. Several neuromodulatory agents such as calcium-magnesium infusions, antiepileptic drugs like carbamazepine or gabapentin, amifostine, alpha-lipoic acid, and glutathione have shown promising activity in prophylaxis and treatment of oxaliplatin-induced neurotoxicity. However, larger confirmatory trials are still lacking so that, to date, no evidence-based recommendation can be given for the prophylaxis of oxaliplatin-induced neurotoxicity. 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.
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PMID:Oxaliplatin-safety profile: neurotoxicity. 1452 89


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