Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irinotecan (CPT-11, Camptosar) is one of the new generation of chemotherapeutic agents that has activity in advanced colorectal cancer. It has antitumor efficacy as a single agent, and also has been combined with fluorouracil (5-FU) and leucovorin (IFL) to treat these patients. Randomized studies have confirmed the superiority of IFL to 5-FU and leucovorin alone with regard to patient survival, time to progression, and tumor response rate. The optimal schedule for combining these agents remains uncertain, but in the United States, the schedule of IFL weekly for 4 consecutive weeks repeated every 6 weeks, according to the schedule reported by Saltz et al, has been widely used, although with some toxicity (especially myelosuppression and diarrhea). In an attempt to improve the tolerability of IFL, some have advocated modifying the schedule of IFL to weekly for 2 weeks, with repeated cycles every 21 days. Twenty-three patients with advanced colorectal cancer have been treated on this schedule at a single institution. Therapy was well tolerated, with 35% of patients experiencing grade 3/4 neutropenia, two of whom had episodes of febrile neutropenia, and 9% with grade 3/4 diarrhea. The median relative dose intensity of irinotecan administered in the first 18 patients treated with this regimen was 94%. These data support the hypothesis that modifying the schedule of administration of IFL improves the tolerability and ability to deliver the regimen, but must be confirmed by randomized prospective studies, which may also attempt to evaluate the role of bolus 5-FU in the treatment of advanced colorectal cancer.
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PMID:Improving the toxicity of irinotecan/5-FU/leucovorin: a 21-day schedule. 1456 47

Irinotecan hydrochloride has been administered to patients with breast cancer resistant to anthracyclines and/or taxanes in our department. A retrospective analysis of the efficacy and toxicity of irinotecan therapy was conducted to clarify its clinical usefulness. A total of 35 consecutive patients with advanced or recurrent breast cancer were treated with irinotecan between June 1996 and March 2002. The patients ranged in age from 37 to 66 years old (median, 52). The most frequent metastatic lesion was in the liver. The number of previous chemotherapy was 2 to 7 regimens (median, 3). Ninety-one percent and 97% of the tumors were anthracycline- and taxane-resistant, respectively. The weekly dose of irinotecan was 40-160 mg/body (median, 100), and the total dose was 40-6, 110 mg/body (median, 840). An objective response rate of 6% and a clinical benefit rate of 23% were obtained. The median time-to-progression and overall survival were 3 months and 8 months, respectively. Severe toxicity (grade 3 or 4) was observed in 34% of the patients for a decrease in the white blood count, in 26% for neutropenia, in 17% for nausea/vomiting and in 6% for diarrhea. Although this study suggests that irinotecan is a clinically useful treatment of anthracycline- and/or taxane-resistant breast cancer, its anti-tumor effect was not satisfactory. The activity of first-line irinotecan therapy or the combined use of irinotecan with other agents should be investigated in clinical studies.
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PMID:[Retrospective study on utility of irinotecan hydrochloride in patients with advanced and recurrent breast cancer]. 1458 75

Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is active in the treatment of non-small cell lung cancer (NSCLC). In this report we describe our experience with this drug when used as a single agent in patients with advanced NSCLC refractory to chemotherapy with platinum and taxanes. Nineteen NSCLC patients (thirteen males and six females; 53% adenocarcinoma and 26% squamous cell carcinoma) with a median age of 52 years (range 34-71) and a Karnofsky performance status of 60% (60-80%) were included in the study. At baseline, the patients had a median of two disease sites and had been treated with a median of two prior regimens. Irinotecan was given at a dose of 100 mg/m(2) i.v.) weekly for 4 weeks followed by 1 week of rest. A total of 123 weekly infusions were administered, and each patient received a median of 4 weeks of treatment (range 1-32). All patients were evaluated by intention-to-treat analysis for efficacy and safety. Main toxicities reported were grade 3 neutropenia (10% of patients), diarrhea (10% of patients), and grade 4 thrombocytopenia (5% of patients). The overall clinical response rate was 16% (95% CI: 8-24) with three partial responses and 9 (47%) patients with stable disease. The median time to progression and the median survival time were 7 and 15 weeks, respectively. In conclusion, weekly irinotecan showed antitumoral activity and minimum toxicity in NSCLC patients refractory to platinum and taxanes.
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PMID:Activity of weekly irinotecan (CPT-11) in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes. 1458 14

The combination of irinotecan (CPT-11), oxaliplatin (L-OHP), 5-fluorouracil (5-FU) and folinic acid (FA) is one of the possibilities to overcome chemoresistance in advanced colorectal cancer (ACRC) patients. The aim of this study was to determine the tolerability and activity of CPT-11 plus chronomodulated infusion of L-OHP, 5-FU and FA in ACRC patients. A total of 35 patients (91% pretreated, 77% with CPT-11, 54% with L-OHP, 42% with both) were treated every 3 weeks with CPT-11, 180 mg m(-2) day 1 i.v., plus L-OHP, 20 mg m(-2) day(-1), 5-FU, 700 mg m(-2) day(-1) and FA, 150 mg m(-2) day(-1), all three drugs from day 2 to day 5 by chronomodulated infusion. The patients' (pt) data were as follows: male/female 21/14; median age 58 years (range: 38-70); PS 0: 26 pts (74%), PS 1: 8 pts (23%), PS 2: 1 pt (3%); primary tumour colon/rectum 26/9; involved organs: 1, 14 pts (40%); 2, 17 pts (48%); >or=3: 4 pts (11%); previous chemotherapy lines 1: 12 pts (34%), 2: 10 pts (28%), >or=3: 10 pts (28%). A total of 221 courses (c) were performed; no grade 4 toxicity was observed with only one grade 3 (G3) neutropenia and thrombocytopenia (3%) in one out of 221 courses (<1%). Maximal toxicity (G3) was nausea and diarrhoea in 10 pts (28%), occurring in 14 out of 221 c (6%) and 12 out of 221 c (5%) respectively. Seven patients achieved a partial response (20%, confidence interval (c.i.) 6.8-33.3) and one patient a complete response (2.9%, c.i. 0-8.4), for a total overall response rate of 22.9% (c.i. 9-36.8); 15 out of 35 (42.9%, c.i. 26.5-59.3) had stable disease and 12 out of 35 (34.3%, c.i. 18.6-50) patients underwent a progression. In conclusion, this four-drug regimen is feasible in advanced pretreated ACRC patients with no significant haematological toxicity and acceptable diarrhoea. The activity of this combination is currently studied in EORTC 05011 study.
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PMID:A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients. 1461 95

Peritoneal mesothelioma is a rare malignancy that is seen in patients exposed to asbestos or in young women with no known exposure to asbestos. The clinical features of the disease are similar in these two groups, and include peritoneal carcinomatosis, ascites, thrombocytemia, systemic symptoms (fever and night sweats), and hypercoagulability. There is no known curative therapy for this disease. Cisplatin has activity in 25% of patients. Mesothelial cells are known to contain high levels of carboxylesterase, a key enzyme in the activation of Irinotecan (CPT-11) to SN-38. This retrospective review of our experience in combining cisplatin 50 or 60 mg/m2 i.v. or i.p. on day 1 with CPT-11 50 or 60 mg/m2 i.v. on day 1, 8, and 15. Courses were repeated every 4 weeks x 6. If i.p. administration of cisplatin were feasible, it was the preferred route. Response to treatment was based on RECIST criteria. Fourteen men and 3 women, median age 62 years (35-76 years) and median PS 1 (0-2) were treated. Median number of courses was two for nonresponders and six for responders. The overall response rate was 24%, but 76% of patients improved on treatment. Median survival is not reached. Grade > or = 2 side effects included anemia (n = 6), neutropenia (n = 3), nausea/vomiting (n = 4), and constipation (n = 2). Grade 1 side effects were fatigue, anorexia, weight loss, alopecia, diarrhea, neuropathy, and gastric reflux. There were no grade > or = 3 hematologic toxicities. The combination of cisplatin and CPT-11 is well tolerated and has clinical benefits in patients with peritoneal mesothelioma.
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PMID:Cisplatin and irinotecan (CPT-11) for peritoneal mesothelioma. 1462 25

The efficacy and toxicity of irinotecan (CPT-11) 350 mg/m(2) i.v. once every 3 weeks was assessed in 60 patients with advanced colorectal cancer (CRC) showing failure to 5-fluorouracil (5-FU) treatment. The overall objective response rate was 13.6% (1 complete response and 4 partial responses) and 25 patients (42.4%) showed stable disease; the median time to disease progression was 4.4 months and the median survival was 10.5 months. The main non-hematological toxicities were alopecia (80.3% of patients), diarrhea (75.0%), and nausea/vomiting (71.7%); neutropenia was the main hematological toxicity. Grade 3 or 4 diarrhea appeared in 21 of 131 cycles (16.1%), whereas grade 3 or 4 neutropenia appeared in 78 cycles (25.0%). In conclusion, the present phase II study confirms that CPT-11 350 mg/m(2) every 3 weeks is active and well tolerated as second-line chemotherapy for CRC in 5-FU resistant patients.
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PMID:Irinotecan (CPT-11) in metastatic colorectal cancer patients resistant to 5-fluorouracil (5-FU): a phase II study. 1467 82

The objectives of this phase I/II trial were to determine the maximum tolerated dose, toxicities, and the dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non small-cell lung cancer (NSCLC). Seventy-three patients with stage IIIB/IV NSCLC were enrolled in this multicenter, phase I/II study. The initial regimen was paclitaxel 225 mg/m2 over 3 hours, followed by carboplatin at an area under the curve (AUC) of 6 over 30 minutes on day 1 and CPT-11 starting at 40 mg/m2 over 90 minutes on days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of the original seven patients. The regimen was amended with doses reduced to paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 at 40 mg/m2, all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m2 and 125 mg/m2 before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m2. Doses suitable for phase II study were determined to be paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 100 mg/m2. The pri-mary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia. On the phase I portion of the study, objective tumor response was observed in 39% (12 of 31, 95% confidence interval: 22%-58%). The median time to tumor progression was 6.8 months, median survival was 11.0 months, and 1-year survival probability was 0.46. These data were confirmed in the phase II portion with a 30% objective response rate, median time to progression of 5.6 months, median survival of 12.5 months, and a 1-year survival probability of 0.50. In conclusion, CPT-11 100 mg/m2, paclitaxel 175 mg/m2, and carboplatin AUC = 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable, warranting further study of this regimen. A review of other irinotecan-containing triplet combinations is presented.
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PMID:Irinotecan (CPT-11) in triplet combinations in patients with advanced non small-cell lung cancer: a review and report of a phase I/II trial. 1472 27

Standard chemotherapy in advanced colorectal carcinoma (CRC) has not yet been established. The present study was conducted to assess the efficacy and toxicity profile of CPT-11, leucovorin (LV), and bolus 5-fluorouracil (5-FU) in a weekly schedule. Fifty-five patients were entered with no prior chemotherapy for advanced disease or adjuvant treatment ended at least 6 months preceding study entry, and 45 were assessable for response. Patients were treated with CPT-11 80 mg/m2 (7 patients) or 70 mg/m2 (48 patients). After completion of CPT-11 infusion, LV 200 mg/m2 was administered over 2 hr followed immediately by 5-FU 450 mg/m2, IV bolus, weekly for 6 weeks followed by a 2-week rest period. Treatment was continued for four cycles. Because of grade 3 and 4 diarrhea in four of the first seven patients, the study was amended to reduce the starting dose of CPT-11 from 80 to 70 mg/m2 weekly. Four complete and 10 partial responses were observed (response rate: 25.5%), the median time to progression (TTP) was 7.7 months, 1-year survival rate was 62.3%, and the median overall survival was 15.0 months. Grade 3 and 4 diarrhea occurred in seven patients (12.7%), four of them treated with CPT-11 80 mg/m2. Grade 3 myelotoxicity occurred in five patients (9.0%). Toxic death because of diarrhea, neutropenia, bacteremia, and sepsis occurred in a patient treated with CPT-11 80 mg/m2. Our results confirm the efficacy of CPT-11, LV, and 5-FU in a weekly schedule in patients with advanced CRC. Further studies are needed to compare the present regimen with higher doses of CPT-11 with LV plus different schedules of 5-FU administration in the treatment of metastatic CRC.
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PMID:A phase II study with CPT-11 plus leucovorin and bolus IV 5-fluorouracil in patients with advanced colorectal carcinoma. 1473 89

Colorectal cancers (CRC) express the epidermal growth factor receptor (EGF-R), a type I transmembrane receptor with tyrosine kinase activity. EGF-R signaling inhibition is a promising target for cancer therapy. ZD1839 (Iressa, AstraZeneca) and OSI-774 (Tarceva, Roche) are small molecular weight molecules with selective and reversible tyrosine kinase inhibition properties directed to EGF-R. Orally administered, these molecules induce sustained tumor stabilizations in previously treated metastatic CRC patients. The most frequent treatment-related toxicities are fatigue, diarrhea and acne-like follicular rash. The addition in the clinic of 5-FU, lOHP or CPT-11 to ZD1839 or OSI-774 does not seem to increase the own toxicity of each cytotoxic agents. Cetuximab (Erbitux, Merck) is an intravenously administered humanized monoclonal antibody which bind with high affinity with the extracellular domain of the EGF-R. The most frequent treatment-related toxicities are diarrhea, fatigue, nausea and cutaneous toxicity (allergic or acne-like follicular rashes, folliculitis). Most, if not all of these adverse events are mild. Partial responses were observed with cetuximab either alone (RR: 10%) or in combination with CPT-11 (RR: 22%) in patients with CPT-11 refractory advanced CRC which expressed EGF-R. The combination of cetuximab to folinic acid, 5-FU and CPT-11 seems tolerable at the cost of a slight increase of severe diarrhea and neutropenia. Finally, the promising activity of these EGF-R inhibitors has to be confirmed throughout randomized studies.
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PMID:[Inhibitors of epidermal growth factor receptor and colorectal cancer]. 1476 44

Irinotecan (CPT-11) is a semisynthetic derivative of camptothecin, an alkaloid extracted from the Chinese plant Camptotheca acuminata. It bears a bis-piperidine moiety and was selected for its water solubility and promising preclinical antitumor activity in in vitro and in vivo models. The target of drugs of the camptothecin family is DNA topoisomerase I, a nuclear enzyme involved in the relaxation of the DNA double helix required for replication and transcription activities. They stabilize the enzyme-DNA complex and prevent the religation of the single-strand breaks created by the enzyme, which are converted to double-strand breaks upon the collision with a replication fork during the S-phase. Resistance to irinotecan appears not to be mediated by P-glycoprotein, but by qualitative and/or quantitative alterations of its target, topoisomerase I, or by alterations occurring downstream of this interaction. As with all camptothecin derivatives, irinotecan contains a lactone ring that can be spontaneously and reversibly hydrolyzed to a carboxylate open ring form, which predominates at neutral and alkaline pH and is inactive on topoisomerase I-DNA complexes. Irinotecan is, in fact, much less active than its metabolite SN-38 and is generally considered as a prodrug of this compound. The carboxylesterase which carries out this conversion is preferentially active on the lactone form of irinotecan and directly generates the lactone form of SN-38, which may explain the superiority of irinotecan over SN-38 in vivo. Further metabolism of SN-38 to a beta-glucuronide conjugate is a major pathway of detoxification and plays an important role in determining irinotecan toxicity in the clinical setting. Other metabolic pathways of irinotecan involve oxidations occurring on the bis-piperidine rings, which are carried out by cytochrome P450. Irinotecan has shown an important activity in advanced and metastatic colorectal carcinoma and is now used for this indication in several countries, with two different recommended schedules: weekly administration of 125 mg/m(2) with a 2-week drug-free interval every 4 administrations or 3-weekly administration of 350 mg/m(2), a dose that can be increased to 500 mg/m(2) with the support of antidiarrhetics. Other possible indications of irinotecan include lung and cervix cancer, which are presently under investigation. The dose-limiting toxicity of irinotecan is mainly diarrhea, which occurs 7-10 days after treatment and can be life-threatening when associated with neutropenia, another frequent side effect. High-dose loperamide has shown good efficacy for treating this diarrhea and has allowed an increase in irinotecan doses tolerated by patients. The pharmacokinetics of irinotecan are characterized by a 2- or 3-compartment decay, with a terminal half-life of about 10 h, a total volume of distribution of 150 l/m(2) and a total plasma clearance of 15 l/h/m(2). SN-38 AUC is only a small fraction of that of irinotecan (2-4%) and SN-38 is eliminated from plasma with a half-life of about 12 h. SN-38 glucuronide is present in plasma at higher concentrations than SN-38 and is eliminated at the same rate. APC, produced by the action of cytochrome P450, isoenzyme 3A4, is present in plasma at concentrations close to those of irinotecan itself. Only a small fraction of irinotecan and its metabolites is eliminated in urine and a higher proportion in the bile, with an enterohepatic cycle of SN-38 glucuronide and SN-38. Significant relationships have been established between the AUCs of both irinotecan and SN-38 and hematological and intestinal toxicities, suggesting a potential use for monitoring of this drug.
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PMID:Pharmacology of irinotecan. 1498 54


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