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

The combination of CPT-11 with 5-fluorouracil (5-FU) in advanced colorectal cancer (ACC) represents an attractive approach. A phase II study was conducted to assess the tolerance and efficacy of CPT-11 in combination with leucovorin-modulated bolus plus infusional 5-FU given according to the de Gramont regimen in chemonaive patients with ACC. Fifty-four patients with histologically confirmed ACC were enrolled. The patients' median age was 65 years; 30 (55.5%) patients were men; performance status (World Health Organization) was 0 in 27 (50%) patients, 1 in 22 (41%), and 2 in 5 (9%). Patients received leucovorin (200 mg/m2/d) as a 2-hour intravenous infusion, followed by 5-FU as an intravenous bolus at 400 mg/m2/d, and then as a 22-hour continuous infusion at 600 mg/m2/d, repeated on 2 consecutive days. CPT-11 (180 mg/m2; 30-minute intravenous infusion) was administered on day 1, simultaneously with leucovorin administration. This cycle was repeated every 2 weeks. Complete response was achieved in 4 patients (8%) and partial response in 19 (37%) (overall response rate: 45%; 95% CI: 24-50.5%). Stable disease was achieved in 16 (31%) patients and progressive disease in 13 (25%). The median duration of response and the median TTP were 5 and 8 months, respectively. After a median follow-up period of 11 months, 33 (61%) patients are still alive; the median overall survival has not yet been reached. Thrombocytopenia and anemia were very rare. Grade III/IV neutropenia developed in 19 patients (36%); febrile neutropenia developed in 4 patients, and 1 of them died of sepsis. Grade IV diarrhea was seen in 7 (13%) patients, and 4 of them required hospitalization. Grade III and IV mucositis was observed in two (4%) and one (2%) patients, respectively. Other toxicities were mild. The combination of CPT-11 and bolus plus infusional 5-FU is a relatively well-tolerated and effective first-line treatment in ACC. Final results from large phase III trials are awaited to clarify whether the CPT-11/5-FU combinations should be considered as "standard" first-line treatment in ACC.
 ...
PMID:Irinotecan (CPT-11) in combination with infusional 5-fluorouracil and leucovorin (de Gramont regimen) as first-line treatment in patients with advanced colorectal cancer: a multicenter phase II study. 1182

A phase II study of irinotecan (CPT-11) was conducted at Duke University Medical Center, Durham, NC, to evaluate the activity of this agent in children with high-risk malignant brain tumors. A total of 22 children were enrolled in this study, including 13 with histologically verified recurrent malignant brain tumors (glioblastoma multiforme [GBM] 4, anaplastic astrocytoma 1, ependymoma 5, and medulloblastoma/primitive neuroectodermal tumor 3), 5 with recurrent diffuse pontine glioma, and 4 with newly diagnosed GBM. All patients with recurrent tumor had prior chemotherapy and/or irradiation. Each course of CPT-11 consisted of 125 mg/m ( 2 ) per week given i.v. for 4 weeks followed by a 2-week rest period. Patients with recurrent tumors received therapy until disease progression or unacceptable toxicity. Patients with newly diagnosed tumors initially received 3 cycles of treatment to assess tumor response and then were allowed radiotherapy at physician's choice; patients who demonstrated a response to CPT-11 prior to radiotherapy were allowed to continue the drug after radiation until disease progression or unacceptable toxicity. A 25% to 50% dose reduction was made for grade III-IV toxicity. Responses were assessed after every course by gadolinium-enhanced MRI of the brain and spine. Twenty-two patients received a median of 2 courses of CPT-11 (range, 1-16). Responses were seen in 4 of 9 patients with GBM or anaplastic astrocytoma (44%; 95% confidence interval, 11%-82%) (complete response in 2 patients with recurrent GBM lasting 9 months and 48+ months; partial response in one patient with a newly diagnosed midbrain GBM lasting 18 months prior to radiotherapy; and partial response lasting 11 months in 1 patient with recurrent anaplastic astrocytoma), 1 of 5 patients with recurrent ependymoma (partial response initially followed by stable disease lasting 11 months), and none of 5 patients with recurrent diffuse pontine glioma. Two of 3 patients with medulloblastoma/primitive neuroectodermal tumor had stable disease for 9 and 13 months. Toxicity was mainly myelosuppression, with 12 of 22 patients (50%) suffering grade II-IV neutropenia. Seven patients required dose reduction secondary to neutropenia. CPT-11, given in this schedule, appears to be active in children with malignant glioma, medulloblastoma, and ependymoma with acceptable toxicity. Ongoing studies will demonstrate if activity of CPT-11 can be enhanced when combined with alkylating agents, including carmustine and temozolomide.
 ...
PMID:Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the Duke experience. 1191 1

This phase II study was designed to evaluate the safety, tolerability, and efficacy of irinotecan (CPT-11) in the treatment of adults with malignant glioma. Patients with progressive or recurrent malignant gliomas were enrolled. CPT-11 was administered as a 90-minute intravenous infusion at a dose of 300 mg/m(2) once a week every 3 weeks. After 2 treatments, doses were increased to 350 mg/m(2) in those patients without grade III/IV toxicities. Dose modifications were made for toxicities. All 14 patients who enrolled (11 males and 3 females) were treated with CPT-11 and were assessable for survival, response, and toxicity. The majority of patients (86%) had prior surgery. Two patients had a confirmed partial response and 2 patients (14%) had stable disease. Median survival was 24 weeks. Median time to tumor progression was 6 weeks. The primary hematologic toxicity was grade III/IV neutropenia, which was observed in 14% of patients. Infrequent grade III/IV nonhematologic toxicity was observed, possibly because of the concomitant use of anticonvulsants, which may have altered pharmacokinetics. These results suggest that CPT-11 has activity against recurrent malignant glioma using a dosing regimen of 300 mg/m(2) every 3 weeks showing limited toxicity. The concurrent use of anticonvulsant medications may have played a role in altering pharmacokinetics and thus the maximum tolerated dose in this patient population.
 ...
PMID:Irinotecan treatment for recurrent malignant glioma using an every-3-week regimen. 1194 4

The metabolism of irinotecan (CPT-11) involves sequential activation to SN-38 and detoxification to the pharmacologically inactive SN-38 glucuronide (SN-38G). We have previously demonstrated the role of UGT1A1 enzyme in the glucuronidation of SN-38 and a significant correlation between in vitro glucuronidation of SN-38 and UGT1A1 gene promoter polymorphism. This polymorphism (UGT1A1*28) is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ((TA)7TAA, instead of (TA)6TAA). Here we report the results from a prospective clinical pharmacogenetic study to determine the significance of UGT1A1*28 polymorphism on irinotecan disposition and toxicity in patients with cancer. Twenty patients with solid tumors were treated with a 90 min i.v. infusion of irinotecan (300 mg m(-2)) once every 3 weeks. The frequency of UGT1A1 genotypes was as follows: 6/6--45%, 6/7--35% and 7/7--20%, with allele frequencies of 0.375 and 0.625 for (TA)7TAA and (TA)6TAA, respectively. Patients with the (TA)7TAA polymorphism had significantly lower SN-38 glucuronidation rates than those with the normal allele (6/6>6/7>7/7, P = 0.001). More severe grades of diarrhea and neutropenia were observed only in patients heterozygous (grade 4 diarrhea, n = 1) or homozygous (grade 3 diarrhea/grade 4 neutropenia, n = 1 and grade 3 neutropenia, n = 1) for the (TA)7TAA sequence. The results suggest that screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity.
 ...
PMID:UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. 1199 Mar 81

We examined the role of neoadjuvant therapy in downstaging locally advanced gastric cancer. Preoperative staging was performed with a combination of CT scans, endoscopic ultrasonography and/or laparoscopy, and laparoscopic ultrasonography. Patients with T > or =3 tumors and/or node-positive disease by preoperative clinical staging were eligible for entry. Neoadjuvant therapy consisted of two cycles of CPT-11 (75 mg/m(2)) with cisplatin (25 mg/m(2)) weekly four times every 6 weeks. This was followed by resection with D2 lymph node dissection and two cycles of intraperitoneal chemotherapy with floxuridine and cisplatin. Twenty-two patients were entered into the study (4 with T3N0 disease and 18 with T3N1 disease). Induction chemotherapy was well tolerated with major toxicities being neutropenia and diarrhea. A median of 78%/75% of the planned dosage of CPT-11/cisplatin was delivered. Two patients withdrew consent during the first cycle and were lost to follow-up. One patient progressed to stage IV disease during induction chemotherapy and did not undergo surgery. Nineteen patients underwent surgery. One patient had undetected stage IV disease (liver) and underwent a palliative R2 resection. Of the 18 remaining patients, 17 had curative R0 resections and one had a palliative R1 resection. A median of 21 lymph nodes (range 1 to 121) were examined histologically. There was one postoperative death. Surgical morbidity did not appear to increase after the neoadjuvant regimen. The median postoperative length of hospital stay was 9 days (range 3 to 75 days). Postoperative pathologic staging yielded 16% T3 lesions compared to 85% before treatment based on clinical staging; postoperative American Joint Committee on Cancer staging yielded 37% stage IIIA disease compared to 70% stage IIIA before treatment. With a median follow-up of 15 months, median survival has not yet been reached. We conclude that CPT-11-based neoadjuvant therapy downstages locally advanced gastric cancer. Further follow-up is necessary to determine the ultimate impact of this combination therapy on recurrence and survival.
 ...
PMID:Neoadjuvant chemotherapy with CPT-11 and cisplatin downstages locally advanced gastric cancer. 1199 7

We conducted a phase II study to assess the response rate and toxicity profile of the irinotecan (CPT-11, Camptosar) plus cisplatin combination administered weekly to patients with at least one previous chemotherapy for advanced adenocarcinoma of the stomach or gastroesophageal junction. Patients with histologic proof of adenocarcinoma of the stomach orgastroesophageal junction with adequate liver, kidney, and bone marrow functions were treated with 50 mg/m2 of irinotecan plus 30 mg/m2 of cisplatin, both administered intravenously 1 day a week for 4 consecutive weeks, followed by a 2-week recovery period. Response rate, time to disease progression, survival, and toxic effects were analyzed. Of 32 registered patients, 29 were assessable. Nine patients (31%) achieved a partial response. Median time to disease progression was 7 weeks (range: 5-48+ weeks) and median survival time was 5 months (range: 2.5-31 months). There were no treatment-related deaths. Major toxic effects included diarrhea, neutropenia, and fatigue. Of 260 doses administered in 65 6-week courses, 46 doses were either delayed or missed. Most delayed or missed doses occurred in the third or fourth week of the cycle. We concluded that the combination of irinotecan and cisplatin is an active second-line therapy for patients with advanced gastric or gastroesophageal adenocarcinoma in whom one previous chemotherapy has failed. Modifications in doses and schedule are warranted to increase the tolerability of the regimen. Phase III trials are necessary to establish the clinical utility of irinotecan/cisplatin in these patient populations.
 ...
PMID:Irinotecan/cisplatin in advanced, treated gastric or gastroesophageal junction carcinoma. 1210

Early clinical studies combining irinotecan (CPT-11, Camptosar) and gemcitabine (Gemzar) have yielded encouraging results. Gemcitabine administered via a twice-weekly schedule results in an enhanced radiation-sensitizing effect. This multi-institution phase II trial of induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation has been initiated to determine the activity of this regimen in patients with unresectable pancreatic cancer. Patients received two cycles of induction irinotecan (100 mg/ m2 IV) and gemcitabine (1,000 mg/m2 IV) on days 1 and 8 of each 3-week cycle. Following the induction therapy, patients without disease progression received twice-weekly gemcitabine at 40 mg/m2 and radiation. Nine patients have been enrolled in the study to date. Median patient age was 71 years (range: 65-85 years). The major toxicity observed thus far was grade 3/4 neutropenia. Grade 3/4 nonhematologic toxicity was rarely observed and included dehydration (12%) and diarrhea (12%), which were likely related to the irinotecan. No treatment-related deaths have occurred. These preliminary data suggest that this regimen is well tolerated. Although the data are limited, tumor progression during the induction chemotherapy has not been observed thus far (radiographically or biochemically [CA-19-9]).
 ...
PMID:Irinotecan/gemcitabine followed by twice-weekly gemcitabine/radiation in locally advanced pancreatic cancer. 1210 2

Ovarian cancer, the second most common gynecologic malignancy, accounts for approximately 14,000 deaths annually in the United States. Disease relapse after primary treatment, which consists mainly of surgery followed by platinum-based therapy, occurs in more than 60% of ovarian cancer patients overall, and in more than 80% of those diagnosed initially with advanced-stage disease. Responses to second-line chemotherapy agents range from 15% to 25%, and are usually partial responses of short duration. Irinotecan (CPT-11, Camptosar), a camptothecin derivative that inhibits topoisomerase I, is undergoing assessment for the treatment of ovarian cancer. Preclinical studies demonstrated antitumor activity in ovarian cancer. Early phase I or II trials showed response rates of 20% to 25% in patients with recurrent or refractory disease, with some responses noted in the relatively chemoresistant mucinous and clear cell tumors. Irinotecan has also been studied in combination regimens, most commonly irinotecan plus cisplatin. In a phase II trial of irinotecan plus cisplatin in platinum-sensitive or -resistant patients, response rates were 75% and 33%, respectively. Irinotecan seems to be relatively well tolerated; dose-limiting toxicities appear to be diarrhea, nausea and vomiting, and leukopenia/neutropenia.
 ...
PMID:Irinotecan in epithelial ovarian cancer. 1210 3

We conducted a phase I study of paclitaxel and irinotecan (CPT-11) in advanced non-small cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated doses (MTD). The pharmacokinetics of CPT-11 and its major active metabolite, SN-38, were also analysed. Patients received paclitaxel (day 1) followed by CPT-11 (days 1, 8 and 15), in a 4-week cycle, and paclitaxel and CPT-11 were escalated from 120 and 40 mg/m(2), respectively. 28 patients were enrolled, who were evaluated for toxicity. 2 of 6 patients at 210 mg/m(2) paclitaxel and 50 mg/m(2) CPT-11, and 2 of 4 at 180 and 60 mg/m(2) developed dose-limiting toxicity (DLT) (neutropenia, fever, neurotoxicity and diarrhoea). The area under the plasma concentration-time curve (AUC) of CPT-11 on day 1 was significantly higher than that on days 8 or 15 at each dose level (P=0.002). The AUC of SN-38 on day 1 was significantly increased using paclitaxel doses >or=150 mg/m(2). A preceding paclitaxel administration changed the pharmacokinetics of CPT-11 and SN-38. However, the toxicity was tolerable. Paclitaxel 180 mg/m(2) and CPT-11 50 mg/m(2) were the recommended doses for further phase II study of this combination.
 ...
PMID:Phase I and pharmacokinetic study of paclitaxel and irinotecan for patients with advanced non-small cell lung cancer. 1220 69

A 30-year-old man, who had a repeated history of relapsed Hodgkin's lymphoma over 7 years, developed bilateral pleural effusion and chest wall involvement. He was treated with weekly irinotecan hydrochloride (CPT-11; 80 mg/m2/week). Partial response was observed after two cycles of irinotecan. Neutropenia and diarrhea were tolerable. This case demonstrated that irinotecan has a therapeutic effect in patients with relapsed Hodgkin's lymphoma.
 ...
PMID:Successful salvage therapy of irinotecan for relapsed Hodgkin's lymphoma. 1221 35


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>