Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based on the results of our previous pilot study, we conducted a multi-institutional phase II study of combination chemotherapy consisting of oral UFT (Taiho Pharmaceutical Co. Ltd, Tokyo) plus cisplatin (CDDP) in patients with advanced non-small cell lung cancer (NSCLC). UFT capsule containing 100 mg tegafur and 224 mg uracil was orally administered in two divided doses on days 1 through 21 making the total tegafur dose 400 mg/m(2)/day (maximum 600 mg/body). CDDP was administered by drip infusion at a dose of 20 mg/m(2) on a 5-day schedule from day 8 to 12. Treatment was repeated every 4 weeks as long as the criteria for initiation of therapy were still met. Between April 1995 and March 1997, 51 patients were entered into the study. The mean age of all 50 eligible patients was 64 years(range: 40-78). There were 21 patients with clinical stage IIIB disease and 29 patients with IV disease. Thirty-two patients had adenocarcinoma, 14 had epidermoid carcinoma, and four had large cell carcinoma. Of the 47 assessable patients, 18 achieved a partial response with an overall response rate of 38.3% (95% confidence interval: 24.4-52.2%). The median response duration was 113 days. The median survival time of the eligible patients was 12.8 months, and the 1-year survival rate was 54%. Among the 51 patients enrolled, grade 3 or 4 leukopenia developed in one patient (2%), neutropenia in six patients (11. 8%), thrombocytopenia in six patients (11. 8%), and anemia in three patients (5. 9%). Non-hematological grade 3 or 4 toxicities included anorexia in 10 patients (19.6%), nausea in ten (19.6%), vomiting in two (3.9%), and diarrhea in two (3. 9%). Grade 3 abnormal laboratory data included bilirubinemia in four (7. 8%), GPT elevation in one (2.0%), and hematuria in one (2.0%). In conclusion, combination of CDDP plus oral UFT is efficacious, with low toxicity, in the treatment of advanced NSCLC. In particular, the low hematological toxicity may warrant application of this regimen to the treatment of elderly patients and in trials of concurrent chemoradiotherapy in patients with locally advanced NSCLC.
Lung Cancer
PMID:A phase II trial of oral UFT plus cisplatin (CDDP) in patients with non-small cell lung cancer (NSCLC). 1116 9

BBR 2778 is a novel aza-anthracenedione with no cardiotoxicity in preclinical models. This Phase I dose escalation trial of BBR 2778 was conducted to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetic profile of BBR 2778 in patients with advanced solid tumors. BBR 2778 was given in three consecutive weekly 30-min i.v. infusions over a 4-week cycle (cy). Thirty patients (pts) were treated with BBR 2778 at doses ranging from 5 to 150 mg/m2/week. The dose levels 5, 10, 16.5, 25, 37.5, 75, 112.5, and 150 mg/m2/week were investigated in 4 pts (9 cy), 3 pts (3 cy), 3 pts (5 cy), 6 pts (9 cy), 1 pt (1 cy), 4 pts (9 cy), 6 pts (18 cy), and 3 pts (4 cy), respectively. The dose-limiting toxicity was neutropenia, typically occurring at day 14. Other toxicities were mild to moderate and were principally thrombocytopenia, lymphopenia, alopecia, nausea, and vomiting and blue coloration of the skin and urine. No significant cardiac toxicity was observed. The plasma dose concentration curve fitted a biexponential profile, with a rapid distribution phase followed by a prolonged elimination phase (mean t1/2,z, 12 h). BBR 2778 displayed a large volume of distribution (range, 9.7-29.7 l/kg) with a high plasma clearance rate (0.75-1.31 l/h/kg). Less than 10% of the dose was recovered in urine as unchanged drug. The maximum tolerated dose was 150 mg/m2/week for 3 weeks, every 4 weeks. On the basis of this study, the recommended dose for Phase II studies is 112.5 mg/m2/week days 1 and 8 with individual optional administration at day 15, every 4 weeks. Antitumor activity was observed in patients with breast, small cell lung carcinoma, and facial cylindroma. This trial showed that BBR 2778 has a manageable toxicity profile on a weekly schedule. This lead compound of the aza-anthracenedione family shows promising antitumor activity and deserves Phase II investigation in patients with high risk of cumulative cardiotoxicity, such as anthracycline-pretreated breast cancer patients.
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PMID:A phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies. 1120 16

This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity of a weekly docetaxel (TXT) and cisplatin (CDDP) combination regimen in advanced non-small cell lung cancer (NSCLC). Patients with stage IIIB or IV NSCLC who were previously untreated were eligible. Docetaxel, at a starting dose of 20 mg m(-2) per week on days 1, 8 and 15, was combined with a fixed dose of cisplatin 80 mg m(-2) on day 1. Docetaxel was increased in 5 mg m(-2) per week steps. Chemotherapy was given in a 4-weeks cycle. Dose-limiting toxicities (DLTs) were defined as grade 3-4 leukopenia, thrombocytopenia, anemia, fever with grade 4 neutropenia and more than grade 2 non-hematologic toxicity, with the exception of nausea, vomiting, and alopecia. Omission of chemotherapy on day 8 and/or 15 was also considered DLT. Eighteen patients were enrolled in this study. Leukopenia, anemia and fatigue were the DLTs. No grade 4 toxicities were seen in any patients. The overall response rate was 44.4% (95% confidence interval, 21.5-67.4%). The recommended dose of TXT to be combined with CDDP 80 mg m(-2) on day 1 is 35 mg m(-2) per week on days 1, 8 and 15. This is a promising regimen, therefore a multicenter phase II study is now under way.
Lung Cancer 2001 Jul
PMID:A phase I study of weekly docetaxel and cisplatin in advanced non-small cell lung cancer. 1142 97

The phase I study was conducted to evaluate the maximum tolerated dose (MTD) and toxicity of weekly administered docetaxel combined with cisplatin in patients with non-small-cell lung cancer (NSCLC). In a dose escalation study, 22 patients, under 75 years old, with unresectable and metastatic untreated NSCLC with performance status (0-1) were enrolled. Patients were treated with cisplatin (day 1) and weekly docetaxel (days 1, 8, 15). Dose escalation levels in mg/m(2) were for cisplatin and docetaxel; 70 and 15 (level 1), 80 and 15 (level 2), 80 and 20 (level 3), 80 and 25 (level 4), 80 and 30 (level 5), respectively. Chemotherapy was repeated for at least two cycles every 28 days. All patients were assessable for toxicities. Although grade 3 neutropenia occurred in one case in level 4, there were no significant modifications of chemotherapy schedule until level 4. Grade 3 neutropenia occurred in all cases receiving level 5. One patient developed an infection, and two had incomplete recovery of neutropenia by the 28th day after the first cycle of chemotherapy. Nonhematological toxicities, including nephrotoxicity, nausea/vomiting, alopecia and hypersensitivity reaction, were tolerable. However, one case developed severe hyponatremia. Among 21 patients evaluable for response, eight cases achieved partial response, thus the overall response was 39%. Weekly administration of docetaxel at 25 mg/m(2) (days 1, 8, 15) combined with cisplatin 80 mg/m(2) (day 1) is recommended for phase II studies. The responses observed in the present study suggest an identical high degree of activity against NSCLC with less hematotoxicity compared with a standard schedule of cisplatin and docetaxel.
Lung Cancer 2001 Oct
PMID:Phase I trial of weekly docetaxel combined with cisplatin in patients with non-small cell lung cancer. 1155 22

The study compares docetaxel plus cisplatin (DC) and docetaxel plus gemcitabine (DG) regimens for the treatment of advanced non-small cell lung cancer (NSCLC). Patients were randomized to receive either the DC or the DG combination. They were stratified according to age, performance status (PS) and stage of disease. Three hundred seventeen patients entered the study. Of them, 162 received the DC regimen and 155 the DG regimen. There were no differences in the patients' characteristics between the two study arms. Preliminary analysis included 132 evaluable patients in the DC arm and 114 in the DG arm. Three complete responses (CR) (2.3%) and 39 partial responses (PR) (30%) were documented in the DC arm (response rate (RR) 32.3%; 95% CI 23.87-39.76%), whereas 1 CR (0.9%) and 38 PR (33%) were documented in the DG arm (RR: 33.9%; 95% CI 25.5-42.92%). No differences in the RR, response duration, time to tumor progression, overall survival and 1-year survival were observed between the two groups. Regarding toxicity, there were no significant differences in grade 3-4 anaemia and thrombocytopenia between the two arms. However, grade 3-4 neutropenia occurred in 40 patients (33%) treated with the DC regimen and in 31 patients (22%) treated with the DG regimen (P=0.01). Twenty-four (16%) patients in the DC arm and 20 (14%) in the DG arm developed febrile neutropenia. There was one death due to sepsis in each arm. Non-haematological toxicity was mild and equal in the two arms, with the exception of grade 3-4 nausea and diarrhoea, which were more frequent in the DC arm. In conclusion, preliminary results showed that the DG regimen was as effective as the DC regimen. The toxicity profile of the DG combination was relatively milder. Hence, cisplatin cannot be considered longer as a mandatory component of chemotherapy against NSCLC.
Lung Cancer 2001 Dec
PMID:Comparison of docetaxel/cisplatin to docetaxel/gemcitabine as first-line treatment of advanced non-small cell lung cancer: early results of a randomized trial. 1174 2

The low surgical cure rate in patients with stage III non-small cell lung cancer has prompted an exploration of multimodality treatment strategies. Mature results are presented from a phase II trial of accelerated hyperfractionated radiation therapy, concurrent paclitaxel/cisplatin chemotherapy and surgery for these patients. Between 1994 and 1997, 45 patients with surgically demonstrated stage III non-small cell lung cancer underwent induction treatment with a 96 h continuous cisplatin infusion (20 mg/m(2) per day) and a 24 h infusion of paclitaxel (175 mg/m(2)) given concurrently with accelerated hyperfractionated radiation therapy (1.5 Gy twice daily) to a total dose of 30 Gy. Induction was completed in ten treatment (12 total) days. Surgical resection was scheduled 4 weeks later with a second identical course of chemoradiotherapy given 4-6 weeks post-operatively, to a total radiation dose of 60-63 Gy. Thirty-five patients had stage III(A) disease and ten had stage III(B) disease (eight with N(3) tumors). Induction toxicity included nausea in 89%, dysphagia in 89%, and neutropenia <1000/mm(3) in 84% which required hospitalization for fever in 40%. There were no toxic deaths during induction. About 40 of the 45 patients (89%) were operable and 32 (71%) were resectable for cure. A pathologic response was identified in 22 patients (49%); five patients (11%) had no residual disease. Fourteen patients (31%) were downstaged to mediastinal node negativity. With a median follow-up of 60 months, the Kaplan-Meier projected 5-year overall survival was 29%; locoregional control 79%; and distant metastatic disease control 38%. The projected 5-year survival for the 14 patients downstaged to mediastinal node negativity was 50%. For the 19 patients with residual ipsilateral mediastinal node involvement at surgery it was 32%. This short-course of paclitaxel and cisplatin chemotherapy and concurrent accelerated fractionation radiation is tolerable despite significant myelosuppression. Locoregional control is excellent and survival is better than historical expectations. Patients downstaged to mediastinal node negativity have a prognosis similar to those with de novo stage I(B) and II disease. Distant metastases are the major cause of treatment failure.
Lung Cancer 2002 May
PMID:Accelerated hyperfractionated radiation, concurrent paclitaxel/cisplatin chemotherapy and surgery for stage III non-small cell lung cancer. 1195 51

Autoimmune impairment and destruction of the enteric nervous plexus are thought to play a central role in the pathogenesis of paraneoplastic motility disorders. We present a case of a small-cell lung carcinoma-related paraneoplastic motility disorder associated with abnormal interstitial cells of Cajal networks. Antibodies against c-Kit and protein gene product 9.5 were used to selectively stain interstitial cells of Cajal and the enteric nervous plexus, respectively. A 68-yr-old man presented with anorexia, early satiety, nausea, and weight loss. Investigations revealed gastroparesis, delayed small intestinal transit, and mediastinal lymphadenopathy. The patient was seropositive for type 1 antineuronal nuclear autoantibody and P/Q-type calcium channel antibody. Biopsy of mediastinal lymph nodes revealed metastatic small-cell carcinoma cells that were immunoreactive for c-Kit. Immunohistochemical staining of a full-thickness small intestinal biopsy revealed a relatively intact myenteric plexus but a sparse and disorganized interstitial cells of Cajal network. The histopathology of this case suggests that interstitial cells of Cajal may be a target in the pathogenesis of paraneoplastic motility disorders.
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PMID:Paraneoplastic dysmotility: loss of interstitial cells of Cajal. 1213 44

Vinorelbine is a semisynthetic vinca alkaloid that is effective as monotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC). In the large comparative Elderly Lung Cancer Vinorelbine Italian Study (ELVIS), patients receiving vinorelbine monotherapy achieved an objective response rate of 19.7%. The median survival time and the 1-year survival rate were significantly higher in recipients of vinorelbine plus best supportive care than in recipients of best supportive care alone. Vinorelbine recipients generally scored better than recipients of best supportive care on quality-of-life (QOL) functioning scales and experienced significantly fewer lung cancer-related symptoms; however, QOL scores were worse with vinorelbine for parameters relating to drug tolerability. Comparative phase III trials investigating the efficacy of combination therapy with vinorelbine and other agents specifically in elderly patients with advanced NSCLC have been conducted only for the combination of vinorelbine and gemcitabine [the Southern Italy Cooperative Oncology Group (SICOG) trial and the Multicenter Italian Lung Cancer in the Elderly Study (MILES)]. Objective response rates for vinorelbine/gemcitabine combination therapy in these phase III trials were 22 and 20%, respectively. The SICOG trial was closed early when an interim analysis demonstrated a significant survival advantage for combination therapy with vinorelbine plus gemcitabine over vinorelbine monotherapy. However, a survival advantage for combination therapy versus vinorelbine monotherapy was not demonstrated in the larger MILES trial. The main adverse effect of vinorelbine monotherapy in the elderly is myelosuppression. Adverse events associated with most antineoplastic agents, such as mild alopecia, nausea, vomiting and mucositis, were reported in clinical trials; however, these events were rarely severe. Mild-to-moderate neurotoxicity, including constipation (presumably from autonomic neuropathy), was also reported. The addition of gemcitabine to vinorelbine increased the incidence of both haematological and nonhaematological adverse events. However, there was no significant increase in the incidence of life-threatening toxicity. Vinorelbine as a single agent is effective in elderly patients with NSCLC and is associated with improved survival and at least a trend towards improved QOL parameters compared with best supportive care alone. Vinorelbine was associated with a generally manageable tolerability profile. The benefit of adding gemcitabine to vinorelbine for the treatment of NSCLC in the elderly is equivocal; improved survival was reported in one comparative trial, but not in another larger one. Vinorelbine is an effective and well tolerated palliative treatment option for elderly patients with advanced NSCLC.
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PMID:Vinorelbine: a review of its use in elderly patients with advanced non-small cell lung cancer. 1238 Dec 38

A phase II study was conducted to assess the activity and toxicity of irinotecan (CPT-11) and carboplatin (CBDCA) combination chemotherapy for advanced non-small-cell lung cancer (NSCLC). Eligibility included chemo-naive advanced NSCLC patients with measurable disease and a good performance status. CPT-11 of 50 mg/m(2) was administered as a 90-min intravenous infusion on days 1, 8, and 15. CBDCA dosed to an area under the concentration-time curve of 5 mgmin/ml, using Calvert's formula, was administered by 90-min infusion after the CPT-11 infusion on day 1. Treatment was repeated 28 days interval for at least two cycles. Haematopoietic growth factors were not routinely used. From December 1997 to January 1999, 36 patients were entered into the study. The overall response rate was 25.0% (95% confidence interval: 12.1-42.2%). The median survival time and the 1-year survival rate were 10.2 months and 42.2%, respectively. Major toxicity by Japan Clinical Oncology Group criteria was as follows: grade 3-4 neutropenia 76.5%; grade 3 anemia 26.5%; grade 3/4 thrombocytopenia 47.1%; grade 3 nausea/vomiting 36.1%; grade 3-4 diarrhoea 5.9%; grade 3 alopecia 5.9%; grade 3-4 skin rush 2.9%. Four patients developed febrile neutropenia and only one had serious diarrhea induced by CPT-11. Actual relative delivery dose of CPT-11 to the projected one on days 8 and 15 were 0.86 and 0.43, respectively. It seemed that CPT-11 and CBDCA was more toxic regimen than CPT-11 and CDDP in advanced NSCLC. The relatively disappointing response rate could be related with low dose intensity of CPT-11.
Lung Cancer 2002 Dec
PMID:Phase II study of irinotecan and carboplatin for advanced non-small cell lung cancer. 1244 53

Aberrations in cell cycle progression occur in the majority of human malignancies. The main pathway affected is the retinoblastoma (Rb) pathway. The tumor suppressor gene Rb is an important component in the G(1)/S transition and its function is abnormal in most human neoplasms. Loss in Rb function occurs by the hyperactivation of the cyclin-dependent kinases (cdk's). Therefore, modulation of cdk's may have an important use for the therapy and prevention of human neoplasms. Efforts to obtain small-molecule cdk modulators yielded two classes of modulators: direct and indirect modulators. Direct cdk modulators are small molecules that specifically target the ATP binding site of cdk's. Examples for this group include flavopiridol, roscovitine and BMS-387032. In contrast, indirect cdk modulators affect cdk function due to modulation of upstream pathways required for cdk activation. Some examples include perifosine, lovastatin, and UCN-01. The first example of a direct small-molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. Clinical trials with this agent were performed with at least three different schedules of administration: 1-, 24- and 72-h infusions. The main toxicities for infusions >/=24-h are secretory diarrhea and proinflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. A phase II trial of patients with advanced non-small-cell lung carcinoma using the 72-h infusion every 2 weeks was recently completed. The median overall survival for the 20 patients who received treatment was 7.5 months, a survival similar to that obtained in a randomized trial of four chemotherapy regimens containing platinum analogues in combination with taxanes or gemcitabine, or with gefitinib, a recently approved EGFR inhibitor for the treatment of advanced lung cancer. Based on these encouraging results, a phase III trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small-molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca(2+)-dependent PKCs, promotes apoptosis, arrests cell cycle progression at G(1)/S, and abrogates checkpoints upon DNA damage. The first phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72-h continuous infusion every 4 weeks (in second and subsequent cycles UCN-01 is administered as a 36-h infusion). Other shorter schedules (i.e. 3 h) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia, and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, phase I trials with two novel small-molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. In summary, novel small-molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies.
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PMID:Small-molecule cyclin-dependent kinase modulators. 1452 86


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