Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based on nonoverlapping toxicity profiles and at least additive cytotoxicity in preclinical models, chemo-therapy regimens have been developed that feature the combination of irinotecan and a taxane drug. In the first study, the optimal doses of paclitaxel and irinotecan were 75 mg/m2 and 50 mg/m2, respectively, when chemotherapy was administered weekly for 4 consecutive weeks, followed by a 2-week rest. The dose-limit-ing toxicity for this regimen was neutropenia, and the most prominent nonhematologic toxicities were mild diarrhea and fatigue. Pharmacokinetic studies failed to demonstrate any sequence-dependent interaction be-tween these agents on the metabolism of irinotecan or its major metabolite. This regimen has been modified, with chemotherapy given on day 1 and day 8 every 3 weeks, and is being tested further in previously un-treated advanced non small-cell lung cancer (NSCLC). In a second trial, irinotecan was combined with docetaxel on a weekly schedule. When chemotherapy was given weekly for 4 weeks, followed by a 2-week rest, the recommended doses of docetaxel and irinotecan were 35 mg/m2 and 50 mg/m2, respectively. Low-grade gastrointestinal toxicity and asthenia were the dose-limiting toxicities. The treatment schedule was modified, with chemotherapy given on days 1 and 8 of a 21-day cycle, and patients are currently being treated with docetaxel 35 mg/m2 and irinotecan 65 mg/m2. Among the 10 evaluable patients with NSCLC in this second study, there was one partial response lasting 24 weeks and four patients with stable disease, including one patient who had progressive disease on a prior paclitaxel-containing regimen. The combinations of irinotecan and a taxane on a weekly schedule are active and well tolerated and deserve further evaluation in the treatment of NSCLC.
Clin Lung Cancer 2001 May
PMID:Irinotecan and taxane combinations for non small-cell lung cancer. 1472 26

Docetaxel was chosen for study in the combination chemotherapy of advanced non small-cell lung cancer on the basis of its reproducible high single-agent activity, novel mechanism of action, and relative lack of neurotoxicity. Preclinical and clinical data suggested schedule-dependent synergism with vinorelbine. Trials of docetaxel and vinorelbine have explored a variety of schedules. One approach has been to give docetaxel on day 1 of a 3-week cycle with vinorelbine on day 0 or days 1 and 5. Febrile neutropenia and non-neutropenic infections have been dose limiting, and low-dose intensity (8-13 mg/m2/week) of vinorelbine has been achieved. Our phase I study showed that docetaxel 60 mg/m2 and vinorelbine 45 mg/m2 every 2 weeks could be safely given with prophylactic filgrastim. In the ensuing phase II trial, we observed a 51% confirmed response rate in 35 patients (95% confidence interval [CI]: 34-68). With a median follow-up of 12 months, the predicted median and 1-year survivals are 14 months and 60%, respectively. Use of prophylactic filgrastim and the every-2-week schedule of administration allowed for single-agent dose intensity of both drugs to be given. Febrile neutropenia occurred in five patients and 5/384 cycles. Cumulative toxicities of excessive lacrimation, fatigue, and onycholysis were observed. More recently, a weekly schedule of administration for both drugs has been studied. Docetaxel and vinorelbine appear highly active together when given on an every-2-week schedule with prophylactic filgrastim, and the combination may offer one alter-native to cisplatin-based therapy. However, confirmatory phase II and III studies are needed. Certain cumulative toxicities (onycholysis, lacrimation) may limit the duration of therapy. Application of this regimen for a shorter period, such as in induction or postoperative settings, may provide optimal benefit while minimizing toxicity.
Clin Lung Cancer 2000 Apr
PMID:Trials of vinorelbine and docetaxel in the treatment of advanced non small-cell lung cancer. 1472 39

We performed a pilot study to assess the safety of thalidomide in combination with standard chemo-therapy in patients with advanced non small-cell lung cancer. Patients with unresectable stage IIIA, IIIB, or IV disease were enrolled starting in July 1999. Patients received paclitaxel 225 mg/m2 over 3 hours and carboplatin area under the curve = 6.0 with thalidomide at a starting daily dose of 200 mg. The thalidomide dose was escalated, if tolerated, by 200 mg per week to a target dose of 1000 mg per day and could continue for up to 6 months. Patients with stages IIIA and IIIB disease without effusion received radiotherapy with concurrent thalidomide after 2 cycles of chemotherapy. Nine patients were enrolled: one with IIIA disease, three with IIIB disease, and five with stage IV disease. Five of nine patients had previously been treated with chemotherapy and/or radiotherapy. The most frequent side effects noted were fatigue, myalgia, constipation, neuropathy, and myelosuppression. Sixteen of the 17 (94%) episodes of grade 3 or 4 hematologic toxicity occurred in the five patients who had previously received chemotherapy, although no patients developed neutropenic fever. The median tolerated daily thalidomide dose was 600 mg. One patient with IIIA disease had a partial response after 2 cycles of chemotherapy and went on to receive radiotherapy with thalidomide. One patient with stage IV disease continues on this study with stable disease at 187 days. The median time to progression was 118 days. This preliminary data supports the further investigation of this combination in chemotherapy-naive patients with advanced non small-cell lung cancer.
Clin Lung Cancer 2000 Aug
PMID:Pilot and safety trial of carboplatin, paclitaxel, and thalidomide in advanced non small-cell lung cancer. 1473 37

GEM 231 is a second-generation antisense oligonucleotide targeted against the RIalpha regulatory subunit of cAMP-dependent protein kinase type I (PKA-I). Excessive expression of PKA-I is associated with cell proliferation and transformation, and increased levels of secreted extracellular PKA (ECPKA) are found in the serum of cancer patients. Preclinical studies have demonstrated single-agent antitumor activity of GEM 231 in a variety of human cancer xenograft models, and additive or synergistic antitumor activity has been observed with taxane and/or camptothecin-based combinations. Based on prior safety (MTD) data demonstrating dose-dependent, reversible, and cumulative transaminitis, and high peak plasma concentration (Cmax)-dependent changes in activated partial thromboplastin time (aPTT) with GEM 231 2-h twice-weekly infusions, an alternative schedule of GEM 231 given as a single agent was evaluated in patients with advanced solid tumors. Fourteen patients (median age approximately 60 yrs) with advanced solid malignancies received a total of 78 weeks of therapy. GEM 231 was infused via a CADD pump at 80 mg/m2/day (d) for 3 d/wk (n = 1), then for 5 d/wk at 80 (n = 3), 120 (n = 8), and 180 mg/m2/d (n = 2). One cycle was defined as 4 weeks of therapy. Apparent dose dependency for the occurrence of transaminitis was readily reversible. At 180 mg/m2/d, 2 of 2 patients had cycle 1 dose-limiting toxicity (DLT) transaminitis. One patient treated at 120 mg/m2/d experienced grade 3 transaminase elevations after 8 weeks of therapy, but when serum transaminase values rapidly improved he resumed treatment at 80 mg/m2/d for 6 weeks until tumor progression was documented. Another patient at 120 mg/m2/d developed grade 3 esophagitis after 3 weeks, limiting further dosing. One patient (lung cancer) demonstrated stable disease for 9 weeks. Overall, plasma aPTT was minimally prolonged and changes were transient, peaked at the end of each infusion, and were not associated with spontaneous bleeding. A constitutive symptom (e.g., low-grade fatigue) was common, cumulative, and reversible following discontinuation of therapy. Serum ECPKA was measured by enzymatic assay and Western blotting from blood drawn at the beginning and end of each infusion. Serum ECPKA levels demonstrated a trend to decline with the treatment. In addition to single agent schedules, combination trials were undertaken to assess safety and possible interaction of GEM 231 with taxanes (paclitaxel, docetaxel), given once every 3 weeks (one cycle). While trials using the 2-h twice-weekly GEM 231 infusions are ongoing, preliminary results from both studies show that it is safe to combine paclitaxel or docetaxel with GEM 231. Overall, it is also feasible to administer GEM 231 in combination with taxane or nontaxane chemotherapy (e.g., camptothecins). Phase I combination studies are currently underway to further explore the clinical, pharmacokinetic, and biologic profile of GEM 231 with chemotherapy.
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PMID:Clinical studies in patients with solid tumors using a second-generation antisense oligonucleotide (GEM 231) targeted against protein kinase A type I. 1475 40

The German Lung Cancer Cooperative Group (GLCCG) is assessing the impact of chemoradiation in addition to chemotherapy in the neoadjuvant treatment of stage III NSCLC. After three cycles of cisplatin/etoposide patients receive either hyperfractionated radiotherapy (RT) with concurrent carboplatin/vindesine and then surgery (arm A) versus surgery and then conventional RT (arm B). Quality of life (QL) was assessed throughout therapy using the EORTC QLQ-C30 and EORTC QLQ-LC 13. Of 126 eligible patients, 54 completed treatment. For patients in both treatment arms physical functioning decreased, whereas dyspnoea, fatigue and pain increased from beginning to the end of treatment. For self-assessed QL no statistically significant effect was found in or between the two treatment arms. The combined modality approach with preoperative radio/chemotherapy proves to be feasible in treating locally advanced NSCLC patients without decreasing their subjective QL.
Lung Cancer 2004 Apr
PMID:Combined modality treatment for locally advanced non-small cell lung cancer: preoperative chemoradiation does not result in a poorer quality of life. 1501 87

To determine the maximum-tolerated dose (MTD) and the recommended dose (RD) of paclitaxel administered weekly with a fixed dose of cisplatin, and to assess the toxicity and activity of this combination, we conducted a phase I/II trial in patients with advanced non-small-cell lung cancer (NSCLC). In this study, patients with stage IIIB/IV NSCLC were eligible. Paclitaxel, at a starting dose of 40 mg x m(-2) week(-1) on days 1, 8, and 15, was combined with a fixed dose of cisplatin 80 mg x m(-2) on day 1. Chemotherapy was given in a 4-week cycle. In this phase I/II study, 38 patients were enrolled. Dose-limiting toxicities (DLT) were neutropenia, fatigue, and omission of treatment due to leucopenia, thrombocytopenia, or febrile neutropenia. The MTD and RD were estimated to be 70 mg x m(-2). Of the 37 assessable patients, 23 had a partial response and one had a complete response. Overall response rate was 62.1% (95% confidence interval (CI): 46.5-77.7%). The progression-free survival, the median survival time, and the 1-year survival rate were 5.5 months, 13.7 months, and 56.9%, respectively. This regimen is tolerable and very active against advanced NSCLC, and its efficacy should be confirmed in a phase III study.
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PMID:Phase I/II study of cisplatin combined with weekly paclitaxel in patients with advanced non-small-cell lung cancer. 1502 99

The Turkish version of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire version 2.0 (EORTC QLQ-C30 v.2.0) has started to be used in clinical trials recently. The objective of the study was to evaluate the validity and reliability of the Turkish version of the EORTC QLQ-C30 v.2.0 and the correlation between the Karnofsky Performance Scale (KPS) and the EORTC QLQ-C30. Two hundred and two lung cancer patients were included in the study between January and March 2000. All the subscales met the minimal standards of reliability (Cronbach's alpha > or = 0.70). Only the role functioning scale differed among the three disease stages of patients (local, locoregional and metastatic). There was no statistically significant difference among therapy types. All interscale correlations were statistically significant (P < 0.01). The strongest correlations were found among the physical functioning, role functioning and fatigue scales. Social functioning was closely related with physical, role, emotional and cognitive functioning. The weakest correlations were between nausea/vomiting and the other scales. Global quality of life (QOL) was substantially correlated with most of the scales except cognitive functioning. The coefficients for the correlation between the items differed between 0.12 and 0.97 and all the subscales were strongly correlated with the scales which they formed. The highest correlation between the EORTC QLQ-C30 and KPS was for physical functioning (r = 0.62, P < 0.05). The Turkish version of the EORTC QLQ-C30 is a valid (by means of interscales validity) and reliable instrument for Turkish lung cancer patients and can be used in clinical studies but needs supporting by the reference data on the QOL of the Turkish population.
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PMID:The European Organization for Research and Treatment of Cancer QLQ-C30: an examination into the cultural validity and reliability of the Turkish version of the EORTC QLQ-C30. 1511 69

Patients with advanced non-small cell lung cancer (NSCLC) who fail to respond to cytotoxic chemotherapy or who cannot tolerate chemotherapy have limited treatment options. In addition, patients with advanced NSCLC often experience disease-related symptoms that impact their quality of life. Treatment goals in this setting include palliation of symptoms and improvement in quality of life, in addition to tumor response or disease stabilization and increased survival. ZD1839 (Iressa, gefitinib) is an orally active, small-molecule, epidermal growth factor receptor-tyrosine kinase inhibitor that has shown single-agent efficacy for previously treated advanced NSCLC. In phase I clinical trials, ZD1839 provided relief from symptoms often associated with lung cancer, including fatigue, shortness of breath, and chest pain. The IRESSA Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 clinical trials evaluated ZD1839 treatment at 250 mg/day and 500 mg/day in patients with advanced NSCLC for objective tumor response and safety, as well as for improvements in NSCLC-related symptoms and health-related quality of life. The majority of patients enrolled in these studies had received multiple prior treatments. Rapid, sustained symptom improvement was documented for many patients receiving ZD1839 at 250 mg/day or 500 mg/day in both IDEAL trials and was positively associated with clinical benefits, such as tumor response and increased survival.
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PMID:Effects of ZD1839 (Iressa, gefitinib) treatment on symptoms and quality of life in patients with advanced non-small cell lung cancer. 1520 79

A 69-year-old man presented with progressive dyspnea, hemoptysis and fatigue for the previous 4 weeks. Chest radiograph and CT-scan were suggestive of lung cancer. The patient's condition worsened and within in few days he developed respiratory failure and acute cor pulmonale. Despite intensive care measures directed at suspected lung thromboembolism, the patient died on day 12. Autopsy revealed disseminated obstruction of small pulmonary arteries by microscopic tumor emboli. No signs of venous thromboembolism were found. Pulmonary tumor microembolism should be considered whenever a patient with malignancy presents with unexplained progressive dyspnea or pulmonary hypertension.
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PMID:[Right heart failure due to pulmonary tumor microembolism -- a rare differential diagnosis]. 1521 32

Aim of this study was to evaluate activity and toxicity of docetaxel and carboplatin as second-line treatment in advanced non-small-cell lung cancer (NSCLC) patients who failed or relapsed after previous chemotherapy. Patients had to have unresectable stage IIIb or IV NSCLC, previous chemotherapy, a performance status < or = 2, a normal bone marrow reserve, and an adequate renal and liver function. Treatment consisted of docetaxel 75 mg/m2 and carboplatin AUC 6 mg/ml min administered every 3 weeks for a maximum of 5 cycles. Fifty-seven patients with a median age of 57 years were included. Prior treatment consisted of gemcitabine alone (n = 2) or gemcitabine in combination with cisplatin (n = 26) or epirubicin (n = 29). Median number of cycles for carboplatin and docetaxel was 4. Granulocytopenia and thrombocytopenia common toxicity criteria (CTC) grades 3 and 4 occurred in 79 and 30% of patients, respectively. Febrile neutropenia occurred in eight patients (14%), of whom two patients died. Fatigue grades 2 and 3 occurred in 42% of patients. Other non-haematological toxicity was mild. Tumour response rate was 37%, irrespective of the previous regimen. Median survival was 31 weeks, 1-year survival was 32%. In conclusion, the combination of docetaxel and carboplatin is active as second-line treatment in platinum and non-platinum pre-treated patients.
Lung Cancer 2004 Aug
PMID:Phase II study of docetaxel and carboplatin as second-line treatment in NSCLC. 1524 98


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