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

We present a case of pancreatic cancer demonstrating symptomatic improvement with systemic chemotherapy using 5-fluorouracil and cisplatin (FP therapy). A 43 year-old man had pancreatic cancer with para-aortic lymph node metastases. He received FP therapy and achieved a partial response. After the initiation of chemotherapy, his symptoms such as severe pain and fatigue improved remarkably. Serum interleukin-6 levels correlated with these symptoms; the level was high before chemotherapy, but the levels were decreased during the courses of FP therapy. It is important to achieve symptomatic improvement in patients with pancreatic cancer, and serum interleukin-6 levels may be useful to evaluate a symptomatic response to chemotherapy.
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PMID:A case of pancreatic cancer achieving symptomatic improvement with systemic chemotherapy. 1052 52

Initial clinical results of concurrent chemoradiotherapy combined with high-dose intraoperative radiotherapy (IOR) for locally advanced pancreatic cancer were analyzed. Between June 1996 and May 1999, 6 patients with locally advanced pancreatic cancer without distant metastasis were treated with preoperative concurrent chemoradiotherapy followed by IOR. Preoperative radiation therapy was given by the dynamic arc conformal technique with a daily fraction of 1.8 Gy to a total dose of 45 Gy in 5 weeks. Cisplatin (5 mg/day for 4 weeks) and 5-fluorouracil (250 mg/day for 5 weeks) were administered continuously during preoperative radiation therapy. IOR as a single dose of 28 or 30 Gy was given to the gross tumor volume using electron beams of 15- to 22-MeV. Concurrent chemoradiotherapy was well tolerated, although all of the patients complained of nausea and fatigue. Two patients developed grade III leukopenia. No other serious acute toxicity was noted. The median survival time of the 6 patients was 17.5 months, which was significantly longer than that of our historical control treated with external radiation therapy with IOR (8 months), although the difference in survival was borderline significant (p=0.068). Concurrent chemoradiotherapy followed by high-dose IOR was well tolerated in patients with locally advanced pancreatic cancer, and the initial clinical results appeared promising.
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PMID:Concurrent chemoradiotherapy combined with intraoperative radiotherapy for locally advanced pancreatic cancer: a feasibility study. 1085 42

Gemcitabine has modest activity in the treatment of advanced pancreatic cancer and is a potent radiosensitizer. We conducted a Phase I trial to determine the maximum tolerated dose of weekly gemcitabine delivered concurrently with radiation therapy for the treatment of locally advanced adenocarcinoma of the pancreatic head and to assess the treatment-related toxic effects associated with such a regimen. Eighteen patients with pathologically proven, locally advanced adenocarcinoma of the pancreatic head were enrolled in this study. Patients received seven weekly doses of gemcitabine with 3000 cGy of external beam radiation therapy delivered during the first 2 weeks of therapy. Six patients received gemcitabine at 350 mg/m(2)/week, nine at 400 mg/m(2)/week, and three at 500 mg/m(2)/week. Grade 3-4 hematological toxicity was observed in over half the patients treated. Nonhematological toxicities were significant and included fatigue, anorexia, nausea, vomiting, and dehydration. Forty-four % of the patients required admission to the hospital for management of nausea/vomiting and dehydration. The risk of hospitalization appeared to be dose-related; all of the three patients treated at 500 mg/m(2)/week required hospital admission during treatment. Seventeen patients were evaluated for response, and eight patients (47%) had evidence of a local anticancer effect. Four of these eight patients (24%) had a partial response to therapy. The median survival for the entire group was 6 months. The 1-year survival rate for patients with an objective response to therapy was 66%. The clinical responses observed in this group of patients suggest gemcitabine is a clinically relevant radiosensitizer in patients with pancreatic adenocarcinoma. However, the toxic effects are significant, suggesting that until dose and scheduling issues are explored further, concomitant administration of gemcitabine and radiation therapy should still be considered investigational.
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PMID:Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma. 1148 98

Background. Docetaxel and irinotecan have additive or synergistic activity in vitro and in vivo as well as differing toxicities and unique mechanisms of action. We conducted a phase I trial to determine the maximum-tolerated dose of docetaxel and irinotecan given on a weekly schedule. Methods. Eligible patients had advanced, incurable, solid tumors. Docetaxel was administered as a 1-hour infusion and escalated over four dose levels (25, 30, 35, and 40 mg/m(2)) followed by irinotecan administered over 30 minutes at a fixed dose of 50 mg/m(2). Treatment was administered weekly for four weeks followed by two weeks of rest. To improve tolerability, the schedule was modified to weekly administration for two weeks with one week of rest, and irinotecan was escalated over 3 dose levels (55, 60, and 65 mg/m(2)) with docetaxel fixed at 35 mg/m(2). Results. Forty-four patients were treated and the most common dose-limiting toxicity was diarrhea observed in 11% of patients. Severe neutropenia was rare (grade 4: 2%, grade 3: 23%). Other nonhematologic toxicities included nausea/vomiting, dehydration and fatigue. Partial responses occurred in two patients with pancreatic cancer, and one patient each with non-small cell lung and esophageal cancer. Conclusions. Weekly docetaxel and irinotecan is a promising non-cisplatin doublet with preliminary evidence of activity in advanced solid tumors. Diarrhea is the predominant dose-limiting toxicity but unlike the every 3 weeks schedule myelosuppression is modest. The recommended phase II doses are docetaxel 35 mg/m(2) and irinotecan 60 mg/m(2) on days 1 and 8 of a 21-day schedule. Phase II trials of this regimen are ongoing or planned in lung, head and neck, stomach, esophageal, and pancreatic cancers.
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PMID:Phase I dose escalation trial of weekly docetaxel plus irinotecan in patients with advanced cancer. 1264 88

Farnesyl transferase (FT) inhibitors block the main post-translational modification of the Ras protein, thus interfering with its localisation to the inner surface of the plasma membrane and subsequent activation of downstream effectors. Although initially developed as a strategy to target Ras in cancer, FT inhibitors have subsequently been acknowledged as acting by additional and more complex mechanisms that may extend beyond Ras, involving RhoB, centromere-binding proteins and probably other farnesylated proteins. SCH66336 (lonafarnib, Sarasar( trade mark ); Schering-Plough), a tricyclic orally active FT inhibitor, was the first of these compounds to undergo clinical development. Gastrointestinal tract toxicities and fatigue have qualified as dose-limiting toxicities in all Phase I/II studies. Evidence of clinical activity has been reported. Lonafarnib combination studies with both gemcitabine and paclitaxel have been carried out. No unexpected toxicities were observed in these Phase I studies, while encouraging clinical activity was observed mainly in pancreatic cancer and non-small cell lung cancer. Further combination studies are ongoing. R115777 (Zarnestra( trade mark ); Janssen Pharmaceutica) is another orally active FT competitive inhibitor in clinical development. Single-agent Phase I/II studies have shown that myelotoxicity and neurotoxicity are dose-limiting toxicities; intermittent schedule is probably better tolerated; antitumour activity is observed particularly in breast cancer and haematological malignancies. A number of combination studies with R115777 have been carried out. A recently completed, large Phase III trial comparing gemcitabine plus R115777 versus gemcitabine plus placebo in advanced pancreatic cancer has failed to demonstrate any survival benefit in the R115777 arm. BMS-214662 is the third FT inhibitor in clinical development. It has the main advantage of being cytotoxic in nature, rather than cytostatic, and potent in vivo antitumour activity has been reported. A major drawback for BMS-214662 is its severe gastrointestinal and liver toxicities, which prevent the achievement of adequate systemic exposures following the oral route. Alternative ways of interference with the ras oncogene pathway, in particular inhibition of ras downstream effectors, are discussed and early clinical data are presented.
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PMID:Farnesyl transferase inhibitors in clinical development. 1278 99

The efficacy and safety of gemcitabine were investigated in 16 patients with unresectable pancreatic cancer (Arm A), compared with 16 patients who received chemotherapy without gemcitabine (Arm B) and 44 patients who received best supportive care (Arm C). A gemcitabine 30 min i.v. infusion at a starting dose of 1,000 mg/m2 was administered once a week for 3 weeks with a 1 week rest. Dose reduction and cycle delay were applied because of toxicity in 62.5% of the cases in the first cycle and 31.3% in the second cycle. Hematological toxicity was observed in 81.3%, nausea/vomiting in 37.5% and fatigue in 18.8%. Clinical benefit response was observed in 25.0% in Arm A, as compared with the lower rate of 6.25% in Arm B. Response rates were comparable. The median time of outpatient treatment was 98.5 days in Arm A and 34.0 days in Arm B, respectively. The median survival time was 200 days in Arm A, 121 days in Arm B and 82.5 days in Arm C, respectively. In Arm A, the higher dose intensity showed a longer survival time. The results show that gemcitabine can be administered in outpatient clinics with dose reduction and cycle delay, and that higher dose intensity generates clinical benefit, survival advantage and prolonged outpatient treatment time.
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PMID:[Outcomes of treatment with gemcitabine for unresectable pancreatic cancer]. 1499 51

The incidence of pancreatic cancer is about 10,000 cases a year in Germany. The role of surgery as a curative modality is limited. The 5-year survival for all stages remains less than 5%. Pain, cachexia, jaundice, nausea, fatigue and depression are frequent symptoms which reduce the quality of life for affected patients. Therefore, amelioration of symptoms is a major goal of palliative care. Chemotherapy may yield a moderate survival benefit. Gemcitabine is the drug of choice in metastatic pancreatic cancer. In locally advanced disease, radiochemotherapy can be considered. Different treatment strategies against molecular targets are currently tested in clinical trials.
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PMID:[Best supportive care of pancreatic carcinoma]. 1516 Feb 43

To examine the feasibility of radiotherapy with a full dose of gemcitabine (1000 mg/m2 once a week) for unresectable pancreatic carcinoma, we treated 15 patients with 50 Gy/25 fractions/5 weeks concurrent chemoradiotherapy using a limited irradiation field. Eleven patients completed treatment. No lethal side effects were seen during and after these therapies. Two patients quit therapy because of tumor progression; one patient quit radiotherapy owing to general fatigue and nausea; and the other patient stopped gemcitabine administration owing to a grade 4 hematological adverse event. As only two patients stopped this protocol as a result of untoward effects of treatment, limited-field radiotherapy enabled us to treat pancreatic cancer with full-dose gemcitabine.
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PMID:[Concurrent chemoradiotherapy using full-dose gemcitabine for patients with unresectable pancreatic cancer]. 1521 83

Aviscumine is a ribosome-inactivating protein with potent antitumour activity in vitro and in vivo and is an Escherichia coli-derived recombinant counterpart of natural mistletoe lectin-I. The current study was performed to determine the safety profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a prolonged infusion of aviscumine in cancer patients. Aviscumine was given once weekly as a 24 h central intravenous infusion in patients with advanced, refractory progressive solid malignant tumours. Fourteen fully eligible patients (11 male, 3 female) with a median age 58 yrs (range 41-77) were enrolled. They had histologically verified disease, were 18 yrs old, had an ECOG PS 2 and adequate bone marrow, liver and renal function. DLT was defined as any non-haematological grade 3-4 toxicity (Common Toxicity Criteria [CTC] version 2.0), neutrophil count <500/ microl for 7 days, febrile neutropenia or thrombocytopenia grade 4. The MTD was defined as the dose level below the dose at which 2 patients per dose level experienced a DLT during the first treatment cycle. Colorectal cancer, soft tissue sarcoma and pancreatic cancer were the most common tumour types. Dose levels of aviscumine ranged from 4 to 6 microg/kg. The median number of cycles was 2.8 (range, 2-8). Common side effects in cycle 1 were fatigue, fever, nocturia, urticaria, erythema and pruritus. DLTs occurred in 2/3 patients on the 6 microg/kg dose level and consisted of increases in ASAT grade 3, ALAT grade 3, gammaGT grade 3/4, hypokalemia grade 3 and fatigue grade 3. No DLTs were observed on dose levels 4 and 5 microg/kg. The best response (RECIST) was stable disease in 4 pts, lasting for 4-8 cycles. Pharmacokinetics indicated that potentially active plasma levels of the compound were maintained during the entire infusion. We conclude that the recommended dose for weekly 24 h infusions of Aviscumine should be 5 microg/kg.
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PMID:Weekly 24 h infusion of aviscumine (rViscumin): a phase I study in patients with solid tumours. 1591 88

Ninety per cent of pancreatic adenocarcinomas (PC) contain mutations of the K-Ras proto-oncogene resulting in constitutively activated Ras protein. A critical step in Ras activation is farnesylation of Ras protein. Farnesyl transferase inhibitors are compounds that inhibit farnesylation. We report the results of a phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with surgically incurable locally advanced or metastatic PC. Between 6/1/2000 and 11/20/2001, 58 cases were accrued, 53 of whom were eligible and analyzable. Patients were required to have a performance status (PS) 0 to 1, be able to take oral medications, and to have adequate renal, hepatic, and hematologic functions. Fifty-five percent were male. Median age was 64.7 years (38.9 to 80.6), and patients had no previous systemic therapy for advanced PC. Treatment consisted of R115777 300 mg po bid given for 3 out of every 4 weeks. Toxicities were as follows: Grade 3 in 19/53 (36%), grade 4 in 53 (173%), and grade 5 in 53 (8%). Most frequent toxicities were: anemia 35/53 (66%), fatigue and malaise 33/53 (62%), nausea 31/53 (58%). Grade 5 toxicities included: thromboembolism 1, infection 2, other 1. Median survival was 2.6 months (mo) (95% CI 2.1-3.6), 6-mo survival is 19% (95% CI, 8-29%), median time to treatment failure was 1.4 mo (95% GI 1.1-1.6). R115777 is ineffective as monotherapy in advanced pancreatic cancer.
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PMID:A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study. 1613


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