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)

Thirteen patients with metastatic renal cancer were treated in a phase II trial with interleukin-2, 21.6 million IU/m2 intravenously daily for five days on two consecutive weeks, starting 3 days after the administration of low dose cyclophosphamide 350 mg/m2 intravenously. Treatment cycles were repeated every 21 days. No responses were seen (95% Confidence Interval: 0-22%). The most common toxicities were fever, fatigue, hypotension, nausea/emesis, and myalgia/arthralgia. There were 11 episodes of Grade III toxicity including Grade III hypotension in 7 patients. Because of the significant toxicity and the lack of observed response, the study was discontinued. Cyclophosphamide and interleukin-2 at the dose and schedule used in this study has considerable toxicity and is unlikely to improve on response rates previously seen with other IL-2 based regimens in metastatic renal cancer.
 ...
PMID:Phase II study of low dose cyclophosphamide and intravenous interleukin-2 in metastatic renal cancer. 796 Jun 3

Interleukin 6 (IL-6) has antitumor activity comparable to IL-2 in murine models with less toxicity. Because the biological effects of intermittent and continuous infusions may differ, we conducted two concurrent Phase I trials of daily x5, 1-h, and continuous 120-h i.v. infusions to determine the toxicity, biological effects, and maximum tolerated dose of i.v. IL-6. Cohorts of six patients with advanced cancer received escalating doses (1, 3, 10, 30, 100, and 150 microgram/kg/day) of recombinant human IL-6 on days 1-5 and 8-12 of each 28-day course (1-h trial) or on days 1-5 of each 21-day course (120-h trial). Treatment was administered in regular inpatient wards and in outpatient clinics and was withheld in the event of grade 3 toxicity. Sixty-nine patients (1-h trial, n = 40; 120-h trial, n = 29) were enrolled, including 27 with renal cancer and 16 with melanoma. All were ambulatory, and 40 were asymptomatic. Fever (97%), anemia (78%), fatigue (56%), nausea or vomiting (49%), and elevated serum transaminase levels (42%) were the most frequent toxicities. Transient hypotension developed in 23 patients (33%). There were three deaths during the study due to progressive disease and/or infection. There were no objective responses. Dose-related increases in platelet counts and C-reactive protein levels were detected in most patients. Principal dose-limiting toxicities included atrial fibrillation (1 episode in the 1-h trial and 4 episodes in the 120-h trial) and neurological toxicities (3 episodes in the 1-h trial and 4 episodes in the 120-h trial). The neurological toxicities included confusion, slurred speech, blurred vision, proximal leg weakness, paraparesis, and ataxia. These effects were transient and reversed when IL-6 was discontinued. IL-6 can be given by i.v. infusion at biologically active doses with acceptable toxicity. Dose-limiting toxicities consisted mainly of a spectrum of severe but transient neurological toxicities and occasional episodes of atrial fibrillation. The maximum tolerated doses recommended for use with these i.v. schedules in Phase II trials are 100 microgram/kg/day by daily x5 1-h infusion and 30 microgram/kg/day by 120-h infusion. Phase II trials will be performed to determine the antitumor activity of IL-6 and better define its toxicity. Patients in these and other IL-6 studies should be monitored closely for neurological and cardiac effects.
 ...
PMID:Concurrent phase I trials of intravenous interleukin 6 in solid tumor patients: reversible dose-limiting neurological toxicity. 981 35

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.
 ...
PMID:Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. 981 99

Eighteen patients with advanced renal cancer were treated with 0.15 mg/kg/day floxuridine by continuous intravenous infusion for 14 days with 3 million IU/m2/day alpha interferon subcutaneously three times weekly. Treatment cycles were repeated every 28 days. Floxuridine dosages were escalated to a maximum of 0.2 mg/kg/day and alpha interferon dosages were escalated to a maximum of 6 million IU/m2/day depending on patient tolerability. A total of 49 treatment courses were administered with a median of 2.7 courses per patient. Of 14 assessable patients, there were no complete or partial responses. Eight patients (57%) had stabilization of disease. The median survival for patients with stable disease was 20.9 months and for all 18 patients was 7.2 months. Grades 3 and 4 toxicities included diarrhea (44%), nausea/vomiting (28%), mucositis (11%), fever (22%), and fatigue (50%). Dose-limiting toxicities were primarily gastrointestinal symptoms. There were no treatment-related deaths. This combination in the dose schedule used did not result in any significant objective tumor response but was associated with considerable toxicity.
 ...
PMID:Continuous-infusion floxuridine and alpha interferon in metastatic renal cancer: a national biotherapy study group phase II study. 1043 57

A limited institution Phase II pilot study was performed using a very low-dose combination of daily s.c. interleukin (IL)-2 with IFN-alpha-2b in patients with advanced renal cancer in an attempt to duplicate or increase the response documented with higher dose schedules without the attendant toxicity profile. We selected a dose of IL-2 with documented immunological activity and combined it with clinically active low-dose IFN. Between August 1994 and September 1996, 19 patients with metastatic renal cell carcinoma, who had been judged incapable of tolerating high-dose i.v. IL-2, were treated with IL-2 (1 million units/m2/day) and IFN (1 million units/day), administered s.c. daily. All treatments were administered on an outpatient basis. Virtually all patients had bulky tumor burden with multiple sites of involvement, including five patients with bone metastases. No major objective responses were observed; however, one patient experienced a minor response lasting 13 months, with an associated improvement in performance status. Median survival was 6 months, and 1-year survival was 16%. Toxicity was generally mild and consisted almost entirely of constitutional symptoms. No serious grade 3 or 4 toxicity was observed, although two patients withdrew from treatment due to treatment-related fatigue. On therapy, mild eosinophilia but no lymphocytosis was noted; in fact, peripheral lymphocyte counts decreased, only to rebound after treatment was discontinued. No toxic deaths occurred. Despite the reasonable tolerability of this daily low-dose s.c. regimen, we conclude that this regimen is an ineffective treatment in metastatic renal cell carcinoma patients who are incapable of tolerating high-dose i.v. IL-2.
 ...
PMID:Daily subcutaneous ultra-low-dose interleukin 2 with daily low-dose interferon-alpha in patients with advanced renal cell carcinoma. 1049 7

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4-week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.
 ...
PMID:Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study. 1099 27

Twenty patients with either melanoma ( 7) or kidney cancer ( 13) were treated with outpatient bolus interleukin (IL)-2 18-22 MIU/m2 IVPB for 3 consecutive days for 6 consecutive weeks followed by a 2-week rest break (on an 8-week cycle). Patient characteristics included 16 males/4 females, eleven patients had received no prior systemic therapy, median ECOG performance status = 1, and most common disease sites being lung, lymph node, subcutaneous, bone, and liver. Two patients with melanoma (29% response rate) (95% CI: 8-64%) and two with kidney cancer (15%) (95% CI: 3-43%) have achieved partial responses. Two minor responses in kidney cancer were also seen. The most common toxicities were nausea, fatigue, rigors, fever, and myalgias/arthralgias. No cardiac events occurred, and no patients required hospitalization due to toxicity. IL-2 at this outpatient dose and schedule is well tolerated and displays some evidence of activity in melanoma and kidney cancer. Larger patient numbers are required to corroborate these response rates and to determine whether complete responses are possible.
 ...
PMID:Outpatient experience with moderate dose bolus interleukin-2 in metastatic malignant melanoma and kidney cancer. 1280 82

We conducted a prospective quality-of-life analysis during outpatient immunotherapy in 22 patients with progressive metastatic renal cell carcinoma (RCC) treated with subcutaneous interferon-alpha2a and subcutaneous interleukin-2. Patients' quality of life was assessed by the European Organization for Research and Treatment of Cancer quality-of-life questionnaire QLQ-C30 before (week 0) and once during immunotherapy (week 3). Advanced renal cancer patients completed a total of 30 questionnaires before therapy (week 0) and after 3 weeks of therapy. Their mean quality of life (global-quality-of-health status) deteriorated significantly, from 64 to 41 (P</=0.001) during the first 3 weeks after treatment initiation, due to a mean reduction in physical (from 82 to 65; P</=0.001), emotional (from 77 to 61; P</=0.01), social (from 78 to 55; P</=0.01), and role functioning (from 82 to 58; P</=0.01). In contrast, cognitive functioning did not differ significantly from pretreatment scores after 3 weeks of therapy. In addition, during the first 3 weeks, appetite loss (from 18 to 59; P</=0.01), fatigue (from 33 to 56; P</=0.01), nausea/vomiting (from 10 to 26; P</=0.01), sleep disturbance (from 27 to 47; P</=0.01), diarrhoea (from five to 27; P</=0.01), and pain (from 20 to 32; P</=0.05) were significantly increased, while quality-of-life symptoms such as dyspnoea, and constipation were not significantly influenced by therapy. Complete response to RCC outpatient immunotherapy was associated with the most predominant reduction in functional quality of life when compared against patients in progressive or stable disease or partial tumour response. In conclusion, quality-of-life analysis during outpatient immunotherapy yielded modest changes in patients' health status 3 weeks after therapy initiation. Since the rapid decline in functional quality-of-life was associated with therapeutic efficacy, it is suggested that quality-of-life analysis might serve as an early indicator for immunotherapy response in metastatic RCC. British Journal of Cancer (2003) 89, 50-54. doi:10.1038/sj.bjc.6600996 www.bjcancer.com
 ...
PMID:Rapid deterioration in quality of life during interleukin-2- and alpha-interferon-based home therapy of renal cell carcinoma is associated with a good outcome. 1283 99

Protein kinase C (PKC) has a critical role in several signal transduction pathways, and is involved in renal cancer pathogenesis. Bryostatin-1 modulates PKC activity and has antitumour effects in preclinical studies. We conducted a multicentre phase II clinical trial in patients with advanced renal cancer to determine the response rate, immunomodulatory activity and toxicity of bryostatin-1 given as a continuous 24 h infusion weekly for 3 out of 4 weeks at a dose of 25 mug m(-2). In all, 16 patients were recruited (11 males and five females). The median age was 59 years (range 44-68). Patients had been treated previously with nephrectomy (8) and/or interferon therapy (9) and/or hormone therapy (4) and/or radiotherapy (6). Eight, five and three patients had performance statuses of 0, 1 and 2, respectively. A total of 181 infusions were administered with a median of 12 infusions per patient (range 1-29). Disease response was evaluable in 13 patients. Three patients achieved stable disease lasting for 10.5, 8 and 5.5 months, respectively. No complete responses or partial responses were seen. Myalgia, fatigue, nausea, headache, vomiting, anorexia, anaemia and lymphopenia were the commonly reported side effects. Assessment of biological activity of bryostatin-1 was carried out using the whole-blood cytokine release assay in six patients, two of whom had a rise in IL-6 levels 24 h after initiating bryostatin-1 therapy compared to pretreatment values. However, the IL-6 level was found to be significantly lower at day 28 compared to the pretreatment level in all six patients analysed.
 ...
PMID:A multicentre phase II trial of bryostatin-1 in patients with advanced renal cancer. 1456 10

Triapine is a novel small molecule ribonucleotide reductase inhibitor that showed activity in renal cell carcinoma (RCC) cell lines. Evaluating new agents with novel mechanisms remains of interest for patients with incurable RCC. This was a single-arm, multicentre phase II trial where Triapine was given at a schedule of 96 mg/m2 2-h infusion daily x 4 repeated every 2 weeks in patients with recurrent RCC. A median of four cycles of Triapine was administered to 19 eligible patients. One response was seen (7%.) Median time to progression was 3.6 months. Common adverse events (AEs) were grade 1-2, with fatigue in 74%, nausea in 68% and vomiting in 58%. However grade 3/4 neutropenia was seen in 79% and acute reactions of hypoxia, hypotension, methemoglobinemia were seen. Dose reductions/delays due to AEs were common with only 47% of patients receiving > 90% of planned dose intensity. The study closed, at the end of stage 1 as it did not meet the minimal efficacy criteria to proceed. Further evaluation of Triapine at this dose and schedule in patients with advanced kidney cancer is not recommended.
 ...
PMID:Phase II study of Triapine in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC IND.161). 1739 73


<< Previous 1 2 3 4 Next >>