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At least 1,009 records · Page 56Linked to original sources
PubMed1998

A double-blind, placebo-controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Northern European Tiagabine Study Group.

In a multicentre, double-blind, parallel-group, placebo-controlled trial, a three-times daily regimen of tiagabine was evaluated as add-on therapy in 154 adult patients with refractory partial seizures. A total of 77 patients were randomised to treatment in each arm. Tiagabine HCl was titrated from an initial dose of 12-30 mg/day over 4 weeks. During the 12-week fixed-dose period, there was a significant reduction in the median 4-weekly seizure rate for all partial seizures and simple partial seizures (P < 0.05 in each case). Furthermore, the proportion of patients with a reduction of 50% or more in all partial seizures was higher in the tiagabine group than in the placebo group (14 versus 6%), though the difference did not achieve statistical significance. The difference with respect to simple partial seizures was significant (21 versus 6%, P < 0.01). The percentage of patients achieving an increase of at least 50% in the proportion of days free of all partial seizures was significantly greater in the tiagabine group compared to placebo (14 versus 4%, P<0.01). Tiagabine did not appear to influence the plasma concentrations of other concomitant antiepileptic drugs and was generally well tolerated, with most drug-related adverse events being mild or moderate in severity. The most common adverse events were dizziness, asthenia, headache and somnolence. Adverse event incidence was similar between tiagabine and placebo groups, except for dizziness which was more common with tiagabine (29 versus 10%, P < 0.01). Tiagabine had no significant effects on laboratory tests or vital signs. The present study shows that tiagabine, at a dose of 10 mg administered three-times daily, which is at the lower end of the usual recommended dose range (30-50 mg/day, tiagabine base), is generally well tolerated and demonstrates efficacy for the treatment of refractory partial seizures.

Adolescent↗
PubMed2000

[Marshall syndrome: results of a retrospective national survey].

Marshall's syndrome or periodic fever syndrome was first described in 1987 in the USA based on observations of 12 children under the age of five with periodic fever (> 38 degrees C) and accompanying aphtous stomatitis, pharyngitis, and cervical adenopathy (PFAPA). In 1998, a national retrospective study was carried out in France by the pediatric infectious pathology group, and a semeiological analysis was made of 22 cases. The main characteristics of Marshall's syndrome found in this patient population were in agreement with those reported in the literature. The onset of symptoms occurred between the age of 3 months and 12 years, with a mean age of 5 years; no geographical or ethnic predisposing factors were noted. The diagnosis of symptoms was subsequently established at an age ranging from 5 months to 16 years, with a mean age of 6.5 years. It was determined that following an initial phase of generalized clinical manifestations (asthenia, cranial neuritis, dysphagia, anorexia), the symptoms become stereotyped, with the sudden appearance of high fever (> 40 degrees C), shivering, aphtous stomatitis, pharyngitis, and cervical adenopathy. Other symptoms such as cranial neuritis, arthralgia, and abdominal pain may also be present (50% of cases in the present study), but due to their variability of appearance they are of lesser diagnostic value. The main characteristic of Marshall's syndrome is its periodic aspect; with fever occurring every 6 to 9 weeks, with a mean interval of 66 days before recurrence of fever compared to the shorter interval of 21 to 28 days reported in the literature. After excluding the presence of an infection, the differential diagnosis includes the following: familial Mediterranean fever, hyper IgD syndrome, and feverish neutropenia. During the periods of fever, an inflammatory syndrome with hyperleucocytosis and a marked increase in C-reactive protein (CRP) levels and sedimentation rate is observed. The most effective treatment seems to be the early administration of corticoids during the initial phase, prior to the appearance of more specific symptoms. The prognosis is excellent, with a progressive decrease in the incidence of periodic fever and an absence of complications. However, the etiology of Marshall's syndrome has not yet been determined.

Adolescent↗
PubMed1997

[Ectopic intraspinal extradural anaplastic ependymoma in an infant].

BACKGROUND: Ependymomas represent about 10% of the spinal tumors in children. Some of them may be unusually located. CASE REPORT: A 10-month-old boy was admitted for an abdominal mass syndrome with dehydration asthenia and acute bladder dysfunction. A few hours later, he developed a flaccid paraplegia. Ultrasonic and magnetic resonance spinal imaging showed a giant intraspinal tumor extending from T9 to IA level, posteriorly located to the dural compartment, widening the spinal cord. Ultrasonography also showed right ureterohydronephrosis due to the neurological bladder dysfunction. A conservative laminotomy-laminoplasty was performed in emergency. Total removal of the tumor that was attached to the right dorsal root was achieved extradurally, requiring resection of the proximal part of the root. Histological features were typical of malignant ependymoma. Chemotherapy was initiated 2 weeks later. The severe renal destruction and the persistent bladder dysfunction led to a heminephrectomy and a cystostomy, 3 weeks later. The neurological recovery was only partial with a follow-up of 18 months. CONCLUSION: Ectopic intraspinal extradural localization of ependymomas is rare and their development from a nerve root is exceptional.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Muscle metabolism during fatigue and work.

Metabolic fatigue is a characteristic muscle response to intense exercise that has outstripped the rate of ATP replacement. The accumulation of metabolic by-products, namely hydrogen ions and diprotonated phosphate, interferes with actin-myosin interaction, effectively preserving muscle ATP levels by preventing further ATP hydrolysis. Muscle force and metabolite concentrations return to normal in about 5 minutes. Less intense exercise causes a more subtle, non-metabolic fatigue due to a still-undefined disturbance of excitation-contraction coupling, which can last for several hours. In this type of fatigue, greater effort is required to generate submaximal forces. Endurance exercise is mainly limited by the size of muscle glycogen stores and how efficiently they are used. Endurance training permits an athlete to work aerobically at high rates, consuming a mixture of lipid and carbohydrate fuels. When muscle glycogen is used up, exercise can only continue at the relatively low rate supportable by lipid metabolism. Anaerobic exercise is also limited by subjective factors such as dyspnoea and muscle pain, which have objective determinants. Extremely prolonged exercise can lead to general collapse because of dehydration, hyperthermia, or hypoglycaemia. None of these factors explains the phenomenon of asthenia, a subjective sense of exhaustion that produces no objective impairment of physical performance. The metabolic myopathies are experiments of nature that promise to shed new light on the biochemical basis of muscle fatigue. This will require quantitative studies of the kind provided by topical magnetic resonance spectroscopy, correlating physiology and metabolism in vivo.

Adenosine Triphosphate↗
PubMed2003

The syndrome of food-cobalamin malabsorption revisited in a department of internal medicine. A monocentric cohort study of 80 patients.

BACKGROUND: To date, only case reports or small studies have documented the syndrome of food-cobalamin malabsorption in specific populations of patients or situations. In this paper, we present the data from 80 unselected patients with cobalamin deficiency related to food-cobalamin malabsorption. METHODS: We studied 80 patients with well-established food-cobalamin malabsorption who were extracted from an observational cohort study (1995-2000) of 127 consecutive patients with cobalamin deficiency and who were followed in a department of internal medicine. RESULTS: The median age of patients was 66 years and the female to male ratio was 1.2. The mean hemoglobin level was 113+/-27 g/l (range 32-159 g/l) and the mean erythrocyte cell volume was 95.4+/-12.3 fl (range 55-140 fl). Mean serum vitamin B12 and homocysteine levels were 153+/-74 pg/ml (range 35-200 pg/ml) and 20.6+/-15.7 μmol/l (range 8-97 μmol/l), respectively. The main clinical findings noted were peripheral neuropathy (46.2%), stroke (12.5%), confusion or dementia (10%), asthenia (18.7%), leg edema (11.2%), and digestive disorders (7.5%). The commonest associated conditions were atrophic gastritis (39%) with evidence of Helicobacter pylori infection (12.2%) and alcohol abuse (13.7%). Three patients had Sjögren's syndrome and one had systemic sclerosis. Ten percent of all patients were on long-term metformin (10%) and 7.5% on acid-suppressive drugs. Correction of the serum vitamin B12 levels and hematological abnormalities was achieved equally well in all patients treated with either intramuscular or oral crystalline cyanocobalamin. CONCLUSION: This study suggests that food-cobalamin malabsorption may be the leading cause of vitamin B12 deficiency in adults. As other studies have also reported, the condition is often associated with neuro-psychiatric findings and with several other conditions. Oral and parenteral cobalamin appear to be equally effective in correcting serum B12 levels and hematological abnormalities and, in many cases, they also relieve symptoms.

Journal Article↗
PubMed2001

UFT and leucovorin in first-line chemotherapy for patients with metastatic gastric cancer. An Early Clinical Studies Group (ECSG)/European Organization for Research Treatment of Cancer (EORTC) phase II trial.

A phase II study was performed to evaluate 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil (UFT) and leucovorin as first-line chemotherapy in European patients with advanced gastric cancer. From 38 patients, 25 were evaluable for response and 36 for toxicity. Patients received UFT at 300 mg/m(2)/day for 28 days, every 35 days and leucovorin at 90 mg/day on an identical schedule. Overall response rate was 10.5% (95% confidence interval (CI): 3.7-22.5%) in intent-to-treat analysis and 16% (95% CI: 5.7-33%) in evaluable patients. Grade 3-4 common toxicity criteria (CTC) toxicities were diarrhoea (28%; 10/36), nausea (11%; 4/36), vomiting (8%; 3/36) and asthenia (11%; 4/36). 23 patients in 44% (42/96) of the courses had to skip days of treatment due to toxicity or to non-compliance. In conclusion, UFT+leucovorin has a definitive, but low, efficacy in advanced gastric cancer patients. Toxicities were mainly gastrointestinal and treatment needs to be withheld if grade 2 diarrhoea occurs.

Administration, Oral↗
PubMed2001

Phase II trial with ISIS 5132 in patients with small-cell (SCLC) and non-small cell (NSCLC) lung cancer. A European Organization for Research and Treatment of Cancer (EORTC) Early Clinical Studies Group report.

Two multicentre phase II trials were designed to determine if tumour responses can be achieved in progressive small-cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) patients treated with ISIS 5132, an inhibitor of C-raf kinase mRNA expression (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA), and to further characterise the safety of the compound. Between August 1998 and November 1999, 26 patients (18 NSCLC, 8 SCLC) were entered. Out of these, 23 were eligible, 22 (18 NSCLC, 4 SCLC) were treated with ISIS 5132 (2 mg/kg/day, 21 days continuous intravenous (i.v.) infusion every 4 weeks) and were evaluable for toxicity and 18 (15 NSCLC, 3 SCLC) were evaluable for efficacy. For the whole group haematological toxicity did not exceed grade 2. One patient experienced a grade 4 increased prothrombin time. Non-haematological toxicity was mild to moderate, with the observation of asthenia and nausea and vomiting. Progressive disease (PD) was diagnosed in 10 patients (8 NSCLC and 2 SCLC). 8 more patients (7 NSCLC, 1 SCLC) were considered as treatment failures. In conclusion, this study using ISIS 5132 with this dose and schedule of administration excludes a 20% response rate with 95% confidence intervals for NSCLC and cannot draw any conclusions for SCLC patients as only a few were involved in the study.

Adult↗
PubMed2001

Phase I trial of weekly irinotecan combined with UFT as second-line treatment for advanced colorectal cancer.

The aim of this study was to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly Irinotecan (CPT-11) plus UFT, and to assess the antitumour activity of this combination as second-line chemotherapy in patients with advanced colorectal carcinoma, 31 patients with measurable advanced colorectal carcinoma were treated. Cohorts of 3 patients received increasing dose levels of the combination. Levels 1 to 4 included a fixed dose of oral (p.o.) UFT (250 mg/m(2)/day) for 21 days of a 28-day cycle combined with increasing intravenous (i.v.) doses of CPT-11 (80, 100, 110 and 120 mg/m(2)) on days 1, 8 and 15. Levels 5 and 6 included a higher fixed dose of oral UFT (300 mg/m(2)) combined with increasing i.v. doses of CPT-11 (100 and 110 mg/m(2)) on days 1, 8 and 15. 147 courses were administered. MTD were reached at level 4 (2 cases of grade 4 diarrhoea and 1 grade 3 asthenia), and level 6 (1 grade 4 diarrhoea, 1 grade 3 diarrhoea and 1 grade 3 febrile neutropenia). Responses in 30 evaluable patients were: 3 partial responses (10%), 15 stable disease (50%) and progressive disease in 12 patients (40%). Median time to progression was 4.5 months (95% Confidence Interval (CI): 3.4-6.6 months) and median survival was 11 months (95% CI: 7.9-14.1 months). The recommended doses for phase II trials are: (a) CPT-11 110 mg/m(2) i.v. on days 1, 8 and 15 every 28 days plus UFT 250 mg/m(2) p.o. on days 1 through to 21 or (b) CPT-11 100 mg/m(2) and UFT 300 mg/m(2).

Administration, Oral↗
PubMed2002

Impact of two different dose-intensity chemotherapy regimens on psychological distress in early breast cancer patients.

In order to improve outcome, new, often more toxic chemotherapy regimens are continuously investigated in early breast cancer patients. Because the expected survival improvement is small, the possible increase in the negative effects of the new treatments should be carefully evaluated. Negative effects are represented not only by acute and chronic toxicity, but also by the adverse psychological impact of chemotherapy. The aim of this study was to evaluate the effect on patient-reported psychological distress of an increase in the dose-intensity of adjuvant chemotherapy compared with a standard regimen. Psychological distress was evaluated at baseline, during chemotherapy and after 6 and 12 months in breast cancer patients enrolled in a phase III multicentre study comparing the standard adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil every 21 days (CEF21) with the same chemotherapy given every 14 days (CEF14). 392 patients were randomised in participating centres, and 363 were evaluable for this study. Overall, 1095 out of 1446 expected questionnaires (75.7%) were collected and evaluable. At baseline, the mean scores of psychological distress were similar in the two arms. During chemotherapy, a significantly higher psychological distress was observed in the CEF14 compared with the CEF21 arm (32.3 +/- 1.3 versus 27.6 +/- 1.3; P=0.009), as well as a higher cumulative incidence of anaemia, mucositis, diarrhoea, alopecia, bone pain and fatigue was observed in the CEF14 arm. In multivariate analyses, mucositis (P=0.01), asthenia (P=0.059), and CEF14 treatment (P=0.054) were independently associated with a higher psychological distress. After 6 months, psychological distress was again similar in the two arms and significantly lower when compared with baseline within each arm. A dose-intensive adjuvant regimen induces a higher, although transient, psychological distress in early breast cancer patients. Final results of the randomised trial will indicate whether such higher adverse effects of the dose-intensive regimen are counterbalanced by a higher efficacy of the experimental treatment in terms of survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Raltitrexed in the treatment of elderly patients with advanced colorectal cancer: an active and low toxicity regimen.

In spite of the high prevalence of advanced colorectal cancer in the elderly, we have little data on the efficacy and toxicity of chemotherapy in this age group. Raltitrexed is a thymidylate synthetase inhibitor with known activity in the treatment of advanced colorectal cancer. The objective of this study was to analyse the efficacy and tolerance of raltitrexed in elderly patients with advanced colorectal cancer. 92 patients diagnosed with advanced colorectal cancer aged >or=70 years were entered into the study. Raltitrexed was given at a dose of 3 mg/m(2) once every 3 weeks for a minimum of three cycles. A total of 511 cycles were given with a median of five cycles per patient. 20 out of the 90 patients evaluable for response achieved a partial response (PR) (22%, 95% Confidence Interval (CI): 17-36%), 43 (48%) remained stable and 27 showed progression (30%). The mean duration of response was 24 weeks and the progression-free interval was 15 weeks. The overall median survival was 41 weeks. 31 patients (39%, 95% CI: 28-50%) experienced a clinical benefit (improvement of the performance status without a worsening of symptoms or relief of symptoms without a worsening of the performance status). The main toxicities were gastrointestinal and haematological. 12 patients (13%) developed grade 3-4 side-effects: 7 had nausea/vomiting (8%), 6 a transaminase increase (7%), 4 asthenia (4%), 3 diarrhoea (3%), 2 neutropenia (2%), 2 anaemia (2%) and 1 thrombocytopenia (1%). Three toxic deaths occurred (3%). The group of patients with a creatinine clearance <or=1.08 ml/s was found to have a higher risk of developing grade 3-4 toxicity compared with those with adequate renal function (8/18 versus 4/72; P<0.001). In conclusion, raltitrexed is an active, convenient and low toxicity treatment for the elderly with advanced colorectal cancer. However, it must be used cautiously in elderly patients with a creatinine clearance <or=1.08 ml/s since they are at a higher risk of suffering grade 3-4 toxicity.

Age Factors↗
PubMed2002

Phase I study of weekly paclitaxel and liposomal doxorubicin in patients with advanced solid tumours.

The aim of this study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of a weekly administration of paclitaxel and pegylated liposomal doxorubicin (Caelyx; Schering Plough Pharmaceutical) in patients with advanced solid tumours. 19 pretreated patients with solid tumours received escalated doses of pegylated liposomal doxorubicin (6-12 mg/m(2)) as a 1-h intravenous (i.v.) infusion followed by a fixed dose of paclitaxel (80 mg/m(2)) weekly for 4 consecutive weeks in cycles of 6 weeks. DLT was defined as grade 4 neutropenia or thrombocytopenia, febrile neutropenia, grades 3 or 4 non-haematological toxicity or treatment delay due to unresolved toxicity during cycle 1. The MTD was reached at the dose of pegylated liposomal doxorubicin of 10 mg/m(2)/week and paclitaxel of 80 mg/m(2)/week. The DLTs were treatment delay due to grade 3 neutropenia and grade 3 diarrhoea. A total of 55 chemotherapy cycles were administered, and grades 3-4 neutropenia occurred in seven cycles (13%); the non-haematological toxicity was mild with grades 2/3 diarrhoea occurring in 4 (7%), grades 2-4 asthenia in 11 (20%) and grade 2 mucositis in 7 (13%) cycles. There was no case with more than a 10% LVEF decrease after a median of 3 (range 2-6) administered cycles/patients. One patient with breast cancer and 1 with ovarian cancer experienced a major partial response. The weekly administration of pegylated liposomal doxorubicin at the dose of 10 mg/m(2) in combination with paclitaxel at the dose of 80 mg/m(2) for 4 consecutive weeks, in cycles of 6 weeks which represent the recommended doses for further phase II studies, is a well tolerated regimen, which merits further evaluation in tumours known to be sensitive to taxanes and/or anthracyclines.

Adult↗
PubMed2002

Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours.

A single-agent dose-escalating phase I study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile and recommended dose for phase II studies. Plasma pharmacokinetics were determined as well as the SCH 66336-induced inhibition of farnesyl protein transferase in vivo. SCH 66336 was given orally once daily (OD) without interruption to patients with histologically-confirmed solid tumours. Routine antiemetics were not prescribed. 12 patients were enrolled into the study. Dose levels studied were 300 mg (6 patients) and 400 mg (6 patients) OD. Pharmacokinetic sampling was performed on days 1 and 15. Although at 400 mg OD only 1 patient had a grade 3 diarrhoea, 3 out of 6 patients interrupted treatment early due to a combination of various grade 1-3 toxicities (diarrhoea, uremiacreatinine, asthenia, vomiting, weight loss) indicating that this dose was not tolerable for a prolonged period of time. At 300 mg OD, the same pattern of toxicities was observed, but all were grade 1-2. Therefore, this dose can be recommended for phase II studies. Pharmacokinetic analysis showed that peak plasma concentrations as well as the AUCs were dose-related, with increased parameters at day 15 compared with day 1, indicating some accumulation upon multiple dosing. Plasma half-life ranged from 5 to 9 h and appeared to increase with increasing dose. Steady state plasma concentrations were attained by day 14. A large volume of distribution at steady state suggested extensive distribution outside the plasma compartment. There is evidence of inhibition of protein prenylation in some patients after OD oral administration of SCH 66336. SCH 66336 can be safely administered using a continuous oral OD dosing regimen. The recommended dose for phase II studies using this regimen is 300 mg OD.

Administration, Oral↗
PubMed2003

Phase II study of LU 103793 (dolastatin analogue) in patients with metastatic breast cancer.

LU 103793 is a synthetic analogue of Dolastatin 15 that inhibits tubulin polymerisation. The aim of this study was to evaluate the efficacy and tolerability of LU 103793 in patients with metastatic breast cancer who had been previously treated with two lines of chemotherapy for advanced disease. Patients received LU 103793 at a dose of 2.5 mg/m(2)/day over 5 min for 5 consecutive days every 3 weeks. Thirty-four patients were enrolled and 23 patients were eligible for the evaluation of efficacy. Eleven patients experienced grade 4 neutropenia. Other related grade 3/4 adverse events included asthenia (three patients), stomatitis (1), myalgia (1) and increase of serum bilirubin (2). The main toxicity was hypertension occurring in seven out of 34 patients. There were no objective responses, 7 patients had stable disease. These results do not support the further evaluation of LU 103793 in metastatic breast cancer patients using this dose and schedule.

Adult↗
PubMed1993

In vivo biological results of the association between interleukin-2 and interleukin-3 in the immunotherapy of cancer.

The concomitant generation of macrophage-mediated suppressive events, as documented by the increase in neopterin and soluble interleukin-2 (IL-2) receptor (SIL-2R), and the enhanced production of cortisol, would represent the most investigated phenomena responsible for the reduced anticancer efficacy of IL-2 immunotherapy in humans. Based on our preliminary experimental studies suggesting a modulatory role of IL-3 on immune and endocrine effects induced by IL-2, a study was performed to evaluate the influence of IL-3 on biological effects of IL-2 cancer immunotherapy. We have evaluated 12 immunotherapeutic courses with IL-3 plus IL-2, which were performed in 6 patients with metastatic non-small cell lung cancer. The results were compared to those seen in 22 courses with IL-2 alone, carried out in 12 patients with metastatic non-small cell lung cancer. IL-3 was given intravenously at a daily dose of 1 microgram/kg/b.w. at 6 p.m. for 14 consecutive days, starting 7 days before IL-2. IL-2 was given subcutaneously at a dose of 3 million IU twice/daily for 5 days/week for 3 weeks. The increase in serum levels of the specific macrophage marker neopterin, induced by IL-2, was completely blocked by IL-3. The IL-2-induced SIL-2R rise was significantly lower during IL-3 plus IL-2 than under IL-2 alone. The increase in cortisol levels in response to IL-2 was neutralised by IL-3. The increase in lymphocyte, T lymphocyte, natural killer (NK) cell, activated T lymphocyte and eosinophil mean number was significantly higher during IL-3 plus IL-2 than during IL-2 alone. Episodes of fever, asthenia, anorexia, vomiting, anaemia and thrombocytopenia were significantly more frequent in patients receiving IL-2 alone than in those treated with IL-3 and IL-2. This preliminary study would suggest that IL-3 may improve the tolerability of IL-2 immunotherapy and enhance the biological antitumour properties of IL-2 by neutralising cortisol increase and macrophage-mediated suppressive events, with a following potential amplification of Il-2 anticancer efficacy.

Aged↗
PubMed1997

A double-blind crossover study comparing prophylactic intravenous granisetron alone or in combination with dexamethasone as antiemetic treatment in controlling nausea and vomiting associated with chemotherapy.

The efficacies of granisetron plus dexamethasone and granisetron alone in controlling nausea and vomiting during two consecutive cycles of moderately emetogenic chemotherapy given for up to 5 days were compared in a two-centre, randomised, double-blind, placebo-controlled crossover study. In all, 110 evaluable patients received either dexamethasone, 20 mg i.v., or matching placebo, plus open-label granisetron, 3 mg i.v., given on each chemotherapy day. At cycle 2, patients crossed over to the alternative treatment; 72 patients completed the crossover. In these 72 patients, the complete response rates over 24 h for granisetron plus dexamethasone and granisetron plus placebo in cycle 1 were 87% and 70% (ns), respectively. In cycle 2 the complete response rates over 24 h were 73% and 62% (ns). Combining the two cycles, the complete response rates over 24 h were 80.6% (granisetron plus dexamethasone) and 65.3% (granisetron plus placebo; P = 0.015). Granisetron plus dexamethasone was significantly more effective in terms of times to less than complete response (P = 0.041), to first episode of moderate/severe nausea (P = 0.04), to first episode of vomiting (0.03) and to use of rescue medication (P = 0.02). Adverse events tended to be minor, with asthenia and insomnia the most common. Of those patients who expressed a preference, 67% preferred granisetron plus dexamethasone (P < 0.05). A single dose of dexamethasone added to granisetron thus enhances the efficacy of granisetron alone in preventing nausea and vomiting after moderately emetogenic chemotherapy.

Adolescent↗
PubMed1997

Higher doses of alpha-interferon do not increase the activity of the weekly cisplatin-interferon combination in advanced malignant mesothelioma.

Management of advanced malignant mesothelioma (MM) still requires innovative systemic therapy as its prognosis is poorly affected by currently available chemotherapy. The combination cisplatin and alpha-interferon (alpha-INF) has synergistic antitumoral activity in preclinical models and interesting activity in phase I-II clinical trials. Weekly CDDP (60 mg/m2) and alpha-IFN (3 MUI/d: d1-d4) in combination was tested in a previous phase I-II study in 23 MM patients, with a 36% objective response rate (ORR). A trial with higher doses of alpha-IFN in the same combination schedule was conducted to explore an incrementalist hypothesis. Thirty patients with MM received the same CDDP dose (60 mg/m2/w) and doubled doses of alpha-IFN (6 MUI/d: d1-d4). The treatment protocol consisted of two cycles of 4 weeks on/4 weeks off followed by two shorter cycles of 3 weeks on/3 weeks off, in the absence of life-threatening toxicity or progressive disease. All patients were evaluable for toxicity. The main treatment-limiting side-effects were digestive intolerance (nausea, vomiting) and severe asthenia. Antitumoral efficacy was not increased (ORR = 27%). Haematological and neurological toxicities were moderate and manageable. The antitumoral activity of the CDDP-alpha-IFN combination with higher doses of the latter is similar to our previous experience, but tolerance issues make it a poorer choice for eventual comparative trials, or as a standard therapeutic indication.

Adult↗
PubMed1998

Weekly docetaxel and concomitant boost radiotherapy for non-small cell lung cancer. A phase I/II dose escalation trial.

In this phase I/II study, we investigated the radiosensitising effects of docetaxel in non-small cell lung cancer (NSCLC). 30 patients with stage IIIb (18 patients) and IV (12 patients) NSCLC were treated with 64 Gy of accelerated chest radiotherapy (5-week schedule using a concomitant boost technique) and docetaxel on a weekly basis. The docetaxel starting dose level was 20 mg/m2/week and was escalated by 10 mg/m2 increments in cohorts of 10 patients. Dose-limiting toxicity (grade 3 asthenia) was observed in 6 of 10 patients treated at the 40 mg/m2/week dose level, enforcing a 50% dose reduction in 4 patients. Grade 3 neutropenia was observed in 5 of 30 patients (17%), 3 of which were treated at the high dose level. Peripheral neuropathy occurred in 3 (10%) patients. A significant decrease in the absolute lymphocyte count was observed in all patients; the nadir was reached on day 28 (mean +/- standard deviation (S.D.) = 539 +/- 363/ml) compared with pretreatment values (mean +/- S.D. = 1842 +/- 863/ml; P = 0.002). 6 out of 30 patients (20%) experienced grade 3 oesophagitis, resulting in a 1-2 week delay in overall treatment time. Complete response of the primary tumour was observed in 8 (27%) patients assessed 2 months after treatment. 4 of these patients had disease resistant to previous docetaxel-containing chemotherapy. A partial response occurred in 15 of 30 patients (50%) for an overall response rate of 77% (95% confidence interval (CI) 60-92%). Radiosensitisation with docetaxel is feasible and the recommended dose for further phase II studies is 30 mg/m2/week. Further phase II studies are required to confirm the remarkably high response rate observed in the present trial.

Adult↗
PubMed1997

Prospects with docetaxel in the treatment of patients with breast cancer.

Docetaxel (Taxotere) has been shown to be one of the most active cytotoxic agents in patients with breast cancer, achieving response rates of 41% when used as second-line treatment for metastatic breast cancer (34% in anthracycline-refractory patients) and 50-72% when used as first-line therapy. In both situations meaningful response durations of 7-8 months have been obtained. Based on these results, docetaxel is a promising candidate for new therapeutic strategies in patients with breast cancer. Studies comparing docetaxel with paclitaxel or anthracyclines in first-line therapy are ongoing. These studies should allow for an unequivocal definition of activity of docetaxel, yet not alter--as such--therapeutic strategies. A number of regimens are currently being explored combining docetaxel with anthracyclines, vinorelbine, 5-fluorouracil, cyclophosphamide and cisplatin. The preliminary conclusions are as follows: the main side-effect is non-cumulative neutropenia of short duration, and response rates are > 75%. Further, no cumulative cardiotoxicity has been observed with doxorubicin. The duration of response and length of the progression-free survival cannot yet be defined. Another option for combination chemotherapy is sequential combinations, the value of which has been demonstrated in advanced breast cancer as well as in the adjuvant setting. The short duration and non-cumulative character of docetaxel-induced neutropenia are good rationales for the use of dose-densified docetaxel-containing regimens. A dose of 100 mg/m2/14 days can be used as single-agent therapy. A phase I trial combining cyclophosphamide at doses increased from 750 to 1200 mg/m2 and docetaxel at doses increased from 66 to 100 mg/m2 every 2 weeks, is ongoing; at the first dose-levels, the combination appears feasible although cumulative asthenia has been observed. Further, responses have been observed at all dose levels. The value of single-agent chemotherapy added to tamoxifen has been emphasised for stage I-II breast cancer in postmenopausal patients. A randomised phase III study comparing tamoxifen (20 mg/day for 5 years) and epirubicin (50 mg/m2 days 1 and 8/28 days for 6 cycles) with the same regimen with epirubicin for 3 months followed by docetaxel (100 mg/m2/21 days x 3) was initiated at the end of 1996. Thus, docetaxel is currently under study in most therapeutic situations to better define its impact on the prognosis and curability of patients with breast cancer.

Antineoplastic Agents, Phytogenic↗