Requiring Discontinuation Of Treatment Research Articles

Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients

Background: Exclusive liver metastases occur in up to 40% of patients with uveal melanoma associated with a median survival of 2–7 months. Single agent response rates with commonly available chemotherapy are below 10%. We have investigated the use of fotemustine via direct intra-arterial hepatic (i.a.h.) administration in patients with uveal melanoma metastases.Patients and methods: A total of 101 patients from seven centers were treated with i.a.h. fotemustine, administered intra-arterially weekly for a 4-week induction period, and then as a maintenance treatment every 3 weeks until disease progression, unacceptable toxicity or patient refusal.Results: A median of eight fotemustine infusions per patient were delivered (range 1–26). Catheter related complications occurred in 23% of patients; however, this required treatment discontinuation in only 10% of the patients. The overall response rate was 36% with a median overall survival of 15 months and a 2-year survival rate of 29%. LDH, time between diagnosis and treatment start and gender were significant predictors of survival.Conclusions: Locoregional treatment with fotemustine is well tolerated and seems to improve outcome of this poor prognosis patient population. Median survival rates are among the longest reported and one-third of the patients are still alive at 2 years.

Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: systematic review and meta-analysis of randomized clinical trials

This study aims to systematically identify and summarize the effects of antifungal prophylaxis in non-neutropenic critically ill adult patients on all-cause mortality and the incidence of invasive fungal infections. Systematic review and meta-analysis of randomized controlled trials in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal or another antifungal agent or regimen in non-neutropenic critically ill adult patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to 2 September 2005) and EMBASE (1980 to week 36, 2005). We also hand-searched reference lists, abstracts of conference proceedings and scientific meetings (1998-2004) and contacted authors of included studies and pharmaceutical manufacturers. The primary outcomes assessed were all-cause mortality and proven invasive fungal infections. Two reviewers independently applied selection criteria, performed quality assessment and extracted data using an intention-to-treat approach. Data were synthesized using the random effects model and expressed as relative risk with 95% confidence intervals. Twelve unique trials (eight comparing fluconazole and four ketoconazole with no antifungal or a non-absorbable agent) involving 1606 randomized patients were included. For both outcomes of total mortality and invasive fungal infections, almost all trials of fluconazole and ketoconazole separately showed a non-significant risk reduction with prophylaxis. When combined, fluconazole/ketoconazole reduced total mortality by one-quarter (relative risk 0.76, 95% confidence interval 0.59-0.97) and invasive fungal infections by about one-half (relative risk 0.46, 95% confidence interval 0.31-0.68). No significant increase in the incidence of infection or colonization with the azole-resistant fungal pathogens Candida glabrata or Candida krusei was demonstrated, although the confidence intervals of the summary effect measures were wide. Adverse effects requiring treatment discontinuation were not more common amongst patients receiving prophylaxis. Results across all trials were homogeneous despite considerable heterogeneity in clinical and methodological characteristics. Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one-half and total mortality by one-quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.

Pegylated interferon α-2b plus ribavirin for the treatment of chronic hepatitis C in HIV-coinfected patients

HIV-coinfection accelerates the course of HCV-related liver disease. Since, highly active anti-retroviral therapy significantly improved survival of HIV-patients more coinfected patients develop end stage liver disease. Therefore, treatment options for chronic hepatitis C in HIV-coinfected patients need to be evaluated. Efficacy and safety of pegylated interferon alpha-2b (peg IFN) plus ribavirin (RBV) was examined within this prospective, uncontrolled, multicentre trial. Patients received peg IFN (1.5 microg/kg) once weekly plus RBV 800 mg daily for 48 weeks for HCV genotypes (GT) 1/4 and 24 weeks for GT 2/3. One hundred and twenty-two patients were enrolled. Patients were predominantly male (68%) and former i.v. drug users (61%). Baseline characteristics (median) were as follows: age 39 years (range 23-58), CD4 count 494 cells/microl (range 150-1578/microl), HIV-RNA 2.3log copies/ml (range <1.7-5.4log copies/ml). 61% currently received anti-retroviral treatment. Fifty-six percent had HCV GT 1. EOT response was achieved by 52%. However, only 25% achieved sustained response (SR) due to a high relapse rate. SR rates were significantly higher among patients with GT 2/3 compared to those with GT 1/4 (44 vs. 18%). SR was observed in only one patient without early response (ER). Discontinuation rate was 30%, 21% discontinued due to adverse events. Peg IFN/RBV appears safe and effective in HIV/HCV-coinfected patients. GT 2/3 is associated with better SR. Lack of ER strongly predicts non-response. High relapse rates substantially reduce treatment success. In terms of toxicity neuro-psychiatric side effects frequently required treatment discontinuation.

Shock wave therapy for lateral elbow pain.

This review is one in a series of reviews of interventions for lateral elbow pain. To determine the effectiveness and safety of extracorporeal shock wave therapy (ESWT) for lateral elbow pain. Searches of the Cochrane Controlled Trials Register (Cochrane Library Issue 2, 2004), MEDLINE, EMBASE, CINAHL, and Science Citation Index (SCISEARCH) were conducted in February 2005, unrestricted by date. We included nine trials that randomised 1006 participants to ESWT or placebo and one trial that randomised 93 participants to ESWT or steroid injection. For each trial two independent reviewers assessed the methodological quality and extracted data. Methodological quality criteria included appropriate randomisation, allocation concealment, blinding, number lost to follow up and intention to treat analysis. Where appropriate, pooled analyses were performed. If there was significant heterogeneity between studies or the data reported did not allow statistical pooling, individual trial results were described in the text. Eleven of the 13 pooled analyses found no significant benefit of ESWT over placebo. For example, the weighted mean difference for improvement in pain (on a 100-point scale) from baseline to 4-6 weeks from a pooled analysis of three trials (446 participants) was -9.42 (95% CI -20.70 to 1.86) and the weighted mean difference for improvement in pain (on a 100-point scale) provoked by resisted wrist extension (Thomsen test) from baseline to 12 weeks from a pooled analysis of three trials (455 participants) was -9.04 (95% CI -19.37 to 1.28). Two pooled results favoured ESWT. For example, the pooled relative risk of treatment success (at least 50% improvement in pain with resisted wrist extension at 12 weeks) for ESWT in comparison to placebo from a pooled analysis of two trials (192 participants) was 2.2 (95% CI 1.55 to 3.12). However this finding was not supported by the results of four other individual trials that were unable to be pooled. Steroid injection was more effective than ESWT at 3 months after the end of treatment assessed by a reduction of pain of 50% from baseline (21/25 (84%) versus 29/48 (60%), p<0.05). Minimal adverse effects of ESWT were reported. Most commonly these were transient pain, reddening of the skin and nausea and in most cases did not require treatment discontinuation or dosage adjustment. Based upon systematic review of nine placebo-controlled trials involving 1006 participants, there is "Platinum" level evidence that shock wave therapy provides little or no benefit in terms of pain and function in lateral elbow pain. There is "Silver" level evidence based upon one trial involving 93 participants that steroid injection may be more effective than ESWT.

Pegylated Liposomal Doxorubicin and Cyclophosphamide as First-Line Therapy for Patients with Metastatic or Recurrent Breast Cancer

Purpose Pegylated liposomal doxorubicin (PLD) is an active agent for breast cancer. The efficacy and safety of PLD in combination with cyclophosphamide as first-line treatment of metastatic breast cancer (MBC) was evaluated in this phase II study. Patients and Methods Eligible patients had metastatic or recurrent breast cancer with no previous chemotherapy for metastatic disease. Patients were enrolled into 3 sequential cohorts: cohort I (n = 10) received PLD 50 mg/m 2 intravenously (I.V.) on day 1 and cyclophosphamide 100 mg/m 2 orally on days 1–14 every 28-day cycle; cohort II (n = 20) received PLD 30 mg/m 2 plus cyclophosphamide 600 mg/m 2 I.V. on day 1 every 21 days; and cohort III (n = 21) received PLD 35 mg/m 2 plus cyclophosphamide 600 mg/m 2 I.V. on day 1 every 21 days. Results An objective response was exhibited in 26 of 51 patients (4 complete responses [CRs], 22 partial responses [PRs]; 51%) in the intent-to-treat population and responses were similar among cohorts. The clinical benefit rate (CR plus PR plus stable disease) was 86%. The median duration of response was 35.1 weeks. The most common adverse events were nausea (71%), asthenia (69%), and neutropenia (67%). There was less toxicity in cohort II than in other cohorts. No clinical cardiac toxicity was observed. Only 2 of 20 patients in cohort II (10%) required treatment discontinuation as a result of adverse events. Conclusion First-line combination therapy with PLD and cyclophosphamide is active and well tolerated in patients with MBC. The recommended doses from this study are PLD 30 mg/m 2 and cyclophosphamide 600 mg/m 2 I.V. every 21 days.

Utilisation and Safety of Bemiparin, a??Low-Molecular-Weight Heparin, in??Medical Patients

Venous thromboembolism (VTE) is the cause of approximately 10-12% of all deaths occurring in hospitalised patients. In a previous study, bemiparin suppressed markers of hypercoagulability in acutely ill medical patients with heart failure. To estimate the rate of symptomatic VTE, bleeding events, thrombocytopenia and death in acutely ill medical patients treated with low and high prophylactic doses of bemiparin in standard clinical practice. This was a prospective, open, multicentre, non-randomised cohort study. Acutely ill patients hospitalised in medical departments were included and treated with bemiparin 2500 IU/day or 3500 IU/day, depending on the degree of VTE risk (moderate or high) as assessed by the investigator. The main efficacy and safety endpoints were: symptomatic confirmed VTE (deep vein thrombosis and pulmonary embolism), major bleeding, thrombocytopenia and death. The observation period was 41 days. A total of 297 medical patients hospitalised for several reasons (lung disease: 87 [29.3%], heart disease: 80 [26.9%], neurological disease 25 [8.4%], gastrointestinal disease: 18 [6.1%], rheumatic disorder: 14 [4.7%], haematological disease: 11 [3.7%], renal disease: 8 [2.7%], other: 54 [18.2%]) were included from 13 centres in Spain. The median age of the patients included was 78 years (range 31-100). Overall, 208 patients received bemiparin 2500 IU/day and 89 patients received bemiparin 3500 IU/day. There was one case of symptomatic VTE in 297 patients (0.3%). Four patients (1.3%) experienced a major bleeding event. There were two cases (0.7%) of mild-moderate type I heparin-induced thrombocytopenia (HIT) during the treatment period that did not require treatment discontinuation. There were no cases of severe type II HIT. A total of 22 (7.4%) patients died during the treatment period as a result of factors unrelated to VTE. Bemiparin appears to be effective and safe in the prevention of VTE in acutely ill medical patients.

Erectile dysfunction in essential arterial hypertension and effects of sildenafil: results of a Spanish national study

Background The aim of this study was to establish the prevalence of erectile dysfunction (ED) in hypertensive patients in specialized care hypertension units (SCHUs) and to assess the effectiveness and tolerability of sildenafil treatment. Methods This was a multicenter, prospective, open, observational pharmacoepidemiology study conducted in 25 Spanish SCHUs. A total of 2130 men with essential hypertension under treatment were recruited. In a second phase, 291 subjects with a score ≤ 21 in the Sexual Health Inventory for Men (SHIM) received sildenafil (50 mg/day) as required 30 to 60 minutes before sexual activity, and were evaluated by the International Index of Erectile Function (IIEF). Results A total of 975 subjects (45.8%) had a score ≤ 21 in the SHIM. In the second phase, sildenafil improved the score in the erectile function domain in 232 patients (83.2%). Severity of ED significantly improved ( P < .001); severe (22.3% to 7.7%), moderate (23% to 5.6%), and mild impairment (36.3% to 44.8%). The IIEF was normalized in 39.1% of patients who completed post-treatment IIEF. In all, 33 subjects (11.8%) failed to complete the study: two (0.7%) because of lack of efficacy, two (0.7%) intercurrent disease, 10 (3.6%) failure to return to the visits, three (1.1%) fear of therapy, four (1.4%) adverse effects requiring treatment discontinuation, and 12 (4.3%) protocol violations. No statistically significant association was found between the prevalence of adverse effects and antihypertensive treatment with single drug or combination therapy. Conclusions A high incidence of ED was found in hypertensive patients from Spanish SCHUs. Sildenafil showed an excellent response and safety profile.

Evaluation of montelukast in 8 to 14 year old children with mild persistent asthma and compared with inhaled corticosteroids

ObjectivesTo determine the clinical effectiveness, tolerability and reliability of montelukast and to compare this drug with inhaled corticosteroids MethodsWe performed a randomized, 14-week, 2-period, prospective parallel group study. After a 2-week run-in period, patients received treatment for 12 weeks. Sixty-three clinically stable outpatients aged 8 to 14 years with a history of mild persistent asthma for at least 1 year and a forced expiratory volume in one second (FEV1) greater than 80 % of the predicted value were evaluated ResultsMontelukast produced improvement in airway obstruction, daily symptom scores, total daily as-needed β-agonist use, nocturnal awakenings, percentage of days and percentage of patients with asthma exacerbations, and urinary leukotriene E4 levels. These beneficial effects were similar to those produced by inhaled corticosteroids. There were no significant adverse effects requiring treatment discontinuation ConclusionsMontelukast may be a well-tolerated and effective therapeutic option in 8 to 14-year-old patients with mild persistent asthma

Celecoxib versus indomethacin in the prevention of heterotopic ossification after total hip arthroplasty

A cyclo-oxygenase (COX)-1 and COX-2 inhibitor (indomethacin) and a selective COX-2 inhibitor (celecoxib) were compared in the prevention of heterotopic ossification after total hip arthroplasty. In 250 patients receiving indomethacin and in 150 patients receiving celecoxib for 20 days after surgery, an overall incidence of heterotopic ossification of 17.5% and 14.3% was seen, respectively (difference not statistically significant: P > .05). No grade III or IV ossifications were seen in either group. Twenty-one patients in the indomethacin group (8.4%) and 3 patients in the celecoxib group (2.0%) required treatment discontinuation, because of side effects ( P < .05). Celecoxib, a selective COX-2 inhibitor, shows the same efficacy as indomethacin in the prevention of heterotopic ossification after hip prosthesis with significantly fewer side effects.

Phase I–II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma

BackgroundThe aim of this study was to determine the toxicity profile, the recommended dose (RD) and the pharmacokinetic parameters, and to evaluate the antitumor activity of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer (NSCLC) and ovarian carcinoma (OC). MethodsGemcitabine was administered as a 30-min infusion followed by a 2-h infusion of oxaliplatin, repeated every 2 weeks. Doses of gemcitabine and oxaliplatin ranged from 800 to 1500 and 70 to 100 mg/m2, respectively. ResultsForty-four patients (26 males, 18 females; median age 55 years) including 35 NSCLC (five platinum pretreated) and nine OC patients (all platinum pretreated) received a total of 355 cycles. All patients were evaluable for toxicity. No dose-limiting toxicity at any dose level occurred during the first two cycles; therefore, the highest dose-level of gemcitabine (1500 mg/m2) and oxaliplatin (85 mg/m2) was considered as the RD. Hematological toxicity was moderate amongst the 22 patients treated(167 cycles) at that dose level. Thirteen cycles were associated with grade 3–4 non-febrile neutropenia in six patients, and eight cycles with grade 3–4 thrombocytopenia in two patients. Other toxicities were mild to moderate, consisting of asthenia and peripheral neurotoxicity. Four of the 35 patients treated with oxaliplatin 85 mg/m2 experienced grade 3 neurotoxicity requiring treatment discontinuation at cycle 10. In the range of the doses used, gemcitabine and its main metabolite 2′,2′-difluorodeoxyuridine appeared not to be affected by oxaliplatin 70–100 mg/m2. Of the 44 patients evaluable for activity, 12 NSCLC patients experienced objective responses (one complete and 11 partial responses) and three OC patients showed tumor stabilization lasting for 6 months with a 50% decrease of CA 125 level. Two partial responses (NSCLC) and one tumor stabilization (OC) occurred in platinum-resistant patients. ConclusionsThe combination of gemcitabine and oxaliplatin could be safely administered on an out-patient schedule in patients with advanced NSCLC and OC. The RD was gemcitabine 1500 mg/m2 and oxaliplatin 85 mg/m2 every 2 weeks. Promising antitumor activity was reported in patients with NSCLC and platinum-pretreated OC, and thus, deserves further evaluation.

Selective serotonin reuptake inhibitors in children and adolescents.

This article will review the tolerability, side effects, and effectiveness of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents. We aimed to familiarise the readers with the available data on the pharmacological treatment of childhood psychiatric disorders, especially of depressive disorder and obsessive compulsive disorder. Tricyclic antidepressants (TCAs) have questionable efficacy, definite problems with safety (e.g., cardiotoxicity, lethality in overdose, anticholinergic side effects), and compliance issues. Therefore it is suggested suggest that SSRIs should be the first-line treatment for these disorders in children and adolescents. Studies have shown a significant clinical response to SSRIs and their efficiency has been demonstrated in open and controlled trials. It is often recommended that clinicians should start low and go slow when using SSRIs, and maintain the patient in a symptom-free state for at least six months. The side effects of SSRIs are generally mild, manageable, and seldom require discontinuation of treatment. Children should be monitored closely for infrequent side effects such as gastrointestinal upset, headache, and behavioural activation which may be as severe as mania. There is a great need for controlled trials in childhood psychiatric disorders, especially in anxiety disorders.

Thalidomide in refractory and relapsing multiple myeloma

Patients with multiple myeloma (MM) refractory to chemotherapy can only benefit from supportive measures and have a very short survival. Thalidomide has recently shown antitumor activity in patients with refractory myeloma. Twenty-three patients (12 men and 11 women; median age, 72 years) with advanced MM were treated with thalidomide. Sixteen patients had refractory disease and seven had untested relapse. The median dose of thalidomide was 400 mg d (range, 200 to 800 mg/d). The drug was generally administered in two divided doses. Five patients required treatment discontinuation because of toxicity. Twelve of 23 patients (52%) responded. Three (13%) achieved a partial response, with greater than 50% reduction in serum monoclonal (M)-protein levels, and nine (39%) attained a minimal response, with a greater than 25% decrease in serum M-protein levels. No decrease in the size of soft tissue plasmacytomas was observed in six patients with extramedullary involvement.

Four cases of tendinopathy in patients on statin therapy

During the last decade, statins have been widely prescribed as lipid-lowering drugs. Their overall safety profile is good. The main musculoskeletal side effects have consisted of muscle pain and weakness, peripheral neuropathy, and a few cases of drug-induced lupus. We report the first four cases of tendinopathy in patients receiving statin therapy. There were three men and one woman. The diagnoses were extensor tenosynovitis at the hands (case 1), tenosynovitis of the tibialis anterior tendon (case 2), and Achilles tendinopathy (cases 3 and 4). Two patients were on simvastatin and two on atorvastatin. The tendinopathy developed 1 to 2 months after treatment initiation. The outcome was consistently favorable within 1 to 2 months after discontinuation of the drug. Similar cases have been reported to French pharmacovigilance centers. This report of four cases of tendinopathy draws attention to a possible and heretofore unrecognized side effect of a drug class that is becoming increasingly popular. Statins are effective in lowering high cholesterol levels in patients with type IIa or IIb hypercholesterolemia. They have been widely used for the last decade, particularly in the secondary and primary prevention of major coronary events. Statins act by inhibiting the enzyme hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Although most patients tolerate statins extremely well, a few experience side effects requiring treatment discontinuation. Reported musculoskeletal side effects include myalgia and a few cases of rhabdomyolysis and polymyositis. Induced lupus and peripheral neuropathy are exceedingly rare.

High-Dose Epirubicin in the Prophylactic Treatment of T1G2 Superficial Bladder Tumors

Objectives: To evaluate the activity and safety of intravesical instillations of 80 mg epirubicin in a selected patient population with T1G2 primary and multiple superficial bladder tumors. To assess the completeness of the transurethral resection (TUR) at 4 weeks (second look) and to compare the histology of local and review pathology. Methods: One hundred and sixty-nine patients have been histologically assessed both locally and extramurally for T1G2 superficial bladder tumors. Epirubicin (80 mg/instillation) started within 20 days after TUR was administered weekly during the first month and then monthly for another 11 months. Assessments for relapse were carried out according to the standard methods. Results: Histological consistency for T1G2 between local and extramural assessments was found in 85.2% of cases. At the median follow-up time of 38 months, the overall relapse rate was 43.3%. Treatment was very well tolerated: no systemic adverse events were reported and local adverse events were confined to chemical cystitis which in 3% required treatment discontinuation. Conclusions: Epirubicin (80 mg/instillation) appeared effective in the prophylaxis of relapse in primary and multiple T1G2 superficial bladder tumors. A second TUR at 3–4 weeks is necessary in T1 tumors. Excellent concordance between local and review pathology was found.

Litotricia extracorpórea por ondas de choque: ansiedad y percepción del dolor

Three factors in extracorporeal shock-wave lithotripsy (ESWL) result in pain: shock wave pressure, size of focal area and pressure distribution at entry in the skin. Our Lithotripsy Unit has performed 21,000 outpatient treatments (Dornier HM-4 Lithotripter) with no sedation or anaesthetics. Pain requiring treatment discontinuation resulted in 10% instances. Anxiety-associated pain increases the perceived intensity of pain and influences the emotional response to pain. ObjectiveTo determine whether the variability in the response to the pain stimulus caused by ESWL is related to the patient's status/trait of anxiety.METHOD: Sample 20 patients; inclusion criteria: pyelic lithiasis > 2 cm, no previous SWEL and no obesity. One SWEL session (2500 pulses, 22 Kv). Anxiety was first evaluated using the status/trait of anxiety index (STAI) questionnaire; after treatment, pain was evaluated on a Numerical Analogic Scale. ResultsPain scores ranged from 2 to 8, mean score 4.1 (S.D. = 1.67); mean score for trait of anxiety 21.8 (S.D. = 8.52), and status of anxiety 29 (S.D. = 5.89). A significant correlation was found between pain-anxiety trait (R =.51; p =.02), which was higher when compared to pain-anxiety status (R =.67; p =.001). ConclusionsSWEL is a painful therapy (95% of sample had mild-to-moderate pain); pain perception is increased by status of anxiety (45% of pain variance) more than by the trait of anxiety (26.3%); therefore, usage of sedation-analgesia in patients with high anxiety status would improve the lithotripter efficacy ratio.

Relapse and Survival After Barbiturate Anesthetic Treatment of Refractory Status Epilepticus

Pentobarbital is standard treatment for refractory status epilepticus (SE) and is almost uniformly effective, but the morbidity of treatment and the mortality of refractory SE are high. Recurrence of SE after pentobarbital discontinuation may predict a worsened outcome. We sought to determine the optimal use of barbiturate anesthetic treatment of refractory SE. We reviewed 44 episodes of barbiturate anesthetic treatment for refractory SE in 40 patients, seeking factors predicting freedom from relapse to clinical or electrographic SE after treatment and predicting survival. Eight of 9 patients with relapse of seizures after barbiturate treatment died, whereas only 9 of 26 with persistently controlled seizures died (p < 0.005). Both likelihood of relapse and survival correlated strongly with etiology, with 19 of 20 patients with chronic epilepsy, infections, or focal lesions having good control as compared with 2 of 9 with multiple medical problems (p < 0.001). Treatment delay did not predict a worsened outcome. Hypotension caused dose reduction but never required treatment discontinuation. Patients with more prolonged treatment and those receiving phenobarbital (PB) at the time of pentobarbital taper were less likely to relapse. Relapse of SE after barbiturate anesthetic treatment is a poor prognostic sign and should be prevented, if possible. Etiology was the primary predictor of outcome, but more prolonged treatment and the use of PB during pentobarbital withdrawal appeared to provide protection against relapse.

Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer.

The objective of this multicenter study was to compare the therapeutic index of two different doses of paclitaxel given as a 3-hour infusion in patients with metastatic breast cancer (MBC), who had failed to respond to previous chemotherapy. A total of 471 patients with MBC were randomized to receive intravenous paclitaxel at a dose of 175 or 135 mg/m2 every 3 weeks. Better treatment results were achieved with high-dose (HD) versus low-dose (LD) paclitaxel: overall response rate, 29% versus 22% (P = .108); complete response (CR) rate, 5% versus 2% (P = .088); median time to disease progression, 4.2 versus 3.0 months (P = .027); and median survival time, 11.7 versus 10.5 months (P = .321). Patients previously exposed or resistant to anthracyclines were as likely to respond as those without such prior exposure. Treatment was well tolerated, as documented by the number of administered treatment courses (median, six v five; range, one 17 v one to 18), the low frequency of dose reductions (14% v 7%, P = .024), and the small number of patients (n = 9 or 4% vn = 5 or 2%) who required treatment discontinuation for adverse reactions. The incidence and severity of neutropenia and peripheral neuropathy were dose-related. After quality-of-life-adjusted time-to-progression analysis, the HD arm (175 mg/m2) retained its advantage over the LD arm (135 mg/m2). The results of this trial substantiate the activity of paclitaxel in the treatment of MBC. The observed superior efficacy with a dose of 175 mg/m2 over 135 mg/m2 suggests a dose-effect relationship. The clinical activity in anthracycline-resistant patients is particularly noteworthy. Paclitaxel in breast cancer needs further evaluation in large trials that use combination chemotherapy and involve earlier disease stages.

Vinorelbine and epirubicin in metastatic breast cancer. A dose finding study

The aim of the study was to define the maximum tolerated dose (MTD) of vinorelbine given as one or two weekly doses in combination with epirubicin 60 mg/m2 every third week. The MTD was defined as the dose resulting in a WHO grade III or IV leucopenia exceeding 50% of patients. Patients were treated in groups of 10 at escalating doses of vinorelbine. The number of patients at the final dose level was expanded to 20. The dose of epirubicin was kept constant at 60 mg/m2 every third week. At dose level 1, 15 mg/m2 vinorelbine was given on day 1 at level 2, 20 mg/m2 was given on day 1 and at level 3, 20 mg/m2 was given on days 1 and 8. The MTD was reached at dose level 3. WHO haematological toxicity grade IV occurred in 0, 10 and 45% and grade III at 60, 30 and 30% of patients at dose levels 1, 2 and 3, respectively. Despite the common occurrence of grade IV haematological toxicity, only two serious infections were noted. Non-haematological toxicity of vinorelbine included neurotoxicity, manifesting as muscle weakness, constipation and paresthesias in the majority of patients. Neurotoxicity was usually mild and did not require treatment discontinuation. Phlebitis at the injection site was troublesome in many patients. Alopecia and nausea, probably due to epirubicin, occurred in most patients. The response rates were 22% (95% CI (confidence interval) 3-60%), 40% (12-74%) and 60% (36-81%) at levels 1, 2 and 3, respectively (non-significant).

Home treatment with interleukin 2 and beta-interferon in patients with colorectal cancer and hepatocellular carcinoma.

Biological response modifiers have been extensively investigated in the management of patients with cancer, but few data are available on tumors of the gastrointestinal tracts. To evaluate the feasibility and activity of the combination of interleukin 2 (IL-2) and beta-interferon (beta-IFN), 15 patients with colorectal cancer and 10 patients with hepatocellular carcinoma were treated with the following outpatient schedule: beta-IFN 3 x 10(6) U i.m. 3 times weekly from day 1 to day 14; IL-2 4.5 x 10(6) U s.c. every 12 for 5 consecutive days a week from day 7 to day 21, the cycles being repeated every 28 days. All of the patients had been previously treated with chemotherapy; 7 unresectable locally advanced, and 18 had metastatic disease. All of the treatment courses were administered in an outpatient setting. No grade 4 side effects were recorded. The worst side effects were grade 3 fever (4 patients) and asthenia (2 patients) requiring treatment discontinuation in 4 cases. Twenty-four patients were evaluated for response (14 with colorectal cancer and 10 with hepatocellular carcinoma). One partial response, 4 stable disease, 9 progressive disease were recorded among the colorectal patients; 4 stable disease and 6 progressive disease among the hepatocellular carcinoma patients. The median duration of stable disease was 3 months for hepatocellular carcinoma and 4 months for colorectal cancer patients. Our results suggest that the schedule is feasible in an outpatient setting. Its limited hematological toxicity makes it suitable to be combined with cytotoxic drugs.

Terlipressin or vasopressin plus transdermal nitroglycerin in a treatment strategy for digestive bleeding in cirrhosis: A randomized clinical trial

Between 1988 and 1990 an unblinded, randomized trial of terlipressin or vasopressin plus transdermal nitroglycerin, as part of a treatment strategy including emergency sclerotherapy for actively bleeding varices, was conducted during 165 admissions in 137 patients with cirrhosis and upper digestive bleeding. Eighty-four patient admissions were assigned to terlipressin (2 mg every 6 h) and 81 to vasopressin (0.4 to 0.8 unit per min) plus transdermal nitroglycerin (20 to 80 mg). The two groups were comparable for relevant clinical data, but there were slightly more patients with hepatocellular carcinoma or terminal conditions in the terlipressin group. After the 24-h study period, failure to control bleeding was 20/84 (25%) in the vasopressin and 14/81 (17%) in the terlipressin group (p = 0.19). Corresponding figures for patients bleeding from varices (emergency sclerotherapy in 43 and 45, respectively) were 13/55 (24%) and 5/56 (9%; p = 0.035), from other sources 5/16 (31%) and 2/15 (13%; p = 0.23), from undefined sources 2/10 (20%) and 7/13 (54%; p = 0.1). In a logistic multivariate regression model the odds ratio for terlipressin adjusted for prognostic factors was 0.45 (p = 0.07). There were seven major side effects requiring treatment discontinuation in the vasopressin and one in the terlipressin group. These results suggest that terlipressin alone is as effective as vasopressin plus transdermal nitroglycerin, with less severe side effects, in 24-h control of upper gastrointestinal bleeding in patients with cirrhosis.