The impact of patient management guidelines on the care of breast, colorectal, and ovarian cancer patients in Italy

The impact of a national education program based on the dissemination of written guidelines for the treatment of breast, colorectal, and ovarian cancer was investigated in Italy. Through a survey of 770 physicians exploring their knowledge and attitudes and a review of medical records of 1,483 patients assessing current clinical practice, this study examined whether 1) the guidelines reached the target population of physicians, 2) they were effective in shaping doctors' opinions, and 3) care patterns conformed with the guidelines. Overall, the net effect of the intervention appeared to be limited in terms of actual diffusion, attributable influence, and impact. As for diffusion, only 60%, 47%, and 44% of doctors were aware of breast, colorectal, and ovarian cancer guidelines, respectively. Although doctors who were aware of the guidelines had more appropriate opinions than those who were not, overall agreement with recommendations was often unsatisfactory. With reference to guidelines recommendations, quality of care was far from optimal, especially in relation to diagnosis and staging. Marked variations in compliance with recommendations emerged with values ranging from 37% to 89%, from 48% to 82%, and from 10% to 97% for breast, colorectal, and ovarian cancer, respectively, and this held true even in hospitals where the larger awareness of the guidelines might have been expected to result in better quality care. It was concluded that any thorough assessment of the impact of educational interventions should include a careful analysis of the strategy and process of dissemination. The availability of clinically relevant messages must also be realistically considered before deciding whether the "guidelines approach" is the strategy most likely to succeed.     

Spiromustine: a new agent entering clinical trials

Investigational New Drugs - Spiromustine is a new alkylating agent, of interest since it was rationally designed as a lipophilic compound capable of penetrating the CNS. This lipophilicity may also...     

Phase IB and pharmacological study of the novel taxane BMS-184476 in combination with doxorubicin

The aim of this study was to define the maximum tolerated dose (MTD) and the pharmacological profile of the paclitaxel analogue BMS-184476 given once every 3 weeks, or on days 1 and 8 every 3 weeks (d1&8), in combination with a fixed dose of 50 mg/m(2) of Doxorubicin (Doxo) administered on day 1 of a 21-day cycle. Adult patients with advanced solid malignancies received escalating doses of BMS-184476 infused over 1 h after bolus Doxo. Pharmacokinetics (PK) of BMS-184476, Doxo and metabolites were investigated. The effect of BMS-184476 on doxorubicinol formation was studied in the cytosol from human myocardium. The MTD of 3-weekly BMS-184476 was 30 mg/m(2). The MTD/recommended Phase II dose was 35 mg/m(2)/week (70 mg/m(2) per cycle) in the d1&8 schedule. The dose-limiting toxicity was neutropenia for both schedules. Other toxicities were loss of appetite, asthenia, and mild, cumulative peripheral neuropathy. The objective response rate in 17 previously untreated or minimally pretreated patients with breast cancer treated at 35 mg/m(2)/week of BMS-184476 was 59% (95% Confidence Interval (CI): 33-82%). Two of the 7 patients not responding to the study regimen later responded to Doxo and paclitaxel. Plasma disposition of BMS-184476 at 30, 35 and 40 mg/m(2) was linear without evidence of a PK interaction with Doxo. In studies with cytosol from human myocardium, the formation of cardiotoxic doxorubicinol was not enhanced by BMS-184476. Dosing of BMS-184476 for 2 consecutive weeks allowed the administration of larger doses of the taxane with a promising antitumour activity in patients with untreated or minimally pretreated breast cancer. The higher than expected myelotoxicity of the 3-weekly schedule is unexplained by the investigated interactions. Lack of enhanced doxorubicinol formation in human myocardium is consistent with the cardiac safety of the regimen.     

Amsacrine-associated cardiotoxicity: an analysis of 82 cases

Amsacrine is an antileukemia drug being widely used in North America, Europe, Australia, and New Zealand. In the initial clinical trials, patients treated with amsacrine developed occasional instances of acute cardiac arrhythmias and cardiomyopathy. We review and analyze the features of cardiac abnormalities associated with amsacrine in 82 patients, 27 of whom have not been previously reported. The rest have been reported in the literature, but we have included a large amount of additional information about these patients in our analysis. We conclude that amsacrine-related cardiac events are less common than those related to anthracycline chemotherapeutic agents. Manifestations of such toxicity include ECG abnormalities, ventricular and atrial arrhythmias, sudden death, and congestive heart failure. There is little or no cumulative dose effect. Hypokalemia may be a risk factor for development of serious tachyarrhythmias, but such problems can occur despite a normal serum potassium level. Amsacrine appears to affect depolarization and repolarization of the heart, but the mechanism is unknown.     

The impact of cancer treatment guidelines on actual practice in Italian general hospitals: the case of ovarian cancer

Over the past ten years the Italian National Research Council (C.N.R.) has carried out an educational program based on the preparation and dissemination of guidelines to facilitate delivery in community hospitals of the most up-to-date care to patients with ovarian cancer. In 1988 an assessment was begun to determine (a) whether the guidelines reached the target physician population; (b) whether they were accepted by those they reached, and (c) whether treatment patterns thereafter conformed to the guidelines. Overall results of this evaluation provide no evidence of clinically relevant effects of the program. The guidelines were not widely disseminated: only 44% of responders were aware of them. Moreover, analysis of practice patterns showed serious deficiencies in diagnostic procedure and surgical staging (information on grading and residual tumour was available only in 30% and 45% of cases, respectively, and only 10% of the patients had random biopsies as part of their surgical staging). The only observation supporting some effect of this educational intervention in terms of knowledge modification was of certain therapeutic preferences among those aware of the guidelines. This finding, however, is highly susceptible to confounding by other factors (e.g. physicians' greater expertise, spillover effect of the program) not entirely avoidable in an observational study. We conclude that any assessment of procedures based on dissemination of information must include a careful analysis of the method of dissemination. The availability of clinically applicable information must also be realistically appraised before the guidelines approach can be accepted as the most effective.     

Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex

Objectives:To define the maximum tolerated dose (MTD), thetoxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. Patients and methods:Fourteen patients with advanced solid tumorsnot responsive to previous antitumor treatments received BBR 3464 on a daily× 5 schedule every twenty-eighth day. The drug was given as a one-hourinfusion with pre-and post-treatment hydration (500 ml in one hour) and noantiemetic prophylaxis. The starting dose was 0.03 mg/m²/day. Amodified accelerated titration escalation design was used. Total and freeplatinum (Pt) concentrations in plasma and urine were assessed by ICP-MS ondays 1 and 5 of the first cycle. Results:Dose was escalated four times up to 0.17mg/m²/day. Short-lasting neutropenia and diarrhea of late onsetwere dose-limiting and defined the MTD at 0.12 mg/m². Nausea andvomiting were rare, neither neuro- nor renal toxic effects were observed.BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-lifeof several days. At 0.17 mg/m² plasma Cmax and AUC on day 5 werehigher than on day 1, indicating drug accumulation. Approximately 10%of the equivalent dose of BBR3464 (2.2%–13.4%) wasrecovered in a 24-hour urine collection. Conclusions:The higher than expected incidence of neutropenia andGI toxicity might be related to the prolonged half-life and accumulation oftotal and free Pt after daily administrations. Lack of nephrotoxicity and thelow urinary excretion support the use of the drug without hydration. Thesingle intermittent schedule has been selected for clinical development.     

Personalized therapeutic strategies in HER2-driven gastric cancer

Gastric Cancer - Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them...     

Incidence, risk factors and clinical implications of venous thromboembolism in cancer patients treated within the context of phase I studies: the 'SENDO experience'

BackgroundTo investigate the incidence, risk factors and clinical implications of venous thromboembolism (VTE) in advanced cancer patients treated in phase I studies.Patients and methodsPatients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organization) Foundation between 2000 and 2010 in 15 experimental centers were considered for the study. Clinical data, including adverse events, were prospectively collected during the studies and retrospectively pooled for VTE analysis.ResultsData of 1415 patients were considered for analysis. Five hundred and twenty-six (37.2%) patients were males, and median age was 57.3 years (range: 13–85). Eighty-five percent of patients had metastatic disease, while the remaining had locally advanced irresectable disease. For 706 (49.9%) of the patients, the study treatment was with cytotoxic agent(s) only, for 314 with target therapy(ies) only, while the remaining patients received a target therapy in combination with a cytotoxic drug. Fifty-six (3.96%) patients who developed a VTE, almost all (89.3%) during the course of treatment, the remaining during the follow-up. At univariate analysis, the Khorana score, the combination of an antiangiogenic agent with a cytotoxic drug, and the time from first cancer diagnosis to study entry (as continuous variable) were associated with a statistically significant increase of VTE occurrence. The multivariate analysis confirmed only a statistically significant association for the Khorana score. The hazard ratio of VTE occurrence was 7.88 [95% confidence interval (CI) 2.86–21.70) and 2.74 (95% CI 1.27–5.92) times higher for the highest (≥3) and intermediate (1–2) scores as compared with score = 0.ConclusionsVTE is a relatively common complication among patients treated in the context of phase I studies. The Khorana score predicts VTE development and can be used to identify patients at high of VTE.