A phase i pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours

Background: The vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours. Methods: Ombrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42 mg m -2 with 75 mg m -2 docetaxel, then from 30 to 35 mg m -2 with 100 mg m -2 docetaxel. Recommended phase II dose cohorts were expanded. Results: Fifty-eight patients were treated. Recommended phase II doses were 35 mg m -2 ombrabulin with 75 mg m -2 docetaxel (35/75 mg m -2; 13 patients) and 30 mg m -2 ombrabulin with 100 mg m -2 docetaxel (30/100 mg m -2; 16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients; 42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/100). Toxicities were consistent with each agent; mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mg m -2 docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mg m -2 ombrabulin), eight lasting >3 months. Conclusions: Sequential administration of ombrabulin with 75 or 100 mg m -2 docetaxel every 3 weeks is feasible

Programmed health surveillance and detection of emerging diseases in occupational health: contribution of the French national occupational disease surveillance and prevention network (RNV3P)

Objective The French national occupational disease surveillance and prevention network (RNV3P) includes the 30 occupational disease consultation centres in university hospitals to which patients are referred for potentially work-related diseases, and an occupational health service. The aim of this work is to demonstrate the contribution of RNV3P to national health surveillance.Methods Data from consultations are recorded in standardised occupational health reports and coded using international or national classifications. Programmed health surveillance is carried out through annual follow-up of annual referrals to experts for pre-selected disease–exposure associations, as well as incidence estimations for the well characterised working population followed by the occupational health service. Hypotheses on new emerging diseases are generated using statistical methods employed in pharmacosurveillance and by modelling as an exposome to analyse multiple exposures. Results 58 777 occupational health reports were collected and analysed from 2001 to 2007. Referrals to the 30 university hospital centres increased significantly for asbestos-related diseases, mood disorders and adjustment disorders related to psychological and organisational demands, and for elbow and shoulder disorders related to manual handling. Referrals significantly decreased for asthma and for rhinitis related to exposure to organic dusts (vegetable or animal) or chemicals, except for cosmetics and cleaning products. Estimation of incidences by the occupational health services showed different patterns in different sectors of activity. The methods for detecting emerging diseases are presented and illustrated using the example of systemic sclerosis, identifying new exposures and new sectors of activity to be investigated. Conclusion The RNV3P collects data from two complementary samples: 30 university hospital centres (workers or former workers) and an occupational health service (current workers). This dual approach is useful for surveillance and for hypothesis generation on new emerging disease–exposure associations

Relationship between job stress, temperament and depressive symptoms in female nurses

Objectives: A casual relationship between temperament, job stress and depressive symptoms has not been established yet. The purpose of this study was to assess the relationships between job stress, temperament and depressive symptoms in female nurses at a Japanese general hospital. Material and Methods: A self-report survey was conducted among 706 nurses. We measured job stress, temperament, and depressive symptoms using the Brief-Job Stress Questionnaire, the TEMPS-A and a screening scale of items from the Ministry of Health, Labour and Welfare of Japan. In order to examine the causal relationship between the measures the stepwise multiple regression and path analyses were used. Results: Depressive symptoms were modestly correlated with job stress (γ = -0.23-0.30). Except for hyperthymic temperament measures, the correlations between depressive symptoms and temperament types were significant and moderate (γ = 0.36-0.50). Overtime, job control as well as depressive and cyclothymic types of temperament were significantly correlated with depressive symptoms (β = 0.15, p < 0.05; β = 0.19, p < 0.01; β = 0.26, p < 0.001; β = 0.32, p < 0.001, respectively). Path-analysis revealed that depressive and cyclothymic types of temperament influenced depressive symptoms both directly (β = 0.67, p < 0.001) and indirectly via job stress (β = 0.35, p < 0.001 from temperament to job stress; β = 0.20, p < 0.05 from job stress to depressive symptoms). Irritable and anxious types of temperament and quantitative job overload did not contri­bute to the path-analytic model. Conclusions: Health care professionals should consider temperament, especially depressive and cyclothymic types, in order to help employees cope better with job stress factors. We need further research about the effective intervention to help employees better cope with their job stress

Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure

This multicentre, randomised phase III study compared docetaxel with 5-fluorouracil+vinorelbine in patients with metastatic breast cancer after failure of neo/adjuvant or one line of palliative anthracycline-based chemotherapy. One hundred and seventy-six metastatic breast cancer patients were randomised to receive docetaxel (100 mg m−2) every 3 weeks or 5-fluorouracil+vinorelbine: 5-fluorouracil (750 mg m−2 per day continuous infusion) D1–5 plus vinorelbine (25 mg m−2) D1 and D5 of each 3-week cycle. Eighty-six patients received 516 cycles of docetaxel; 90 patients received 476 cycles of 5-fluorouracil+vinorelbine. Median time to progression (6.5 vs 5.1 months) and overall survival (16.0 vs 15.0 months) did not differ significantly between the docetaxel and 5-fluorouracil+vinorelbine arms, respectively. Six (7%) complete responses and 31 (36%) partial responses occurred with docetaxel (overall response rate 43%, 95% confidence interval: 32–53%), while 4 (4.4%) complete responses and 31 (34.4%) partial responses occurred with 5-fluorouracil+vinorelbine (overall response rate 38.8%, 95% confidence interval: 29–49%). Main grade 3–4 toxicities were (docetaxel vs 5-fluorouracil+vinorelbine): neutropenia 82% vs 67%; stomatitis 5% vs 40%; febrile neutropenia 13% vs 22%; and infection 2% vs 7%. There was one possible treatment-related death in the docetaxel arm and five with 5-fluorouracil+vinorelbine. In anthracycline-pretreated metastatic breast cancer patients, docetaxel showed comparable efficacy to 5-fluorouracil+vinorelbine, but was less toxic

A systematic review of taxane-containing regimens for metastatic breast cancer

We compared the results of randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing a taxane in women with metastatic breast cancer. The specialised register of the Cochrane Breast Cancer Group was searched in March 2004. Eligibility was assessed and data extracted from eligible studies by two reviewers. Hazard ratios (HR) were derived for time-to-event outcomes, and a fixed-effect model was used for meta-analysis. Tumour response rates were analysed as dichotomous variables. Of 21 eligible trials, 16 had published some results and 12 data on overall survival. An estimated 2621 deaths among 3643 women suggest a significant difference in overall survival in favour of taxane-containing regimens (HR 0.93, 95% confidence interval (CI) 0.86–1.00, P=0.05). The treatment effect on survival was similar if only trials of first-line chemotherapy were included, although not statistically significant. There appeared to be an advantage for taxanes in time to progression (HR 0.92, 95% CI 0.85–0.99, P=0.02) and overall response (odds ratio (OR) 1.34, 95% CI 1.18–1.52, P<0.001). There was significant heterogeneity across the trials (P<0.001), partly because of the varying efficacy of the comparator regimens. Taxane-containing regimens improved overall survival in women with metastatic breast cancer. Taxane-containing regimens are more effective than some, but not all, nontaxane-containing regimens

Health profiles of 996 melanoma survivors: the M. D. Anderson experience

BACKGROUND: The incidence and survival of melanoma are increasing, but little is known about its long-term health effects in adult survivors. METHODS: A health survey was available from 996 melanoma survivors (577 treated with surgery alone, and 391 with combined treatments). Their medical/physiologic and psychosocial responses were analyzed and compared with those of the survivors from other cancers. RESULTS: The melanoma survivors were 44.8 ± 12.8 years of age at diagnosis (significantly younger than the survivors of other cancers) and 63.7 ± 12.8 years at survey. Melanoma survivors were less likely to report that cancer had affected their health than survivors of other cancers (15.8% vs. 34.9%). The 577 individuals treated with surgery alone reported arthritis/osteoporosis, cataracts, and heart problems most frequently (less often than survivors of other cancers). The 391 individuals who had undergone combined treatments reported circulation problems and kidney problems generally as often as survivors of other cancers. Health problems were not associated with number of decades since diagnosis but with age at diagnosis, treatment modality, and family relationships. CONCLUSION: We present information from a large cohort of long-term survivors of melanoma. As a group, they were less likely to report that cancer had affected their overall health than survivors of other cancers; a number of disease related and psychosocial factors appear to influence their health profiles

Sequential or alternating administration of docetaxel (Taxotere®) combined with FEC in metastatic breast cancer: a randomised phase II trial

The aim of this study, using a Fleming single-stage design, was to explore the efficacy and safety of Taxotere® 100 mg m−2 docetaxel and FEC 75 cyclophosphamide 500 mg m−2, fluorouracil 500 mg m−2 and epirubicin 75 mg m−2, in alternating and sequential schedules for the first-line treatment of metastatic breast cancer. One hundred and thirty-six women were randomly allocated, to one of three treatment regimens: DTX 100 plus FEC 75, alternated for eight courses (ALT); four courses of DTX 100 followed by four courses of FEC 75 (SEQ T); or four courses of FEC 75 followed by four courses of DTX 100 (SEQ F). One hundred and thirty-one women were evaluable for tumour response. Although the treatment outcome was equivalent in the two sequential arms and the alternating regimen (P=0.110, not significant), the response rate was less encouraging in the SEQ F arm (52.3%) than in the other two arms (71.1% for ALT and 70.5% for SEQ T), in which docetaxel was administered first. Time to progression was similar in the ALT, SEQ T and SEQ F arms (9.5, 9.3 and 10.4 months respectively). Grade 3–4 neutropenia was observed in nearly all patients; febrile neutropenia occurred in 9% (ALT), 16% (SEQ T) and 2% (SEQ F) of patients. Few patients (⩽9%) developed grade 3–4 non-haematological toxicities. Relative dose intensity was 97–99% for all regimens. All treatment regimens were active and well tolerated