Second- and third-line chemotherapy in patients with metastatic pancreatic adenocarcinoma: feasibility and potential benefits in a retrospective series of 117 patients.

BACKGROUND: Chemotherapy is effective in metastatic pancreatic adenocarcinoma (PAC), but the benefits of second- and third-line chemotherapy remain unclear. METHODS: We studied all patients followed consecutively for metastatic PAC, and registered at our institution between 1997 and 2006. We retrospectively analyzed the following data in terms of chemotherapy: tumor response; time to tumor progression (TTP) for each line; and overall survival (OS). Efficacy of second-line regimens was assessed using the growth modulation index (GMI). RESULTS: Out of 117 patients, 99 (85%) received at least one line of chemotherapy, 53 (45%) received two lines and 24 (21%) had three or more lines. Median OS was 6.7 months for all 117 patients, 1.8 months for 18 patients who never received chemotherapy, 4.6 months for 46 patients who received one-line chemotherapy and 11.5 months for 53 patients who received at least two lines. Median OS from the beginning of the second-line was 4.7 months. The GMI demonstrated beneficial effects of second-line treatment on disease progression, with a GMI greater than 1.33 in 57% (30/53) of patients. CONCLUSION: More than half the patients with metastatic PAC progression while receiving one-line chemotherapy achieved better disease control on receiving two lines of treatment.

Thermal hyperalgesia as a marker of oxaliplatin neurotoxicity: a prospective quantified sensory assessment study.

Neurotoxicity represents a major complication of oxaliplatin. This study aimed to identify early clinical markers of oxaliplatin neurotoxicity, in comparison with cisplatin, and detect predictors of chronic neuropathy. Forty-eight patients with mainly colorectal cancer were evaluated prospectively before oxaliplatin (n=28) or cisplatin (n=20) administration and then 2 weeks after the third (C3), sixth (C6) and ninth (C9) cycles. Eighteen oxaliplatin patients were re-assessed at 12+/-2 months. Evaluation included quantitative sensory testing, i.e., detection/pain thresholds for mechanical, vibration, cold and heat stimuli; pain induced by suprathreshold cold (5-25 degrees C) and heat (38-48 degrees C) stimuli and quantified assessment of symptoms (neuropathic pain symptom inventory). Symptoms of oxaliplatin neurotoxicity (cold-triggered dysesthesia of the hands; 96% of the cases) were reversible between cycles for up to C6. In contrast, thermal testing identified sustained (irreversible between cycles) neurotoxicity two weeks after C3 in the oxaliplatin group only, characterized by hyperalgesia to cold (5-25 degrees C) (F=11.4; p=0.0002 relative to cisplatin patient responses in the hand) and heat stimuli (38-48 degrees C) (F=4.1; p=0.049 for the hand). Cold-evoked symptoms lasting 4 days or more after C3 predicted chronic neuropathy (OR: 22; 95% CI: 1.54-314.74; p=0.02) whereas enhanced pain in response to cold (20 degrees C stimulus on the hand) predicted severe neuropathy (OR: 39; 95% CI: 1.8-817.8 p=0.02). Thermal hyperalgesia is a relevant clinical marker of early oxaliplatin neurotoxicity and may predict severe neuropathy.

Combination of folinic acid, 5-fluorouracil bolus and infusion, and cisplatin (LV5FU2-P regimen) in patients with advanced gastric or gastroesophageal junction carcinoma.

BACKGROUND: Combination chemotherapy with continuous 5-fluorouracil (5-FU) and cisplatin in a monthly regimen is one of the standard treatments for advanced gastric carcinoma. This study evaluated the new LV5FU2-P regimen, designed to improve efficacy and tolerance of the 5-FU plus cisplatin combination. PATIENTS AND METHODS: Forty-three patients with advanced or metastatic gastroesophageal junction or gastric carcinoma were prospectively included in the study. They were treated every 14 days with cisplatin 50 mg/m(2) on day 2 plus folinic acid 200 mg/m(2)/day as a 2-h intravenous (i.v.) infusion on days 1 and 2, plus bolus 5-FU 400 mg/m(2)/day on days 1 and 2, plus continuous 5-FU 600 mg/m(2)/day as a 22-h i.v. infusion on days 1 and 2. Ten patients received a simplified regimen (folinic acid 40 mg/m(2) day 1 + bolus 5-FU 400 mg/m(2) day 1 + continuous 5-FU 2400 mg/m(2) on days 1 and 2 with cisplatin 50 mg/m(2) on day 2). RESULTS: All the patients were assessable for response and 42 for toxicity. One patient achieved a complete response and 15 a partial response, for an overall response rate of 37.2% [95% confidence interval (CI) 22.1% to 52.3%]. The median progression-free survival was 7.2 months (95% CI 5.4-10.9) and the overall survival was 13.3 months (95% CI 10.1-16.4). There were no treatment-related deaths. Hematological and gastrointestinal toxicities were the most common severe toxicities. CONCLUSIONS: LV5FU2-P is an active and well tolerated regimen in the treatment of advanced gastroesophageal junction or gastric carcinomas. It warrants evaluation comparatively with other active regimens.

Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma.

BACKGROUND: Unresectable biliary tract carcinoma (BTC) is associated with a very poor prognosis. To improve efficacy and tolerance of the 5-fluorouracil (5-FU)/cisplatin combination in BTC, we designed a new therapeutic schedule, the LV5FU2-P regimen. PATIENTS AND METHODS: Twenty-nine patients with advanced or metastatic BTC were prospectively enrolled in the study. The treatment (LV5FU2-P regimen) consisted of a biweekly administration of a 2-h infusion of leucovorin 200 mg/m(2), a 400 mg/m(2) bolus of 5-FU followed by a 22-h continuous infusion of 600 mg/m(2) 5-FU on two consecutive days and cisplatin 50 mg/m(2) on day 2. Clinical symptoms, performance and weight changes were monitored. RESULTS: Objective responses were observed in 10 patients (34%) (95% confidence interval 23% to 45%) including one complete response and nine partial responses (stabilization 38%, progression 28%). Median progression-free survival and overall survival were 6.5 and 9.5 months, respectively. Weight gain was observed in 45% of patients and performance status improved in 60%. One patient had a grade 4 thrombocytopenia, and grade 3 toxicity occurred in 41% of patients. There were no treatment-related deaths. CONCLUSIONS: This study, one of the largest phase II trials performed for this disease, shows that the LV5FU2-P regimen is an active and well-tolerated chemotherapy for advanced and metastatic BTC.

A survey of physicians' vaccine risk perception and immunization practices for subjects with immunological diseases.

Various publications have caused concern by implying that immunization may be linked to new cases or flare-ups of immunological diseases (IDs). In view of the resulting uncertainty, we studied physicians' vaccine risk perception and immunization practices for adults with IDs. A questionnaire was mailed to three groups of physicians in France: internal medicine specialists, general practitioners, and travel clinic physicians. Thirteen vaccines currently used for adults in France were studied. Risk perception was rated on a 10 cm visual analog scale (VAS). The distribution of the answers was compared between and within groups of physicians. Potential associations between risk perception and reported practices were investigated by multivariate analysis. In the three groups of physicians (n=762), the tetanus and Salk poliomyelitis vaccines had the lowest risk perception. The yellow fever, BCG and Sabin poliomyelitis vaccines were the least well perceived. The distribution of risk perception for these three live vaccines and the hepatitis B vaccine was uniform according to VAS grading. For the other vaccines studied, the distribution was skewed to the low-risk perception side of the VAS. Risk perception was greater for physicians who stated: (1) that certain IDs carried a high risk of adverse events following immunization; (2) that they sought the advice of the referent physician before immunization; (3) warned their patients of the risk of an ID flare-up after vaccination; (4) sought information about recent immunization in patients with a flare-up; and (5) had experience of the side effects of immunization in adults with ID. Risk perception was lower for physicians who said they updated immunizations, and for the internists. The worse the vaccine risk perception by physicians, the more uniform the distribution of perception, thus reflecting the disagreement of the scientific community about the risk of using such vaccines for adults with an ID. Risk perception and immunization practices were related in adults with ID. Understanding of decisions concerning immunization may help to improve immunization updating and prevent risk amplification when evidence is lacking.

[Systemic lupus erythematosus and risk of hepatitis B vaccination: from level of evidence to prescription]. / Lupus érythémateux systémique et risque de la vaccination contre l'hépatite B: du niveau de preuve à la prescription.

INTRODUCTION: Case reports focusing on immunological diseases occurring subsequently to vaccination are often described in the literature. Reporting of such cases may influence physicians' perception of risks related to immunization, and thereby immunization practices. The decision to vaccinate a patient with an immunological disease should not rely on such case reports, but on the level of evidence of a causal relationship between vaccination and the occurrence of an adverse event. This article describes the search for available data supporting such causality before taking the decision to introduce vaccination against hepatitis B in a female patient with systemic lupus erythematosus (SLE). CURRENT KNOWLEDGE AND KEY POINTS: Data extracted from Medline and surveillance system showed that: 1) biologic plausibility of a relationship between the HBs antigen and SLE was unlikely; 2) case reports or case series were seldom and not convincing regarding potential causality; and 3) there were neither controlled observational studies nor controlled clinical trials. The only available clinical study was of poor quality and did not show any adverse event. The level of evidence of a causal relationship between vaccination against hepatitis B and the occurrence of an adverse event in patients with SLE was low, in-between levels 4 and 5 as defined by the Center for evidence-based medicine. The risk-benefit ratio may therefore rely on these results and guide the decision whether or not vaccination should be introduced. FUTURE PROSPECTS AND PROJECTS: The type of reasoning reported in this paper can be used for other vaccines or other immunological diseases, and have wider applicability in terms of therapeutic risk management when data and evaluation are lacking that could guide decisions.

Severe valvular heart disease in patients on chronic dialysis. A five-year multicenter French survey.

A retrospective multicenter survey of the 230 chronic dialysis centers in metropolitan France, conducted between January 1 1998 and December 31 1992, to assess the incidence, causes and features of severe valvular heart disease among chronic dialysis patients, identified 98 patients. The annual incidence was estimated to be 15 to 19 cases per 10,000 dialysed patients. The most common etiologies were calcific valvular disease (69%) and endocarditis (19%). Calcific valvular disease led mostly to aortic stenosis, whereas endocarditis primarily caused mitral insufficiency. Two valves were damaged in 32% of the endocarditis patients versus 9% of those with calcific valvular disease. Sixty-one patients underwent surgery. Median overall survival after surgery was 25 +/- 3.0 months. Patients who underwent surgery for calcific valvulopathy, aortic stenosis or only aortic valve replacement had a median survival of 36 months. Patients who underwent surgery for endocarditis or replacement of 2 valves had a median survival of < 12 months. Actuarial survival of surgical patients differed significantly between: i) the patients for whom presurgical evaluation showed a single valvular lesion and those with multiple valvular lesions (p = 0.002), ii) the patients who had surgery to replace a single heart valve and those who had another type of surgery (p = 0.001), and iii) the patients who had surgery to insert a single aortic prosthetic heart valve and those who had another type of surgery (p = 0.004). Multivariate analysis (including etiologies, number of valvular lesions and type of surgery) showed that survival was significantly dependent only on the number of severe valvular lesions (p = 0.002). Five patients with severe calcific aortic stenosis died before scheduled surgery could be performed. These data suggest that, for patients on chronic dialysis, calcific aortic stenosis is the most frequent form of severe valvular disease. Because aortic stenosis progresses rapidly in these patients and thus quickly leads to irreversible cardiac failure, the operative risk, although high in this population, seems acceptable when only one valve is affected.

Bronchoalveolar lavage in adult sickle cell patients with acute chest syndrome: value for diagnostic assessment of fat embolism.

Fat embolism of necrotic bone marrow could be a frequent cause of acute chest syndrome (ACS) in sickle cell syndromes (SC), as suggested by postmortem findings. To check this hypothesis in living patients, we evaluated the presence of fatty macrophages recovered by bronchoalveolar lavage (BAL) in ACS. We investigated 20 consecutive cases of ACS by BAL, and identification of alveolar cells containing fat droplets was performed using oil red O (ORO), a specific neutral fat stain. The specificity of the method was determined on control groups, including eight SC patients without acute chest syndrome and 15 non-SC patients. A cut-off of > 5% of alveolar macrophages containing fat droplets was determined from the control groups to assess the diagnosis of fat embolism. In 12 ACS episodes, BAL exhibited > 5% of fatty macrophages, ranging from 10% to 100% (median value 46.5%). In 11 cases, fat embolism was associated with proven (n = 8) or probable (n = 3) bone marrow infraction, which mostly predated ACS. Eight ACS episodes were associated with a low percentage (< or = 5%) of fatty alveolar macrophages and could be related to a cause other than fat embolism in six episodes, such as sepsis, in-situ thrombosis, or rib infarcts generating hypoventilation. This study supports the diagnostic yield of BAL for fat embolism, which can be incriminated in 60% of cases of ACS in this adult population.