Sylvie Chevret

Preoperative Chemotherapy Followed by Surgery Compared With Primary Surgery in Resectable Stage I (Except T1N0), II, and IIIa Non–Small-Cell Lung Cancer

PURPOSE To evaluate whether preoperative chemotherapy (PCT) could improve survival in resectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS A randomized trial compared PCT to primary surgery (PRS). PCT consisted of two cycles of mitomycin (6 mg/m(2), day 1), ifosfamide (1.5 g/m(2), days 1 to 3) and cisplatin (30 mg/m(2), days 1 to 3), and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy. RESULTS Three hundred fifty-five eligible patients were randomized. Overall response to PCT was 64%. There were two preoperative toxic deaths. Postoperative mortality was 6.7% in the PCT arm and 4.5% in the PRS arm (P =.38). Median survival was 37 months (95% confidence interval [CI], 26.7 to 48.3) for PCT and 26.0 months (95% CI, 19.8 to 33.6) for PRS (P =.15). Survival differences between both arms increased from 3.8% (95% CI, 1.3% to 25.1%) at 1 year to 8.6% (95% CI, 2.64% to 24.4%) at 4 years. A quantitative interaction between N status and treatment was observed, with benefit confined to N0 to N1 disease (relative risk [RR], 0.68; 95% CI, 0.49 to 0.96; P =.027). After a nonsignificant excess of deaths during treatment, the effect of PCT was significantly favorable on survival (RR, 0.74; 95% CI, 0.56 to 0.99; P =.044). Disease-free survival time was significantly longer in the PCT arm (P =.033). CONCLUSION Although impressive differences in median, 3-year, and 4-year survival were observed, they were not statistically significant, except for stage I and II disease.

Half the families of intensive care unit patients experience inadequate communication with physicians.

ObjectiveEffective communication of simple, clear information to families of intensive care unit (ICU) patients is a vital component of quality care. The purpose of this study was to identify factors associated with poor comprehension by family members of the status of ICU patients. DesignProspective study. SettingUniversity-affiliated medical intensive care unit. Patients and MethodsA total of 102 patients admitted to an ICU for >2 days. InterventionThe representatives of 76 patients who were visited by at least one person during their ICU stay were interviewed. ResultsMean patient age was 54 ± 17 yrs and mean Simplified Acute Physiology Score II at admission was 40 ± 20. The representative was the spouse in 47 cases (62%). Among representatives, 25 (33%) were of foreign descent and 12 (16%) did not speak French. Mean duration of the first meeting with a physician was 10 ± 6 mins. In 34 cases (54%), the representative failed to comprehend the diagnosis, prognosis, or treatment of the patient.Factors associated with poor comprehension by representatives included patient-related, family-related, and physician- related factors. Patient-related factors included age <50 yrs (p = .03), unemployment (p = .01), referral from a hematology or oncology ward (p = .006), admission for acute respiratory failure (p = .005) or coma (p = .01), and a relatively favorable prognosis (p = .04). Family-related factors were foreign descent (p = .007), no knowledge of French (p = .03), representative not the spouse (p = .03), and no healthcare professional in the family (p = .01). Physician-related factors were first meeting with representative <10 mins (p = .03) and failure to give the representative an information brochure (p = .02). Moreover, after the first meeting, caregivers accurately predicted poor comprehension by representatives (p = .03). ConclusionsPatient information is frequently not communicated effectively to family members by ICU physicians. Physicians should strive to identify patients and families who require special attention and to determine how their personal style of interrelating with family members may impair communication.

Symptoms of anxiety and depression in family members of intensive care unit patients: Ethical hypothesis regarding decision-making capacity

ObjectiveAnxiety and depression may have a major impact on a person’s ability to make decisions. Characterization of symptoms that reflect anxiety and depression in family members visiting intensive care patients should be of major relevance to the ethics of involving family members in decision-making, particularly about end-of-life issues. DesignProspective multicenter study. SettingForty-three French intensive care units (37 adult and six pediatric); each unit included 15 patients admitted for longer than 2 days. PatientsSix hundred thirty-seven patients and 920 family members. InterventionsIntensive care unit characteristics and data on the patient and family members were collected. Family members completed the Hospital Anxiety and Depression Scale to allow evaluation of the prevalence and potential factors associated with symptoms of anxiety and depression. Measurements and Main ResultsOf 920 Hospital Anxiety and Depression Scale questionnaires that were completed by family members, all items were completed in 836 questionnaires, which formed the basis for this study. The prevalence of symptoms of anxiety and depression in family members was 69.1% and 35.4%, respectively. Symptoms of anxiety or depression were present in 72.7% of family members and 84% of spouses. Factors associated with symptoms of anxiety in a multivariate model included patient-related factors (absence of chronic disease), family-related factors (spouse, female gender, desire for professional psychological help, help being received by general practitioner), and caregiver-related factors (absence of regular physician and nurse meetings, absence of a room used only for meetings with family members). The multivariate model also identified three groups of factors associated with symptoms of depression: patient-related (age), family-related (spouse, female gender, not of French descent), and caregiver-related (no waiting room, perceived contradictions in the information provided by caregivers). ConclusionsMore than two-thirds of family members visiting patients in the intensive care unit suffer from symptoms of anxiety or depression. Involvement of anxious or depressed family members in end-of-life decisions should be carefully discussed.

A new prognostic classification for predicting survival in patients with hepatocellular carcinoma

BACKGROUND/AIMS In patients with hepatocellular carcinoma, prediction of survival is difficult. The aim of this prospective study was to provide a simple classification for predicting survival of patients with hepatocellular carcinoma, based on a multivariable Cox model. METHODS Seven hundred and sixty-one patients who presented with hepatocellular carcinoma from 24 Western medical centers were enrolled over a 30-month period. Patients were randomly assigned to either a training sample (n=506, with 418 deaths) from which a classification system was established, or a test sample (n=255, with 200 deaths) for validating its prognostic significance. RESULTS Five prognostic factors were selected at the 0.0001 level: Karnofsky index <80% (relative risk of death=2.2, 95% confidence interval: 1.7-2.7), serum bilirubin >50 micromol/l (relative risk=2.1, 95% confidence interval: 1.7-2.6), serum alkaline phosphatase at least twice the upper limit of normal range (relative risk=1.6, 95% confidence interval: 1.3-2.0), serum alpha-fetoprotein >35 microg/l (relative risk=1.7, 95% confidence interval: 1.4-2.1), and ultrasonographic portal obstruction (relative risk=1.3, 95% confidence interval: 1.1-1.7). Three risk groups with different 1-year survival rates (72%, 34%, 7%) were derived, and independently validated in the test sample (79%, 31%, 4%). CONCLUSION This classification could be useful in the assessment of prognosis from homogeneous groups of patients with respect to their expected outcome.

Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study

BACKGROUND The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity. METHODS In a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50-70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without five doses of intravenous gemtuzumab ozogamicin (3 mg/m(2) on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36. FINDINGS 280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (odds ratio 1·46, 95% CI 0·20-2·59; p=0·25). At 2 years, EFS was estimated as 17·1% (10·8-27·1) in the control group versus 40·8% (32·8-50·8) in the gemtuzumab ozogamicin group (hazard ratio 0·58, 0·43-0·78; p=0·0003), OS 41·9% (33·1-53·1) versus 53·2% (44·6-63·5), respectively (0·69, 0·49-0·98; p=0·0368), and RFS 22·7% (14·5-35·7) versus 50·3% (41·0-61·6), respectively (0·52, 0·36-0·75; p=0·0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (22 [16%] vs 4 [3%]; p<0·0001), without an increase in the risk of death from toxicity. INTERPRETATION The use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukaemia. The findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for acute myeloid leukaemia. FUNDING Wyeth (Pfizer).

Improved survival in cancer patients requiring mechanical ventilatory support: Impact of noninvasive mechanical ventilatory support

OBJECTIVE When a cancer patient becomes critically ill, mechanical ventilation (MV) is often considered futile. However, recent studies have found that outcomes of critically ill cancer patients have been improving over the years and that classic predictors of high mortality have lost their relevance. DESIGN We retrospectively determined outcomes and predictors of 30-day mortality in 237 mechanically-ventilated cancer patients admitted to the intensive care unit (ICU). PATIENTS The 132 (55.7%) patients who were admitted between 1990 and 1995 were compared with 105 (44.3%) patients who were admitted between 1996 and 1998. The malignancy was leukemia/lymphoma in 119 (50.3%) patients, myeloma in 50 (21%), and a solid tumor in 68 (28.7%). Forty-two (17.7%) patients had bone marrow transplantation, and 91 (38.4%) were neutropenic. Median Simplified Acute Physiology Score II (SAPS II) was 58 (range, 40-75). Reasons for MV were acute hypoxemic respiratory failure in 148 (62.5%) patients, coma in 54 (22.8%), and cardiogenic pulmonary edema in 35 (14.7%). Conventional MV was used first in 189 (79.8%) patients, and noninvasive MV (NIMV) was used in 48 (20.2%). Overall mortality rate was 72.5% (172 deaths). RESULTS Logistic regression identified three variables associated with mortality: ICU admission between 1996 and 1998 (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.12-0.50) and the use of NIMV (OR, 0.34; 95% CI, 0.16-0.73) were protective, and the SAPS II was aggravating (OR, 1.04 per point; 95% CI, 1.02-1.06). To better define the impact of NIMV, we performed a pairwise-matched exposed-unexposed analysis. Forty-eight patients who did and 48 who did not receive NIMV as the first ventilation method were matched for SAPS II, type of malignancy, and period of ICU admission. Crude ICU mortality rates from exposed patients and controls were 43.7% and 70.8%, respectively. NIMV remained protective from mortality after adjustment for matching variables (OR, 0.31; 95% CI, 0.12-0.82). CONCLUSION Our results confirm that mortality has improved over the past decade in critically ill cancer patients, even those who require MV, and suggest that this may be, in part, because of a protective effect of NIMV.

Effects of Fluid Resuscitation With Colloids vs Crystalloids on Mortality in Critically Ill Patients Presenting With Hypovolemic Shock The CRISTAL Randomized Trial

IMPORTANCE Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear. OBJECTIVE To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012. INTERVENTIONS Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay. MAIN OUTCOMES AND MEASURES The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy. RESULTS Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03). CONCLUSIONS AND RELEVANCE Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00318942.

Outcome of and Prognostic Factors for Herpes Simplex Encephalitis in Adult Patients: Results of a Multicenter Study

Management of herpes simplex encephalitis (HSE) has been considerably improved by the availability of acyclovir therapy and rapid polymerase chain reaction (PCR)-based diagnostic assays. Prognostic factors for this rare affliction are, however, misestimated. We conducted a large retrospective multicenter study that included 93 adult patients in whom HSE was diagnosed by PCR from 1991 through 1998 and who were treated with intravenous acyclovir. Among the 85 patients assessed at 6 months, 30 (35%) had a poor outcome, which led to death in 13 patients (15%) and severe disability in 17 (20%). The outcome was favorable for 55 patients (65%). A multivariate analysis identified 2 factors that were found to be independently associated with poor outcome: a Simplified Acute Physiology Score II >/=27 at admission and a delay of >2 days between admission to the hospital and initiation of acyclovir therapy. Early administration of antiviral therapy is the only parameter that can be modified to improve the prognosis of patients with HSE.

High-Dose Therapy and Autologous Blood Stem-Cell Transplantation Compared With Conventional Treatment in Myeloma Patients Aged 55 to 65 Years: Long-Term Results of a Randomized Control Trial From the Group Myelome-Autogreffe

PURPOSE To study the impact of high-dose therapy (HDT) with autologous stem-cell support in patients with symptomatic multiple myeloma (MM) between the ages of 55 and 65 years. PATIENTS AND METHODS One hundred ninety patients between 55 and 65 years old who had newly diagnosed stage II or III MM were randomly assigned to receive either conventional chemotherapy (CCT; ie, monthly courses of a regimen of vincristine, melphalan, cyclophosphamide, and prednisone) or HDT and autologous blood stem-cell transplantation (using either melphalan alone 200 mg/m(2) intravenous [IV] or melphalan 140 mg/m(2) IV plus busulfan 16 mg/kg orally as pretransplantation cytoreduction). RESULTS Within a median follow-up of 120 months, median event-free survival (EFS) times were 25 and 19 months in the HDT and CCT groups, respectively. Median overall survival (OS) time was 47.8 months in the HDT group compared with 47.6 months in the CCT group. A trend to better EFS (P = .07) was observed in favor of HDT, whereas OS curves were not statistically different (P = .91). The period of time without symptoms, treatment, and treatment toxicity (TwiSTT) was significantly longer for the HDT patients than for the CCT patients (P = .03). CONCLUSION With a median follow-up time of approximately 10 years, this randomized trial confirmed a benefit of HDT in terms of EFS and TwiSTT but did not provide evidence for superiority of HDT over CCT in OS of patients aged 55 to 65 years with symptomatic newly diagnosed MM.

A Controlled Trial in Intensive Care Units of Selective Decontamination of the Digestive Tract with Nonabsorbable Antibiotics

BACKGROUND Selective decontamination of the digestive tract with topical nonabsorbable antibiotics has been reported to prevent nosocomial infections in patients receiving mechanical ventilation, and the procedure is used widely in Europe. However, it is unclear whether selective decontamination improves survival. METHODS We conducted a randomized, double-blind multicenter study in which 445 patients receiving mechanical ventilation in 15 intensive care units were given either prophylactic nonabsorbable antibiotics (n = 220) or a placebo (n = 225). Topical antibiotics (tobramycin, colistin sulfate, and amphotericin B) or a placebo was administered through a nasogastric tube and applied to the oropharynx throughout the period of ventilation. The main end points were the mortality rate in the intensive care unit and within 60 days of randomization. RESULTS A total of 142 patients died in the intensive care unit; 75 (34 percent) in the treatment group and 67 (30 percent) in the placebo group (P = 0.37). Mortality within 60 days of randomization was similar in the two groups (P = 0.40), even after adjustment for factors that were either unbalanced or individually predictive of survival in the two groups (P = 0.70). Pneumonia developed in 59 patients (13 percent) in the intensive care unit within 30 days of enrollment in the study (33 in the placebo group and 26 in the treatment group, P = 0.42). Pneumonia acquired in the intensive care unit and due to gram-negative bacilli was less frequent (P = 0.01) in the treatment group than in the placebo group. The total charges for antibiotics were 2.2 times higher in the treatment group. CONCLUSIONS Selective decontamination of the digestive tract does not improve survival among patients receiving mechanical ventilation in the intensive care unit, although it substantially increases the cost of their care.