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PubMed2005

Optimizing chemotherapy for advanced non-small cell lung cancer: focus on docetaxel.

Systemic chemotherapy with platinum-based combinations provides modest improvements in both survival and quality of life for patients with advanced non-small cell lung cancer (NSCLC). For first-line treatment of advanced NSCLC patients with a good performance status, the accepted standard of care is a platinum agent combined with docetaxel, paclitaxel, gemcitabine, vinorelbine or irinotecan. Several studies have attempted to identify an optimal platin-based regimen, however, all regimens offer some combination of clinical benefit with characteristic toxicities and no regimen appears clearly superior. Non-platinum regimens have also shown equivalent efficacy compared to platinum combinations, but again, none are clearly superior. Most recently, the existing standard of care is being amended to reflect the survival advantage gained from adding a new targeted agent, bevacizumab, to traditional platinum-doublet therapy for patients with non-squamous NSCLC. Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platin-docetaxel regimens for first-line treatment of advanced NSCLC. Improvements in various lung cancer related symptoms and global quality of life indices have also been noted with docetaxel-based regimens. Based on the efficacy of platin-docetaxel regimens in advanced disease, they are now being incorporated into the adjuvant and neoadjuvant treatment of early-stage disease.

Adult↗
PubMed2005

Prolonged topotecan infusion with cisplatin in the first-line treatment of ovarian cancer: an NYGOG and ECOG study.

OBJECTIVE: To determine the toxicity and efficacy of combined therapy with cisplatin and prolonged infusion topotecan as front line therapy in women with epithelial ovarian cancer. PATIENTS AND METHODS: Women with previously untreated, measurable and non-measurable epithelial ovarian cancer, stages Ic-IV were eligible. Patients were treated with cisplatin 75 mg/m(2) on day 1, followed by topotecan 0.3 to 0.4 mg/m(2)/day given as a continuous infusion over 14-21 days, every 28 days. Dose levels and duration of infusion were adjusted for toxicity as appropriate. Patients were evaluated for response to treatment and treatment toxicity by standard NYGOG criteria. RESULTS: Sixty patients were enrolled. Among the 20 patients with post-surgical residual disease >2 cm, 80% [95% CI (56.3%, 94.3%)] demonstrated an objective response to therapy. The median progression-free survival for all 60 patients enrolled was 19.3 months with a median overall survival of 45.6 months given the median follow-up of 55 months (range 6-81 months). Five year survival is estimated to be 41%. Toxicity was observed in the first four patients treated with topotecan (0.4 mg/m(2)/day x 21 days) and dosing was continued at 0.3 mg/m(2)/day x 14 days thereafter. Of the 56 patients treated at the amended dose level, marrow suppression continued to be dose-limiting, with 86% of patients experiencing grade 3 or 4 neutropenia, 55% experiencing grade 3 or 4 thrombocytopenia and 50% of patients experiencing grade 3 or 4 anemia. Nonetheless, only 11/245 cycles administered were associated with febrile neutropenia and/or infection (8 port-related). Other non-hematologic toxicity was as expected. There were no treatment-related deaths. CONCLUSION: This large, multicenter phase II study of prolonged infusion topotecan in combination with cisplatin demonstrated similar response, time to progression and survival compared with reported results of taxane and platinum combinations. Hematologic toxicity was greater but tolerated. Further studies investigating topotecan in combination with platinum therapy as a first line agent are warranted.

Adult↗
PubMed1990

Phosphorus in waters from sewage sludge amended lysimeters.

In surface waters, phosphorus (P) concentrations exceeding 0.05 mg liter(-1) may cause eutrophic conditions. This study was undertaken to measure total P concentrations in runoff and tile drainage waters from land receiving either inorganic fertilizer or anaerobically digested sewage sludge. Total P was measured in runoff and tile drainage waters during 2 years of sample collections from instrumented, large-scale lysimeters planted to corn (Zea mays L.). During the 3 years prior to monitoring P concentrations, six of the lysimeter plots had been amended with anaerobically digested sewage sludge which supplied 5033 kg P per ha. Additional sludge applications supplied 1058 and 1989 kg P per ha during the first and second years of monitoring operations, respectively. Another six lysimeters were annually treated with fertilizer which included P applications amounting to 112 kg ha(-1). For years 1 and 2, respectively, annual losses from lysimeters treated with sewage sludge were 4.27 and 0.35 kg P per ha in runoff and 0.91 from 0.91 and 0.51 kg Per P per ha in drainage waters. Parallel annual losses of P from lysimeters treated with superphosphate were 2.15 and 0.17 kg ha(-1) in runoff and 0.53 and 0.35 kg ha(-1) in tile drainage waters. Sludge applications did not significantly change absolute soil contents of organic P, but did decrease the per cent of total P present in organic forms. Sludge and soil, respectively, contained 21 and 36% of their total P contents in organic forms. In sludge and soil about 85 and 64% of their respective total inorganic P contents were associated with the Al and Fe fractions. Sludge applications significantly increased soil contents of P in the saloid (water-soluble plus P extracted with 1 N NH(4)Cl), Al, Fe and reductant soluble P fractions, but contents of Ca-bound P were not changed. Total P contents of the soil below a depth of 30 cm were not affected by sludge incorporated to a depth of about 15 cm by plowing.

Journal Article↗
PubMed1999

Multiple regression analysis of interference effects from a hemoglobin-based oxygen carrier solution.

The use of hemoglobin-based oxygen carrier solutions in patients requiring blood transfusion will necessitate that clinical laboratories have mechanisms in place to evaluate the potential interference effect of these substances on testing methods. Because these oxygen carrier solutions contain acellular hemoglobin, but do not contain many of the intracellular enzymes and ions present in erythrocytes, interference effects from blood substitutes may be quite different when compared to in vivo or in vitro lysis of erythrocytes. We evaluated the potential interference effect of Diaspirin Cross-linked Hemoglobin on 29 different clinical laboratory analytes. Various combinations of these analytes were tested using the Hitachi 747 and 911 systems, a Beckman CX3, an Abbott AxSym, a Bayer Immuno I, and a Dade ACA IV; a total of 60 analyte/instrument combinations. We used the method of multiple regression analysis to classify interferences as analyte-dependent, analyte-independent, or a combination of the first two types. The presence of clinically significant test interference was derived by using the criteria for maximum allowable error specified in the Clinical Laboratory Improvement Amendments of 1988. Using these criteria, we found significant interference from Diaspirin Cross-linked Hemoglobin with 13 of 29 analytes tested. Interference was noted with the Hitachi 747 and 911 methods for albumin, alkaline phosphatase, total and conjugated bilirubin, cholesterol, total carbon dioxide, iron, lactate dehydrogenase, magnesium, total protein, and triglyceride. In addition, Diaspirin Cross-linked Hemoglobin interfered with measurement of L-lactate using the ACA IV and minor interference was noted with glucose measured using the Beckman CX3. Data from the interference studies was graphically displayed in the form of interference plots. These plots show the maximum allowable test error, due to Diaspirin Cross-linked Hemoglobin, as a function of analyte and interferent concentrations. Evaluation of the potential interference effect of hemoglobin-based oxygen carrier solutions with use of multiple regression analysis and graphical display of the resultant data in the form of interference plots allows for more reliable reporting of test results from specimens containing these products.

Aspirin↗
PubMed2001

Formation of chloropyromorphite in a lead-contaminated soil amended with hydroxyapatite.

Conversion of soil Pb to pyromorphite [Pb5(PO4)3Cl] was evaluated by reacting a Pb contaminated soil collected adjacent to a historical smelter with hydroxyapatite [Ca5(PO4)3OH]. In a dialysis experiment where the soil and hydroxyapatite solids were placed in separate dialysis bags suspended in 0.01 M NaNO3 solution a crystalline precipitate, identified as chloropyromorphite, formed on the dialysis membrane containing the soil. The aqueous composition of the solution indicated that dissolution of solid-phase soil Pb was the rate-limiting step for pyromorphite formation. Addition of hydroxyapatite to the soil caused a decrease in each of the first four fractions of sequential extractable Pb and a 35% increase in the recalcitrant extraction residue. After a 240-d incubation at field-moisture content there was a further increase in the recalcitrant extraction residue fraction of the hydroxyapatite-amended soil to 45% of the total soil Pb. The increase in the extraction residue fraction in the hydroxyapatite amended 0-d incubated soil as compared to the control soil illustrates that the chemical extraction procedure itself caused changes in extractability. Thus, the chemical extraction procedure cannot easily be utilized to confirm changes occurring in amended soils. The further increase after the 240-d incubation implies that the reaction also occurs in the soil during incubation. Extended X-ray absorption fine structure (EXAFS) spectroscopy indicated that after the 240-d incubation the hydroxyapatite treatment caused a change in the average, local molecular bonding environment of soil Pb. Low-temperature EXAFS spectra (chi data and radial structure functions--RSFs) showed a high degree of similarity between the chemical extraction residue and synthetic pyromorphite, providing additional evidence that the change of soil Pb to pyromorphite is possible by simple amendments of hydroxyapatite to soil.

Absorptiometry, Photon↗
PubMed2006

Effects of anthracene, pyrene and benzo[a]pyrene spiking and sewage sludge compost amendment on soil ecotoxicity during a bioremediation process.

The fate of spiked anthracene, pyrene and benzo[a]pyrene in soil with or without sewage sludge compost was assessed during a 6-month bioremediation process simulating landfarming. Bioassays and physico-chemical analyses were employed to monitor toxicity change in soil samples and elutriates through ten sampling campaigns. Pearson product-moment correlation coefficient was determined to measure the strength of relationship between bioassays and physico-chemical analyses. The PAH dissipation in soil was enhanced after the first water addition, and the remaining amounts at the end of the experiment were positively correlated to the number of benzene rings and the presence of sewage sludge compost. Toxicity of soil elutriates to Daphnia magna was evident at early stages, originating exclusively from sewage sludge compost amendment. The lettuce root elongation was continuously inhibited by elutriates for all the treatments including control soil, probably due to high salinity or to unaddressed leachable phytotoxic compounds that were present in the experimental soil. The newly developed direct solid-phase chronic toxicity test using ostracod (Heterocypris incongruens) succeeded in evaluating the soil-bound PAH toxicity, as PAHs could not be detected in elutriates.

Animals↗
PubMed1988

Act to amend the Indian Act (minor's funds and surviving spouse's preferential share), 13 September 1988.

Among other things, this Canadian Act: 1) raises the preferential share due a "widow" upon the death of an intestate to the first $75,000 and authorizes the Governor in Council to fix another amount in the future; 2) authorizes the council of a band of Indians to determine that up to $3000, or another amount as set by the Governor in Council, of the share of a distribution due to a minor infant upon the age of majority "is necessary to be paid for the maintenance, advancement, or other benefit of the child;" and 3) authorizes the competent Minister to make a payment of some or all of the distribution due to an Indian child for the same purposes.

Adolescent↗
PubMed2006

Microbial biomass and activity of an agricultural soil amended with the solid phase of pig slurries.

Information about the mineralisation rates and effects on soil microorganisms must be obtained prior to the rational use of organic wastes in agriculture or forestry. The objective of this work was to study the mineralisation of two manures derived from the solid phase of pig slurries and the effects on the soil microbial biomass of an agricultural soil. Samples of this soil were mixed at two different rates with two manures derived from the solid phase of pig slurry (composted, CSP, and non-composted, NSP), and then were incubated during 163 days. Carbon mineralised from manures was fitted to first-order kinetic model, and small differences were found between manures despite the composting of one of them. Approximately 45% of the C added was mineralised in the experimental period. The soil microbial biomass C (C(mic)) was increased by the amendments according to the application rate. The sudden increases of the qCO(2) in the treated samples were ephemeral. The most appreciable differences between these manures were those related with net N mineralisation, being greater in the NSP-treated samples. The application of the solid phase of pig slurries, composted or not, could be a feasible practice to enhance in a short-term the microbial biomass of agricultural soils. In order to avoid an excessive release of inorganic N, the use of composted materials is preferred.

Agriculture↗
PubMed1983

Development of the concept of immunologic specificity: IV.

We have attempted, in this series of essays on the development of the concept of immunologic specificity, to trace the history of one of the most central ideas in immunology (and indeed in biology in general). The result must be viewed as preliminary and incomplete and as an invitation to others to add, to amend, and even to disprove. Nevertheless, several interesting conclusions may be drawn, which reveal much about the workings of immunology in particular, and perhaps science in general. First, the roots of any important scientific concept (such as that of immunologic specificity) do not grow in isolation; they draw nourishment from many other disciplines. Similarly, the growth of an important concept within a given discipline will have far-reaching implications and fruits for other fields of science. Second, we may note a marked change in the manner in which immunology is currently practiced, compared with that of the end of the last century. The quantum leaps forward in funding, in numbers of scientists, and in masses of crucial data have not been without a certain cost--the substantial reduction in elegant personal style that characterized so many of our scientific forebears, and that makes so pleasant the reading of their reports. Finally, we see again and again how much his philosophical bases and disciplinary upbringing determine a scientist's approach, the questions that he asks, and the type of answers he will accept. Throughout much of immunology's history, as Jerne put it so well (44), cis- and trans-immunologists hardly spoke to one another. Or rather, a cis-immunologist sometimes spoke to a trans-immunologist, but the latter rarely answered! Fortunately, one of the attributes of scientific progress is a merging of these disparate languages, and eventual mutual comprehension.

Allergy and Immunology↗
PubMed2002

Stalker profiles with and without protective orders: reoffending or criminal justice processing?

Research indicates that stalking is an extension of intimate partner violence. The overall purpose of this study was to better understand stalkers by examining the association between a protective order history and the court's processing of subsequent stalking, and to examine patterns of reoffending. This study examined a sample of 346 males who were charged with stalking in 1999 in one state. Subjects were partitioned into three groups: (1) males without protective orders; (2) males with one prior protective order; and (3) males with two or more prior protective orders. Almost two-thirds of the stalkers had a protective order against them at some point in the study, suggesting that stalking is associated with intimate partner violence. Results also found a linear trend with many of the criminal justice involvement variables and protective order history prior to 1999. Those charged with first-degree stalking were more likely to be found guilty initially, and about one-third of all three study groups had the initial felony stalking charge amended. Of those charged with second-degree stalking, only 7% of the group with two or more protective orders was initially found guilty, which was substantially less than the other two groups. And, when all the amendment dispositions were considered, there were no significant differences by group in guilty and dismissed dispositions for the index stalking charge. Further, consistent with previous criminal justice involvement, the group with two or more protective orders was more likely to have subsequent felony charges than the other two groups. Implications are discussed.

Adolescent↗
PubMed1977

Children can't fly: a program to prevent childhood morbidity and mortality from window falls.

"Children Can't Fly" is a health education program developed by the New York City Department of Health to combat the high incidence of child mortality and morbidity due to falls from windows. The success of the program, begun in 1972, in drastically reducing death and injury persuaded the New York City Board of Health to amend the Health Code in 1976 to require that landlords provide window guards in apartments where children ten years old and younger reside. The law is the first and only one of its kind in the nation. The program has four major components: 1) reporting of falls by hospital emergency rooms and police precincts, followed up by counseling, referral, and data collecting by public health nurses; 2) a media campaign to inform the public and elevate their awareness of the hazards; 3) community education for prevention through door-to-door hazard identification, counseling by outreach workers, community organization efforts with schools, tenant groups, clinics, churches, health care providers, etc; 4) provision of free, easily installed window guards to families with young children living in high-risk areas. Significant reduction in falls resulted, particularly in the Bronx, where reported falls declined 50 percent from 1973 to 1975. The program is one solution to an urgent urban problem which other cities might consider to avert the loss of life and limb, and the corollary financial burden for hospitalization, rehabilitation, and maintenance of the injured and permanently disabled.

Accidents, Home↗
PubMedDate not supplied

[Hourly (ultradian) cellular rhythms: initial studies and some results].

Circahoralian cellular rhythms have been revealed after the amendment of quantitative cytochemical methods initiated at the Department of Histology (Moscow State University) and Laboratory of Cytology (Institute of Animal Morphology, Russian Academy of Sciences). The first findings have been confirmed in many laboratories. Circumhoralian kinetics proved to be specific for various cell types (from bacteria to mammalian cells) and cellular functions. Independent physiological investigations found circahoralian rhythms for various tissue functions. Distribution of the rhythms as well as their possible nature and significance for tissue biology are reviewed.

Animals↗
PubMed2003

Incomplete degradation of polycyclic aromatic hydrocarbons in soil inoculated with wood-rotting fungi and their effect on the indigenous soil bacteria.

Soil artificially contaminated with fluorene, phenanthrene, pyrene, and benz[a]anthracene was inoculated with the wood-rotting fungi Plrurotus ostreatus and Antrodia vaillantii. During 12 weeks of incubation, polycyclic aromatic hydrocarbon (PAH) degradation and the formation of persistent degradation products were monitored by chemical analysis. In addition, the effect on the indigenous soil bacteria was studied by plate count techniques and by measuring the concentration of bacteria-specific phospholipid fatty acids (PLFAs). In both soils inoculated with fungi, the PAH degradation was enhanced compared to the control soil without fungi. The white-rot fungus P. ostreatus accelerated the degradation rate radically the first weeks, while the effect of the brown-rot fungus was more pronounced at later stages during the 12-week study. In a soil with no amendments, the final degradation result was similar to that in the soil with added fungi, although the degradation pattern for the individual PAHs was different. Furthermore, the degradation by P. ostreatus was accompanied by an accumulation of PAH metabolites, that is, 9-fluorenone, benz[a]anthracene-7,12-dione, and two compounds identified as 4-hydroxy-9-fluorenone and 4-oxapyrene-5-one, that was not seen in the other soils. The inoculation with the white-rot fungus also had a large negative effect on the indigenous soil bacteria. This could be an important drawback of using the white-rot fungus P. ostreatus in soil bioremediation since a sequential fungal-bacterial degradation probably is needed for a complete degradation of PAHs in soil. In the soil inoculated with A. vaillantii, on the other hand, no metabolites accumulated, and no negative effects were observed on the indigenous microorganisms.

Basidiomycota↗
PubMed2004

Enhanced remediation of carbon tetrachloride by Fe(II)-Fe(III) systems in the presence of copper ions.

The effect of Cu(II) ion on the dechlorination of carbon tetrachloride (CT) by Fe(II) associated with various iron oxides was investigated. Iron oxides including goethite, hematite, ferrihydrite and magnetite were selected as the model compounds. CT was dechlorinated to chloroform (CF) by 3 mM Fe(II) in iron oxide suspensions at pH 7.2. The dechlorination followed pseudo first-order kinetics and the pseudo first-order rate constants (k(obs)) were 0.048 h(-1), 0.0836 h(-1), 0.0609 h(-1) and 0.0144 h(-1) in goethite-, hematite-, ferrihydrite- and magnetite-amended systems, respectively. Addition of Cu(II) into systems increased the k(obs) for CT dechlorination significantly. A 3- to 120-fold increase in k(obs) relative to the systems without Cu(II) was observed when 0.5 mM Cu(II) was added to the Fe(II)-Fe(III) suspensions. The pH of the system is an important factor controlling the dechlorination rate of CT. The increase in concentrations of Fe(II) and iron oxides also enhanced the dechlorination efficiency and rate of CT. Moreover, a linear relationship between the k(obs) and Cu(II) concentration ranging between 0 and 0.4 mM was observed. Results obtained demonstrate the feasibility of using surface-bound iron species with Cu(III) for the detoxification of chlorinated solvents in the contaminated aquifers.

Carbon Tetrachloride↗
PubMed2002

Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial.

OBJECTIVES: This phase II study was conducted to evaluate the efficacy and safety of gemcitabine in patients with metastatic breast cancer (MBC). METHODS: Women with histologically or cytologically confirmed bidimensionally measurable MBC not amendable to curative surgery or radiation were eligible. Prior chemotherapy for metastatic disease was not permitted. Patients received gemcitabine 1,200 mg/m(2) on days 1, 8 and 15 for 3 weeks every 28 days for a maximum of 8 cycles. RESULTS: Thirty-nine patients, with a median age of 58 years, were enrolled. The overall response rate for the 35 evaluable patients was 37.1% (95% confidence interval [CI], 21.5-55.1%), with 2 complete responses and 11 partial responses. Median time to progression and survival were 5.1 months (95% CI, 3.5-8.8 months) and 21.1 months (95% CI, 11.0-26.9 months), respectively. Chemotherapy was well tolerated, with a median of 4 cycles completed. Grade 4 toxicities were 1 infection and 1 abnormal pulmonary function. Grade 3 neutropenia and thrombocytopenia occurred in 30.3% and 6.3% of patients, respectively. The most common grade 3 non-hematologic toxicity was nausea/vomiting (10.3%). Five of 21 patients had improved Karnofsky performance status (KPS) scores. CONCLUSION: Single-agent gemcitabine is active and well tolerated as first-line treatment in patients with MBC.

Adolescent↗
PubMed2001

An evaluation of analytic goals for assays of drugs: a College of American Pathologists Therapeutic Drug Monitoring Survey Study.

OBJECTIVE: To determine if the levels of imprecision of the commonly used analytic methods for drug measurements are suitable for long-term therapeutic drug monitoring. DESIGN: In 1996, 4 identical lyophilized samples (2 in the first mailing and 2 in the second mailing 4 months later) were sent to laboratories participating in a nationwide proficiency testing program. Similarly, in 1999, replicates from a liquid pool of spiked sera were mailed 3 times, 4 months apart, to participating laboratories. For each of 11 drugs regulated under the Clinical Laboratory Improvement Amendments of 1988 and 1 metabolite, the total variance for each method was partitioned into within- and between-laboratory components. The total within-laboratory and the total survey coefficients of variation (CVs) for each method were then compared with the "acceptable" precision criteria of Glick, Burnett, and Fraser for each drug. SETTING: The first 2 mailings of the College of American Pathologists Therapeutic Drug Monitoring surveys for 1996, sets Z and ZM, and the 3 mailings of 1999, sets ZM, Z, and Z2. MAIN OUTCOME MEASURES: For each drug studied, the CV of each method was compared with the various imprecision criteria, and if greater than any of the criteria, the method was then tabulated as not meeting that specific criterion.Participants.-The approximately 5000 participants of the survey. RESULTS: The number of methods deemed as not having acceptable total long-term within-laboratory precision by the various criteria ranged from 35% to 88% in 1996 and from 22% to 77% in 1999. CONCLUSION: The number of failures possibly indicates that many of the reagent assays being utilized are not precise enough for long-term therapeutic drug monitoring of chronically administered drugs or that the published criteria used to evaluate the data in this study are too stringent.

Data Collection↗
PubMed1993

Mortality in broiler chicks on feed amended with Fusarium proliferatum culture material or with purified fumonisin B1 and moniliformin.

Two hundred twenty-eight male chicks (Columbia x New Hampshire) were given feed amended with autoclaved culture material (CM) of Fusarium proliferatum Containing fumonisin B1 (FB1), fumonisin B2 (FB2) and moniliformin in 3 separate feeding trials. Purified FB1 and moniliformin were given separately and in combination in a fourth feeding trial. Birds were given amended rations at day 1 (Trial 1 and 4), day 7 (Trial 2), and day 21 (Trial 3) and their respective ration was given for 28 days (Trial 1), 21 days (Trial 2), 7 days (Trial 3), and 14 days (Trial 4). FB1 concentrations were 546, 193, and 61 ppm; FB2 were 98, 38 and 14 ppm; and moniliformin were 367, 193, and 66 ppm in the first 3 feeding trial regimens. Chicks in Trial 4 were given dietary concentrations of purified FB1 at 274 and 125 ppm, and moniliformin at 154 and 27 ppm. FB1 and moniliformin, both alone and in combination, produced dose-responsive clinical signs, reduced weight gains and mortality in chicks. Age of birds given amended feeds had little difference in the clinical response; however, those given the rations from days 7 or 21 were slightly less susceptible than those given rations beginning at 1 day of age. Additive effects were noted when the toxins were given in combination. When toxins were given separately, adverse effects took longer to occur. A system to monitor pattern and rate of defecation (RD) was developed for assessing the chicks' approach to feed, water and heat source as illness progressed. Our results indicate that chicks fed corn heavily infected with F. proliferatum under field conditions could suffer acute death similar to that described for 'spiking mortality syndrome' during the first 3 weeks of age.

Animal Feed↗
PubMed2005

Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.

BACKGROUND: We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. METHODS: The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel. RESULTS: By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P<0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831. CONCLUSIONS: Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. (ClinicalTrials.gov numbers, NCT00004067 and NCT00005970.)

Adult↗