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PubMed1998

Which interventions for neonatal respiratory failure are effective?

AIM: To review the evidence from clinical trials of various interventions to treat and prevent respiratory failure in the neonate and to determine which interventions are effective and which require further study. METHODS: Randomized controlled trials and/or meta-analyses of trials of interventions for neonatal respiratory failure were sought from databases including the Cochrane Collaboration. The results were synthesized as typical relative risks and typical risk differences, with 95% confidence intervals (CI). RESULTS: The following interventions were effective: conventional mechanical ventilation (absolute reduction in mortality 12%, 95% CI 4-21%), continuous positive airway pressure (absolute reduction in mortality 15%, 95% CI 1-28%), surfactant therapy (absolute reduction in mortality 4 to 9%, 95% CI 1-13%), and extracorporeal membrane oxygenation (absolute reduction in mortality 29%; 95% CI 15-42%). High frequency oscillatory ventilation with a volume recruitment strategy and inhaled nitric oxide appeared promising, but have not yet reduced mortality. Prenatal corticosteroids (absolute reduction in mortality 4%; 95% CI 2-6%) and amnioinfusion (effect on mortality not yet possible to estimate) prevented respiratory failure, but routine endotracheal intubation and suctioning of the airways at birth in vigorous meconium-stained term babies did not prove effective. CONCLUSIONS: Assisted ventilation, surfactant therapy, and extra-corporeal membrane oxygenation are effective, but it is uncertain how each should be applied in an individual infant. More research is needed to evaluate combinations of effective interventions, and effectiveness of high frequency oscillation and inhaled nitric oxide. Routine intubation and suctioning of the airways at birth in meconium-stained vigorous neonates is not recommended.

Humans↗

PubMed1998

Revascularization in coronary artery disease. A review of randomized trial data.

Since the advent of bypass surgery in the late 1960s and catheter-based intervention in the late 1970s, the treatment of coronary artery disease has been revolutionized by the concept of revascularization. Surveys have demonstrated that the practice patterns around the world and within the US are inconsistent for these important treatment options and are often driven by availability and economics rather than evidence-based data. In addition, the studies examining the use of medical therapy, balloon angioplasty, atherectomy, coronary stenting, and bypass surgery are consistently lagging behind the technological advances in this field. This article reviews the data that randomized trials and meta-analyses provide to compare these modalities. We attempt to provide a framework for reasoned clinical decision making to help guide patient care. While the breakpoints between the medicine bottle, cath lab, and operating room will continue to evolve, we offer a revascularization strategy for patient subgroups based on what clinical data supports.

Angioplasty, Balloon, Coronary↗

PubMed1998

SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability.

A meta-analysis of the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) against nonselective and noradrenergic reuptake inhibitors (mainly tricyclic antidepressants, TCAs) in depressed inpatients was carried out. Twenty-five double-blind studies provided data on relative efficacy which was determined by a summary variance-weighted mean effect size calculated from the difference in the reduction in mean Hamilton Depression Rating Scale (HDRS) scores for the two antidepressants in each study. Twenty-three studies provided data on dropouts and relative tolerability which was determined as the variance-weighted pooling of the relative risk (RR) of dropout for all reasons and for adverse effects from each study. TCAs were significantly more effective than SSRIs (effect size = -0.23, 95% CI -0.40 to -0.05, P = 0.011), although sensitivity analyses by analysing larger studies (> 100 patients) and those providing complete data reduced the advantage to TCAs to a trend (P < 0.10). When the TCAs were grouped into those with dual action on 5-hydroxytryptamine (HT) and noradrenaline reuptake (clomipramine and amitriptyline) and those with predominantly noradrenaline reuptake (imipramine, desipramine and maprotiline), only the dual action TCAs had greater efficacy than SSRIs (effect size = -0.30, 95% CI -0.54 to -0.05, P = 0.017). When TCAs were considered individually, only amitriptyline was significantly more effective than comparator SSRIs (effect size = -0.37, 95% CI -0.67 to -0.07, P = 0.015). More patients overall discontinued treatment on TCAs than on SSRIs (29.0% vs. 25.5%), although this did not reach statistical significance (RR = 0.88, 95% CI 0.75 to 1.03, P = 0.121). However, significantly more patients stopped treatment due to adverse effects on TCAs compared to SSRIs (14.2% vs. 9.1%, RR = 0.66, 95% CI 0.50 to 0.87, P = 0.003) with no difference in discontinuations due to treatment failure (10% vs. 11.6%, RR = 1.13, 95% CI 0.84 to 1.51, P = 0.42). This meta-analysis suggests that at least some TCAs may be more effective than SSRIs in depressed inpatients, with there being the strongest evidence for amitriptyline. A possible explanation is that this is related to a dual action in inhibiting both 5-HT and noradrenaline reuptake. In agreement with previous meta-analyses, TCAs appear less well tolerated than SSRIs, although the absolute risk difference for discontinuation due to adverse effects (4.9%, 95% CI -8.1 to -1.7%) is of uncertain clinical significance.

Antidepressive Agents, Tricyclic↗

PubMed1998

[Evidence-based medicine. How to use biomedical literature to solve clinical problems. Italian Group on Evidence-Based Medicine-GIMBE].

Clinical practice is constantly changing, the rate of changing is accelerating and consequently it may even take years before the results of clinical research will be incorporated in day-to-day practice. So, there is a large gap between what the biomedical literature contains and the care that most of patients receive. The gap is widened by the extensive processing that results of clinical research require before they can be used. Evidence-based medicine is a new approach to health care promoting the collection, interpretation, and integration of valid, important and applicable research-derived evidence. The best available evidence, moderated by patient circumstances and preferences, is applied to improve the quality of clinical judgements. There are many information tools that facilitate the practice of evidence-based medicine. These include users' guides to the medical literature, strategies to improve the yield of MEDLINE searches, standardized formats for abstracts of journal articles and guidelines, new journals, systematic reviews and meta-analyses, resources on-line and software tools bringing high quality information to the point of clinical decision making. However, these tools are poorly spread and physicians lack of necessary skills for their effective utilization. In this article the authors describe guidelines for efficient and effective utilization of biomedical information tools to solve clinical problems and improve the quality and the cost/effectiveness of health care.

Evidence-Based Medicine↗

PubMed1998

Evidence-based practice.

Evidence-based practice (EBP) is spreading in popularity in many health care disciplines. One of its main features is the reliance on the partnership among hard scientific evidence, clinical expertise, and individual patient needs and choices. Librarians play an important role in the spread of EBP because of the importance of identifying and retrieving appropriate literature from various sources for use in making health care decisions. This article gives an overview of how to search for therapy, diagnosis, etiology, and prognosis both for original studies and secondary publications such as systematic reviews, meta-analyses, and clinical practice guidelines. Understanding how this research is done, how it is indexed, and how to retrieve the clinical evidence are an important set of skills that librarians can provide for clinicians interested in EBP.

Evidence-Based Medicine↗

PubMedDate not supplied

The role of H2-receptor antagonists in the pathogenesis of nosocomial pneumonia in mechanically ventilated patients.

We conducted a computerized MEDLINE search and selected controlled studies and meta-analyses correlating the frequency of nosocomial pneumonia (NP) with the administration of histamine2-receptor antagonists (H2RAs) as stress ulcer prophylaxis in critically ill patients. Although such a correlation does exist, the literature supports the theory that gastric bacterial overcolonization through alkalinization by H2RAs is not a risk factor for NP in critically ill patients. Further well-designed studies are necessary to resolve the issue and clarify the role of H2RAs in the pathogenesis of NP.

Cross Infection↗

PubMed1998

Reporting of gender-related information in clinical trials of drug therapy for myocardial infarction.

BACKGROUND: Concern has been expressed that women are not adequately represented in clinical trials evaluating treatments for medical conditions they commonly experience. This study was designed to assess the reporting of data on women in recently published trials of drug therapy for myocardial infarction, including those funded by an agency with a gender-related policy. METHODS: All randomized controlled trials and meta-analyses of drug therapies for myocardial infarction published in The New England Journal of Medicine, The Lancet, The Journal of the American Medical Association, the Annals of Internal Medicine and the British Medical Journal from January 1992 to December 1996 were evaluated. On preliminary review 102 articles met the inclusion criteria; these were reviewed in detail, and 59 were excluded. Two reviewers independently extracted gender-related information from the 43 articles; discrepancies were resolved by consensus. RESULTS: Women presented up to 48% of the trial participants (mean 24.1%). In the trials funded by an agency with a gender-related policy, only 16.8% of participants, on average, were women. Of the 43 articles in the sample, only 14 (32%) provided gender-related results. Funding from an agency with gender-related policy did not affect the reporting of gender-related information. Subgroup analyses were provided for 14 (32%) of the 43 trials, including 2 (29%) of 7 trials funded by an agency with a gender-related policy. Of the 12 trials that included interaction analyses (excluding the 2 trials in which secondary analyses were conducted specifically to identify differences between women and men), 7 (58%) conducted an interaction analysis to determine if women responded differently than men; for one of these the interaction analysis was for a secondary outcome measure (drug safety). Only 5 (12%) of the 43 articles mentioned the differences between men and women in the Discussion section; 2 of these were studies that used secondary analyses to examine sex differences. Of the 5, only 1 was funded by an agency with a gender-related policy. INTERPRETATION: Women were poorly represented in the randomized controlled trials in this sample, regardless of whether the trials were funded by an agency with a gender-related policy. Structured reporting of gender-related information for clinical trials may improve the quality of information available about women and therefore facilitate the application of research findings to the care of women.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Beta-blocker therapy for congestive heart failure: a systemic overview and critical appraisal of the published trials.

OBJECTIVE: To evaluate the effect of beta-blockers on mortality and morbidity, and to provide an appraisal of the reliability of the available data. DATA SOURCES: MEDLINE search for trials of beta-blockers for congestive heart failure (CHF). STUDY SELECTION: All randomized trials of beta-blockers versus placebo, or greater than one month's duration, in patients with CHF. Eighteen published trials involving 2986 patients were selected. DATA EXTRACTION: Independently by two authors. DATA SYNTHESIS: The Yusuf-Peto method for combining data was used. Data were available on mortality in 2841 patients (95%), on hospitalization for heart failure in 1514 (51%) and on heart transplantation in 2330 (79%). There was a lower rate of death in the active treatment group (131 of 1606) [8.2] versus 155 of 1235 [12.6%]; OR = 72; 99% CI 0.51 to 1.00), a lower rate of hospitalization for heart failure (137 of 756 [18.1%] versus 218 of 758 [28.7%]; OR = 0.54; 99% CI 0.39 to 0.74) and a trend towards a lower proportion of patients receiving heart transplantation (15 of 1354 [l.1%] versus 26 of 976 [2.7%]; OR = 0.45; 99% CI 0.20 to 1.03). Ventricular function improved; however, there was no effect on exercise duration. Although the effects on mortality were nominally statistically significant, the use of formal methods of interim monitoring adapted for meta-analyses suggests that substantially more patients still need to be studied in large scales trials to provide reliable and conclusive evidence. CONCLUSIONS: While the available data on the use of beta-blockers in CHF appear to be promising, they are neither complete nor robust. The routine use of beta-blockers in patients with heart failure should wait the results of ongoing studies.

Adrenergic beta-Antagonists↗

PubMed1996

Suicidal risk during controlled clinical investigations of fluvoxamine.

BACKGROUND: Suicide is a serious risk factor in major depressive disorder. Paradoxical emergence of suicidal ideation or behavior during antidepressant treatment has been reported in isolated cases. An evaluation was undertaken to assess the risk of suicidality during treatment with fluvoxamine, a serotonin selective reuptake inhibitor. METHOD: Meta-analyses were conducted on pooled data from double-blind, randomized, placebo-controlled, parallel-group clinical trials. The primary outcome measure was the suicide item of the Hamilton Rating Scale for Depression. Tests for emergence of substantial suicidal ideation and improvement or worsening in suicidal ideation were performed using the Mantel-Haenszel adjusted incidence difference. The Breslow-Day test was used to test for lack of homogeneity across trials. Secondary analysis, which consisted of Pearson's chi-square test, was used to confirm the Mantel-Haenszel result. RESULTS: In comparison to placebo, fluvoxamine was associated with significantly greater improvement in suicidal ideation (p = .01) and significantly less worsening of suicidal ideation (p < .01). No differences were found in the emergence of substantial suicidal ideation. CONCLUSION: These findings demonstrate that fluvoxamine is not associated with an increased risk of emergence of substantial suicidal thoughts among depressed patients. On the contrary, the results are suggestive of a protective effect of fluvoxamine upon the risk of suicidal ideation.

Adult↗

PubMed1998

Salt and hypertension at the close of the millenium.

"Can that which is unsavory be eaten without salt?" This question was directed at none other than God by Job, who also had other important problems to ponder. The question posed in this review is the notion that essential hypertension is induced and/or sustained by an unnecessarily high salt intake. If this is indeed the case, then a reduction of salt intake might prevent or effectively treat essential hypertension. A cross-sectional epidemiological study of salt intake in populations showed a positive association of sodium excretion with median blood pressure and the prevalence of hypertension; however, when four disparate populations were deleted, the associations disappeared. A Scottish report on a similarly large population minimized the importance of dietary sodium. A recently analysis of the National Health and Nutrition Examination Survey (NHANES) data base does not support the idea that lower salt intake improves all-cause or cardiovascular mortality; however, the analysis is not without weaknesses. Salt-sensitivity is based on the idea that some persons might be more susceptible to salt-induced effects on blood pressure than others. Indeed, several monogenic syndromes exhibit marked salt-sensitivity and their clarification has facilitated our understanding of basic mechanisms. Allelic variants of several genes may be important in salt-sensitive patients with essential hypertension. Meta-analyses of intervention trials in patients with essential hypertension show about a 5 mm Hg decrease in blood pressure with salt restriction. Among the normotensive, this decrease is less than 2 mm Hg. In terms of efficacy, salt restriction has not been shown superior to weight loss or a "vegetable" diet. Nonpharmacological approaches in hypertensive patients should be based on a comprehensive approach.

Diet, Sodium-Restricted↗

PubMed1997

Chemotherapy in stage IV (metastatic) non-small-cell lung cancer. Provincial Lung Disease Site Group.

GUIDELINE QUESTION: In patients with metastatic, stage IV non-small-cell lung cancer (NSCLC) does chemotherapy improve survival and quality of life? OBJECTIVE: To make recommendations about the role of chemotherapy in the treatment of metastatic (stage IV) NSCLC. OUTCOMES: Survival and quality of life are the primary endpoints of interest. Specifically, 1-year survival will be considered. PERSPECTIVE: Evidence was selected and reviewed by 3 medical oncologists and the project coordinator of the Ontario Cancer Treatment Practice Guidelines Initiative. Drafts of this document have been circulated and reviewed by the Provincial Lung Disease Site Group (Lung DSG). The Lung DSG comprises medical and radiation oncologists, pathologists, surgeons, epidemiologists, a psychologists and a medical sociologist. There was no consumer participation in the development of this guideline. QUALITY OF EVIDENCE: There were 3 meta-analyses available for review, but only 1 is discussed in detail. The largest and most comprehensive meta-analysis is based on 11 randomized controlled trials involving 1190 patients. The main comparisons were chemotherapy plus supportive care versus supportive care alone. The largest trial included in the meta-analysis involved randomization of 188 patients, and the smallest trial involved randomization of 32 patients. Only trials that had accrued patients between Jan. 1, 1965, and Dec. 31, 1991, were included in the analysis. BENEFITS: A survival benefit at 1 year was seen for the group of patients treated with chemotherapy (pooled hazard ratio 0.84; 95% confidence interval [CI], 0.74 to 0.95). Subgroup analyses suggested a benefit for patients receiving chemotherapy regimens containing cisplatin (pooled hazard ratio, 0.73; 95% CI, 0.63 to 0.85; relative risk reduction for death, 27%; absolute improvement in 1 year survival, 10%; 95% CI, 5% to 18%; gain in median survival 1.5 months; 95% CI, 1 to 2.5 months). No benefit for patients treated with chemotherapy was found beyond 1 year. None of the randomized trials successfully measured quality of life using QOL assessment instruments. No firm conclusions can be made about the potential benefits (as measured by quality of life) that chemotherapy has for patients with metastatic NSCLC, as there are no available data from randomized controlled trials. However, several trials have documented relief of cancer-related symptoms, such as pain, cough, hemoptysis or dyspnea in the majority (approximately 70%) of patients. HARMS: In a subgroup analysis of trials that used long-term alkylating agents other than cisplatin (an approach no longer used as therapy in NSCLC) as part of the chemotherapy regimen, the meta-analysis demonstrated a detrimental effect of chemotherapy on survival (pooled hazard ratio, 1.26; 95% CI, 0.96 to 1.66, p = 0.09). In general, myelosuppression, sepsis resulting in hospitalization, drug-specific toxicities and death are potential complications of chemotherapy.

Carcinoma, Non-Small-Cell Lung↗

PubMed1997

Adjuvant therapy for stage III colon cancer after complete resection. Provincial Gastrointestinal Disease Site Group.

GUIDELINE QUESTIONS: Should patients with resected stage III colon cancer receive adjuvant therapy? If so, which therapy should be recommended? OBJECTIVE: To make recommendations regarding the use of adjuvant therapy in the treatment of resected stage III colon cancer. OUTCOMES: Overall survival is the primary outcome of interest. Secondary outcomes are disease-free survival and adverse effects of the treatment regimens. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 4 members of the Gastrointestinal Disease Site Group (GI DSG) of the Ontario Cancer Treatment Practice Guidelines Initiative. Earlier drafts of the guideline were reviewed, discussed and approved by the GI DSG, which comprises medical and radiation oncologists, surgeons and epidemiologists. Community representatives did not participate in the development of this guideline but will participate in future guidelines development. QUALITY OF EVIDENCE: There are 3 meta-analyses, 33 published randomized controlled trials (RCTs) and 1 consensus statement. The GI DSG pooled data from 10 of the 33 RCTs that allowed for such an analysis. BENEFITS: Two of 3 RCTs reported improved survival rates with 5-fluorouracil (5-FU) plus semustine or mitomycin C (MMC) compared with no treatment (observation) after surgical resection. Three trials reported a benefit in both overall and disease-free survival with 5-FU plus levamisole compared with observation after surgery. In 2 trials, levamisole alone did not produce a survival benefit compared with observation. One trial reported improved disease-free, but not overall, survival rates with oral HCFU (1-hexylcarbamoyl-5-fluorouracil) compared with observation. In 3 trials of 5-FU plus leucovorin, disease-free and overall survival rates were improved compared with observation. Nine trials compared portal vein infusion (PVI) of 5-FU with observation after surgery. In 2 of the trials, for which data were available for stage III patients only, improved overall survival was reported. There was a trend in all studies favouring PVI. One trial reported a survival benefit for stage III and IV patients who received oral HCFU maintenance therapy for 1 year compared with no maintenance therapy. In a trial comparing MMC plus oral HCFU with MMC alone, a survival benefit was reported in the combined treatment group; however, the stages of cancer were unevenly distributed among the treatment groups. Only 1 study tested monoclonal antibody; a benefit was reported for both overall and disease-free survival. A meta-analysis of 10 trials comparing adjuvant therapy with observation in patients with stage III disease detected a significant reduction in the odds ratio (OR) for death (OR 0.69; 95% confidence interval [CI] 0.57 to 0.85), with an absolute improvement in survival of 4% to 13%. When trials were separated according to the type of treatment given, the significant ORs were for 5-FU plus either levamisole (OR 0.61; 95% CI 0.46 to 0.80) or leucovorin (OR 0.51; 95% CI 0.36 to 0.73). Three recently reported trials comparing various combinations of 5-FU plus leucovorin, with or without levamisole, showed similar improvements in disease-free and overall survival.

Chemotherapy, Adjuvant↗

PubMed1998

Antibiotic-resistant Streptococcus pneumoniae. Implications for medical practice.

OBJECTIVE: To review the definition and prevalence of antibiotic-resistant Streptococcus pneumoniae, its links with antibiotic prescribing, data on antibiotic prescribing and prescribing appropriateness, and evidence-based treatment guidelines for common respiratory tract syndromes. QUALITY OF EVIDENCE: Primary studies consist of cross-sectional surveys and case-control studies. Treatment guidelines are based on clinical trials, meta-analyses, and cohort studies. Study designs were appropriate for the specific study questions. MAIN FINDINGS: The increasing prevalence of penicillin-resistant S pneumoniae is concurrent with increasing antibiotic prescribing. Individual patients show a twofold to ninefold increase in nasopharyngeal carriage of resistant bacteria or invasion with resistant bacteria (among those who have received antibiotics in the preceding 3 months). Cross-sectional data as well as data from medicaid and drug databases attest to overprescribing of antibiotics for respiratory tract infections. Physician surveys and focus groups blame this on parental pressure for antibiotic prescriptions. However, parents in focus groups and surveys deny they pressure their physicians and indicate their main purpose for office visits is to obtain a diagnosis and to seek reassurance that their children are not seriously ill. Evidence-based guidelines suggest treatment strategies that would reduce antibiotic prescribing. CONCLUSIONS: The few antibiotics that can be used with resistant organisms are expensive and are increasingly being needed. To control the rise of antibiotic resistance, it is important to limit antibiotic overprescribing.

Anti-Bacterial Agents↗

PubMed1998

The comparative effectiveness of treatments for obsessive-compulsive disorder.

With the exception of neurosurgery, treatments for obsessive-compulsive disorder were largely ineffective until 1996. That year, clomipramine became available and the first article describing modern behavior therapy was published. Potent serotonin reuptake inhibitors and behavior therapy involving exposure and ritual prevention have been established as the cornerstones of effective treatment for obsessive-compulsive disorder. Methods for optimizing effectiveness of these two main modalities are more widely recognized, although overdosing may hamper effective pharmacotherapy. The comparative efficacies of pharmacotherapy and behavior therapy remain in dispute, although all meta-analyses have identified behavior therapy as more effective both in terms of magnitude of improvement short term and lasting gains long term. Finally, neurosurgery still merits consideration for the tiny minority of patients who are incapacitated by OCD and unresponsive to serotonin reuptake inhibitors and behavior therapy.

Behavior Therapy↗

PubMed1998

Pharmaco-economic aspects of lipid-lowering therapy: is it worth the price?

The increased incidence and prevalence of coronary heart disease (CHD) in recent years has produced a great economic burden on total health care expenditure in many countries. This includes the increased cost of prevention as well as the enormous cost of treatment of CHD and related events. The clinical usefulness and benefits of statins in primary and secondary prevention of CHD has been well established. However, an important issue is whether health care decision-makers will pay for these medicines. Pharmaco-economic analyses of statins have become extremely important in substantiating the true economic value of these lipid-lowering therapies. Recently published, large-scale outcome studies demonstrate a reduction in cardiovascular morbidity and mortality with statins, and the data from these trials have been used to conduct pharmaco-economic appraisals. Statin treatment was shown to be cost-effective in comparison with other health care interventions, and cost-effectiveness was related to the efficacy of the drug and the risk of cardiovascular disease at baseline. In addition, the cost-effectiveness of statins was improved by about 40% if high density lipoprotein cholesterol levels were taken into account. It has been suggested that the cost-effectiveness of statins has been underestimated, since early large-outcome trials did not use stroke as a primary endpoint. When the costs of managing stroke were taken into consideration in recent meta-analyses, the cost-effectiveness of statins was significantly greater than had been previously thought.

Coronary Disease↗

PubMed1998

Regional and systemic therapies for advanced colorectal carcinoma: randomized clinical trial results.

The treatment of advanced colorectal cancer has been evaluated in a series of randomized trials, including infusional and modulated 5-fluorouracil (5-FU), and three meta-analyses encompassing trials of 5-FU plus leucovorin, continuous-infusion 5-FU, and intra-arterial fluoropyrimidines. A Southwest Oncology Group seven-arm phase II trial suggested that infusional 5-FU produced the most favorable toxicity spectrum and the longest survival, warranting further investigation in phase III trials. In a randomized phase III five-arm trial conducted by the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B, significant toxicity differences noted among the arms favored high-dose infusional 5-FU. In addition, the trial showed that 5-FU modulated by leucovorin or interferon was not more effective than 5-FU given as a 24-hour high-dose infusion weekly, and N-(phosphonacetyl)-L-aspartic acid did not enhance the activity of the weekly infusional 5-FU. Oral leucovorin provided no advantage over IV dosing. There was a significant difference in survival for patients with nonmeasurable disease (16.9 months) compared to those with measurable disease (12.6 months, P = .001). The Advanced Colorectal Cancer Meta-analysis Project demonstrated a response advantage for patients receiving 5-FU plus leucovorin (23%) compared to those receiving bolus 5-FU (11%, P = 10(-7); however, there was no survival advantage of 5-FU plus leucovorin over 5-FU alone (P = 0.57). The Meta-Analysis Group in Cancer showed that continuous-infusion 5-FU resulted in a statistically significantly higher response rate than bolus 5-FU (22% vs 14%, P = .0002). Overall survival also favored continuous-infusion 5-FU (P = .04). Continuous-infusion 5-FU was less toxic than bolus treatment. Data from six select randomized trials comparing hepatic intra-arterial infusion of FUDR to systemic therapy demonstrated a significant difference favoring intra-arterial therapy. Future directions for the treatment of advanced colorectal cancer include ongoing trials comparing low-dose vs high-dose infusional 5-FU, intra-arterial FUDR, leucovorin and dexamethasone vs systemic leucovorin plus 5-FU and proposed trials evaluating the dihydropyrimidine dehydrogenase inhibitor eniluracil plus oral 5-FU. Other drugs of interest include UFT, capecitabine, thymidylate synthase inhibitors, oxaliplatin, and irinotecan combinations.

Antimetabolites, Antineoplastic↗

PubMed1998

[Critical review of the randomized trials assessing the role of adjuvant thoracic irradiation and chemotherapy in the treatment of limited-stage small cell lung cancer].

The role of chest irradiation in the treatment of small cell lung cancer remains controversial. Two meta-analyses have shown a significant improvement of survival when this therapy is associated to chemotherapy but the controlled studies individually lead to contradictory conclusions. We have performed qualitative and quantitative evaluation of the literature on this topic in order to try to clarify this problem. On 15 published trials, 8 only give sufficient data allowing a meta-analysis. This does not show that chest irradiation improves statistically significantly survival in comparison to chemotherapy alone (odds ratio = 0.82; 95% CI: 0.63-1.07). The qualitative evaluation has been performed with the Chalmers and ELCWP scales. The scores obtained by both methods are highly correlated. There is no significant difference between the scores obtained by studies showing a survival improvement with irradiation or by negative studies. Very few trials report important criteria like definition of the primary end-point or the a priori estimate of the population size, attesting important methodological deficiencies. In conclusion, the quantitative aggregation of studies seems difficult to interpret because of the non optimal quality of the studies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

ICON2: randomised trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer. ICON Collaborators. International Collaborative Ovarian Neoplasm Study.

BACKGROUND: A series of meta-analyses of randomised controlled trials raised the question of whether the three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) was more or less effective than optimal-dose single-agent carboplatin for women with advanced ovarian cancer. METHODS: We carried out an international, multicentre, randomised trial to compare CAP with single-agent carboplatin in women with ovarian cancer requiring chemotherapy. 1526 patients were entered from 132 centres in nine countries. Analyses were by intention to treat. FINDINGS: 728 patients have died (368/766 allocated CAP vs 360/760 allocated carboplatin) and the survival curves show no evidence of a difference between CAP and carboplatin (hazard ratio 1.00 [95% CI 0.86-1.16]; p=0.98). The results indicate a median survival of 33 months and a 2-year survival of 60% for both groups. We found no evidence that CAP or carboplatin were more or less effective in different subgroups defined by age, stage, residual disease, differentiation, histology, and coordinating centre. CAP was substantially more toxic than carboplatin, causing more alopecia, leucopenia, and nausea. More thrombocytopenia occurred with carboplatin. INTERPRETATION: Single-agent carboplatin, with the dose calculated by the area-under-the-curve method, is a safe, effective, and appropriate standard of treatment for women with advanced ovarian cancer.

Aged↗