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The Lancet. Neurology Mar 2014Neurodevelopmental disabilities, including autism, attention-deficit hyperactivity disorder, dyslexia, and other cognitive impairments, affect millions of children... (Review)
Review
Neurodevelopmental disabilities, including autism, attention-deficit hyperactivity disorder, dyslexia, and other cognitive impairments, affect millions of children worldwide, and some diagnoses seem to be increasing in frequency. Industrial chemicals that injure the developing brain are among the known causes for this rise in prevalence. In 2006, we did a systematic review and identified five industrial chemicals as developmental neurotoxicants: lead, methylmercury, polychlorinated biphenyls, arsenic, and toluene. Since 2006, epidemiological studies have documented six additional developmental neurotoxicants-manganese, fluoride, chlorpyrifos, dichlorodiphenyltrichloroethane, tetrachloroethylene, and the polybrominated diphenyl ethers. We postulate that even more neurotoxicants remain undiscovered. To control the pandemic of developmental neurotoxicity, we propose a global prevention strategy. Untested chemicals should not be presumed to be safe to brain development, and chemicals in existing use and all new chemicals must therefore be tested for developmental neurotoxicity. To coordinate these efforts and to accelerate translation of science into prevention, we propose the urgent formation of a new international clearinghouse.
Topics: Animals; Brain; Developmental Disabilities; Environmental Exposure; Humans; Methylmercury Compounds; Neurotoxicity Syndromes; Polychlorinated Biphenyls
PubMed: 24556010
DOI: 10.1016/S1474-4422(13)70278-3 -
The American Journal of Gastroenterology Jun 2021Constipation is commonly treated with over-the-counter (OTC) products whose efficacy and safety remain unclear. We performed a systematic review of OTC therapies for...
INTRODUCTION
Constipation is commonly treated with over-the-counter (OTC) products whose efficacy and safety remain unclear. We performed a systematic review of OTC therapies for chronic constipation and provide evidence-based recommendations.
METHODS
We searched PubMed and Embase for randomized controlled trials of ≥4-week duration that evaluated OTC preparations between 2004 and 2020. Studies were scored using the US Preventive Services Task Force criteria (0-5 scale) including randomization, blinding, and withdrawals. The strengths of evidence were adjudicated within each therapeutic category, and recommendations were graded (A, B, C, D, and I) based on the level of evidence (level I, good; II, fair; or III, poor).
RESULTS
Of 1,297 studies identified, 41 met the inclusion criteria. There was good evidence (grade A recommendation) for the use of the osmotic laxative polyethylene glycol (PEG) and the stimulant senna; moderate evidence (grade B) for psyllium, SupraFiber, magnesium salts, stimulants (bisacodyl and sodium picosulfate), fruit-based laxatives (kiwi, mango, prunes, and ficus), and yogurt with galacto-oligosaccharide/prunes/linseed oil; and insufficient evidence (grade I) for polydextrose, inulin, and fructo-oligosaccharide. Diarrhea, nausea, bloating, and abdominal pain were common adverse events, but no serious adverse events were reported.
DISCUSSION
The spectrum of OTC products has increased and quality of evidence has improved, but methodological issues including variability in study design, primary outcome measures, trial duration, and small sample sizes remain. We found good evidence to recommend polyethylene glycol or senna as first-line laxatives and moderate evidence supporting fiber supplements, fruits, stimulant laxatives, and magnesium-based products. For others, further validation with more rigorously designed studies is warranted.
Topics: Bisacodyl; Cathartics; Chronic Disease; Citrates; Constipation; Defecation; Fruit; Gastrointestinal Agents; Glucans; Humans; Inulin; Laxatives; Magnesium; Nonprescription Drugs; Oligosaccharides; Organometallic Compounds; Picolines; Polyethylene Glycols; Psyllium; Senna Extract; Yogurt
PubMed: 33767108
DOI: 10.14309/ajg.0000000000001222 -
The Cochrane Database of Systematic... Jul 2017Burn wounds cause high levels of morbidity and mortality worldwide. People with burns are particularly vulnerable to infections; over 75% of all burn deaths (after... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Burn wounds cause high levels of morbidity and mortality worldwide. People with burns are particularly vulnerable to infections; over 75% of all burn deaths (after initial resuscitation) result from infection. Antiseptics are topical agents that act to prevent growth of micro-organisms. A wide range are used with the intention of preventing infection and promoting healing of burn wounds.
OBJECTIVES
To assess the effects and safety of antiseptics for the treatment of burns in any care setting.
SEARCH METHODS
In September 2016 we searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations), Ovid Embase, and EBSCO CINAHL. We also searched three clinical trials registries and references of included studies and relevant systematic reviews. There were no restrictions based on language, date of publication or study setting.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that enrolled people with any burn wound and assessed the use of a topical treatment with antiseptic properties.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed study selection, risk of bias assessment and data extraction.
MAIN RESULTS
We included 56 RCTs with 5807 randomised participants. Almost all trials had poorly reported methodology, meaning that it is unclear whether they were at high risk of bias. In many cases the primary review outcomes, wound healing and infection, were not reported, or were reported incompletely.Most trials enrolled people with recent burns, described as second-degree and less than 40% of total body surface area; most participants were adults. Antiseptic agents assessed were: silver-based, honey, Aloe Vera, iodine-based, chlorhexidine or polyhexanide (biguanides), sodium hypochlorite, merbromin, ethacridine lactate, cerium nitrate and Arnebia euchroma. Most studies compared antiseptic with a topical antibiotic, primarily silver sulfadiazine (SSD); others compared antiseptic with a non-antibacterial treatment or another antiseptic. Most evidence was assessed as low or very low certainty, often because of imprecision resulting from few participants, low event rates, or both, often in single studies. Antiseptics versus topical antibioticsCompared with the topical antibiotic, SSD, there is low certainty evidence that, on average, there is no clear difference in the hazard of healing (chance of healing over time), between silver-based antiseptics and SSD (HR 1.25, 95% CI 0.94 to 1.67; I = 0%; 3 studies; 259 participants); silver-based antiseptics may, on average, increase the number of healing events over 21 or 28 days' follow-up (RR 1.17 95% CI 1.00 to 1.37; I = 45%; 5 studies; 408 participants) and may, on average, reduce mean time to healing (difference in means -3.33 days; 95% CI -4.96 to -1.70; I = 87%; 10 studies; 979 participants).There is moderate certainty evidence that, on average, burns treated with honey are probably more likely to heal over time compared with topical antibiotics (HR 2.45, 95% CI 1.71 to 3.52; I = 66%; 5 studies; 140 participants).There is low certainty evidence from single trials that sodium hypochlorite may, on average, slightly reduce mean time to healing compared with SSD (difference in means -2.10 days, 95% CI -3.87 to -0.33, 10 participants (20 burns)) as may merbromin compared with zinc sulfadiazine (difference in means -3.48 days, 95% CI -6.85 to -0.11, 50 relevant participants). Other comparisons with low or very low certainty evidence did not find clear differences between groups.Most comparisons did not report data on infection. Based on the available data we cannot be certain if antiseptic treatments increase or reduce the risk of infection compared with topical antibiotics (very low certainty evidence). Antiseptics versus alternative antisepticsThere may be some reduction in mean time to healing for wounds treated with povidone iodine compared with chlorhexidine (MD -2.21 days, 95% CI 0.34 to 4.08). Other evidence showed no clear differences and is of low or very low certainty. Antiseptics versus non-antibacterial comparatorsWe found high certainty evidence that treating burns with honey, on average, reduced mean times to healing in comparison with non-antibacterial treatments (difference in means -5.3 days, 95% CI -6.30 to -4.34; I = 71%; 4 studies; 1156 participants) but this comparison included some unconventional treatments such as amniotic membrane and potato peel. There is moderate certainty evidence that honey probably also increases the likelihood of wounds healing over time compared to unconventional anti-bacterial treatments (HR 2.86, 95% C 1.60 to 5.11; I = 50%; 2 studies; 154 participants).There is moderate certainty evidence that, on average, burns treated with nanocrystalline silver dressings probably have a slightly shorter mean time to healing than those treated with Vaseline gauze (difference in means -3.49 days, 95% CI -4.46 to -2.52; I = 0%; 2 studies, 204 participants), but low certainty evidence that there may be little or no difference in numbers of healing events at 14 days between burns treated with silver xenograft or paraffin gauze (RR 1.13, 95% CI 0.59 to 2.16 1 study; 32 participants). Other comparisons represented low or very low certainty evidence.It is uncertain whether infection rates in burns treated with either silver-based antiseptics or honey differ compared with non-antimicrobial treatments (very low certainty evidence). There is probably no difference in infection rates between an iodine-based treatment compared with moist exposed burn ointment (moderate certainty evidence). It is also uncertain whether infection rates differ for SSD plus cerium nitrate, compared with SSD alone (low certainty evidence).Mortality was low where reported. Most comparisons provided low certainty evidence that there may be little or no difference between many treatments. There may be fewer deaths in groups treated with cerium nitrate plus SSD compared with SSD alone (RR 0.22, 95% CI 0.05 to 0.99; I = 0%, 2 studies, 214 participants) (low certainty evidence).
AUTHORS' CONCLUSIONS
It was often uncertain whether antiseptics were associated with any difference in healing, infections, or other outcomes. Where there is moderate or high certainty evidence, decision makers need to consider the applicability of the evidence from the comparison to their patients. Reporting was poor, to the extent that we are not confident that most trials are free from risk of bias.
Topics: Adult; Anti-Bacterial Agents; Anti-Infective Agents, Local; Apitherapy; Bacterial Infections; Bandages; Burns; Chlorhexidine; Disinfectants; Honey; Humans; Merbromin; Plant Preparations; Povidone-Iodine; Randomized Controlled Trials as Topic; Silver Sulfadiazine; Sodium Hypochlorite; Sulfadiazine; Wound Healing
PubMed: 28700086
DOI: 10.1002/14651858.CD011821.pub2 -
Annals of Oncology : Official Journal... Jul 2018The role of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients is highly controversial and it is not endorsed by current... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The role of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients is highly controversial and it is not endorsed by current guidelines. Our meta-analysis aimed to better elucidate its activity, efficacy and safety.
MATERIAL AND METHODS
A systematic search of Medline, Web of Science and conferences proceedings up to 30 October 2017 was carried out to identify randomized controlled trials (RCTs) investigating platinum-based versus platinum-free neoadjuvant chemotherapy in TNBC patients. Using the fixed and random effects models, pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CI) were calculated for pathological complete response (pCR, defined as ypT0/is pN0), event-free survival (EFS), overall survival (OS) and grade 3 and 4 adverse events (AEs: neutropenia, anemia, thrombocytopenia and neuropathy).
RESULTS
Nine RCTs (N = 2109) were included. Overall, platinum-based neoadjuvant chemotherapy significantly increased pCR rate from 37.0% to 52.1% (OR 1.96, 95% CI 1.46-2.62, P < 0.001). Platinum-based neoadjuvant chemotherapy remained significantly associated with increased pCR rate also after restricting the analysis to the three RCTs (N = 611) that used the same standard regimen in both groups of weekly paclitaxel (with or without carboplatin) followed by anthracycline and cyclophosphamide (OR 2.53, 95% CI 1.37-4.66, P = 0.003). Conversely, among the 96 BRCA-mutated patients included in two RCTs, the addition of carboplatin was not associated with significantly increased pCR rate (OR 1.17, 95% CI 0.51-2.67, P = 0.711). Two RCTs (N = 748) reported survival outcomes: no significant difference in EFS (HR 0.72, 95% CI 0.49-1.06, P = 0.094) and OS (HR 0.86, 95% CI 0.46-1.63, P = 0.651) was observed. A significant higher risk of grade 3 and 4 hematological AEs, with no increased risk of grade 3 and 4 neuropathy was observed with platinum-based neoadjuvant chemotherapy.
CONCLUSION
In TNBC patients, platinum-based neoadjuvant chemotherapy is associated with significantly increased pCR rates at the cost of worse hematological toxicities. Platinum-based neoadjuvant chemotherapy may be considered an option in TNBC patients.
PROSPERO REGISTRATION NUMBER
CRD42018080042.
Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Female; Humans; Neoadjuvant Therapy; Organoplatinum Compounds; Prognosis; Triple Negative Breast Neoplasms
PubMed: 29873695
DOI: 10.1093/annonc/mdy127 -
The Lancet. Oncology Jun 201635% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population.
METHODS
We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan-Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model.
FINDINGS
We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0-16·0) to 32·7 months (23·1-42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7-26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5-34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8-16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3-81·6, I(2) 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2-31·9, I(2) 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2-92·2, I(2) 64%).
INTERPRETATION
Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months-longer than that reported with gemcitabine (6-13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX.
FUNDING
None.
Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Survival Rate; Gemcitabine
PubMed: 27160474
DOI: 10.1016/S1470-2045(16)00172-8 -
Gut Sep 2017To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis.
DATA SOURCES
We conducted searches (inception to May 2015) of MEDLINE, EMBASE, Scopus and Cochrane Central, as well as original data from authors or drug companies for the medications used for CIC.
STUDY SELECTION
Phase IIB and phase III randomised, placebo-controlled trials (RCT) of ≥4 weeks' treatment for CIC in adults with Rome II or III criteria for functional constipation; trials included at least one of four end points.
DATA EXTRACTION AND SYNTHESIS
Two investigators independently evaluated all full-text articles that met inclusion criteria and extracted data for primary and secondary end points, risk of bias and quality of evidence.
OUTCOMES
Primary end points were ≥3 complete spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. Secondary end points were change from baseline (Δ) in the number of SBM/week and Δ CSBM/week.
RESULTS
Twenty-one RCTs (9189 patients) met inclusion and end point criteria: 9 prucalopride, 3 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each velusetrag, elobixibat, bisacodyl and sodium picosulphate (NaP). All prespecified end points were unavailable in four polyethylene glycol studies. Bisacodyl, NaP, prucalopride and velusetrag were superior to placebo for the ≥3 CSBM/week end point. No drug was superior at improving the primary end points on network meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary end point, Δ in number of SBM/week.
CONCLUSIONS
Current drugs for CIC show similar efficacy. Bisacodyl may be superior to prescription medications for Δ in the number of SBM/week in CIC.
Topics: Azabicyclo Compounds; Benzofurans; Bisacodyl; Chronic Disease; Citrates; Constipation; Defecation; Drug Monitoring; Gastrointestinal Agents; Humans; Organometallic Compounds; Picolines; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 27287486
DOI: 10.1136/gutjnl-2016-311835 -
BMJ Clinical Evidence Apr 2015It is estimated that approximately 30% to 70% of international travellers will develop diarrhoea during their travels or after returning home. (Review)
Review
INTRODUCTION
It is estimated that approximately 30% to 70% of international travellers will develop diarrhoea during their travels or after returning home.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute mild-to-moderate diarrhoea in adults from resource-rich countries travelling to resource-poor countries? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 24 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (empirical), antibiotics plus antimotility agents, antimotility agents, bismuth subsalicylate, diet, oral rehydration solutions, and racecadotril for travellers' diarrhoea.
Topics: Anti-Bacterial Agents; Antidiarrheals; Bismuth; Diarrhea; Diet; Fluid Therapy; Humans; Organometallic Compounds; Salicylates; Thiorphan; Travel-Related Illness
PubMed: 25928418
DOI: No ID Found -
JAMA Internal Medicine Feb 2020Risk of nephrogenic systemic fibrosis (NSF) to individual patients with stage 4 or 5 chronic kidney disease (CKD; defined as estimated glomerular filtration rate of <30... (Meta-Analysis)
Meta-Analysis
Risk of Nephrogenic Systemic Fibrosis in Patients With Stage 4 or 5 Chronic Kidney Disease Receiving a Group II Gadolinium-Based Contrast Agent: A Systematic Review and Meta-analysis.
IMPORTANCE
Risk of nephrogenic systemic fibrosis (NSF) to individual patients with stage 4 or 5 chronic kidney disease (CKD; defined as estimated glomerular filtration rate of <30 mL/min/1.73 m2) who receive a group II gadolinium-based contrast agent (GBCA) is not well understood or summarized in the literature.
OBJECTIVE
To assess the pooled risk of NSF in patients with stage 4 or 5 CKD receiving a group II GBCA.
DATA SOURCES
A health sciences informationist searched the Ovid (MEDLINE and MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citation, and Daily and Versions), Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Open Grey databases from inception to January 29, 2019, yielding 2700 citations.
STUDY SELECTION
Citations were screened for inclusion in a multistep process. Agreement for final cohort inclusion was determined by 2 blinded screeners using Cohen κ. Inclusion criteria consisted of stage 4 or 5 CKD with or without dialysis, administration of an unconfounded American College of Radiology classification group II GBCA (gadobenate dimeglumine, gadobutrol, gadoterate meglumine, or gadoteridol), and incident NSF as an outcome. Conference abstracts, retracted manuscripts, narrative reviews, editorials, case reports, and manuscripts not reporting total group II GBCA administrations were excluded.
DATA EXTRACTION AND SYNTHESIS
Data extraction was performed for all studies by a single investigator, including publication details, study design and time frame, patient characteristics, group II GBCA(s) administered, total exposures for patients with stage 4 or stage 5 CKD, total cases of unconfounded NSF, reason for GBCA administration, follow-up duration, loss to follow-up, basis for NSF screening, and diagnosis.
MAIN OUTCOMES AND MEASURES
Pooled incidence of NSF and the associated upper bound of a 2-sided 95% CI (risk estimate) for the pooled data and each of the 4 group II GBCAs.
RESULTS
Sixteen unique studies with 4931 patients were included (κ = 0.68) in this systematic review and meta-analysis. The pooled incidence of NSF was 0 of 4931 (0%; upper bound of 95% CI, 0.07%). The upper bound varied owing to different sample sizes for gadobenate dimeglumine (0 of 3167; upper bound of 95% CI, 0.12%), gadoterate meglumine (0 of 1204; upper bound of 95% CI, 0.31%), gadobutrol (0 of 330; upper bound of 95% CI, 1.11%), and gadoteridol (0 of 230; upper bound of 95% CI, 1.59%).
CONCLUSIONS AND RELEVANCE
This study's findings suggest that the risk of NSF from group II GBCA administration in stage 4 or 5 CKD is likely less than 0.07%. The potential diagnostic harms of withholding group II GBCA for indicated examinations may outweigh the risk of NSF in this population.
TRIAL REGISTRATION
PROSPERO identifier: CRD42019123284.
Topics: Contraindications, Drug; Contrast Media; Gadolinium; Glomerular Filtration Rate; Heterocyclic Compounds; Humans; Meglumine; Nephrogenic Fibrosing Dermopathy; Organometallic Compounds; Practice Guidelines as Topic; Renal Insufficiency, Chronic; Risk; Severity of Illness Index; United States; United States Food and Drug Administration
PubMed: 31816007
DOI: 10.1001/jamainternmed.2019.5284 -
The Cochrane Database of Systematic... Jun 2017Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer. Most of these studies were... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer. Most of these studies were conducted prior to the 'intrinsic subtype' era, and did not specifically focus on metastatic triple-negative breast cancers (mTNBCs).
OBJECTIVES
To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer.
SEARCH METHODS
For this review update, we searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov on 28 May 2015. We identified further potentially relevant studies from handsearching references of previous trials, systematic reviews, and meta-analyses. Prior to this review update, the most recent search for studies was conducted in May 2003 for the original 2004 review.
SELECTION CRITERIA
Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer.
DATA COLLECTION AND ANALYSIS
At least two independent reviewers assessed studies for eligibility and quality, and extracted all relevant data from each study. Hazard ratios (HRs) were derived for time-to-event outcomes, where possible, and fixed-effect models were used for meta-analyses. Objective tumour response rates (OTRRs) and toxicities were analysed as binary (dichotomous) outcomes with risk ratios (RRs) used as measures of effects. Quality of life data were extracted where available. GRADE was used to rate the quality of evidence for survival and tumour response outcomes at the level of subgroups selected and unselected for mTNBC, and for toxicity outcomes based on combining data from selected and unselected populations.
MAIN RESULTS
This update includes 15 new eligible treatment-comparisons from 12 studies. In total, 28 treatment-comparisons, involving 4418 women, from 24 studies are now included in one or more meta-analyses. Of the 28 treatment-comparisons, 19 and 16 had published or provided extractable time-to-event data on overall survival (OS) or progression-free survival/time to progression (PFS/TTP), respectively. All 28 treatment-comparisons provided OTRR data that could be included in meta-analyses. Most women recruited to the studies were not selected on the basis of mTNBC status.In a subgroup of three treatment-comparisons assessing women with mTNBC, platinum-containing regimens may have provided a survival benefit (HR 0.75, 95% CI 0.57 to 1.00; low-quality evidence). In women unselected for intrinsic subtypes such as mTNBC, there was little or no effect on survival (HR 1.01, 95% CI 0.92 to 1.12; high-quality evidence). This effect was similar to the combined analysis of survival data for both populations (HR 0.98, 95% CI 0.89 to 1.07; I =39%, 1868 deaths, 2922 women; 19 trials). The difference in treatment effects between mTNBC women compared with unselected women was of borderline statistical significance (P = 0.05).Data from three treatment-comparisons with mTNBC participants showed that platinum regimens may improve PFS/TTP (HR 0.59, 95% CI 0.49 to 0.72; low-quality evidence). Thirteen treatment-comparisons of unselected metastatic participants showed that there was probably a small PFS/TTP benefit for platinum recipients, although the confidence interval included no difference (HR 0.92, 95% CI 0.84 to 1.01; moderate-quality evidence). Combined analysis of data from an estimated 1772 women who progressed or died out of 2136 women selected or unselected for mTNBC indicated that platinum-containing regimens improved PFS/TTP (HR 0.85, 95% CI 0.78 to 0.93). There was marked evidence of heterogeneity (P = 0.0004; I = 63%). The larger treatment benefit in mTNBC women compared with unselected women was statistically significant (P < 0.0001).There was low-quality evidence of better tumour response in both subgroups of women with mTNBC and unselected women (RR 1.33, 95% CI 1.13 to 1.56; RR 1.11, 95% CI 1.04 to 1.19, respectively). Combined analysis of both populations was closer to the effect in unselected women (RR 1.15, 95% CI 1.08 to 1.22; 4130 women). There was considerable evidence of heterogeneity (P < 0.0001; I = 64%), which may reflect between-study differences and general difficulties in assessing response, as well as the varying potencies of the comparators.Compared with women receiving non-platinum regimens: rates of grade 3 and 4 nausea/vomiting were probably higher among women receiving cisplatin- (RR 2.65, 95% CI 2.10 to 3.34; 1731 women; moderate-quality evidence) but the effect from carboplatin-containing regimens was less certain (RR 0.77, 95% CI 0.47 to 1.26; 1441 women; moderate-quality evidence); rates of grade 3 and 4 anaemia were higher among women receiving cisplatin- (RR 3.72, 95% CI 2.36 to 5.88; 1644 women; high-quality evidence) and carboplatin-containing regimens (RR 1.72, 95% CI 1.10 to 2.70; 1441 women; high-quality evidence); rates of grade 3 and 4 hair loss (RR 1.41, 95% CI 1.26 to 1.58; 1452 women; high-quality evidence) and leukopenia (RR 1.38, 95% CI 1.21 to 1.57; 3176 women; moderate-quality evidence) were higher among women receiving platinum-containing regimens (regardless of platinum agent).
AUTHORS' CONCLUSIONS
In women with metastatic breast cancer who do not have triple-negative disease, there is high-quality evidence of little or no survival benefit and excess toxicity from platinum-based regimens. There is preliminary low-quality evidence of a moderate survival benefit from platinum-based regimens for women with mTNBC. Further randomised trials of platinum-based regimens in this subpopulation of women with metastatic breast cancer are required.
Topics: Alopecia; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Cisplatin; Disease-Free Survival; Female; Humans; Leukopenia; Nausea; Organoplatinum Compounds; Pyridines; Randomized Controlled Trials as Topic; Survival Rate; Triple Negative Breast Neoplasms; Vomiting
PubMed: 28643430
DOI: 10.1002/14651858.CD003374.pub4 -
The Cochrane Database of Systematic... Jan 2017The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge.
OBJECTIVES
To determine the efficacy and toxicity of second-line systemic therapy in people with metastatic CRC.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 4), Ovid MEDLINE (1950 to May 2016), Ovid MEDLINE In-process & Other Non-Indexed Citations (1946 to May 2016) and Ovid Embase (1974 to May 2016). There were no language or date of publication restrictions.
SELECTION CRITERIA
Randomized controlled trials (RCTs) assessing the efficacy (survival, tumour response) and toxicity (incidence of severe adverse effects (SAEs)) of second-line systemic therapy (single or combined treatment with any anticancer drug, at any dose and number of cycles) in people with metastatic CRC that progressed, recurred or did not respond to first-line systemic therapy.
DATA COLLECTION AND ANALYSIS
Authors performed a descriptive analysis of each included RCT in terms of primary (survival) and secondary (tumour response, toxicity) endpoints. In the light of the variety of drug regimens tested in the included trials, we could carry out meta-analysis considering classes of (rather than single) anticancer regimens; to this aim, we applied the random-effects model to pool the data. We used hazard ratios (HRs) and risk ratios (RRs) to describe the strength of the association for survival (overall (OS) and progression-free survival (PFS)) and dichotomous (overall response rate (ORR) and SAE rate) data, respectively, with 95% confidence intervals (CI).
MAIN RESULTS
Thirty-four RCTs (enrolling 13,787 participants) fulfilled the eligibility criteria. Available evidence enabled us to address multiple clinical issues regarding the survival effects of second-line systemic therapy of people with metastatic CRC.1. Chemotherapy (irinotecan) was more effective than best supportive care (HR for OS: 0.58, 95% CI 0.43 to 0.80; 1 RCT; moderate-quality evidence); 2. modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT; moderate-quality evidence); 3. irinotecan-based combinations were more effective than irinotecan alone (HR for PFS: 0.68, 95% CI 0.60 to 0.76; 6 RCTs; moderate-quality evidence); 4. targeted agents improved the efficacy of conventional chemotherapy both when considered together (HR for OS: 0.84, 95% CI 0.77 to 0.91; 6 RCTs; high-quality evidence) and when bevacizumab was used alone (HR for PFS: 0.67, 95% CI 0.60 to 0.75; 4 RCTs; high-quality evidence).With regard to secondary endpoints, tumour response rates generally paralleled the survival results; moreover, higher anticancer efficacy was generally associated with worse treatment-related toxicity, with the important exception of bevacizumab-containing regimens, where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE. Finally, we found that oral (instead of intravenous) fluoropyrimidines significantly reduced the incidence of adverse effects (without compromising efficacy) in people treated with oxaliplatin-based regimens.We could not draw any conclusions on other debated aspects in this field of oncology, such as ranking of treatments (not all possible comparisons have been tested and many comparisons were based on single trials enrolling a small number of participants) and quality of life (virtually no data available).
AUTHORS' CONCLUSIONS
Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment, especially when targeted agents are combined with conventional chemotherapeutic drugs. Further research is needed to define the optimal regimen and to identify people who most benefit from each treatment.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Randomized Controlled Trials as Topic; Survival Rate
PubMed: 28128439
DOI: 10.1002/14651858.CD006875.pub3