To inform evidence-based practice in health care, guidelines and policies require accurate identification, collation, and integration of all available evidence in a comprehensive, meaningful, and ...time-efficient manner. Approaches to evidence synthesis such as carefully conducted systematic reviews and meta-analyses are essential tools to summarize specific topics. Unfortunately, not all systematic reviews are truly systematic, and their quality can vary substantially. Since well-conducted evidence synthesis typically involves a complex set of steps, we believe formulating a cohesive, step-by-step guide on how to conduct a systemic review and meta-analysis is essential. While most of the guidelines on systematic reviews focus on how to report or appraise systematic reviews, they lack guidance on how to synthesize evidence efficiently. To facilitate the design and development of evidence syntheses, we provide a clear and concise, 24-step guide on how to perform a systematic review and meta-analysis of observational studies and clinical trials. We describe each step, illustrate it with concrete examples, and provide relevant references for further guidance. The 24-step guide (1) simplifies the methodology of conducting a systematic review, (2) provides healthcare professionals and researchers with methodologically sound tools for conducting systematic reviews and meta-analyses, and (3) it can enhance the quality of existing evidence synthesis efforts. This guide will help its readers to better understand the complexity of the process, appraise the quality of published systematic reviews, and better comprehend (and use) evidence from medical literature.
Background Addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy (R-chemo) has been shown to improve response rates and progression-free survival in patients with indolent or mantle ...cell lymphoma. However, the impact of R-chemo on overall survival is unclear. We performed a comprehensive systematic review and meta-analysis to examine the efficacy of combined immunochemotherapy using R-chemo compared with the identical chemotherapy alone with respect to overall survival in patients with advanced indolent lymphoma or mantle cell lymphoma. Methods Medical databases and conference proceedings were searched for randomized controlled trials published from January 1990 through December 2005 that compared R-chemo with chemotherapy alone in patients with newly diagnosed or relapsed indolent lymphoma or mantle cell lymphoma. We included full-text and abstract publications. Endpoints were overall survival, disease control, overall response, and toxicity. A fixed-effects model was assumed in all meta-analyses. For binary data, the relative risk was used as an indicator of treatment effect, and the Mantel–Haenszel method was used to pool relative risks. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided. Results Seven randomized controlled trials involving 1943 patients with follicular lymphoma, mantle cell lymphoma, or other indolent lymphomas were included in the meta-analysis. Five studies were published as full-text articles, and two were in abstract form. Patients treated with R-chemo had better overall survival (hazard ratio HR for mortality = 0.65; 95% confidence interval CI = 0.54 to 0.78), overall response (relative risk of tumor response = 1.21; 95% CI = 1.16 to 1.27), and disease control (HR of disease event = 0.62; 95% CI = 0.55 to 0.71) than patients treated with chemotherapy alone. R-chemo improved overall survival in patients with follicular lymphoma (HR for mortality = 0.63; 95% CI = 0.51 to 0.79) and in patients with mantle cell lymphoma (HR for mortality = 0.60; 95% CI = 0.37 to 0.98). However, in the latter case, there was heterogeneity among the trials (P = .07), making the survival benefit less reliable. Conclusion In patients with indolent or mantle cell lymphoma, R-chemo is superior to chemotherapy alone with respect to overall survival.
The objective of this study was to map place of cancer diagnosis in relation to Human Immunodeficiency Virus (HIV) care centre among people living with HIV (PLHIV) within South Africa (SA) using ...national laboratory database. We linked HIV and cancer laboratory data from 2004-2014 using supervised machine-learning algorithms. We performed a cross-sectional analysis comparing province where individuals accessed their HIV care versus where they had their cancer diagnosis. We used laboratory test records related to HIV diagnostics and care, such as CD4 cell counts and percentages, rapid tests, qualitative Polymerase Chain Reaction (PCR), antibody and antigen tests for HIV data that was documented as HIV positive and laboratory diagnosed cancer records from SA. The study population was 68,284 individuals with cancer and documented HIV related laboratory test. The median age at cancer diagnosis was 40 IQR, 33-48 years for the study population with most cancers in PLHIV diagnosed in females 70.9% n = 46,313. Of all the PLHIV and cancer, 25% (n = 16,364 p < 0.001) sought treatment outside their province of residence with 60.7% (n = 10,235) travelling to Gauteng. KZN had 46.6% (n = 4,107) of its PLHIV getting cancer diagnosis in Gauteng. Western Cape had 95% (n = 6,200) of PLHIV getting cancer diagnosis within the province. Our results showed health systems inequalities across provinces in SA with respect to cancer diagnosis. KZN for example had nearly half of the PLHIV getting cancer diagnosis outside the province while Western Cape is able to offer cancer diagnostic services to most of the PLHIV in the province. Gauteng is getting over burdened with referral for cancer diagnosis from other provinces. More effort is required to ensure equitable access to cancer diagnostic services within the country.
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Data on invasive cervical cancer (ICC) incidence in HIV‐positive women and the effect of cervical cancer screening in sub‐Saharan Africa are scarce. We estimated i) ICC incidence rates in women (≥18 ...years) who initiated antiretroviral therapy (ART) at the Themba Lethu Clinic (TLC) in Johannesburg, South Africa, between 2004 and 2011 and ii) the effect of a Pap‐based screening program. We included 10,640 women; median age at ART initiation: 35 years interquartile range (IQR) 30–42, median CD4 count at ART initiation: 113 cells/µL (IQR 46–184). During 27,257 person‐years (pys), 138 women were diagnosed with ICC; overall incidence rate: 506/100,000 pys 95% confidence interval (CI) 428–598. The ICC incidence rate was highest (615/100,000 pys) in women who initiated ART before cervical cancer screening became available in 04/2005 and was lowest (260/100,000 pys) in women who initiated ART from 01/2009 onward when the cervical cancer screening program and access to treatment of cervical lesions was expanded adjusted hazard ratio (aHR) 0.42, 95% CI 0.20–0.87. Advanced HIV/AIDS stage (4 versus 1, aHR 1.95, 95% CI 1.17–3.24) and middle age at ART initiation (36–45 versus 18–25 years, aHR 2.51, 95% CI 1.07–5.88) were risk factors for ICC. The ICC incidence rate substantially decreased with the implementation of a Pap‐based screening program and improved access to treatment of cervical lesions. However, the risk of developing ICC after ART initiation remained high. To inform and improve ICC prevention and care for HIV‐positive women in sub‐Saharan Africa, implementation and monitoring of cervical cancer screening programs are essential.
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Data on invasive cervical cancer (ICC) incidence in HIV‐positive women and the effect of cervical cancer screening in sub‐Saharan Africa are scarce. This South African cohort analysis found that ICC incidence substantially decreased after the implementation of a Pap‐based screening program and improved access to treatment of cervical lesions. However, ICC risk remained high in women who initiated ART at low CD4 cell counts. Patient‐level monitoring of screening programs is essential to improve ICC prevention.
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Vaccines induce antigen-specific immunity, which provides long-lived protection from the target pathogen. Trials from areas with high incidence rates for infectious diseases indicated that the ...tuberculosis vaccine Bacillus Calmette-Guérin (BCG) induces in addition non-specific immunity against various pathogens and thereby reduces overall mortality more than would have been expected by just protecting from tuberculosis. Although recent trials produced conflicting results, it was suggested that BCG might protect from non-tuberculosis respiratory infections and could be used to bridge the time until a specific vaccine against novel respiratory diseases like COVID-19 is available.
We performed a systematic search for randomized controlled trials (RCTs) published between 2011 and December 9
, 2022, providing evidence about non-specific effects after BCG vaccination, assessed their potential for bias, and meta-analyzed relevant clinical outcomes. We excluded RCTs investigating vaccination with an additional vaccine unless outcomes from a follow-up period before the second vaccination were reported.
Our search identified 16 RCTs including 34,197 participants. Vaccination with BCG caused an estimated 44% decrease in risk for respiratory infections (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.39-0.82) with substantial heterogeneity between trials (I
= 77%). There was evidence for a protective effect on all-cause mortality of 21% if follow-up was restricted to one year (HR 0.79, 95% CI 0.64-0.99). We did not find evidence for an effect when we considered longer follow-up (HR 0.88, 95% CI 0.75-1.03). Infection-related mortality after BCG vaccination was reduced by 33% (HR 0.67; 95% CI 0.46-0.99), mortality for sepsis by 38% (HR 0.62, 95% CI 0.41-0.93). There was no evidence for a protective effect of BCG vaccination on infections of any origin (HR 0.84, 95% CI 0.71-1.00), COVID-19 (HR 0.88, 95% CI 0.68-1.14), sepsis (HR 0.78, 95% CI 0.55-1.10) or hospitalization (HR 1.01, 95% CI 0.91-1.11).
According to these results, depending on the setting, vaccination with BCG provides time-limited partial protection against non-tuberculosis respiratory infections and may reduce mortality. These findings underline BCG's potential (1) in pandemic preparedness against novel pathogens especially in developing countries with established BCG vaccination programs but limited access to specific vaccines; (2) in reducing microbial infections, antimicrobial prescriptions and thus the development of antimicrobial resistance. There is a need for additional RCTs to clarify the circumstances under which BCG's non-specific protective effects are mediated.
Summary Background Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a ...meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. Methods Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. Findings Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio cHR 1·17, 95% CI 1·06–1·30) and worsened overall survival (1·06, 1·00–1·12), with little heterogeneity between trials ( I2 0%, p=0·87 for mortality during the active study period, and I2 7·1%, p=0·33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1·10 (0·98–1·24), and 1·04 (0·97–1·11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0·42). Interpretation Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. Funding German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).
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To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.
An Update Committee ...reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched.
The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews.
For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.
The impact of South Africa's high human immunodeficiency virus (HIV) burden on cancer risk is not fully understood, particularly in the context of antiretroviral treatment (ART) availability. We ...examined national cancer trends and excess cancer risk in people living with HIV (PLHIV) compared to those who are HIV-negative.
We used probabilistic record linkage to match cancer records provided by the National Cancer Registry to HIV data provided by the National Health Laboratory Service (NHLS). We also used text search of specific HIV terms from the clinical section of pathology reports to determine HIV status of cancer patients. We used logistic and Joinpoint regression models to evaluate the risk and trends in cancers in PLHIV compared to HIV-negative patients from 2004 to 2014. In sensitivity analysis, we used inverse probability weighting (IPW) to correct for possible selection bias.
A total of 329,208 cancer cases from public sector laboratories were reported to the NCR from 2004 to 2014 with the HIV status known for 95,279 (28.9%) cancer cases. About 50% of all the female cancer cases (
= 30,486) with a known status were HIV-positive. PLHIV were at higher risk of AIDS-defining cancers (Kaposi sarcoma adjusted OR:134, 95% CI:111-162, non-Hodgkin lymphoma adjusted OR:2.73, 95% CI:2.56-2.91 and, cervix adjusted OR:1.70, 95% CI:1.63-1.77, conjunctival cancer adjusted OR:21.5, 95% CI:16.3-28.4 and human papilloma virus (HPV) related cancers (including; penis adjusted OR:2.35, 95% CI:1.85-2.99, and vulva adjusted OR:1.94, 95% CI:1.67-2.25) compared to HIV-negative patients. Analysis using the IPW population yielded comparable results.
There is need for improved awareness and screening of conjunctival cancer and HPV-associated cancers at HIV care centres. Further research and discussion is warranted on inclusive HPV vaccination in PLHIV.
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Of women with cervical cancer (CC) and HIV, 85% live in sub-Saharan Africa, where 21% of all CC cases are attributable to HIV infection. We aimed to generate internationally acceptable facility-based ...indicators to monitor and guide scale up of CC prevention and care services offered on-site or off-site by HIV clinics.
We reviewed the literature and extracted relevant indicators, grouping them into domains along the CC control continuum. From February 2021 to March 2022, we conducted a three-round, online Delphi process to reach consensus on indicators. We invited 106 experts to participate. Through an anonymous, iterative process, participants adapted the indicators to their context (round 1), then rated them for 5 criteria on a 5-point Likert-type scale (rounds 2 and 3) and then ranked their importance (round 3).
We reviewed 39 policies from 21 African countries and 7 from international organizations; 72 experts from 15 sub-Saharan Africa countries or international organizations participated in our Delphi process. Response rates were 34% in round 1, 40% in round 2, and 44% in round 3. Experts reached consensus for 17 indicators in the following domains: primary prevention (human papillomavirus prevention, n = 2), secondary prevention (screening, triage, treatment of precancerous lesions, n = 11), tertiary prevention (CC diagnosis and care, n = 2), and long-term impact of the program and linkage to HIV service (n = 2).
We recommend that HIV clinics that offer CC control services in sub-Saharan Africa implement the 17 indicators stepwise and adapt them to context to improve monitoring along the CC control cascade.
Cervical cancer (CC) is the leading cause of cancer-related death among women in sub-Saharan Africa. It occurs most frequently in women living with HIV (WLHIV) and is classified as an AIDS-defining ...illness. Recent World Health Organisation (WHO) recommendations provide guidance for CC prevention policies, with specifications for WLHIV. We systematically reviewed policies for CC prevention and control in sub-Saharan countries with the highest HIV prevalence.
We included countries with an HIV prevalence ≥ 10% in 2018 and policies published between January 1
2010 and March 31
2022. We searched Medline via PubMed, the international cancer control partnership website and national governmental websites of included countries for relevant policy documents. The online document search was supplemented with expert consultation for each included country. We synthesised aspects defined in policies for HPV vaccination, sex education, condom use, tobacco control, male circumcision,cervical screening, diagnosis and treatment of cervical pre-cancerous lesions and cancer, monitoring mechanisms and cost of services to women while highlighting specificities for WLHIV.
We reviewed 33 policy documents from nine countries. All included countries had policies on CC prevention and control either as a standalone policy (77.8%), or as part of a cancer or non-communicable diseases policy (22.2%) or both (66.7%). Aspects of HPV vaccination were reported in 7 (77.8%) of the 9 countries. All countries (100%) planned to develop or review Information, Education and Communication (IEC) materials for CC prevention including condom use and tobacco control. Age at screening commencement and screening intervals for WLHIV varied across countries. The most common recommended screening and treatment methods were visual inspection with acetic acid (VIA) (88.9%), Pap smear (77.8%); cryotherapy (100%) and loop electrosurgical procedure (LEEP) (88.9%) respectively. Global indicators disaggregated by HIV status for monitoring CC programs were rarely reported. CC prevention and care policies included service costs at various stages in three countries (33.3%).
Considerable progress has been made in policy development for CC prevention and control in sub Saharan Africa. However, in countries with a high HIV burden, there is need to tailor these policies to respond to the specific needs of WLHIV. Countries may consider updating policies using the recent WHO guidelines for CC prevention, while adapting them to context realities.
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