A step-by-step guide to the systematic review and meta-analysis of diagnostic and prognostic test accuracy evaluations

In evidence-based medicine (EBM), systematic reviews and meta-analyses have been widely applied in biological and medical research. Moreover, the most popular application of meta-analyses in this field may be to examine diagnostic (sensitivity and specificity) and prognostic (hazard ratio (HR) and its variance, standard error (SE) or confidence interval (CI)) test accuracy. However, conducting such analyses requires not only a great deal of time but also an advanced professional knowledge of mathematics, statistics and computer science. Regarding the practical application of meta-analyses for diagnostic and prognostic markers, the majority of users are clinicians and biologists, most of whom are not skilled at mathematics and computer science in particular. Hence, it is necessary for these users to have a simplified version of a protocol to help them to quickly conduct meta-analyses of the accuracy of diagnostic and prognostic tests. The aim of this paper is to enable individuals who have never performed a meta-analysis to do so from scratch. The paper does not attempt to serve as a comprehensive theoretical guide but instead describes one rigorous way of conducting a meta-analysis for diagnostic and prognostic markers. Investigators who follow the outlined methods should be able to understand the basic ideas behind the steps taken, the meaning of the meta-analysis results obtained for diagnostic and prognostic markers and the scope of questions that can be answered with Systematic Reviews and Meta-Analyses (SRMA). The presented protocols have been successfully tested by clinicians without meta-analysis experience.     

Sentinel lymph node biopsy in vulval cancer: systematic review and meta-analysis

Background:

The purpose of this study was to determine the accuracy of sentinel lymph node (SLN) biopsy with technetium 99 (99mTc) and/or blue dye-enhanced lymphoscintigraphy in vulval cancer.

Methods:

Sensitive searches of databases were performed upto October 2013. Studies with at least 75% of women with FIGO stage IB or II vulval cancer evaluating SLN biopsy with 99mTc, blue dye or both with reference standard of inguinofemoral lymphadenectomy (IFL) or clinical follow-up were included. Meta-analyses were performed using Meta-Disc version 1.4.

Results:

Of the 2950 references, 29 studies (1779 women) were included; most of them evaluated 99mTc combined with blue dye. Of these, 24 studies reported results for SLN followed by IFL, and 5 reported clinical follow-up only for SLN negatives. Pooling of all studies was inappropriate because of heterogeneity. Mean SLN detection rates were 94.0% for 99mTc, 68.7% for blue dye and 97.7% for both. SLN biopsy had pooled sensitivity of 95% (95% CI 92–98%) with negative predictive value (NPV) of 97.9% in studies using 99mTc/blue dye, ultrastaging and immunohistochemistry with IFL as reference. Pooled sensitivity for SLN with clinical follow-up for SLN-negatives was 91% (85–95%) with NPV 95.6%. Patients undergoing SLN biopsy experienced less morbidity than those undergoing IFL.

Conclusions:

Sentinel lymph node biopsy using 99mTC, blue dye and ultrastaging with immunohistochemistry is highly accurate when restricted to carefully selected patients, within a rigorous protocol, with close follow-up and where sufficient numbers for learning curve optimisation exist. Patients must make an informed choice between the slightly higher groin recurrence rates of SLN biopsy vs the greater morbidity of IFL.     

Sentinel node biopsy performance after neoadjuvant chemotherapy in locally advanced breast cancer: A systematic review and meta‐analysis

The use of sentinel node biopsy (SNB) after neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer is debated. Our aim was to quantitatively review the available evidence on the performance of SNB after NAC in patients with locally advanced breast cancer. We performed a systematic review (by searching the PubMed, Cochrane and Scopus databases) and random effects meta‐analysis to investigate on the feasibility and accuracy of SNB in these patients. The two outcomes of interest were the sentinel node identification rate (SIR) and the false negative rate (FNR). Sensitivity analysis and meta‐regression were used to investigate the potential sources of between‐study heterogeneity. We retrieved 72 eligible studies enrolling 7,451 patients. Upon meta‐analysis, summary SIR resulted 89.6% [95% confidence interval (CI): 87.8–91.2; heterogeneity I²: 76.9%], which poorly compares with the 95% SIR observed in some recent series of early breast cancer. The summary FNR resulted 14.2% (CI: 12.5–16.0; heterogeneity I²: 29.1%), which was significantly higher than the 8–10% reference value. Considering an average post‐NAC lymph node positivity rate of 50%, the downstaging due to false negative SNB would occur in 7/100 patients (with an excess error rate of 2–3/100 as compared to the early‐stage setting). No plausible source of between‐study heterogeneity was found. Based on the largest series of studies ever meta‐analyzed, our findings highlight the limits of SNB performance in this population, where the impact of SNB on patient survival is still to be defined.     

Dietary patterns and oesophageal squamous cell carcinoma: a systematic review and meta-analysis

Background/Objective:

Dietary patterns, which represent a complex integration of food and nutrients, have been used to explore the association between dietary factors and the risk of oesophageal cancer. However, the association remains unclear. This systematic review was performed to evaluate the relationship between dietary patterns and oesophageal squamous cell carcinoma (ESCC) by pooling available data from existing studies.

Methods:

Pertinent articles published up to the end of 2013 were systematically searched and retrieved. The most common dietary patterns with high loadings of foods/nutrients were selected. Adjusted odds ratios (ORs) were derived by comparing the highest with the lowest categories of dietary pattern scores and by using a random-effect model. Heterogeneity was tested using I² statistic.

Results:

From nine available case–control studies, in which smoking and other confounding factors were considered, three most common dietary patterns were selected: western pattern, healthy pattern, and drinker/alcohol pattern. Healthy pattern was significantly associated with a decreased risk of ESCC (OR=0.36, 95% confidence interval (CI): 0.23, 0.49); drinker/alcohol pattern was related to a significantly increased risk (OR=2.34, 95% CI: 1.22, 3.45), while no significant association with western pattern was observed (OR=1.29, 95% CI: 0.83, 1.75).

Conclusions:

Based on available studies, though limited in number, this meta-analysis suggests that some dietary patterns may be associated with the risk of ESCC.     

The worldwide incidence and prevalence of primary brain tumors: a systematic review and meta-analysis

Background

Primary brain tumors are a heterogeneous group of benign and malignant tumors arising from the brain parenchyma and its surrounding structures. The epidemiology of these tumors is poorly understood. The aim of our study is to systematically review the latest literature on the incidence and prevalence of primary brain tumors.

Methods

The systematic review and meta-analysis were conducted according to a predetermined protocol and established guidelines. Only studies reporting on data from 1985 onward were included. Articles were included if they met the following criteria: (i) original research, (ii) population based, (iii) reported an incidence or prevalence estimate of primary brain tumors.

Results

From the 53 eligible studies overall, 38 were included in the meta-analysis. A random-effects model found the overall incidence rate of all brain tumors to be 10.82 (95% CI: 8.63–13.56) per 100 000 person-years. The incidence proportion estimates were heterogeneous, even among the same tumor subtypes, and ranged from 0.051 per 100 000 (germ cell tumors) to 25.48 per 100 000 (all brain tumors). There were insufficient data to conduct a meta-analysis of the prevalence of primary brain tumors.

Conclusions

There is a need for more accurate and comparable incidence and prevalence estimates of primary brain tumors across the world. A standardized approach to the study of the epidemiology of these tumors is needed to better understand the burden of brain tumors and the possible geographical variations in their incidence.     

Delayed versus immediate exercises following surgery for breast cancer: a systematic review

SummaryBackground Seroma formation, wound healing and fluid drainage are a concern for both surgeons and patients. Excessive fluid production can result in seroma formation, and inadequate drainage of seromas is known to cause infection, pain, discomfort and longer periods of hospitalisation. Postoperative exercises given to maintain movement of the arm are believed to increase the amount of fluid production following surgery. This review aimed to determine whether a program of delayed exercises reduces the risk of seroma formation, fluid loss and hospital stay, without loss of arm movement.Method A systematic review. RCTs of early versus delayed shoulder mobilisation after surgery in females with breast cancer were included in the review. Outcomes. One or more measurements of shoulder range of motion, wound complications, fluid drainage volumes and incidence of seroma formation. Design. Randomised controlled trials, control group of delayed exercise/mobilisation. Validity assessment was carried out using a data extraction form based on the CONSORT statement. Study characteristics recorded include sample size, intervention, control, period of exercise delay, surgical procedure and conclusions drawn. Data synthesis was carried out using random effects and weighted mean differences to test for heterogeneity and combined effects.Results 12 RCTs were included in the review of which 6 were included for meta-analysis. Delaying exercises significantly decreases seroma formation (OR=0.4; 95%CI 0.2–0.5; p=0.00001). No significant differences were found for drainage volume or hospital stay.Conclusion Current evidence from RCTs supports the use of a delayed program of arm exercises to reduce seroma formation. Clinical and statistical inconsistencies between studies did not allow any conclusions to be drawn regarding the effects of delayed exercises on fluid drainage, hospital stay and immediate or long term ability to move the arm.     

P53 abnormalities and outcomes in colorectal cancer: a systematic review

We performed a systematic review of studies that investigated the effect of abnormalities of the tumour suppressor gene p53 upon prognosis in patients with colorectal cancer. The methods used to assess p53 status were immunohistochemistry (IHC), indicating abnormal accumulation of p53, and sequence analysis, indicating presence of p53 mutations (mut). We identified 168 reports, with 241 comparisons of relevant end points and survival data on 18 766 patients. We found evidence of both publication bias and heterogeneity of results. Our analysis was hampered by variability in both the assessment of p53 status and the reporting of results. We used a trim and fill method to correct for publication bias and minimised heterogeneity by using well-defined clinical subgroups for the assessment of outcomes. Overall, patients with abnormal p53 were at increased risk of death: relative risk (RR) with IHC 1.32 (95% confidence interval (c.i.) 1.23-1.42) and with mutation analysis 1.31 (95% c.i. 1.19-1.45). The adverse impact of abnormal p53 was greater in patients with lower baseline risk of dying: good prognosis RR (mut) 1.63 (95% c.i. 1.40-1.90) and poor prognosis RR (mut) 1.04 (95% c.i. 0.91-1.19). We found no effect of abnormal p53 on outcome in patients treated with chemotherapy. Abnormal p53 was associated with failure of response to radiotherapy in patients with rectal cancer: RR (mut) 1.49 (95% c.i. 1.25-1.77).     

Surviving childhood cancer: a systematic review of studies on risk and determinants of adverse socioeconomic outcomes

Substantial improvements in childhood cancer survival have resulted in a steadily increasing population of childhood cancer survivors. Whereas somatic late effects have been assessed in many studies, less is known about the impact of childhood cancer on socioeconomic outcomes in survivors. The aim of this article was to evaluate and summarise the evidence on the socioeconomic conditions of childhood cancer survivors and to identify survivors at particular risk of adverse socioeconomic outcomes. An extensive literature search of three electronic databases was conducted. Of 419 articles identified, 52 met the inclusion criteria. All the selected articles were appraised for quality, and findings were summarised in a narrative synthesis. Childhood cancer survivors were at higher risk of adverse socioeconomic outcomes with regard to educational achievement, income and social security benefits than the general population or a sibling comparison group. The risks for unemployment and a lower occupational position were significantly increased only for survivors of a central nervous system tumour. Notably, survivors of central nervous system tumours, survivors treated with cranial radiotherapy and those diagnosed at younger age independent of cancer type were determinants of particular adverse socioeconomic outcomes. Given the increasing population of childhood cancer survivors, targeted follow-up interventions and support strategies addressing not only the somatic and psychiatric late effects but also the socioeconomic difficulties that some childhood cancer survivors face is of high importance to reduce social inequity, and ensure a high quality of life after childhood cancer.     

Sentinel lymph node mapping of a breast cancer of the vulva: Case report and literature review

Ectopic breast tissue is rare and typically presents as an axillary mass. Previous reports have identified ectopic breast tissue in the vulva, but malignancy is exceedingly uncommon. We present a 62 years old with locally advanced breast carcinoma arising in the vulva demonstrates the utilization of sentinel lymph node mapping to identify metastatic lymph nodes previously unable to be identified via traditional surgical exploration. Our case supports the principles of adjuvant therapy for breast cancer to be applied to ectopic breast cancer arising in the vulva. A literature review highlights common key points in similar cases to guide management.     

Clinical outcome of lymphadenectomy in malignant ovarian germ cell tumors: a systematic review and meta-analysis

Malignant ovarian germ cell tumors (MOGCTs) are predominately diagnosed in young patients and account for most preadolescent malignant ovarian tumors. Currently, due to the high sensitivity of MOGCTs to chemotherapy and the optimal survival rate after chemotherapy, some researchers have recommended opting for non-surgical treatment. However, the effect of lymphadenectomy (LND) on the survival of patients with MOGCT remains controversial. We conducted a systematic review and meta-analysis to compare the clinical outcomes of LND and non-LND in MOGCT surgeries in order to summarize the clinical experience. PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and Clinical Trials.gov were searched from inception to December 26, 2021. Data on the rates of survival, relapse, and adverse effects were evaluated using Review Manager software. Fourteen studies with 10,759 participants were included in this review. There were 5863 and 4896 patients in the LND- and LND+ groups, respectively. Pooled results showed that although disease-free survival (DFS) was significantly improved in the LND+ group compared to the LND- group (HR: 0.74; 95% CI: 0.56 to 0.97; 2091 participants), LND did not significantly affect overall survival (OS) (HR: 0.82; 95% CI: 0.51 to 1.31; 5298 participants). The operation time was significantly longer in the LND+ group than in the LND- group (P<0.001). Blood loss (P=0.004) and complication rate (P=0.003) were also significantly higher in the LND+ group than in the LND- group. There was no significant difference in mortality rate (P=0.500). LND was associated with an improvement in DFS. However, there was no significant difference in OS in MOGCTs. We recommend that LND should not be a routine surgery for children or young patients with MOGCTs; although it may be beneficial for older people, advanced stage tumors, specific pathological types, and non-chemotherapy patients.     

Radiofrequency ablation combined with percutaneous ethanol injection for hepatocellular carcinoma: a systematic review and meta-analysis

Background: Radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) are important treatments for patients with hepatocellular carcinoma (HCC) who are not eligible for resection and liver transplantation. Therefore, it is important to establish comparisons between RFA, PEI and the two therapies in combination.

Aims: To evaluate the clinical efficacy and safety of combined RFA-PEI versus monotherapy with either RFA or PEI for HCC to provide references for clinical practice and further research.

Methods: We searched all eligible studies published before September 2015 in the Cochrane Library, PubMed, Embase, Web of Science and Chinese databases, such as CBM, CNKI, VIP and WanFang and also retrieved papers from other sources. All relevant controlled trials were collected. Meta-analyses were performed using RevMan version 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

Results: Thirteen trials with 1621 patients were identified. Compared with PEI, RFA was associated with significant improvement in overall survival (OS) rate at 1, 2, 3 and 4 years, cancer-free survival (CFS) rate at 1, 2 and 3 years and complete tumour necrosis. RFA was associated with a significant reduction in the local recurrence rate at 1, 2 and 3 years. However, RFA was also associated with a higher total risk of complications. Compared with RFA alone, combined RFA-PEI was associated with a significant improvement in the OS rate at 1.5, 2 and 3 years and a significant reduction in the local recurrence rate. However, combined RFA-PEI was also associated with a higher risk of fever.

Conclusion: The combination of RFA and PEI appears to be the optimal treatment strategy when considering combined RFA-PEI or either RFA or PEI alone. Combined RFA-PEI significantly improves OS and reduces the risk of local recurrence without increasing major complications. Further large-scale studies are needed to assess economic outcomes and quality of life.     

Hyperthermia and radiotherapy with or without chemotherapy in locally advanced cervical cancer: a systematic review with conventional and network meta-analyses

Purpose: A systematic review with conventional and network meta-analyses (NMA) was conducted to examine the outcomes of loco-regional hyperthermia (HT) with radiotherapy (RT) and/or chemotherapy (CT) in locally advanced cervix cancer, IIB–IVA (LACC).

Methods and materials: A total of 217 abstracts were screened from five databases and reported as per PRISMA guidelines. Only randomised trials with HT and RT?±?CT were considered. The outcomes evaluated were complete response (CR), long-term loco-regional control (LRC), patients alive, acute and late grade III/IV toxicities.

Results: Eight articles were finally retained. Six randomised trials with HTRT (n?=?215) vs. RT (n?=?212) were subjected to meta-analysis. The risk difference for achieving CR and LRC was greater by 22% (p?p?p?=?.001). No other end points were reported. Bayesian NMA, incorporating 13 studies (n?=?1000 patients) for CR and 12 studies for patients alive (n?=?807 patients), comparing HTCTRT, HTRT, CTRT and RT alone, was conducted. The pairwise comparison of various groups showed that HTRTCT was the best option for both CR and patient survival. This was also evident on ranking treatment modalities based on the “surface under cumulative ranking” values.

Conclusions: In LACC, HTRT demonstrates a therapeutic advantage over RT without significant acute or late morbidities. On NMA, HTCTRT appears promising, but needs further confirmation through prospective randomised trials.     

Phase I study on sentinel lymph node mapping in colon cancer: a preliminary report

BACKGROUND AND OBJECTIVES: Lymph node (LN) metastasis is one of the most significant prognostic factor in colorectal cancer. In fact, therapeutic decisions are based on LN status. However, multiple studies have reported on the limitations of the conventional pathological LN examination techniques, and therefore, the actual number of patients with LN positive colorectal cancer is probably underestimated. We assume that lymphatic tumor dissemination follows an orderly sequential route. We report here a simple and harmless coloration technique that was recently elaborated, and that allows us to identify the sentinel LN(s) (SLN) or first relay LNs in colorectal cancer patients. The main endpoint of this clinical trial is the feasibility of the technique. METHODS: Twenty patients treated by surgery for a colic cancer were admitted in this protocol. A subserosal peritumoral injection of lymphazurin 1% was performed 10 min before completing the colic resection. A pathologist immediately examined the specimens, harvested the colored SLN, and examined them by serial cuts (200 microm) with H&E staining, followed by immunohistochemical staining (AE1-AE3 cytokeratin markers), when serial sections were classified as cancer free. RESULTS: The preoperative identification of the SLN was impossible in at least 50 of the cases, however, SLNs were identified by the pathologist in 90% of cases. In two patients (10%) SLN was never identified. The average number of SLN was 3.9. Immunohistochemical analysis of the SLN has potentially changed the initial staging (from Dukes B to Dukes C) for 5 of the 20 patients (25%). On the other hand, there was one patient (5%) with hepatic metastasis from adenocarcinoma for whom SLN pathology was negative for metastasis (skip metastasis). CONCLUSIONS: SLN biopsy is readily feasible with identification of SLN in at least 90% of patients with colorectal cancers. Our results indicate that 45% of patients initially staged as Dukes B had tumor cells identified in their SLN when these were subjected to our protocol. This represented a 25% upgrading rate when our complete study population is considered. However, controversy persist about the clinical significance and metastatic potential of these often very small clusters of tumor cells.     

The role of mitomycin in the treatment of non-small cell lung cancer: a systematic review with meta-analysis of the literature

In order to clarify the role of mitomycin (MMC) in the treatment of NSCLC, we performed a systematic review of the literature and qualitatively assessed the selected studies using the ELCWP and Chalmers scales. 5 trials (202 patients) assessed the activity of MMC as single-agent chemotherapy in NSCLC. The overall response rate was 25% (95% Cl 19-31). In 10 randomized phase III trials (1769 patients), we studied the role of MMC in combination therapy. A meta-analysis, based on the available published data, failed to show any survival advantage of the MMC containing regimens (hazard ratio = 0.95; 95% Cl 0.83-1.10). Finally, 4 eligible trials (139 patients) assessed the activity of MMC regimens as salvage therapy, 3 in combination with vindesine and one with cisplatin and vinblastine. The overall response rate for the MMC-vindesine regimen was 10.5% (95% Cl 1.7-19.4). In conclusion, MMC is an active drug for NSCLC but does not improve survival when combined with other active drugs, particularly cisplatin. Its use for salvage therapy appears to be associated with marginal activity only.     

Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies

No consensus on the indications for surgical resection of colorectal liver metastases exists. This systematic review has been undertaken to assess the published evidence for its efficacy and safety and to identify prognostic factors. Studies were identified by computerised and hand searches of the literature, scanning references and contacting investigators. The outcome measures were overall survival, disease-free survival, postoperative morbidity and mortality, quality of life and cost effectiveness, and a qualitative summary of the trends across all studies was produced. Only 30 of 529 independent studies met all the eligibility criteria for the review, and data on 30-day mortality and morbidity only were included from a further nine studies. The best available evidence came from prospective case series, but only two studies reported outcomes for all patients undergoing surgery. The remainder reported outcomes for selected groups of patients: those undergoing hepatic resection or those undergoing curative resection. Postoperative mortality rates were generally low (median 2.8%). The majority of studies described only serious postoperative morbidity, the most common being bile leak and associated perihepatic abscess. Approximately 30% of patients remained alive 5 years after resection and around two-thirds of these are disease free. The quality of the majority of published papers was poor and ascertaining the benefits of surgical resection of colorectal hepatic metastases is difficult in the absence of randomised trials. However, it is clear that there is group of patients with liver metastases who may become long-term disease-free survivors following hepatic resection. Such survival is rare in apparently comparable patients who do not have surgical treatment. Further work is needed to more accurately define this group of patients and to determine whether the addition of adjuvant treatments results in improved survival.     

Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis

This paper aims to evaluate the anti-emetic efficacy of cannabinoids in cancer patients receiving chemotherapy using a systematic review of literature searched within electronic databases such as PUBMED, EMBASE, PSYCINFO, LILACS, and 'The Cochrane Collaboration Controlled Trials Register'. Studies chosen were randomized clinical trials comprising all publications of each database until December 2006. From 12 749 initially identified papers, 30 fulfilled the inclusion criteria for this review, with demonstration of superiority of the anti-emetic efficacy of cannabinoids compared with conventional drugs and placebo. The adverse effects were more intense and occurred more often among patients who used cannabinoids. Five meta-analyses were carried out: (1) dronabinol versus placebo [ n  = 185; relative risk (RR) = 0.47; confidence interval (CI) = 0.19–1.16]; (2) Dronabinol versus neuroleptics [ n  = 325; RR = 0.67; CI = 0.47–0.96; number needed to treat (NNT) = 3.4]; (3) nabilone versus neuroleptics ( n  = 277; RR = 0.88; CI = 0.72–1.08); (4) levonantradol versus neuroleptics ( n  = 194; RR = 0.94; CI = 0.75–1.18); and (5) patients' preference for cannabis or other drugs ( n  = 1138; RR = 0.33; CI = 0.24–0.44; NNT = 1.8). The superiority of the anti-emetic efficacy of cannabinoids was demonstrated through meta-analysis.     

Effect of sentinel lymph node biopsy on upper limb function in women with early breast cancer: A systematic review of clinical trials

PurposeAxillary surgery is still essential in the management of early breast cancer. Conservative procedures like sentinel lymph node biopsy (SLNB) are less invasive than the traditional axillary node dissection (ALND). However, some extent of ipsilateral upper limb dysfunction might still occur. This systematic review aimed to describe the incidence of lymphedema, pain, sensory, and motor disorders after SLNB in women with early breast cancer.MethodsWe conducted a systematic review of randomized controlled trials. The search was performed on Pubmed, EMBASE, CINAHAL, and Web of Science. The search was based on the following concepts: breast cancer, sentinel lymph node biopsy, axillary dissection, upper limb complications. The risk of bias was evaluated using the Cochrane Rob 2.0 toll.ResultsWe obtained 979 unique registries from the primary search and 381 additional records from the included articles’ reference lists. Fifty-one articles were assessed as full text. Nine studies were included in the review. A total of 5161 patients undergone SLNB, and 4110 patients were assessed for ipsilateral arm complications. Six months after the surgery, 0–11% of patients presented lymphedema, 11–16% pain, 2–22% sensory disorders, and 0–9% motor disorders.ConclusionsSLNB was associated with persistent postoperative complications. The burden of complications, although lower when compared to ALND, should not be ignored.Protocol registrationPROSPERO registration number CRD42018090540, registered July 09, 2018.