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.

Evaluating PET-CT in routine surveillance and follow-up after treatment for cervical cancer: a cost-effectiveness analysis.

OBJECTIVE: To undertake a cost-effectiveness analysis that compares positron emission tomography - computed tomography (PET-CT) imaging plus standard practice with standard practice alone in the diagnosis of recurrent or persistent cervical cancer during routine surveillance and follow-up of women who have previously been diagnosed and treated. DESIGN: Model-based economic evaluation using data from a systematic review, supplemented with data from other sources, and taking a UK National Health Service (NHS) perspective. SETTING: Secondary Care in England. POPULATION: Women at least 3 months after the completion of treatment, with either recurrent or persistent cervical cancer. METHODS: A state transition (Markov) model was developed using TreeAge Pro 2011. The structure of the model was informed by the reviews of the trials and clinical input. In the model, two diagnostic strategies were examined. A one-way sensitivity analysis, probabilistic sensitivity analysis, and a value of information analysis were also carried out. MAIN OUTCOME MEASURES: Cost-effectiveness based on incremental cost per quality-adjusted life year (QALY). RESULTS: Adding PET-CT to the current treatment strategy of clinical examination and scanning [magnetic resonance imaging (MRI) and/or CT scan] during the routine surveillance and follow-up of women with recurrent or persistent cervical cancer is significantly more costly, with only a minimal increase in effectiveness. The incremental cost-effectiveness ratio (ICER) for the strategy of PET-CT as an adjunct to the standard treatment strategy that included clinical examination, MRI, and/or CT scan, compared with the usual treatment alone, was over £1 million per QALY. CONCLUSION: The results of the current analysis suggest that use of PET-CT in the diagnosis of recurrent or persistent cervical cancer is not cost-effective. Current guidelines recommending imaging using PET-CT as a diagnostic or surveillance tool need to be reconsidered in light of these results. This study did not specifically investigate the use of PET-CT in women with symptoms and radiological suspicion of recurrence where exenteration was considered. More research in that specific area is required.

Evaluating PET-CT in the detection and management of recurrent cervical cancer: systematic reviews of diagnostic accuracy and subjective elicitation.

BACKGROUND: Positron emission tomography-computed tomography (PET-CT) is recommended to triage women for exenterative surgery and surveillance after treatment for advanced cervical cancer. OBJECTIVE: To evaluate diagnostic accuracy of additional whole body PET-CT compared with CT/magnetic resonance imaging (MRI) alone in women with suspected recurrent/persistent cervical cancer and in asymptomatic women as surveillance. DESIGN: Systematic reviews. Subjective elicitation to supplement diagnostic information. SEARCH STRATEGY/SELECTION CRITERIA/DATA COLLECTION AND ANALYSIS: Searches of electronic databases were performed to June 2013. Studies in women with suspected recurrent/persistent cervical cancer and in asymptomatic women undergoing follow up with sufficient numeric data were included. We calculated sensitivity, specificity and corresponding 95% confidence intervals. Meta-analyses employed a bivariate model that included a random-effects term for between-study variations (CT studies) and univariate random effects meta-analyses (PET-CT studies) for sensitivity and specificity separately. SUBJECTIVE ELICITATION: Prevalence of recurrence and the accuracy of imaging elicited using the allocation of points technique. Coherence of elicited subjective probabilities with estimates in the literature examined. RESULTS: We identified 15 relevant studies; none directly compared additional PET-CT with MRI or CT separately. Most CT and MRI studies used older protocols and the majority did not distinguish between asymptomatic and symptomatic women. Meta-analysis of nine PET-CT studies in mostly symptomatic women showed sensitivity of 94.8 (95% CI 91.2-96.9), and specificity of 86.9% (95% CI 82.2-90.5). The summary estimate of the sensitivity of CT for detection of recurrence was 89.64% (95% CI 81.59-94.41) and specificity was 76% (95% CI 43.68-92.82). Meta-analysis for MRI test accuracy studies was not possible because of clinical heterogeneity. The sensitivity and specificity of MRI in pelvic recurrence varied between 82 and 100% and between 78 and 100%, respectively. Formal statistical comparisons of the accuracy of index tests were not possible. Subjective elicitation provided estimates comparable to the literature. Subjective estimates of the increase in accuracy from the addition of PET-CT were less than elicited increases required to justify the use in PET-CT for surveillance. CONCLUSION: Evidence to support additional PET-CT is scarce, of average quality and does not distinguish between application for surveillance and diagnosis. Guidelines recommending PET-CT in recurrent cervical cancer need to be reconsidered in the light of the existing evidence base.

Sentinel lymph node status in vulval cancer: systematic reviews of test accuracy and decision-analytic model-based economic evaluation.

BACKGROUND: Vulval cancer causes 3-5% of all gynaecological malignancies and requires surgical removal and inguinofemoral lymphadenectomy (IFL). Complications affect > 50% of patients, including groin wound infection, lymphoedema and cellulitis. A sentinel lymph node (SLN) is the first groin node with the highest probability of malignancy. SLN biopsy would be useful if it could accurately identify patients in whom cancer has spread to the groin, without removing all groin nodes. SLNs can be identified by isosulfan blue dye and/or technetium-99 ((99m)Tc) radioactive tracer during lymphoscintigraphy. The blue dye/(99m)Tc procedure only detects SLN, not metastases - this requires histological examination, which can include ultrastaging and staining with conventional haematoxylin and eosin (H&E) or immunohistochemistry. OBJECTIVES: To determine the test accuracy and cost-effectiveness of the SLN biopsy with (99m)Tc and/or blue dye compared with IFL or clinical follow-up for test negatives in vulval cancer, through systematic reviews and economic evaluation. DATA SOURCES: Standard medical databases, including MEDLINE, EMBASE, Science Citation Index and The Cochrane Library, medical search gateways, reference lists of review articles and included studies were searched to January 2011. METHODS: For accuracy and effectiveness, standard methods were used and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were to January 2011, with no language restrictions. Meta-analyses were carried out with Meta-Disc version 1.4 (Javier Zamora, Madrid, Spain) for accuracy; none was appropriate for effectiveness. The economic evaluation from a NHS perspective used a decision-tree model in DATA TreeAge Pro Healthcare 2001 (TreeAge Software, Inc., Williamstown, MA, USA). Six options (blue dye with H&E, blue dye with ultrastaging, (99m)Tc with H&E, (99m)Tc with ultrastaging, blue dye/(99m)Tc with H&E, blue dye/(99m)Tc with ultrastaging) were compared with IFL. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: For accuracy, of the 26 included studies, most evaluated (99m)Tc/blue dye combined. Four studies had clinical follow-up only for test negatives and five had clinical follow-up for all and IFL for test negatives. Numbers with no SLN found were difficult to distinguish from those with negative SLN biopsies. The largest group of 11 studies using (99m)Tc/blue dye, ultrastaging and immunohistochemistry had a pooled sensitivity of 95.6% [95% confidence interval (CI) 91.5% to 98.1%] and a specificity of 100% (95% CI 99.0% to 100%). Mean SLN detection rates were 94.6% for (99m)Tc, 68.7% for blue dye and 97.7% for both. One study measured global health status quality of life (QoL) and found no difference between SLN biopsy and IFL. One patient preference evaluation showed that 66% preferred IFL rather than a 5% false-negative rate from SLN biopsy. For effectiveness, of 14,038 references, one randomised controlled trial, three case-control studies and 13 case series were found. Approximately 50% died from vulval cancer and 50% from other causes during follow-ups. Recurrences were in the ratio of approximately 4 : 2 : 1 vulval, groin and distant, with more recurrences in node-positive patients. No studies reported QoL. For cost per death averted, IFL was less costly and more effective than strategies using SLN biopsy. For morbidity-free survival and long-term morbidity-free survival, (99m)Tc with ultrastaging was most cost-effective. Strategies with blue dye only and H&E only were never cost-effective. The incremental cost-effectiveness ratio for (99m)Tc with ultrastaging compared with IFL was £4300 per case of morbidity-free survival and £7100 per long-term morbidity-free survival. LIMITATIONS: The main limitations of this study include the lack of good-quality evidence on accuracy, effectiveness and QoL. A large project such as this takes time to publish, so the most recent studies are not included. CONCLUSIONS: A sensitive and specific combined metastatic SLN detection test and information on generic QoL in vulval cancer is urgently required. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

What do we know about tocolytic effectiveness and how do we use this information in guidelines? A comparison of evidence grading.

BACKGROUND: Evidence summaries of tocolytic effectiveness assign quality levels based on a single dimension: the study design. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system takes into account several domains, including limitations of the study design and ranking the importance of outcomes. OBJECTIVES: The aim of the study was to compare the quality of evidence according to GRADE with the quality as described by existing guidelines. SEARCH STRATEGY: A practitioner survey to rank the importance of outcomes and a systematic review were conducted. For the systematic review, we searched Medline, Embase, and DARE databases from inception to December 2010 using the terms 'tocolytics' and 'threatened preterm labour', without any language restrictions. SELECTION CRITERIA: Inclusion criteria for the review were randomised controlled trials comparing tocolytics with either placebo or betamimetics. DATA COLLECTION AND ANALYSIS: The review and survey teams worked independently. Evidence ratings according to GRADE were performed. MAIN RESULTS: The majority of the survey respondents thought that it was important to use tocolytics to buy the time needed for steroids to promote fetal lung maturation and to allow in utero transfer. Nearly 80% of 'high' ratings in guidelines were downgraded as a result of deficiencies identified by GRADE. AUTHORS' CONCLUSIONS: We propose a move away from the use of evidence rating systems reliant solely on study design, as they have a propensity towards strong recommendations when the underlying evidence is weak.

Positron emission tomography/computerised tomography imaging in detecting and managing recurrent cervical cancer: systematic review of evidence, elicitation of subjective probabilities and economic modelling.

BACKGROUND: Cancer of the uterine cervix is a common cause of mortality in women. After initial treatment women may be symptom free, but the cancer may recur within a few years. It is uncertain whether it is more clinically effective to survey asymptomatic women for signs of recurrence or to await symptoms or signs before using imaging. OBJECTIVES: This project compared the diagnostic accuracy of imaging using positron emission tomography/computerised tomography (PET-CT) with that of imaging using CT or magnetic resonance imaging (MRI) alone and evaluated the cost-effectiveness of adding PET-CT as an adjunct to standard practice. DATA SOURCES: Standard systematic review methods were used to obtain and evaluate relevant test accuracy and effectiveness studies. Databases searched included MEDLINE, EMBASE, Science Citation Index and The Cochrane Library. All databases were searched from inception to May 2010. REVIEW METHODS: Study quality was assessed using appropriately modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. Included were any studies of PET-CT, MRI or CT compared with the reference standard of histopathological findings or clinical follow-up in symptomatic women suspected of having recurrent or persistent cervical cancer and in asymptomatic women a minimum of 3 months after completion of primary treatment. Subjective elicitation of expert opinion was used to supplement diagnostic information needed for the economic evaluation. The effectiveness of treatment with chemotherapy, radiotherapy, chemoradiotherapy, radical hysterectomy and pelvic exenteration was systematically reviewed. Meta-analysis was carried out in RevMan 5.1 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) and Stata version 11 (StataCorp LP, College Station, Texas, USA). A Markov model was developed to compare the relative cost-effectiveness using TreeAge Pro software version 2011 (TreeAge Software Inc., Evanston, IL, USA). RESULTS: For the diagnostic review, a total of 7524 citations were identified, of which 12 test accuracy studies were included in the review: six studies evaluated PET-CT, two evaluated MRI, three evaluated CT and one evaluated both MRI and CT. All studies were small and the majority evaluated imaging in women in whom recurrence was suspected on the basis of symptoms. The PET-CT studies evaluated local and distant recurrence and most used methods similar to current practice, whereas five of the six CT and MRI studies evaluated local recurrence only and not all employed currently used methods. Meta-analysis of PET-CT studies gave a sensitivity of 92.2% [95% confidence interval (CI) 85.1% to 96.0%] and a specificity of 88.1% (95% CI 77.9% to 93.9%). MRI sensitivities and specificities varied between 82% and 100% and between 78% and 100%, respectively, and CT sensitivities and specificities varied between 78% and 93% and between 0% and 95%, respectively. One small study directly compared PET-CT with older imaging methods and showed more true-positives and fewer false-negatives with PET-CT. The subjective elicitation from 21 clinical experts gave test accuracy results for asymptomatic and symptomatic women and the results for symptomatic women were similar to those from the published literature. Their combined opinions also suggested that the mean elicited increase in accuracy from the addition of PET-CT to MRI and/or CT was less than the elicited minimum important difference in accuracy required to justify the routine addition of PET-CT for the investigation of women after completion of primary treatment. For the effectiveness review, a total of 24,943 citations were identified, of which 62 studies were included (chemotherapy, 19 randomised controlled trials; radiotherapy or chemoradiotherapy, 16 case series; radical hysterectomy and pelvic exenteration, 27 case series). None provided the effectiveness of cisplatin monotherapy, the most commonly used chemotherapeutic agent in the NHS, compared with supportive care in a background of other treatment such as radiotherapy in recurrent and persistent cervical cancer. The model results showed that adding PET-CT to the current treatment strategy of clinical examination, MRI and/or CT scan was significantly more costly with only a minimal increase in effectiveness, with incremental cost-effectiveness ratios for all models being > £1M per quality-adjusted life-year (QALY) and the additional cost per additional case of recurrence being in the region of £600,000. LIMITATIONS: There was considerable uncertainty in many of the parameters used because of a lack of good-quality evidence in recurrent or persistent cervical cancer. The evidence on diagnostic and therapeutic impact incorporated in the economic model was poor and there was little information on surveillance of asymptomatic women. CONCLUSIONS: Given the current evidence available, the addition of PET-CT to standard practice was not found to be cost-effective in the diagnosis of recurrent or persistent cervical cancer. However, although probabilistic sensitivity analysis showed that the main conclusion about cost-ineffectiveness of PET-CT was firm given the range of assumptions made, should more reliable information become available on accuracy, therapeutic impact and effectiveness, and the cost of PET-CT reduce, this conclusion may need revision. Current guidelines recommending imaging for diagnosis using expensive methods such as PET-CT need to be reconsidered in the light of the above. FUNDING: The National Institute for Health Research Health Technology Assessment programme.