Fast track — ArticlesMicrovessel density as a prognostic factor in non-small-cell lung carcinoma: a meta-analysis of individual patient data
Introduction
Non-small-cell lung carcinoma has a very high mortality.1 Conventional treatment—ie, radical excision without radiotherapy or chemotherapy—is curative for only 40% of patients who are eligible for this treatment.2
Several biological factors, including measures of angiogenesis, have been investigated for their prognostic role. Such research aims to expand understanding of the disease process, identify patients at risk, and, improve clinical outcome. Although there is much anecdotal evidence to suggest that several biological factors have a prognostic role in non-small-cell carcinoma, their statistical investigation and clinical implementation are limited by a lack of consensus on appropriate investigation methods.
Consideration of all relevant evidence on a particular factor in a systematic way is desirable.3 A systematic review identifies relevant studies, extracts relevant data, appraises study methods, and might combine results statistically (ie, meta-analysis). However, application of systematic review principles to prognostic studies poses practical and methodological difficulties.4, 5 First, identification of all published studies for a particular prognostic variable is not easy. Second, most prognostic factors in cancer are continuous variables, but researchers tend to dichotomise them into high and low levels using a cut-off point that is convenient or arbitrary6 and that differs between studies.7 Third, small studies are likely to give unreliable results, and those that show a large prognostic effect are more likely to be published than are those that do not; such publication bias is well recognised.8, 9 Evidence of publication bias in prognostic studies is accumulating: it has been shown in studies of Barrett's oesophagus as a risk factor for cancer;10 has been suspected in other reviews;11 and a review12 of the prognostic role of P53 in head and neck cancer showed that published studies had larger prognostic effects than did unpublished studies. Fourth, issues associated with the methods of these studies are compounded by a generally poor standard of reporting. Riley and colleagues13 reviewed prognostic markers for neuroblastoma and by use of ten different methods of data extraction were able to estimate log HR (with SE) from only 204 (35%) of 575 reports of markers. Furthermore, many researchers might not be able to provide missing data.12
Systematic reviewers might use only summary information extracted from published studies, or they might attempt to retrieve individual patient data. Methodological concerns suggest that a systematic review of prognostic factors, based only on published data might be unreliable.4, 14 Therefore, a multicentre collaborative framework to obtain raw data from as many relevant studies as possible is a desirable approach for investigation of prognostic factors.
Angiogenesis is the process of haphazard new vessel formation required for tumour growth, invasion, and metastasis. Microvessel density is a measure of angiogenesis and a widely studied putative prognostic factor. We aimed to do a study of individual patient data to assess microvessel-density counts as a prognostic factor in non-metastatic surgically treated non-small-cell lung carcinoma, by obtaining data from all identified sources.
Section snippets
The Prognosis In Lung Cancer project
The Prognosis in Lung Cancer (PILC) project—an international collaborative study group—was set-up to obtain individual patient data for study of potential prognostic factors in non-metastatic, surgically treated non-small-cell lung carcinoma. Microvessel-density count was the first factor we assessed between 1999 and 2003 at the Centre for Statistics in Medicine, Oxford, UK, under the guidance of a steering committee. Details of the conduct of this study have been published previously;15, 16 in
Results
Four datasets (4, 6, 8, and 10) were obtained prospectively by collection of data as patients were diagnosed; the remaining datasets were obtained retrospectively from hospital historical records. Two datasets (5 and 7) were generated from some historical records and by collection of prospective data. Sample sizes varied from about 30 patients to nearly 500. 2146 (75%) patients were men (data for sex not available for dataset 10). 1530 (56%) of cases had died; median survival was about 3–4
Discussion
Overall, our analyses give only weak evidence to suggest that microvessel density is a prognostic factor for survival in patients with non-small-cell lung carcinoma when analysed as a continuous variable and measured by use of the Chalkley method. No prognostic effect was observed by measurement of all vessels.
Laboratory developments have helped identify many potential cancer prognostic factors. However, there is no consensus on how to design and analyse prognostic studies, despite several
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2018, Journal of Clinical EpidemiologyCitation Excerpt :The main issues that make systematic reviews of prognostic studies challenging are: a) poor indexing, b) poor reporting of summary measures, c) heterogeneity of studies, and d) selective reporting/publication bias [2,5,6]. Given these, the use of individual patient data (IPD) has been suggested as the best strategy to obtain valid estimates from systematic reviews of prognostic studies [5,7–11]. However, there are major resource implications and only a handful of reviews have attempted to obtain IPD [5,7,8,12,13].
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