This systematic review, by pooling all randomised studies comparing treatment of SCLC with or without PCI, revealed a positive effect of PCI. As shown by the meta-analysis, PCI reduced brain metastases incidence and improved survival in patients in CR after chemotherapy (especially when brain CT scan was part of the staging work-up). Unfortunately, the performance of brain imagery (CT scan or MRI) and the long-term assessment of neuropsychological toxicities are not well described in the 12 available trials.
To perform a meta-analysis comparing such heterogeneous trials, we have used a methodology that was similar to our prior systematic reviews [14, 15]. All trials were assessed by 9 investigators using two quality scores: the Chalmers and the ELCWP scales. The latter scale was adapted to the present topic by introducing some specific changes: in the work-up, brain CT scan or MRI with neuropsychological assessment was needed to have 2 points; in the treatment description, brain irradiation method had to be described; neuropsychological examination results were added in the patients characteristics and the "local control of tumour" item was changed in a "brain metastases incidence" item. The results obtained with the two scales were compared and a significant correlation was observed. There was no quality difference among the publications, allowing quantitative aggregation (meta-analysis) of the results of the individual trials. The only significant finding in the performed comparisons was an improved quality in favour of more recently published trials, which can be explained by a better knowledge of clinical trials methodology standards over the last years.
Our approach does not however prevent all the potential biases. The most important one is probably the publication bias. Our review took into account only fully published studies. We did not look for unpublished trials and abstracts because the methodology used required data available in full publications only. Meta-analysis based on individual data is considered by some authors as the gold standard . Systematic reviews of the literature and meta-analyses of individual patient data should not be confused. The first approach is only based on the fully published studies and provides an exhaustive and critical analysis of the topic with an adequate methodology based on the criteria of Mulrow  and with data aggregation (meta-analysis) when possible. The second approach is in fact a new study taking into account all performed trials on the topic, whatever published or not, requiring individual data update by the investigators. In that latter, publications are mainly used for identification purposes. Our meta-analysis, based on the published data, has allowed us to find the same results for patients in CR as Auperin et al  in their individual data meta-analysis. This point supports the validity of our approach. Another potential bias is the language problem: we have restricted our review to articles published in English or French. This selection could favour the positive studies that are most often published in English while the negative ones tend to be more reported in native language . The method of extrapolation of HR needs also to be discussed. When HR were not reported by the authors, they were calculated from the data available in the article and, if not possible, they were extrapolated from the survival curves. This approach might have been associated with errors due to imprecision of the reading.
The brain work-up is often poorly documented. Only five studies reported brain CT scan in the initial evaluation and only in two of them, brain CT scan was done just before randomisation for PCI (when patients were in CR after chemotherapy). So, in the majority of the studies, the CR population could contain patients with asymptomatic brain metastases for which the delivered PCI was in fact a consolidation therapy. To be sure that there are no brain involvement, brain CT scan should have been done just before PCI. In addition, the CR status depends on the type of work-up performed and on the presence of lesions due to chest irradiation, explaining probably why some groups report small rates of complete response. Moreover, the recent development of MRI that could reveal smaller asymptomatic brain metastases will require an update of these trials in the next few years. Indeed, in contrast to prior literature which showed a prevalence of brain metastases at presentation of 10%, Hochstenbag et al found a prevalence of 24 %. This difference can been explained by the fact that the prevalence of 10 % is based on clinical signs and confirmation by brain imaging and, that in the Hochstenbag's study, MRI diagnosed 15 % brain metastases in neurologically asymptomatic patients .
The neuropsychological toxicity of PCI was only described in retrospective studies performed with a small number of patients. In our review, two randomised trials reported neuropsychological assessments that was performed only in a part of the patients and during the first years following PCI. They provided no data about long-term toxicity. It should be noted that other factors than radiotherapy toxicity can also contribute to neurological complications. Indeed old age, alcohol, anticancer drugs (vincristine, etoposide,...), paraneoplastic encephalomyelitis [32;33] and tobacco long-term use or can produce demential syndromes. Concomitant administration of some types of chemotherapy is considered to contribute to brain radiotherapy toxicity. The fractionation and the total dose of radiotherapy delivered to the brain can also influence the toxicity. Neurological toxicity may be reduced by using 2 Gy fractions (20 to 40 Gy) and by giving PCI after chemotherapy. All these factors were not analysed in our systematic review because of a total lack of data in the report of the results of the individual randomised trials.
In conclusion, the present systematic review indicates that PCI decreases brain metastases incidence and that PCI improves survival in SCLC patients in CR after chemotherapy. These effects were obtained in patients who had no systematic neuropsychological brain imagery assessments. The long-term toxicity has so far not been prospectively evaluated. If PCI can be recommended in patients with SCLC and CR documented by a work-up including brain CT scan, data are lacking to generalise its use to any CR situations as some would like . Particularly the potential benefits of PCI have to be carefully balanced with the possible long-term effects, in patients who are managed with more modern imagery techniques like MRI. New trials, adapted to these new developments, are necessary.