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  • There are limitations in the present study The first

    2019-09-02

    There are limitations in the present study. The first is that this study is an exploratory study and the size of the study cohort is small. We are now recruiting NSCLC patients treated with pembrolizumab as in-house study cohort. Moreover, we plan to analyze the serum samples from a prospective multicenter study in NSCLC patients treated with atezolizumab (UMIN000033133), which will serve as a large validation cohort [38]. The second is that the follow-up period where clinical data is available is relatively short and we need to evaluate the significance of these serum markers in terms of long-term clinical benefit. The third is that we did not include PD-L1 expression levels as a covariate in multivariate analysis because we did not observe statistical significance in univariate analysis (Supplementary Fig. 5). However, the small sample size may have affected the results of statistical analysis on PD-L1 expression and we should address this in the future study.
    Conflict of interest
    Funding sources This study was supported by Project for Cancer Research and Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and Development, AMED grant numbers 16cm0106418h0001 and 17cm0106418h0002 (Y.K. and N.Y.), and JSPS KAKENHI grant number JP16K18430 (J.O.).
    Acknowledgements
    Introduction Brain metastases from non-small cell lung cancer (NSCLC) occur in approximately one-third of patients and their presence is associated with poor prognosis, neurological deterioration, and diminished quality of life, requiring urgent treatment [1]. For these patients, surgical resection, stereotactic radiosurgery (SRS), and whole Concanamycin A radiation therapy (WBRT) are the most common local treatments. The clinical management of patients with brain metastases is changed substantially in the last years, with a shift away from WBRT to SRS. Currently, SRS alone is the recommended treatment for patients with a limited number of brain metastases, yielding an equivalent survival but lower risk of long-term neurotoxicity compared with SRS plus WBRT [2,3]. Surgical resection is often performed in patients with larger lesions and mass effect, with a reported 1-year local control of 50–60%, which is significantly increased with the use of postoperative radiation [2,[4], [5], [6], [7]]. While postoperative WBRT has been traditionally used in the past, SRS has been increasingly used over the last years to deliver focal radiation to the resection cavity. The efficacy of postoperative SRS given in single or few fractions [[2], [3], [4], [5]] has been reported in several studies [[6], [7], [8], [9], [10], [11], [12]]. Its superiority over surgery alone has been demonstrated in a randomized trial of 131 patients with 140 resected brain metastases who were randomly assigned to receive postoperative SRS or observation [6]. With a median overall survival (OS) of 17 months in both groups, local control (LC) rates were 72% in postoperative SRS group and 45% in observation group at 12 months (p  = 0.01), with no additional toxicity. In another trial of 194 patients with 1–3 brain metastases <5 cm in diameter who were randomly assigned to receive postoperative SRS or WBRT, Brown et al. [6] showed that postoperative SRS resulted in similar survival and better cognitive function and quality of life compared with adjuvant WBRT. Results of these trials suggest that postoperative SRS should be considered the new standard of care for patients with resected brain metastases; however, there are only few comparative studies on effectiveness and safety of combined surgery and SRS versus SRS alone [13,14]. In our Institution, brain metastases larger than 2.5–3 cm in size or even smaller (> 2 cm in size) if located near or in eloquent areas (ie, motor, somatosensory, speech, visual cortices, basal ganglia, thalamus, and the brainstem) are usually treated with multi-fraction SRS (mfSRS) to minimize the increased risk of late radiation-induced brain necrosis (RN) associated with high-dose, single-fraction SRS [15,16]. In a recent study of 289 patients with brain metastases > 2.0 cm in size treated with either single-fraction or multi-fraction SRS (3 x 9 Gy) at the University of Rome Sapienza, Sant’ Andrea Hospital, mfSRS resulted in significantly better LC and reduced risk of RN [17].