Peiyu Huang

Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis

BACKGROUNDnA previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy.nnnMETHODSnWe searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis.nnnFINDINGSnWe analysed data from 19 trials and 4806 patients. Median follow-up was 7·7 years (IQR 6·2-11·9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio [HR] 0·79, 95% CI 0·73-0·86, p<0·0001; absolute benefit at 5 years 6·3%, 95% CI 3·5-9·1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0·01) in favour of concomitant plus adjuvant chemotherapy (HR 0·65, 0·56-0·76) and concomitant without adjuvant chemotherapy (0·80, 0·70-0·93) but not adjuvant chemotherapy alone (0·87, 0·68-1·12) or induction chemotherapy alone (0·96, 0·80-1·16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (HR 0·75, 95% CI 0·69-0·81), locoregional control (0·73, 0·64-0·83), distant control (0·67, 0·59-0·75), and cancer mortality (0·76, 0·69-0·84).nnnINTERPRETATIONnOur results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed.nnnFUNDINGnFrench Ministry of Health (Programme dactions intégrées de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Long-term follow-up of a phase III study comparing radiotherapy with or without weekly oxaliplatin for locoregionally advanced nasopharyngeal carcinoma

BACKGROUNDnPrevious results from our trial showed that adding oxaliplatin to radiotherapy (RT) increased survival in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term efficacy and late toxic effects.nnnPATIENTS AND METHODSnBetween January 2001 and January 2003, 115 Patients with nonkeratinizing/undifferentiated locoregionally advanced NPC were randomly to receive either RT alone (n = 56) or plus concurrent oxaliplatin 70 mg/m(2) weekly for six cycles (n = 59).nnnRESULTSnAfter a median follow-up of 114 months (range 18-139 months), the 5-year overall survival (OS) and metastasis-free survival (MFS) rates in the concurrent chemoradiotherapy (CCRT) group were significantly higher than those observed in the RT-alone group (OS, 73.2% versus 60.2%, P = 0.028; MFS, 74.7% versus 63.0%, P = 0.027). However, CCRT did not improve locoregional failure-free survival significantly. Subgroup analyses showed that the superiorities of CCRT mainly existed in the T3-4N0-1 stage subgroup (OS: HR = 0.394, P = 0.034). The grade 3/4 late toxic effects were similar in the two groups.nnnCONCLUSION(S)nThe long-term follow-up data confirms the role of CCRT as a treatment of locoregionally advanced NPC. Oxaliplatin can be considered as an alternative optional therapeutic regimen for these patients due to its high efficiency and low toxic effect.

Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma

Tumor immune evasion is a hallmark of cancer. The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway has been suggested to play an important role in T cell tolerance and tumor immune escape. In this study, we aimed to evaluate the correlation between the expression of PD-1/PD-L1 and the post-treatment outcome in patients with nasopharyngeal carcinoma (NPC). Formalin-fixed, paraffin-embedded tissue biopsies from 139 patients with histological diagnosis of NPC treated with conventional chemoradiotherapy were studied. By using immunohistochemistry staining, expressions of PD-1 on tumor-infiltrating lymphocyte and PD-L1 on tumor tissue were detected. The staining results were evaluated with H-score. The correlation between PD-1/PD-L1 expression and clinical characteristics and post-treatment outcome were analyzed. PD-1+ immune cell were present in 52 of these 139 tumors (37.4xa0%). PD-L1 expression was detected in 132 patients (95.0xa0%), which located on tumor tissue. High expression of PD-L1 (median H-score >35) in tumor tissue significantly correlated with a poor prognosis of disease-free survival (Pxa0=xa00.009). Co-expression of PD-1 and PD-L1 in NPC at diagnosis correlated with the poorest prognosis of disease-free survival (Pxa0=xa00.038). PD-1/PD-L1 co-expression reflected the selective suppression of cytotoxic lymphocytes in the tumor microenvironment and predicted recurrence and metastasis of NPC after conventional therapies. Blocking this pathway in patients with co-expression of PD-1/PD-L1 provides a potential therapy target for NPC.

Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma

BACKGROUNDnWe aimed to investigate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC).nnnPATIENTS AND METHODSnIt was a Simon two-stage designed trial. Chemotherapy-naive patients with recurrent or metastatic disease were enrolled. The regimen was sorafenib 400 mg orally b.i.d., cisplatin 80 mg/m(2) i.v. day 1, and 5-FU 1000 mg/m(2)/day CIV for 4 days, repeated every 21 days. After a maximum of six cycles of chemotherapy, patients received maintenance of sorafenib.nnnRESULTSnIn total, 54 patients were enrolled. The objective response rate reached 77.8%, including 1 complete response and 41 partial responses. The median progression-free survival was 7.2 months (95% CI 6.8-8.4 months), and the median overall survival was 11.8 months (95% CI 10.6-18.7 months). Major toxic effects included hand-foot skin reaction, myelosuppression, and gastrointestinal (GI) reaction. The incidence of hemorrhage was 22.2%, and one patient with liver metastases died of GI bleeding. Contrast-enhanced ultrasonography was carried out in a subset of patients with liver metastases.nnnCONCLUSIONnCombination of sorafenib, cisplatin (80 mg/m(2)) and 5-FU (3000 mg/m(2)) was tolerable and feasible in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and 5-FU with standard dose of cisplatin plus 5-FU in NPC are warranted.

Osteopontin is a useful predictor of bone metastasis and survival in patients with locally advanced nasopharyngeal carcinoma

Bone is the most common metastatic site in nasopharyngeal carcinoma (NPC). Osteopontin (OPN) and bone sialoprotein (BSP) are demonstrated to be involved in multiple steps of distant metastasis and correlate with bone metastasis (BM) in cancers. We aim to explore the impacts of OPN and BSP on the prognosis of the patients with locally advanced NPC. A tissue microarray including 162 locally advanced NPC specimens was generated for immunohistochemical evaluation. All of the patients received curative treatment. Twenty‐two patients developed BM during follow‐up. The OPN expression level was higher in patients with BM than in those without BM (pu2009=u20090.005), whereas no significant difference of the BSP expression level was noted (pu2009=u20090.634). Univariate analysis demonstrated that a higher level of OPN expression associated with a poorer 8‐year metastasis‐free survival (MFS) rate (pu2009<u20090.001), 8‐year bone metastasis‐free survival (BMFS) rate (93.6 vs. 87.5 vs. 64.5% for immunoreactivity score 1, 2 and 3, respectively; pu2009=u20090.001) and median overall survival (OS) time (pu2009<u20090.001). Multivariate Cox analysis confirmed that high level of OPN expression was independent factor associated with decreased BMFS (pu2009=u20090.02), MFS (pu2009<u20090.001) and OS (pu2009<u20090.001). Our findings indicate that OPN is a prognostic biomarker for BM and survival in patients with locally advanced NPC, and therefore it is useful in identifying the patients with an increased risk of cancer progression and BM to guide tailored therapy.

Development and validation of a nomogram for predicting the survival of patients with non-metastatic nasopharyngeal carcinoma after curative treatment

BackgroundThe TNM staging system is far from perfect in predicting the survival of individual cancer patients because only the gross anatomy is considered. The survival rates of the patients who have the same TNM stage disease vary across a wide spectrum. This study aimed to develop a nomogram that incorporates other clinicopathologic factors for predicting the overall survival (OS) of non-metastatic nasopharyngeal carcinoma (NPC) patients after curative treatments.MethodsWe retrospectively collected the clinical data of 1520 NPC patients who were diagnosed histologically between November 2000 and September 2003. The clinical data of a separate cohort of 464 patients who received intensity-modulated radiation therapy (IMRT) between 2001 and 2010 were also retrieved to examine the extensibility of the model. Cox regression analysis was used to identify the prognostic factors for building the nomogram. The predictive accuracy and discriminative ability were measured using the concordance index (c-index).ResultsWe identified and incorporated 12 independent clinical factors into the nomogram. The calibration curves showed that the prediction of OS was in good agreement with the actual observation in the internal validation set and IMRT cohort. The c-index of the nomogram was statistically higher than that of the 7th edition TNM staging system for predicting the survival in both the primary cohort (0.69 vs. 0.62) and the IMRT cohort (0.67 vs. 0.63).ConclusionWe developed and validated a novel nomogram that outperformed the TNM staging system in predicting the OS of non-metastatic NPC patients who underwent curative therapy.

Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 (CDKN2A) locus and mutations in NF-κB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naïve NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFβ pathway activation signature. Implications: This study represents the first integrated analysis of mutation, copy number, and gene expression data in NPC and suggests how tumor genetics and EBV infection influence the tumor microenvironment in this disease. These insights should be considered for guiding immunotherapy treatment strategies in this disease. Mol Cancer Res; 15(12); 1722–32. ©2017 AACR.

Expression of Aurora-B and FOXM1 predict poor survival in patients with nasopharyngeal carcinoma

PurposeThe purpose of this work was to investigate the relationship between Aurora-B, FOXM1, and clinical outcomes in patients with nasopharyngeal carcinoma (NPC) who were treated with a combination of induction chemotherapy and radiotherapy.Patients and methodsThe expression of Aurora-B and FOXM1 were investigated by immunohistochemistry using a tissue microarray (TMA) containing samples from 166 NPC patients who were treated with cisplatin (DDP) + fluorouracil (5-FU) induction chemotherapy and radiotherapy between 1999 and 2005. The relationship of Aurora-B, FOXM1, and survival of these NPC patients was analyzed.ResultsInformative TMA results were obtained in 91 tumor cases for Aurora-B and 93 tumor cases for FOXM1. The 8-year failure-free survival rate (FFS) for the Aurora-B-negative and Aurora-B-positive group was 65.6 and 37.3u2009%, respectively (pu2009=u20090.024), and the 8-year distant FFS (D-FFS) rate was 65.6 and 41.5u2009%, respectively (pu2009=u20090.047). The 8-year overall survival (OS) in the FOXM1-negative group was moderately higher than in the FOXM1-positive group (58.4 vs 39.1u2009%, pu2009=u20090.081). Cox regression analysis revealed that for FFS, Aurora-B expression was a significant prognostic factor (pu2009=u20090.025), while for D-FFS, Aurora-B expression was a marginally significant prognostic factor (pu2009=u20090.056). When FOXM1 expression was analyzed, the Cox regression analyses showed that FOXM1 expression was a marginally significant prognostic factor (pu2009=u20090.056) for OS. Correlation analysis showed that Aurora-B and FOXM1 expression had no significant correlation.ConclusionAurora-B and FOXM1 were both adverse prognostic markers for NPC patients treated with chemoradiotherapy. However, the two markers had no significant correlation.ZusammenfassungZielZiel war die Untersuchung der Beziehung zwischen Aurora-B, FOXM1 und den klinischen Ergebnissen bei Patienten mit nasopharyngealem Karzinom (NPC), die mit einer Kombinationstherapie aus Induktionschemotherapie und Radiotherapie behandelt wurden.Patienten und MethodenDie Expression von Aurora-B und FOXM1 wurde durch Immunohistochemie mittels Gewebemikroarray (TMA) mit Proben von 166xa0Patienten mit NPC durchgeführt, die zwischen 1999 und 2005 mit Cisplatin (DDP) + Fluorouracil-(5-FU-)Induktionschemotherapie und Radiotherapie behandelt worden waren. Die Beziehung von Aurora-B, FOXM1 und dem Überleben dieser Patienten mit NPC wurde analysiert.ErgebnisseInformative TMA-Ergebnisse zu Aurora-B wurden bei 91xa0Tumorpatienten und zu FOXM1 bei 93xa0Tumorpatienten erzielt. Die 8-Jahres-Überlebensrate ohne Therapieversagen (FFS, “failure-free survival”,) betrug in der Aurora-B-negativen Gruppe 65,6% und in der Aurora-B-positiven Gruppe 37,3% (pu2009=u20090,024). Die fernmetastasenfreie 8-Jahres-FFS-(D-FFS-)Rate betrug jeweils 65,6 bzw. 41,5% (pu2009=u20090,047). Das 8-Jahres-Gesamtüberleben (OS, “overall survival”) in der FOXM1-negativen Gruppe war mittelgradig höher als in der FOXM1-positiven Gruppe (58,4 vs. 39,1%; pu2009=u20090,081). Die Cox-Regressionsanalyse zeigte, dass die Aurora-B-Expression für das FFS ein signifikanter prognostischer Faktor war (pu2009=u20090,025); für das D-FFS war die Aurora-B-Expression ein geringfügig signifikanter prognostischer Faktor (pu2009=u20090,056). Bei der Analyse der FOXM1-Expression zeigten die Cox-Regressionsanalysen, dass die FOXM1-Expression ein geringfügig signifikanter prognostischer Faktor für OS war (pu2009=u20090,056). Die Korrelationsanalyse zeigte, dass die Aurora-B- und FOXM1-Expression nicht signifikant korreliert waren.SchlussfolgerungAurora-B und FOXM1 waren beide ungünstige prognostische Marker für Patienten mit NPC, die mit Chemoradiotherapie behandelt wurden. Dennoch zeigten die beiden Marker keine signifikante Korrelation.

Expression of Aurora-B and FOXM1 predict poor survival in patients with nasopharyngeal carcinoma@@@Expression von Aurora-B und FOXM1 prognostizieren schlechtes Überleben bei Patienten mit nasopharyngealem Karzinom

PurposeThe purpose of this work was to investigate the relationship between Aurora-B, FOXM1, and clinical outcomes in patients with nasopharyngeal carcinoma (NPC) who were treated with a combination of induction chemotherapy and radiotherapy.Patients and methodsThe expression of Aurora-B and FOXM1 were investigated by immunohistochemistry using a tissue microarray (TMA) containing samples from 166 NPC patients who were treated with cisplatin (DDP) + fluorouracil (5-FU) induction chemotherapy and radiotherapy between 1999 and 2005. The relationship of Aurora-B, FOXM1, and survival of these NPC patients was analyzed.ResultsInformative TMA results were obtained in 91 tumor cases for Aurora-B and 93 tumor cases for FOXM1. The 8-year failure-free survival rate (FFS) for the Aurora-B-negative and Aurora-B-positive group was 65.6 and 37.3u2009%, respectively (pu2009=u20090.024), and the 8-year distant FFS (D-FFS) rate was 65.6 and 41.5u2009%, respectively (pu2009=u20090.047). The 8-year overall survival (OS) in the FOXM1-negative group was moderately higher than in the FOXM1-positive group (58.4 vs 39.1u2009%, pu2009=u20090.081). Cox regression analysis revealed that for FFS, Aurora-B expression was a significant prognostic factor (pu2009=u20090.025), while for D-FFS, Aurora-B expression was a marginally significant prognostic factor (pu2009=u20090.056). When FOXM1 expression was analyzed, the Cox regression analyses showed that FOXM1 expression was a marginally significant prognostic factor (pu2009=u20090.056) for OS. Correlation analysis showed that Aurora-B and FOXM1 expression had no significant correlation.ConclusionAurora-B and FOXM1 were both adverse prognostic markers for NPC patients treated with chemoradiotherapy. However, the two markers had no significant correlation.ZusammenfassungZielZiel war die Untersuchung der Beziehung zwischen Aurora-B, FOXM1 und den klinischen Ergebnissen bei Patienten mit nasopharyngealem Karzinom (NPC), die mit einer Kombinationstherapie aus Induktionschemotherapie und Radiotherapie behandelt wurden.Patienten und MethodenDie Expression von Aurora-B und FOXM1 wurde durch Immunohistochemie mittels Gewebemikroarray (TMA) mit Proben von 166xa0Patienten mit NPC durchgeführt, die zwischen 1999 und 2005 mit Cisplatin (DDP) + Fluorouracil-(5-FU-)Induktionschemotherapie und Radiotherapie behandelt worden waren. Die Beziehung von Aurora-B, FOXM1 und dem Überleben dieser Patienten mit NPC wurde analysiert.ErgebnisseInformative TMA-Ergebnisse zu Aurora-B wurden bei 91xa0Tumorpatienten und zu FOXM1 bei 93xa0Tumorpatienten erzielt. Die 8-Jahres-Überlebensrate ohne Therapieversagen (FFS, “failure-free survival”,) betrug in der Aurora-B-negativen Gruppe 65,6% und in der Aurora-B-positiven Gruppe 37,3% (pu2009=u20090,024). Die fernmetastasenfreie 8-Jahres-FFS-(D-FFS-)Rate betrug jeweils 65,6 bzw. 41,5% (pu2009=u20090,047). Das 8-Jahres-Gesamtüberleben (OS, “overall survival”) in der FOXM1-negativen Gruppe war mittelgradig höher als in der FOXM1-positiven Gruppe (58,4 vs. 39,1%; pu2009=u20090,081). Die Cox-Regressionsanalyse zeigte, dass die Aurora-B-Expression für das FFS ein signifikanter prognostischer Faktor war (pu2009=u20090,025); für das D-FFS war die Aurora-B-Expression ein geringfügig signifikanter prognostischer Faktor (pu2009=u20090,056). Bei der Analyse der FOXM1-Expression zeigten die Cox-Regressionsanalysen, dass die FOXM1-Expression ein geringfügig signifikanter prognostischer Faktor für OS war (pu2009=u20090,056). Die Korrelationsanalyse zeigte, dass die Aurora-B- und FOXM1-Expression nicht signifikant korreliert waren.SchlussfolgerungAurora-B und FOXM1 waren beide ungünstige prognostische Marker für Patienten mit NPC, die mit Chemoradiotherapie behandelt wurden. Dennoch zeigten die beiden Marker keine signifikante Korrelation.