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Background Whether the waiting time for radical radiotherapy (WRT) detrimentally impacts nasopharyngeal carcinoma (NPC) prognosis is unclear. We estimated the influence of WRT on overall survival (OS) and disease-specific survival (DSS) of NPC. Patients and methods Patients were identified from prospectively maintained database. WRT was calculated from histological diagnosis to initiation of radiotherapy (RT). Survival analysis was estimated using Weibull parametric model and propensity score analysis (PSA). Recursive partitioning analysis (RPA) identified optimal WRT threshold via conditional inference trees to estimate the greatest survival differences based on randomly selected training and validation sets, and this process was repeated 1000 times to ensure threshold robustness. Sensitivity analysis estimated effects of potential unmeasured confounders. Results A total of 9896 patients were included. In multivariate analysis, WRT of 31–60°d, of 61–90°d and of greater than 90°d independently increased mortality risk compared to less than 30°d. Upon RPA, ranges of 30–35°d with the peak of 30°d were confirmed with 89% of simulations validating optimal thresholds. In threshold-based groups, adjusted hazard ratios (HRs) for WRT of greater than 30°d by both Weibull model and PSA were significantly higher than for WRT of less than 30°d [OS: HR = 1.13, 95% confidence interval (CI) 1.04–1.23, P = 0.003; DSS: HR = 1.15, 95% CI 1.05–1.26, P = 0.002]. Sensitivity analysis revealed robustness of results. Conclusions WRT independently affects survival. Increasing WRT beyond 30°d was most consistently detrimental to survival. WRT of NPC should be as short as reasonably achievable (ASARA). [ABSTRACT FROM AUTHOR]

• Bone metastasis and the number of metastatic lesions > 3 were independent prognostic indicators for M1 NPC patients receiving PICT. • A new two-category M1 subdivision for patients receiving immuno-chemotherapy was generated based on the RPA analysis. • Liver metastasis was no longer an independent prognostic factor for M1 NPC patients receiving PICT. This study aims to better manage de novo metastatic nasopharyngeal carcinoma (NPC) patients receiving palliative immuno-chemotherapy (PICT), thereby easily determining individual survival outcomes. Patients with de novo metastatic NPC from four centers who received first-line PICT were included. We developed a nomogram for the pretherapy overall survival (OS) prediction using a logistic regression model in the training cohort (n = 296). We assessed the performance of this nomogram in a validation cohort. A total of 592 patients were included. The median follow-up time was 29.83 months. Bone metastasis (HR, 2.46; 95 % CI, 1.01–6.21; p = 0.049) and the number of metastatic lesions > 3 (HR, 2.78; 95 % CI, 1.24–6.24; p = 0.013) were independent prognostic indicators. A new two-category M1 subdivision was generated: M1a, defined by the absence of co-existing bone metastasis and the presence of more than three metastatic lesions; and M1b, characterized by the presence of co-existing bone metastasis and the presence of more than three metastatic lesions. The 3-year OS rates of patients with M1a vs. M1b were 87.1 % vs. 60.3 % (p < 0.001). The C-indexes were 0.652 and 0.581 in the training and validation cohorts. The 1-, 2-, and 3-year areas under the curve (AUC) were 0.69, 0.68, 0.68 in the training cohort and 0.64, 0.6, 0.6 in the validation cohort. DCA curves also indicated that the nomogram has good clinical utility. The proposed M1 subdivision provides good OS segregation for patients receiving PICT. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to develop an accurate prognostic model to identify suitable candidates for definitive radiation therapy (DRT) in addition to palliative chemotherapy (PCT) among patients with de novo metastatic nasopharyngeal carcinoma (mNPC).Methods and Materials: Patients with de novo mNPC who received first-line PCT with or without DRT were included. Overall survival for patients who received PCT alone versus PCT plus DRT was estimated using inverse probability of treatment weighting-adjusted survival analyses. We developed and validated a prognostic model to predict survival and stratify risks in de novo mNPC. A model-based trees approach was applied to estimate stratified treatment effects using prognostic scores obtained from the prognostic model and to identify suitable DRT candidates. Dominance analysis was used to determine the relative importance of each predictor of receiving DRT.Results: A total of 460 patients were enrolled; 244 received PCT plus DRT and 216 received PCT alone. The 6-month conditional landmark, inverse probability of treatment weighting-adjusted Cox regression analysis showed that PCT plus DRT was associated with a significant survival benefit (hazard ratio: 0.516; 95% confidence interval, 0.403-0.660; P < .001). A prognostic model based on 5 independent prognostic factors, including serum lactate dehydrogenase, number of metastatic sites, presence of liver metastasis, posttreatment Epstein-Barr virus DNA level, and response of metastases to chemotherapy was developed and subsequently validated. Prognostic scores obtained from the prognostic model were used for risk stratification and efficacy estimation. High-risk patients identified using the proposed model would not benefit from additional DRT, whereas low-risk patients experienced significant survival benefits. Socioeconomic factors, including insurance status and education level, played an important role in receipt of DRT.Conclusions: Additional DRT after PCT was associated with increased overall survival in patients with de novo mNPC, especially low-risk patients identified with a newly developed prognostic model. [ABSTRACT FROM AUTHOR]

Initial 3-year results from our clinical trial in locoregionally advanced nasopharyngeal carcinoma (NPC) patients showed that induction chemotherapy (IC) with cisplatin and fluorouracil resulted in improved disease-free survival (DFS) with a marginally significant effect on distant metastasis-free survival (DMFS), but the effect of IC on locoregional relapse-free survival and overall survival (OS) did not differ significantly. Here, we present 5-year follow-up results. Our trial was a randomised, open-label phase III trial comparing IC followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone in patients with stage III-IVB (except T3N0-1) NPC. The IC followed by CCRT group received cisplatin (80 mg/m2 d1) and fluorouracil (800 mg/m2 d1-5) every 3 weeks for two cycles before CCRT. Both groups were treated with 80 mg/m2 cisplatin every 3 weeks concurrently with radiotherapy. The primary end-points were DFS and DMFS. We did efficacy analyses in the 476 randomised patients (intention-to-treat population). After a median follow-up of 82.6 months, the 5-year DFS rate was 73.4% (95% confidence interval [CI] 67.7–79.1) in the IC followed by CCRT group and 63.1% (95% CI 56.8–69.4) in the CCRT alone group (p = 0.007). The 5-year DMFS rate was also significantly higher in the IC followed by CCRT group (82.8%, 95% CI 77.9–87.7) than in the CCRT alone group (73.1%, 95% CI 67.2–79.0, p = 0.014). Our updated analysis revealed an OS benefit of IC: the 5-year OS rate was 80.8% in the IC followed by CCRT group versus 76.8% in the CCRT alone group (p = 0.040). The proportion of patients with eye damage was significantly higher in the CCRT alone group than the IC followed by CCRT group (16.4% [39/238] versus 9.7% [23/238], p = 0.029). IC followed by CCRT provides long-term DFS, DMFS and OS benefits compared with CCRT alone in locoregionally advanced NPC and, therefore, can be recommended for these patients. • IC followed by CCRT improved not only DMFS and DFS, but also OS at 5 years in patients with locoregionally advanced NPC. • The addition of cisplatin and fluorouracil induction chemotherapy did not significantly increase late toxicities. • IC followed by CCRT can be recommended for patients with locoregionally advanced NPC. [ABSTRACT FROM AUTHOR]

Objectives: Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) was designed to avoid solvent-related toxicities, and improve anti-tumor efficacy via increasing paclitaxel's intratumoral concentration and its uptake by tumor cells. This trial aimed to determine the safety and efficacy of induction NAB-paclitaxel combined with cisplatin followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC).Patients and Methods: Patients with stage III-IVb NPC received NAB-paclitaxel (260mg/m2) combined with cisplatin (80mg/m2) intravenously on days 1 and 22, followed by cisplatin (80mg/m2) on days 43 and 64, concomitant with intensity-modulated radiation therapy. This trial is registered with the Chinese Clinical Trials Registry, number ChiCTR-ONC-12002615.Results: From July 2010 to November 2013, 36 eligible patients with nonmetastatic stage III-IVb NPC were enrolled. The objective response rates were 97.2% (eight complete responses [CRs] and 27 partial responses [PRs]) and 100% (30 CRs and six PRs) after two cycles of induction chemotherapy (ICT) and CCRT, respectively. With a median follow-up time of 45months, the estimated 3-year progression-free survival and cancer-specific survival were 86.1% (95% confidence interval [CI], 69.8-99.8%) and 91.7% (95% CI, 68.9-100.0%), respectively. The most frequent grade 3-4 toxicities were neutropenia (8.6%) and nausea (8.6%) after ICT and thrombocytopenia (34.3%) and leukopenia (28.6%) after CCRT.Conclusion: NAB-paclitaxel combined with cisplatin as an ICT regimen showed encouraging anti-tumor effects and manageable toxicities in LA-NPC. Further randomized controlled trials in phase III of NAB-paclitaxel in patients with LA-NPC are warranted. [ABSTRACT FROM AUTHOR]

Background The role of neoadjuvant chemotherapy (NACT) for locoregionally advanced nasopharyngeal carcinoma (NPC) is unclear. We aimed to evaluate the feasibility and efficacy of NACT followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced NPC. Methods Patients with stage III–IVB (excluding T3N0-1) NPC were randomly assigned to receive NACT followed by CCRT (investigational arm) or CCRT alone (control arm). Both arms were treated with 80 mg/m 2 cisplatin every 3 weeks concurrently with radiotherapy. The investigational arm received cisplatin (80 mg/m 2 d1) and fluorouracil (800 mg/m 2 civ d1–5) every 3 weeks for two cycles before CCRT. The primary end-point was disease-free survival (DFS) and distant metastasis-free survival (DMFS). Secondary end-point was overall survival (OS). Survival curves for the time-to-event endpoints were analyzed by the Kaplan–Meier method and compared using the log-rank test. The P value was calculated using the 5-year endpoints. Results Four hundred seventy six patients were randomly assigned to the investigational (n = 238) and control arms (n = 238). The investigational arm achieved higher 3-year DFS rate (82.0%, 95% CI = 0.77–0.87) than the control arm (74.1%, 95% CI = 0.68–0.80, P = 0.028). The 3-year DMFS rate was 86.0% for the investigational arm versus 82.0% for the control arm, with marginal statistical significance (P = 0.056). However, there were no statistically significant differences in OS or locoregional relapse-free survival (LRRFS) rates between two arms (OS: 88.2% versus 88.5%, P = 0.815; LRRFS: 94.3% versus 90.8%, P = 0.430). The most common grade 3–4 toxicity during NACT was neutropenia (16.0%). During CCRT, the investigational arm experienced statistically significantly more grade 3–4 toxicities (P < 0.001). Conclusion NACT improved tumour control compared with CCRT alone in locoregionally advanced NPC, particularly at distant sites. However, there was no early gain in OS. Longer follow-up is needed to determine the eventual therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Chronic inflammation plays an important role in nasopharyngeal carcinoma (NPC) development and progression. Aim of this study is to determine whether inflammation-related parameters predict distant metastasis in NPC patients. Materials and methods: 335 newly diagnosed non-metastatic NPC patients were recruited. The values of the C-reactive protein (CRP), lactate dehydrogenase, albumin, globulin, white blood cell and neutrophil at baseline were measured. Results: Among the above six parameters, only CRP was independently associated with distant metastasis-free survival (DMFS). CRP concentration of advanced T-/TNM-classification patients was higher than those with early classification (P =0.001). Higher-CRP (CRP⩾2.46mg/L) predicted shorter overall survival, disease-free survival and DMFS than lower-CRP (CRP<2.46mg/L). In a multivariable model, higher-CRP and advanced N-classification were independent predictors of distant metastasis. On the basis of these two parameters, a prognostic NC-model was developed as following: (1) low-risk (early N-classification and lower-CRP); (2) intermediate-risk (advanced N-classification or higher-CRP) and (3) the high-risk distant metastasis (advanced N-classification and higher-CRP). When compared with the low-risk group, the hazard ratios (HRs) for distant metastasis and death for the intermediate-/high-risk patients were 3.6/16.1 and 2.26/7.61, respectively (both P <0.001). Conclusion: We developed a new prognostic model based on CRP and N-classification for predicting distant metastasis and death of NPC patients, which may facilitate patient counselling and individualised treatment. [Copyright &y& Elsevier]

Summary: The aim of this randomized study was to compare the efficacy of induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) versus induction chemotherapy plus radiotherapy (IC+RT) for patients with locoregionally advanced nasopharyngeal carcinoma. From August 2002 to April 2005, 408 patients were randomly divided into two groups: an IC+CCRT group and an IC+RT group. Patients in both groups received the same induction chemotherapy: two cycles of floxuridine (FuDR)+carboplatin (FuDR, 750mg/m2, d1-5; carboplatin, area under the curve [AUC]=6). The patients received radiotherapy 1week after they finished the induction chemotherapy. The patients in the IC+CCRT group also received carboplatin (AUC=6) on days 7, 28, and 49 of radiotherapy. Eight patients did not meet the inclusion criteria, and the remaining 400 cases were analyzed. Grade III or IV toxicity was found in 28.4% of the patients in the IC+CCRT group and 13.1% of those in the IC+RT group (P <.001). Five-year overall survival rates were 70.3% and 71.7% (P =0.734) in the IC+CCRT and IC+RT groups, respectively. No significant differences in failure-free survival, locoregional control, and distant control were found between the two groups. Compared with the IC+RT program, the IC+CCRT program used in the present study did not improve the overall survival and failure-free survival in patients with locoregionally advanced nasopharyngeal carcinoma. Using carboplatin in the concurrent chemoradiotherapy was not suitable for nasopharyngeal carcinoma. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate the prognostic potential of serum CCL2 (sCCL2) and serum TNF-α (sTNF-α) in nasopharyngeal carcinoma (NPC) before treatment by analysing the expression of these two markers. Experimental design: Both sCCL2 and sTNF-α were prospectively detected in 297 NPC patients with enzyme-linked immunosorbent assay (ELISA) before treatment. The correlations between sCCL2 level or sTNF-α level and patient’s survival were evaluated. Results: For sCCL2, the 5-year overall survival (OS) and 5-year distant metastasis-free survival (DMFS) of high expression group and low expression group were 64% versus 81% and 67% versus 84% (P <0.05), respectively. For sTNF-α, the 5-year OS and 5-year DMFS of high expression group and low expression group were 62% versus 79% and 66% versus 82% (P <0.05), respectively. The 5-year OS and 5-year DMFS for both positive patients, one marker positive patient and both negative patients were 53% versus 77% versus 85% and 58% versus 80% versus 86% (P <0.05), respectively. Concentrations of sCCL2 and sTNF-α in patients with large skull base invasion were higher than those without or with small skull invasion (P <0.05). Patients who developed bone metastasis alone after radical treatment had higher pre-treatment concentrations of sCCL2 and sTNF-α than those without metastasis (P <0.001). Multifactorial Cox regression analyses demonstrated that T/N/M classification, chemotherapy, sCCL2 level and sTNF-α level were independent predictors of OS and DMFS of NPC patients. Conclusion: High expression levels of sCCL2 and sTNF-α predict bone invasion, post-treatment distant metastasis and poor overall survival in NPC patients. [Copyright &y& Elsevier]

Objectives: Chemoradiotherapy is the standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). We aimed to reveal factors associated with chemotherapy use and evaluate chemotherapy's benefit in patients with stage III NPC stratified by lymph node status.Patients and Methods: Overall, 1452 patients with stage III NPC who underwent radiotherapy with (n = 1361) or without (n = 91) chemotherapy were identified in the SEER database. We examined predictors for chemotherapy use using logistic regression analysis. We compared all-cause mortality (ACM) and cancer-specific mortality (CSM) using the Kaplan-Meier method. Cox regression and competing risk analyses were used to evaluate the benefit of chemotherapy. The inverse probability of treatment weighting (IPTW) approach was applied to reduce selection bias and adjust for competing risks. Subgroup analyses and interaction effects were explored.Results: Factors including age, sex, insured status, tumor grade, and N category were associated with chemotherapy use. Chemotherapy was associated with decreased 5-year ACM (31.4% vs. 48.4%, p < 0.001) and CSM (25.5% vs. 35.8%; p = 0.017) in stage III NPC patients. The IPTW-adjusted hazard ratio for 5-year ACM was 0.57 (95% CI: 0.38-0.86, p = 0.008), whereas IPTW-adjusted sub-hazard ratio for 5-year CSM was 0.62 (95% CI: 0.42-0.93, p = 0.003). A significant interaction effect existed between lymph node status and treatment modality. Chemotherapy offered a significant survival benefit in node-positive stage III NPC. However, no chemotherapy benefit for the node-negative disease was observed.Conclusion: Chemotherapy adds survival benefit in stage III NPC, especially in patients with node-positive disease. The magnitude of chemotherapy benefit in node-negative stage III NPC warrants further investigation. [ABSTRACT FROM AUTHOR]