Efficacy of sequential chemoradiotherapy combined with toripalimab in de novo metastatic nasopharyngeal carcinoma: A phase II trial.

Locoregional radiotherapy added to chemotherapy has significantly improved survival in de novo metastatic nasopharyngeal carcinoma (mNPC). However, only 54% of de novo mNPC patients who received sequential chemoradiotherapy have complete or partial response 3 months after radiotherapy. This Simon's optimal two-stage design phase II study (NCT04398056) investigates whether PD-1 inhibitor could improve tumor control in combination with chemoradiation. The primary endpoint is objective response rate (ORR) at 3 months after radiotherapy. Twenty-two patients with primary mNPC are enrolled. The ORR at 3 months after radiotherapy is 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the disease control rate is 81.8%. The 3-year progression-free survival (PFS) rate is 44.9% (95% confidence interval 26.4%-76.3%). Fifteen patients (68.2%) experienced grade 3-4 adverse events. Patients with high baseline plasma Epstein-Barr virus DNA copy number (>104 cps/mL) show worse PFS. Addition of toripalimab to sequential chemoradiotherapy suggests promising tumor response in patients with primary mNPC.

A novel screening method of DNA methylation biomarkers helps to improve the detection of colorectal cancer and precancerous lesions.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies, and early detection plays a crucial role in enhancing curative outcomes. While colonoscopy is considered the gold standard for CRC diagnosis, noninvasive screening methods of DNA methylation biomarkers can improve the early detection of CRC and precancerous lesions. METHODS: Bioinformatics and machine learning methods were used to evaluate CRC-related genes within the TCGA database. By identifying the overlapped genes, potential biomarkers were selected for further validation. Methylation-specific PCR (MSP) was utilized to identify the associated genes as biomarkers. Subsequently, a real-time PCR assay for detecting the presence of neoplasia or cancer of the colon or rectum was established. This screening approach involved the recruitment of 978 participants from five cohorts. RESULTS: The genes with the highest specificity and sensitivity were Septin9, AXL4, and SDC2. A total of 940 participants were involved in the establishment of the final PCR system and the subsequent performance evaluation test. A multiplex TaqMan real-time PCR system has been illustrated to greatly enhance the ability to detect precancerous lesions and achieved an accuracy of 87.8% (95% CI 82.9-91.5), a sensitivity of 82.7% (95% CI 71.8-90.1), and a specificity of 90.1% (95% CI 84.3-93.9). Moreover, the detection rate of precancerous lesions of this assay reached 55.0% (95% CI 38.7-70.4). CONCLUSION: The combined detection of the methylation status of SEPT9, SDC2, and ALX4 in plasma holds the potential to further enhance the sensitivity of CRC detection.

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Efficacy of local therapy to metastatic foci in nasopharyngeal carcinoma: large-cohort strictly-matched retrospective study.

Background: Studies of local therapy (LT) to metastatic foci from nasopharyngeal carcinoma (NPC) are inconsistent and controversial. Here, we aimed to explore the survival benefit of LT directed at metastatic foci from NPC. Methods: A retrospective analysis was conducted in NPC patients with liver, lung, and/or bone metastases. The postmetastatic overall survival (OS) rate was analyzed using the Kaplan-Meier method and compared by the log-rank test. Multivariate analysis was performed using the Cox hazard model. Subgroup analyses evaluating the effect of LT were performed for prespecified covariates. Propensity score matching was applied to homogenize the compared arms. Results: Overall, 2041 of 2962 patients were eligible for analysis. At a median follow-up of 43.4 months, the 5-year OS improved by an absolute difference of 14.6%, from 46.2% in the LT group versus 31.6% in the non-LT group, which led to a hazard ratio of 0.634 for death (p < 0.001). Matched-pair analyses confirmed that LT was associated with improved OS (p = 0.003), and the survival benefits of LT remained consistent in the subcohorts of liver and lung metastasis (p = 0.009 and p = 0.007, respectively) but not of bone metastasis (BoM; p = 0.614). Radiotherapy was predominantly used for BoM and biological effective dose (BED) >60 Gy was found to yield more survival benefit than that of BED ⩽ 60 Gy. Conclusions: The addition of LT directed at metastasis has demonstrated an improvement to OS compared with non-LT group in the present matched-pair study, especially for patients with liver and/or lung metastases.

Supplemental folic acid and/or multivitamins in pregnancy is associated with a decreased risk of childhood and adolescent nasopharyngeal carcinoma.

The aim of this study was to evaluate the association between prenatal and neonatal period exposures and the risk of childhood and adolescent nasopharyngeal carcinoma (NPC). From January 2009 to January 2016, a total of 46 patients with childhood and adolescent NPC (i.e., less than 18 years of age) who were treated at Sun Yat-sen University Cancer Center were screened as cases, and a total of 45 cancer-free patients who were treated at Sun Yat-sen University Zhongshan Ophthalmic Center were selected as controls. The association between maternal exposures during pregnancy and obstetric variables and the risk of childhood and adolescent NPC was evaluated using logistic regression analysis. Univariate analysis revealed that compared to children and adolescents without a family history of cancer, those with a family history of cancer had a significantly higher risk of childhood and adolescent NPC [odds ratios (OR) = 3.15, 95% confidence interval (CI) = 1.02-9.75, P = 0.046], and the maternal use of folic acid and/or multivitamins during pregnancy was associated with a reduced risk of childhood and adolescent NPC in the offspring (OR = 0.07, 95% CI = 0.02-0.25, P < 0.001). After multivariate analysis, only the maternal use of folic acid and/or multivitamins during pregnancy remained statistically significant. These findings suggest that maternal consumption of folic acid and/or multivitamins during pregnancy is associated with a decreased risk of childhood and adolescent NPC in the offspring.

Toripalimab plus intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma: an open-label single-arm, phase II trial.

BACKGROUND: Toripalimab is a humanized immunoglobulin G4 monoclonal antibody against programmed death 1. We aimed to investigate the efficacy and safety of toripalimab in combination with intensity-modulated radiotherapy (IMRT) for recurrent nasopharyngeal carcinoma (rNPC). METHODS: We conducted a single-arm, phase II trial with patients with rNPC who had biopsy-proven disease and were unsuitable for local surgery. Eligible patients received IMRT in combination with toripalimab administered via intravenous infusion of 240 mg once every 3 weeks for a maximum of seven cycles. The primary endpoint was the objective response rate at 3 months post radiotherapy. The secondary endpoints included safety profiles, progression-free survival (PFS). RESULTS: Between May 2019 and January 2020, a total of 25 patients with rNPC were enrolled (18 men (72.0%) and 7 women (28.0%); median (IQR) age, 49.0 (43.5-52.5) years). With a median (IQR) follow-up duration of 14.6 months (13.1-16.2) months, 19 patients (79.2%) achieved an overall response, and disease control was achieved in 23 (95.8%) patients at 3 months post radiotherapy. The 12-month PFS was 91.8% (95% CI 91.7% to 91.9%). The incidences of acute (grade ≥3) blood triglyceride elevation, creatine kinase elevation, skin reaction, and mucositis were 1 (4.0%), 1 (4.0%), 2 (8.0%), and 1 (4.0%), respectively. The incidences of late severe (grade ≥3) nasopharyngeal wall necrosis, nasal bleeding, and trismus were 28.0%, 12.0%, and 4.0%, respectively. CONCLUSIONS: Toripalimab combined with IMRT was tolerable and showed promising antitumor activity in patients with rNPC. TRIAL REGISTRATION NUMBER: NCT03854838.

Erratum: Twist promotes tumor metastasis in basal-like breast cancer by transcriptionally upregulating ROR1: Erratum.

[This corrects the article DOI: 10.7150/thno.21477.].

Efficacy and Safety of Locoregional Radiotherapy With Chemotherapy vs Chemotherapy Alone in De Novo Metastatic Nasopharyngeal Carcinoma: A Multicenter Phase 3 Randomized Clinical Trial.

Importance: The role of locoregional radiotherapy in patients with de novo metastatic nasopharyngeal carcinoma (mNPC) is unclear. Objective: To investigate the efficacy and safety of locoregional radiotherapy in de novo mNPC. Design, Setting, and Participants: Patients with biopsy-proven mNPC, who demonstrated complete or partial response (RECIST v1.1) following 3 cycles of cisplatin and fluorouracil chemotherapy, were enrolled. Eligible patients were randomly assigned (1:1) to receive either chemotherapy plus radiotherapy or chemotherapy alone. Overall, 126 of 173 patients screened were eligible to the study, and randomized to chemotherapy plus radiotherapy (n = 63) or chemotherapy alone (n = 63). Median (IQR) follow-up duration was 26.7 (17.2-33.5) months. Interventions: The chemotherapy regimens were fluorouracil continuous intravenous infusion at 5 g/m2 over 120 hours and 100 mg/m2 intravenous cisplatin on day 1, administered every 3 weeks for 6 cycles. Patients assigned to the chemotherapy plus radiotherapy group received intensity-modulated radiotherapy (IMRT) after chemotherapy. Main Outcomes and Measures: The primary end point of the study was overall survival (OS). The secondary end point was progression-free survival (PFS) and safety. Results: Overall, 126 patients were enrolled (105 men [83.3%] and 21 women [16.7%]; median [IQR] age, 46 [39-52] years). The 24-month OS was 76.4% (95% CI, 64.4%-88.4%) in the chemotherapy plus radiotherapy group, compared with 54.5% (95% CI, 41.0%-68.0%) in the chemotherapy-alone group. The study met its primary end point of improved OS (stratified hazard ratio [HR], 0.42; 95% CI, 0.23-0.77; P = .004) in favor of chemotherapy plus radiotherapy. Progression-free survival was also improved in the chemotherapy plus radiotherapy group compared with the chemotherapy-alone group (stratified HR, 0.36; 95% CI, 0.23-0.57). No significant differences in acute hematological or gastrointestinal toxic effects were observed between the treatment arms. The frequency of acute grade 3 or higher dermatitis, mucositis, and xerostomia was 8.1%, 33.9%, and 6.5%, respectively, in the chemotherapy plus radiotherapy group. The frequency of late severe grade 3 or higher hearing loss and trismus was 5.2% and 3.4%, respectively, in the chemotherapy plus radiotherapy group. Conclusions and Relevance: In this randomized clinical trial, radiotherapy added to chemotherapy significantly improved OS in chemotherapy-sensitive patients with mNPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02111460.

Clonal Mutations Activate the NF-κB Pathway to Promote Recurrence of Nasopharyngeal Carcinoma.

The genetic events occurring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 patients with rNPC and 44 primarily diagnosed NPC (pNPC), with 7 patients having paired rNPC and pNPC samples. Previously published pNPC exome data were integrated for analysis. rNPC and pNPC tissues had similar mutational burdens, however, the number of clonal mutations was increased in rNPC samples. TP53 and three NF-κB pathway components (TRAF3, CYLD, and NFKBIA) were significantly mutated in both pNPC and rNPC. Notably, mutations in TRAF3, CYLD, and NFKBIA were all clonal in rNPC, however, 55.6% to 57.9% of them were clonal in pNPC. In general, the number of clonal mutations in NF-κB pathway-associated genes was significantly higher in rNPC than in pNPC. The NF-κB mutational clonality was selected and/or enriched during NPC recurrence. The amount of NF-κB translocated to the nucleus in samples with clonal NF-κB mutants was significantly higher than that in samples with subclonal NF-κB mutants. Moreover, the nuclear abundance of NF-κB protein was significantly greater in pNPC samples with locoregional relapse than in those without relapse. Furthermore, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival in pNPC. Finally, inhibition of NF-κB enhanced both radiosensitivity and chemosensitivity in vitro and in vivo. In conclusion, NF-κB pathway activation by clonal mutations plays an important role in promoting the recurrence of NPC. Moreover, nuclear accumulation of NF-κB is a prominent biomarker for predicting locoregional relapse-free survival. SIGNIFICANCE: This study uncovers genetic events that promote the progression and recurrence of nasopharyngeal carcinoma and has potential prognostic and therapeutic implications.See related commentary by Sehgal and Barbie, p. 5915.

A curative-intent endoscopic surgery for postradiation nasopharyngeal necrosis in patients with nasopharyngeal carcinoma.

BACKGROUND: Postradiation nasopharyngeal necrosis (PRNN) is a severe complication after radiotherapy in patients with nasopharyngeal carcinoma (NPC), which can severely affect the quality of life and threaten the patient's life. Only 13.4%-28.6% of patients can be cured by traditional repeated endoscopic debridement. Here, we introduced an innovative curative-intent endoscopic surgery for PRNN patients and evaluated its clinical efficacy. METHODS: Clinical data of 72 PRNN patients who underwent radical endoscopic necrectomy, followed by reconstruction using a posterior pedicle nasal septum and floor mucoperiosteum flap were analyzed to determine the efficacy of this surgery. The endpoints were complete re-epithelialization of the nasopharyngeal defect, relief of headache, and overall survival (OS). RESULTS: All surgeries were successfully performed without any severe postoperative complications or death. The median value of numeric rating scales of pain decreased from 8 before surgery to 0 after surgery (P < 0.001). Fifty-one patients (70.8%) achieved complete re-epithelialization of the nasopharyngeal defect. The number of cycles of radiotherapy (odds ratio [OR], 7.254; 95% confidence interval [CI] 1.035-50.821; P = 0.046), postoperative pathological result (OR, 34.087; 95% CI 3.168-366.746; P = 0.004), and survival status of flap (OR, 261.179; 95% CI 17.176-3971.599; P < 0.001) were independent risk factors of re-epithelialization of the nasopharyngeal defects. Postoperative pathological result (hazard ratio [HR], 5.018; 95% CI 1.970-12.782; P = 0.001) was an independent prognostic factor for OS. The 2-year OS rate of the entire cohort was 77.9%. CONCLUSION: Curative-intent endoscopic necrectomy followed by construction using the posterior pedicle nasal septum and floor mucoperiosteum flap is a novel, safe, and effective treatment of PRNN in patients with NPC.

Twist promotes tumor metastasis in basal-like breast cancer by transcriptionally upregulating ROR1.

Rationale: Twist is a key transcription factor for induction of epithelial-mesenchymal transition (EMT), which promotes cell migration, invasion, and cancer metastasis, confers cancer cells with stem cell-like characteristics, and provides therapeutic resistance. However, the functional roles and targeted genes of Twist in EMT and cancer progression remain elusive. Methods: The potential targeted genes of Twist were identified from the global transcriptomes of T47D/Twist cells by microarray analysis. EMT phenotype was detected by western blotting and immunofluorescence of marker proteins. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional induction of ROR1 by Twist. A lung metastasis model was used to study the pro-metastatic role of Twist and ROR1 by injecting MDA-MB-231 cells into tail vein of nude mice. Bio-informatics analysis was utilized to measure the metastasis-free survival of breast cancer patients. Results: Twist protein was proved to directly activate the transcription of ROR1 gene, a receptor of Wnt5a in non-canonical WNT signaling pathway. Silencing of ROR1 inhibited EMT process, cell migration, invasion, and cancer metastasis of basal-like breast cancer (BLBC) cells. Knockdown of ROR1 also ameliorated the pro-metastatic effect of Twist. Furthermore, analyses of clinical specimens indicated that high expression of both ROR1 and Twist tightly correlates with poor metastasis-free survival of breast cancer patients. Conclusion: ROR1 is a targeted gene of Twist. Twist/ROR1 signaling is critical for invasion and metastasis of BLBC cells.

A Prognostic Bio-Model Based on SQSTM1 and N-Stage Identifies Nasopharyngeal Carcinoma Patients at High Risk of Metastasis for Additional Induction Chemotherapy.

Purpose: Metastasis is one of the most important causes of treatment failure in nasopharyngeal carcinoma (NPC). In T4 or N2-3 patients at high-risk of metastasis, concurrent chemoradiotherapy (CCRT) is inadequate and additional induction chemotherapy (IC) is controversial. There is a critical need to develop a better patient stratification to efficiently identify patients at high-risk of metastasis for additional IC. Recently, Sequestosome 1 (SQSTM1)/p62, an autophagy adaptor protein, was identified as one of the metastasis-related proteins in NPC. However, the mechanism by which SQSTM1 is involved in NPC metastasis was not investigated.Experimental Design: The effect of SQSTM1 on cell migration and invasion was examined in vitro and in vivo SQSTM1 expression was analyzed in clinical NPC samples using IHC. Luciferase reporter analyses were conducted to identify the effects of SQSTM1 on NF-κB transcriptional activity. A prediction bio-model was constructed by Cox analysis. Retrospective and prospective randomized clinical data were adopted to build and test the model, respectively.Results: SQSTM1 mediated epithelial to mesenchymal transition (EMT) through the NF-κB pathway to promote NPC metastasis. Inhibiting SQSTM1 enhanced sensitivity to cisplatin in NPC cells. In NPC patients, high SQSTM1 expression was associated with increased risk of distant metastasis. Furthermore, we propose a prognostic bio-model based on SQSTM1 and N-stage to predict NPC metastasis. Most importantly, our prospective randomized study suggested that IC is beneficial for NPC patients with high metastasis risk.Conclusions: The prognostic bio-model identifies NPC patients at high-risk of metastasis for additional IC. Clin Cancer Res; 24(3); 648-58. ©2017 AACR.

The Changing Therapeutic Role of Chemo-radiotherapy for Loco-regionally Advanced Nasopharyngeal Carcinoma from Two/Three-Dimensional Radiotherapy to Intensity-Modulated Radiotherapy: A Network Meta-Analysis.

Purpose: We used randomized trials of radiotherapy (RT) with or without chemotherapy in non-metastatic nasopharyngeal carcinoma to investigate the survival benefit of chemoradiotherapy regimens between two/three-dimensional radiotherapy (2D/3D RT) and intensity-modulated radiotherapy (IMRT). Methods: Overall, 27 trials and 7,940 patients were included. Treatments were grouped into seven categories including RT alone, induction chemotherapy (IC) followed by RT (IC-RT), RT followed by adjuvant chemotherapy (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concurrent chemo-radiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). To distinguish between 2D/3D RT and IMRT, three categories in IMRT were newly added, including CRT in IMRT, IC-CRT in IMRT, and CRT-AC in IMRT. The P score was used to rank the treatments. Results: Both fixed- and random-effects frequentist and Bayesian network meta-analysis models were applied, which provided similar results and the same ranking. IC-CRT was the most effective regimen compared with CRT-AC and CRT in the IMRT era for overall survival (OS) (HR, 95% CI, IC-CRT vs. CRT-AC, 0.61 (0.45, 0.82); IC-CRT vs. CRT 0.65 (0.47, 0.91)), progression-free survival (PFS) (0.69 (0.54, 0.88); 0.63 (0.49, 0.80)), and distant metastasis-free survival (DMFS) (0.58 (0.28, 1.21); 0.60 (0.42, 0.85)). CRT-AC achieved the highest survival benefit compared with CRT, and IC-CRT for loco-regional relapse-free survival (LRRFS) (0.44 (0.15, 1.28); 0.72 (0.22, 2.33)). Among these 10 categories, after distinguishing between 2D/3D RT and IMRT, IC-CRT in IMRT ranked first for OS, PFS, and DMFS, and CRT-AC in IMRT ranked first for LRRFS. Conclusion: IC-CRT should be the most suitable regimen for loco-regionally advanced NPC in the IMRT era.

Concurrent Chemoradiotherapy with or without Anti-EGFR-Targeted Treatment for Stage II-IVb Nasopharyngeal Carcinoma: Retrospective Analysis with a Large Cohort and Long Follow-up.

We examined the benefits of the combination of anti-EGFR targeted treatment, cetuximab (CTX) or nimotuzumab (NTZ) and concurrent platinum-based chemoradiotherapy (CCRT) compared with CCRT alone in patients with stage II - IVb nasopharyngeal carcinoma (NPC). A total of 1,628 eligible patients with stage II - IVb NPC, who received CCRT (three cycles of 100 mg/m2 cisplatin every 3 weeks with intensity-modulated radiotherapy) with or without CTX or NTZ between June 2009 and December 2013 were included in the analysis. Using propensity scores to adjust for potential prognostic factors, a well-balanced cohort of 878 patients was created by matching each patient who received CTX or NTZ plus CCRT with no more than four patients who received CCRT alone (1:4). Efficacy and safety were compared between CTX/NTZ plus CCRT and CCRT alone arms. Compared with CCRT alone, treatment with CTX/NTZ plus CCRT was associated with a significantly increased overall survival (3-year OS, 96.6% vs. 92.9%, P = 0.015), improved disease-free survival (3-year DFS, 93.5% vs 86.9%, P = 0.028), and improved distant metastasis-free survival (3-year DMFS, 94.6% vs 89.3%, P = 0.030). Increased rate of CTX related-skin reaction and mucositis was observed in the CTX plus CCRT arm. Multivariate analysis demonstrated the combination of CTX/NTZ was a significant protective factor for OS, DFS, and DMFS in patients treated with CCRT. Our analysis suggests that the addition of CTX/NTZ to CCRT is more effective for maximizing survival in patients with stage II-IVb NPC compared with CCRT alone.

Cetuximab or nimotuzumab plus intensity-modulated radiotherapy versus cisplatin plus intensity-modulated radiotherapy for stage II-IVb nasopharyngeal carcinoma.

To compare intensity-modulated radiotherapy (IMRT) with cisplatin (CDDP) versus cetuximab (CTX) and nimotuzumab (NTZ) for Stage II-IVb Nasopharyngeal Carcinoma (NPC). A total of 1,837 patients with stage II-IVb NPC who received IMRT plus CTX or NTZ, or CDDP between January 2009 and December 2013 were included in the current analysis. Using propensity scores to adjust for potential prognostic factors, a well-balanced cohort of 715 patients was created by matching each patient who underwent IMRT plus concomitant NTZ/CTX with four patients who underwent IMRT plus concomitant CDDP (1:4). Efficacy and safety were compared between the CTX/NTZ and CDDP groups of this well-balanced cohort. Furthermore, we conducted multivariate analysis and subgroup analysis based on all the 1,837 eligible cases. There was no significant difference between CTX/NTZ group and CDDP group in terms of DFS (3-year, 86.7% vs. 86.2%, p > 0.05), LRRFS (96.2% vs. 96.3%, p > 0.05), DMFS (91.1% vs. 92.3%, p > 0.05) and OS (91.7% vs. 91.9%, p > 0.05). Subgroup analysis demonstrated a significant interaction effect between patients with IMRT plus CTX/NTZ and N3 node stage on LRRFS with the highest risk of loco-regional relapse (HR 8.85, p = 0.001). Significantly increased hematologic toxicities, gastrointestinal reactions were observed in the CDDP group (p < 0.05). Patients of 3.4-4.7% experienced severe hematologic toxicities during the treatment with concomitant CTX and NTZ. Increased rate of CTX related-skin reaction and mucositis was observed in the CTX group. CTX/NTZ used concurrently with IMRT may be comparable to those of the standard CDDP-IMRT combination for maximizing survival for patients with stage II-IVb NPC.

Establishment and validation of M1 stage subdivisions for de novo metastatic nasopharyngeal carcinoma to better predict prognosis and guide treatment.

BACKGROUND: To better manage patients with de novo metastatic NPC (mNPC) including easily identifying individuals' survival outcomes and accurately choosing the most suitable treatment. MATERIALS AND METHODS: Three independent cohorts of mNPC patients (a training set of n = 462, an internal prospective validation set of n = 272 and an external prospective validation set of n = 243) were studied. The radiological characteristics of distant metastases, including number of metastatic locations, number of metastatic lesions and size of metastatic lesions, were carefully defined based on imaging data. These three factors and other potential prognostic factors were comprehensively analysed and were further integrated into new subdivisions of stage M1 using a Cox proportional hazards model. RESULTS: We successfully subdivided the M1 stage into three categories: M1a, oligo metastasis without liver involvement; M1b, multiple metastases without liver involvement; and M1c, liver involvement irrespective of metastatic lesions. The 3-year overall survival ranged from 54.5% to 72.8%, from 34.3% to 41.6% and from 22.6.0%-23.6% for M1a, M1b and M1c, respectively (P < 0.001). Systemic chemotherapy combined with radical loco-regional radiotherapy may benefit patients in M1a and M1b, not in M1c. Further aggressive treatment of metastatic lesions based on systemic chemotherapy and definitive loco-regional radiotherapy showed no survival benefit, even for patients in M1a (P > 0.05). CONCLUSION: The subdividing of M1 provided promising prognostic value and could aid clinicians in choosing the most suitable treatment for de novo mNPC patients.

Establishment of an innovative staging system for extramedullary plasmacytoma.

BACKGROUND: Extramedullary plasmacytoma (EMP) is a rare malignant disease that lacks a unique clinical staging system to predict the survival of EMP patients and to design individualized treatment. Instead, clinicians have chosen to use the multiple myeloma (MM) staging system. METHODS: Forty-eight EMP patients treated between 1996 and 2014 were included in this study. The new clinical stages were established according to independent survival factors using Cox regression model. RESULTS: Lymph node metastasis and a larger primary tumor (≥5 cm) were the only two independent poor prognostic factors for overall survival (OS) and disease-free survival (P < 0.05). Stage I was defined as the disease without those two poor prognostic factors. Stage II was defined as the presence of either factor, and Stage III was defined as the presence of both factors. OS was significantly different in each stage of the new staging system (P < 0.001), with a median follow-up time for Stage I, Stage II and Stage III of 68, 23 and 14 months. The new staging system had enhanced prognostic value compared to the MM staging system (the area under ROC 0.763 versus 0.520, P = 0.044). Although no difference was observed between treatments in Stage I, the combination treatment was associated with a significantly beneficial OS in the late stages (5-year OS: 15.3 % versus 79.5 %; P = 0.032). CONCLUSIONS: The new staging system exhibited a promising prognostic value for survival and could aid clinicians in choosing the most suitable treatment for EMP patients.

Unconjugated Bilirubin Is a Novel Prognostic Biomarker for Nasopharyngeal Carcinoma and Inhibits Its Metastasis via Antioxidation Activity.

Distant metastasis is the most common cause of treatment failure and mortality in nasopharyngeal carcinoma (NPC) patients. Thus, it is important to understand the mechanism of NPC metastasis and identify reliable prognostic factors. In this study, we investigated the prognostic value of unconjugated bilirubin (UCB), which was previously considered a byproduct of heme catabolism, in NPC patients and examined the effects of UCB on NPC metastasis. The receiver operating characteristic analysis-generated UCB cutoff point for DMFS was 9.7 µmol/L. We found that higher UCB levels were significantly associated with favorable distant metastasis-free survival (DMFS, 93.3% vs. 84.2%, P < 0.001) in NPC patients and was an independent predictor for DMFS (HR, 0.416; 95% confidence interval, 0.280-0.618; P < 0.001). We next found that UCB treatment impaired the invasion capability of NPC cells and potently inhibited lung metastasis of NPC cells in nude mice. Further investigation showed that UCB inhibited reactive oxygen species production, which is involved in the repression of ERK1/2 activation and matrix metalloproteinase-2 (MMP-2) expression. Moreover, lower levels of ERK1/2 phosphorylation and MMP-2 expression were observed in the NPC lung metastases of nude mice administered UCB. Taken together, our results indicate that UCB is a significantly favorable factor for DMFS in NPC patients and may play an important role in NPC chemoprevention.

Development of a ten-signature classifier using a support vector machine integrated approach to subdivide the M1 stage into M1a and M1b stages of nasopharyngeal carcinoma with synchronous metastases to better predict patients' survival.

The aim of this study was to develop a prognostic classifier and subdivided the M1 stage for nasopharyngeal carcinoma patients with synchronous metastases (mNPC). A retrospective cohort of 347 mNPC patients was recruited between January 2000 and December 2010. Thirty hematological markers and 11 clinical characteristics were collected, and the association of these factors with overall survival (OS) was evaluated. Advanced machine learning schemes of a support vector machine (SVM) were used to select a subset of highly informative factors and to construct a prognostic model (mNPC-SVM). The mNPC-SVM classifier identified ten informative variables, including three clinical indexes and seven hematological markers. The median survival time for low-risk patients (M1a) as identified by the mNPC-SVM classifier was 38.0 months, and survival time was dramatically reduced to 13.8 months for high-risk patients (M1b) (P < 0.001). Multivariate adjustment using prognostic factors revealed that the mNPC-SVM classifier remained a powerful predictor of OS (M1a vs. M1b, hazard ratio, 3.45; 95% CI, 2.59 to 4.60, P < 0.001). Moreover, combination treatment of systemic chemotherapy and loco-regional radiotherapy was associated with significantly better survival outcomes than chemotherapy alone (the 5-year OS, 47.0% vs. 10.0%, P < 0.001) in the M1a subgroup but not in the M1b subgroup (12.0% vs. 3.0%, P = 0.101). These findings were validated by a separate cohort. In conclusion, the newly developed mNPC-SVM classifier led to more precise risk definitions that offer a promising subdivision of the M1 stage and individualized selection for future therapeutic regimens in mNPC patients.

Intensity-modulated radiotherapy prolongs the survival of patients with nasopharyngeal carcinoma compared with conventional two-dimensional radiotherapy: A 10-year experience with a large cohort and long follow-up.

BACKGROUND: To evaluate the survival benefit of intensity-modulated radiotherapy (IMRT) compared with conventional two-dimensional radiotherapy (2D-CRT) in nasopharyngeal carcinoma (NPC) using a large cohort with long follow-up. METHODS: We retrospectively analysed 7081 non-metastatic NPC patients who received curative IMRT or 2D-CRT from February 2002 to December 2011. RESULTS: Of the 7081 patients, 2245 (31.7%) were administered IMRT, while 4836 (68.3%) were administered 2D-CRT. At 5 years, the patients administered IMRT had significantly higher local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS), progression-free survival (PFS) and overall survival (OS) (95.6%, 92.5%, 82.1% and 87.4%, respectively) than those administered 2D-CRT (90.8%, 88.5%, 76.7% and 84.5%, respectively; p<0.001). The distant metastasis-free survival (DMFS) was higher for IMRT than 2D-CRT, with borderline significance (87.6% and 85.7%, respectively; p=0.056). However, no difference was observed between IMRT and 2D-CRT in nodal relapse-free survival (NRFS; 96.3% and 97.4%, respectively; p=0.217). Multivariate analyses showed that IMRT was an independent protective prognostic factor for LRFS, LRRFS and PFS, but not NRFS, DMFS or OS. CONCLUSIONS: IMRT provided an improved LRFS, LRRFS and PFS in both the early and advanced T classifications and overall stage for non-disseminated NPC compared with 2D-CRT. However, no significant advantage was observed in NRFS, DMFS or OS when IMRT was used.