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Purpose:We aimed to evaluate the value of deep learning on positron emission tomography with computed tomography (PET/CT)–based radiomics for individual induction chemotherapy (IC) in advanced nasopharyngeal carcinoma (NPC).Experimental Design:We constructed radiomics signatures and nomogram for predicting disease-free survival (DFS) based on the extracted features from PET and CT images in a training set (n = 470), and then validated it on a test set (n = 237). Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were applied to evaluate the discriminatory ability of radiomics nomogram, and compare radiomics signatures with plasma Epstein–Barr virus (EBV) DNA.Results:A total of 18 features were selected to construct CT-based and PET-based signatures, which were significantly associated with DFS (P < 0.001). Using these signatures, we proposed a radiomics nomogram with a C-index of 0.754 [95% confidence interval (95% CI), 0.709–0.800] in the training set and 0.722 (95% CI, 0.652–0.792) in the test set. Consequently, 206 (29.1%) patients were stratified as high-risk group and the other 501 (70.9%) as low-risk group by the radiomics nomogram, and the corresponding 5-year DFS rates were 50.1% and 87.6%, respectively (P < 0.0001). High-risk patients could benefit from IC while the low-risk could not. Moreover, radiomics nomogram performed significantly better than the EBV DNA-based model (C-index: 0.754 vs. 0.675 in the training set and 0.722 vs. 0.671 in the test set) in risk stratification and guiding IC.Conclusions:Deep learning PET/CT-based radiomics could serve as a reliable and powerful tool for prognosis prediction and may act as a potential indicator for individual IC in advanced NPC.

Purpose: Because of the uneven geographic distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC + CCRT in locoregionally advanced NPC.Experimental Design: Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively.Results: Median follow-up was 5.0 years. The HR for PFS was 0.70 [95% confidence interval (CI), 0.56–0.86; P = 0.0009; 9.3% absolute benefit at 5 years] in favor of IC + CCRT versus CCRT alone. IC + CCRT also improved OS (HR = 0.75; 95% CI, 0.57–0.99; P = 0.04) and reduced distant failure (HR = 0.68; 95% CI, 0.51–0.90; P = 0.008). IC + CCRT had a tendency to improve locoregional control compared with CCRT alone (HR = 0.70; 95% CI, 0.48–1.01; P = 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected.Conclusions: This IPD pooled analysis demonstrates the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control. Clin Cancer Res; 24(8); 1824–33. ©2018 AACR.

Supplementary Method

Figure S1. Flow chart of patient inclusion. NPC, nasopharyngeal carcinoma; PET/CT, positron emission tomography with computed tomography; CCRT, concurrent chemoradiotherapy; IC, induction chemotherapy; IMRT, intensity-modulated radiotherapy. Figure S2. The manual segmentation of (A) a patient with disease progression and (B) a patient without disease progression. Red region, the segmented tumors; green region, the segmented lymph nodes. Figure S3. DCNN architectures used in the study. (A) DCNN for CT image in training step; (B) DCNN for CT image in feature extraction step; (C) DCNN for PET image in training step; (D) DCNN for PET image in feature extraction step. Figure S4. Time-dependent ROC curves of radiomics nomogram in the training (A) and test (B) sets. ROC, receiver operating characteristic; AUC, area under the curve. Figure S5. Radiomics nomogram score for each patients in the training (A) and test (B) sets. Figure S6. Kaplan-Meier survival curves of disease-free survival between high-risk and low-risk groups stratified by age, gender, overall stage, and pre-DNA. Figure S7. Kaplan-Meier survival curves of overall survival between high-risk and low-risk groups stratified by age, gender, overall stage and pre-DNA. Figure S8. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for the whole 707 patients. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; OS, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival. Figure S9. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for the 521 patients with low risk. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy. DFS, disease-free survival; OS, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival. Figure S10. An example of the feature maps generated from the DCNNs. Figure S11. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for nomogram A-defined low-risk group. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; S, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival. Figure S12. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for nomogram A-defined high-risk group. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; S, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival. Figure S13. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for nomogram B-defined low-risk group. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; S, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival. Figure S14. Kaplan-Meier survival curves of DFS (A), OS (B), DMFS (C) and LRRFS (D) between IC+CCRT and CCRT alone for nomogram B-defined high-risk group. IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; S, overall survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival.

Table S1. Numbers of features remained after each selection step for CT-based signature building. Table S2. Numbers of features remained after each selection step for PET-based signature building. Table S3. Results of radiomics feature selection and Rad-score building. Table S4. Comparison of signatures combining features of different categories. Table S5. Results of univariate analysis. Table S6. Multivariate analysis results for disease-free survival in training set. Table S7. Baseline information of nomogram-defined high-risk and low-risk groups. Table S8. Survival outcomes between radiomics nomogram-defined high and low risk groups. Table S9. Results of multivariate analysis for the whole cohort. Table S10. Results of multivariate analysis within the high-risk group. Table S11. Results of multivariate analysis within the low-risk group. Table S12. Results of multivariate analysis within the low-risk group defined by nomogram A. Table S13. Results of multivariate analysis within the high-risk group defined by nomogram A. Table S14. Results of multivariate analysis within the low-risk group defined by nomogram B. Table S15. Results of multivariate analysis within the high-risk group defined by nomogram B.

Supplementary materials including supplementary figures and tables Supplementary Figure S1. Flowchart of randomized controlled trial selection. AC, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; GZ, Guangzhou; HeCOG, Hellenic Cooperative Oncology Group; IC, induction chemotherapy; NCCS, National Cancer Centre Singapore; NPC, nasopharyngeal carcinoma; PWH, Prince of Wales Hospital; RCT, randomized controlled trial Supplementary Figure S2. Forest plots for (A) progression-free survival and (B) overall survival. The estimated hazard ratio (HR) for each individual trial is indicated by the center of the square and the horizontal line gives the 95% confidence interval (CI). The closed diamonds show the overall HR and 95% CI. HR < 1 and 95% CI excluding 1 indicate improved survival for the experimental versus control arm. A fixed effect model was used. CCRT, concurrent chemoradiotherapy; GZ, Guangzhou; HeCOG, Hellenic Cooperative Oncology Group; IC, induction chemotherapy; NCCS, National Cancer Centre Singapore; NPC, nasopharyngeal carcinoma; O-E, observed minus expected deaths or events; PWH, Prince of Wales Hospital. Supplementary Figure S3. Multiple treatment comparison network. Each treatment area is proportional to the cumulative number of patients (in parentheses). Solid lines between treatments represent direct comparisons. AC, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; CEP, cisplatin, epirubicin and paclitaxel; GCP, gemcitabine, carboplatin and paclitaxel; IC, induction chemotherapy; PF, cisplatin and fluorouracil; PX, cisplatin and capecitabine; TP, docetaxel and cisplatin; TPF, TP and fluorouracil. Supplementary Table S1. Description of the Two Trials Included in the Supplementary Analysis Supplementary Table S2. Description of Patient Characteristics Supplementary Table S3. Disease Status and Pattern of FailureSupplementary Table S4. Compliance with Induction Chemotherapy and Concurrent Chemoradiotherapy Supplementary Table S5. Summary of Major Grade 3-4 Adverse Events*

Supplementary Result

Objectives To investigate the prognostic value of magnetic resonance imaging (MRI)‐determined cervical lymph node (CLN) size in nasopharyngeal carcinoma (NPC). Methods We retrospectively reviewed 2066 patients with NPC treated with intensity‐modulated radiotherapy, and randomly divided them into two groups, in a 1:1 ratio. One group was used for training (the training group), and the other one was for internal validation (the validation group). All patients had undergone MRI examination and the maximal axial diameters (MAD) of the axial plane of all positive nodes had been measured and recorded. Results Of 683 patients with CLN metastases in the training group (n = 1033), MAD = 4 cm was associated with worse OS (64.7% vs 84.6%, P, We identified the cut‐off value of the greatest diameter of lymph nodes on axial MRI slices, that is, MAD > 4 cm. MAD = 4 cm was associated with worse survival outcome in nasopharyngeal carcinoma. MAD == 4 cm could be recommended as a prognostic factor in future versions of the UICC/AJCC staging system.

Chlorine-based disinfectants are often used to sanitize fruit and vegetables to produce a product called ready-to-eat (RTE) vegetables. During the disinfection process, disinfection byproducts (DBPs), such as trihalomethanes (THMs) and haloacetic acids (HAAs), might be formed via chlorination.To determine the amounts of DBPs that occur in RTE vegetables in Taiwan, an analytical method which can detect THMs and HAAs simultaneously was developed for this study.For HAAs, dimethyl sulfate (DMS) was first added into the sample as derivatization reagent and tetrabutylammonium hydrogen sulfate (TBA-HA total of 92 single RTE ingredients were analyzed in this study. Among various THMs and HAAs, the results showed that dibromochloromethane (21%) and dichloroacetic acid (12%) had the highest detection rates, respectively. Compared with fruits, vegetables were more easily to contain DBPs. For adults in Taiwan, the maximum daily exposure of THMs and HAAs estimated via the consumption of RTE vegetables were 28.53 and 77.83 μg, respectively.The findings from this study suggest that the exposure of DBPs from RTE vegetables is an important food safety issue in Taiwan.

Background To identify thyroid dose‐volume thresholds for radiotherapy (RT)‐related hypothyroidism (HT) in patients with nasopharyngeal carcinoma (NPC) treated with intensity‐modulated RT (IMRT). In this way, we desired to guide the design of treatment plans and, finally, lower HT prevalence. Methods In total, 345 NPC patients treated with IMRT were evaluated retrospectively during a median follow‐up of 45.2 (range, 11.3‐64.9) months. Serum‐based assessments of thyroid function before and after IMRT were monitored periodically. Thyroid dose‐volume parameters were analyzed for their association with HT risk. Results In total, 44.1% of patients (152/345) developed primary HT. Analyses of thyroid dose‐volume parameters identified a stringent dose‐volume histogram (DVH) threshold defined by V 25Gy (the percentage thyroid volume that receives >25 Gy, not the absolute volume) ≤60%, V 35Gy ≤ 55%, and V 45Gy ≤ 45%. Patients whose thyroid DVHs satisfied these constraints had a lower prevalence of 2‐year HT compared with the overall prevalence (13.2% vs 25.8%, P 95%, V 35Gy > 90%, and V 45Gy > 75%, and patients whose thyroid DVHs satisfied with these constraints had a higher prevalence of 2‐year HT than the overall incidence (36.0% vs 25.8%, P 95%, V 35Gy > 90%, and V 45Gy > 75% as the “inhibition” DVH line, under the precondition of not compromising the target coverage. These findings could help in the design of individual treatment plans and, eventually, to lowering of HT prevalence., The risk of radiation‐related hypothyroidism (RHT) varied significantly depending on the dose‐volume parameters of thyroid radiation. We investigated and identified multiple thyroid dose‐volume thresholds for RHT in nasopharyngeal carcinomas treated with intensity‐modulated radiotherapy (RT), to guide risk stratification of RHT and help in the design of individual RT plans.

Purpose: We aimed to evaluate the value of deep learning on positron emission tomography with computed tomography (PET/CT)–based radiomics for individual induction chemotherapy (IC) in advanced nasopharyngeal carcinoma (NPC). Experimental Design: We constructed radiomics signatures and nomogram for predicting disease-free survival (DFS) based on the extracted features from PET and CT images in a training set (n = 470), and then validated it on a test set (n = 237). Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were applied to evaluate the discriminatory ability of radiomics nomogram, and compare radiomics signatures with plasma Epstein–Barr virus (EBV) DNA. Results: A total of 18 features were selected to construct CT-based and PET-based signatures, which were significantly associated with DFS (P < 0.001). Using these signatures, we proposed a radiomics nomogram with a C-index of 0.754 [95% confidence interval (95% CI), 0.709–0.800] in the training set and 0.722 (95% CI, 0.652–0.792) in the test set. Consequently, 206 (29.1%) patients were stratified as high-risk group and the other 501 (70.9%) as low-risk group by the radiomics nomogram, and the corresponding 5-year DFS rates were 50.1% and 87.6%, respectively (P < 0.0001). High-risk patients could benefit from IC while the low-risk could not. Moreover, radiomics nomogram performed significantly better than the EBV DNA-based model (C-index: 0.754 vs. 0.675 in the training set and 0.722 vs. 0.671 in the test set) in risk stratification and guiding IC. Conclusions: Deep learning PET/CT-based radiomics could serve as a reliable and powerful tool for prognosis prediction and may act as a potential indicator for individual IC in advanced NPC.

We analyzed the number of circulating tumor cells (CTCs) and Epstein-Barr virus DNA (EBV DNA) for diagnosis, monitoring and prognosis of patients with metastatic nasopharyngeal carcinoma (mNPC). The levels of CTCs and EBV DNA were measured at baseline and after first-line chemotherapy in 148 mNPC patients prospectively enrolled between December 2014 and August 2016. We also collected 122 non-mNPC cases within the same time frame for examining CTCs and EBV DNA at baseline. In 270 NPC patients, we observed improved specificity (86.0% vs. 41.0%) and inferior sensitivity (42.3% vs. 81.3%) of CTCs as compared to EBV DNA for diagnosis of distant metastasis. mNPC patients were stratified into unfavorable and favorable prognostic groups, respectively, based on CTC of 12 at baseline and 1 after first-line chemotherapy and EBV DNA of 10,000 at baseline and 4,000 after first-line chemotherapy. Conversion of baseline unfavorable CTCs and EBV DNA to favorable after first-line chemotherapy was associated with significantly longer progression-free survival (PFS) and overall survival (OS) compared to patients with unfavorable CTCs and EBV DNA at both time points. Among patients with a complete/partial response as per imaging evaluation, favorable CTCs and EBV DNA levels after first-line chemotherapy were associated with significantly longer PFS and OS. In conclusion, our data demonstrated the number of CTCs and EBV DNA before, after and during first-line chemotherapy were strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.

Background Intensity‐modulated radiotherapy (IMRT) provides excellent local control in nasopharyngeal carcinoma (NPC). We investigated whether simplifying 8th American Joint Committee on Cancer staging system T categories improves prognostic value. Methods We used 2191 NPC patients as a training set and 414 patients separately as an independent, external validation cohort. Results In the training set, local relapse‐free survival (LRFS), disease‐free survival (DFS), and overall survival (OS) were not significantly different between the 8th edition T2/T3 (P = 0.610, 0.380 and 0.353, respectively). Merging T2 and T3 to proposed T2 (proT2) provided significant differences in LRFS, DFS, and OS between proposed T categories. Proposed T categories had similar c‐indices for LRFS, DFS, and OS (vs the 8th edition), which was validated in the external cohorts. Moreover, for DFS, the adjusted HRs of the proT2N0 (3.8), proT1N1 (3.8), and proT2N1 (6.0) subsets were similar; the adjusted HRs of the proT3N0 (7.0), proT3N1 (11.4), proT1N2 (11.0), proT2N2 (11.6), and proT3N2 (13.3) subsets were similar; the adjusted HRs of the proT1N3 (17.8), proT2N3 (15.3), and proT3N3 (26.4) subsets were similar; the results of the adjusted HRs for OS had the same rule. Defining proT1N0 as stage I; proT1N1/proT2N0‐1 as stage II; proT3N0‐2/proT1‐2N2 as stage III; and proT1‐3N3 as stage IVa generated orderly, significant differences in DFS and OS between stages in the training set and external validation cohort. Conclusions In the IMRT era, three T categories are more reasonable (merging T2/T3 into T2) and proT3N0‐2 (the 8th edition T4N0‐2) should be down‐staged to stage III.

Objectives Epstein-Barr virus (EBV)-positive cervical lymph node (CLN) metastasis of unknown primary origin is classified as nasopharyngeal carcinoma (NPC) T0 by the American Joint Committee on Cancer staging manual (8th edition). We aimed to investigate the possible primary sites and patterns of EBV-positive CLN metastases and to provide implications for the management of NPC T0 classification. Materials and methods We retrospectively reviewed 269 patients with newly diagnosed EBV-positive CLN metastatic disease who underwent EBV detection via EBV-encoded RNA in situ hybridization. Fifteen patients with unknown primary tumors underwent follow-up after initial treatment. Results In patients with EBV-positive CLNs, the most common primary sites after the nasopharynx (51.7%) were the salivary gland (24.5%), lung (7.8%), oropharynx (3.3%), nasal cavity/maxillary (3.3%), oral cavity (2.2%), orbit (1.1%), and liver (0.4%). No primary site was found in 15 patients (5.6%). For salivary gland malignancies, level II and I were the most frequently involved regions. Tumors arising from the lung or liver metastasized to the lower neck (level IV, V, and VI) rather than the upper neck. After initial treatment, 2/15 patients with EBV-positive CLNs of unknown primary exhibited primary NPC and oropharyngeal tumor, respectively. Further, even without prophylactic irradiation to the nasopharynx, only one of 13 unknown primary patients developed NPC. Conclusions The origins of EBV-positive CLNs may not be restricted to the nasopharynx alone, and are likely to involve the head and neck or non-head and neck regions. NPC T0 classification should be cautiously assigned to such tumors.

Objective In cancer trials, prior cancer is a common exclusion criterion. We evaluated the characteristics of prior cancer exclusion criteria in nasopharyngeal carcinoma (NPC) trials and determined its prognostic effect on patients with NPC. Methods We reviewed NPC trials for prior cancer exclusion criteria. Then we estimated the effect of prior cancer among NPC patients using the Surveillance, Epidemiology, and End Results database. Propensity score-matching was used to compensate for differences in baseline characteristics between patients with and without prior cancer. Results There were 109 clinical trials involving 10,437 patients; 49 trials (45%) excluded patients with prior cancer. Prior cancer exclusion was more common in recent or phase III trials. We identified 10,195 NPC patients; 6.2% had prior cancer. More than 70% of these cancers were in situ/localized/regional and diagnosed relatively close to the NPC diagnosis (median 3.3 years). Patients with certain prior cancer type (prostate, breast, gynecological, hematological), time of diagnosis (>5 years ago), or stage (in situ/localized) did not have inferior survival compared with patients with no prior cancer. We tested one form of prior cancer exclusion criteria in an NPC cohort resembling a modern trial population: it did not adversely affect overall and NPC-specific survival. Conclusions Many NPC trials excluded patients with prior cancer, which impacts trial accrual and generalizability. Our findings suggest that broader inclusion in trials of patients with NPC with prior cancer might not affect trial outcomes. More research is needed to understand the appropriateness of this exclusion policy across cancer types and trials.

Background Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive impairment. The aggregation of amyloid β (Aβ) and hyperphosphorylated tau protein are two major pathological features of AD. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) has been indicated in Aβ pathology; however, whether and how it affects tau pathology are not yet clear. Methods The role of NOX2 in cognitive function, amyloid plaque formation, and tau hyperphosphorylation were examined in APP/PS1 transgenic mice mated with p47phox-deficient mice (with deletion of the gene of neutrophil cytosolic factor 1, Ncf1) and/or in p47phox-deficient mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ). The cognitive and non-cognitive functions in these mice were assessed by Morris water maze, Rotarod test, open field, and elevated plus maze. Aβ levels, amyloid plaques, p47phox expression, and astrocyte activation were evaluated using immunofluorescence staining, ELISA, and/or Western blotting. Cultured primary neuronal cells were treated with okadaic acid or conditioned media (CM) from high glucose-stimulated primary astrocytes. The alteration in tau pathology was determined using Western blotting and immunofluorescence staining. Results Deletion of the gene coding for p47phox, the organizer subunit of NOX2, significantly attenuated cognitive impairment and tau pathology in these mice. p47phox deficiency decreased the activation of astrocytes but had no effect on Aβ levels and amyloid plaque formation in the brains of aged APP/PS1 mice, which displayed markedly increased expression of p47phox in neurons and astrocytes. Cell culture studies found that neuronal p47phox deletion attenuated okadaic acid-induced tau hyperphosphorylation at specific sites in primary cultures of neurons. CM from high glucose-treated WT astrocytes increased tau hyperphosphorylation in primary neurons, whereas this effect was absent from p47phox-deficient astrocytes. Conclusions These results suggest that p47phox is associated with cognitive function and tau pathology in AD. p47phox expressed in neurons contributes to tau hyperphosphorylation directly, while p47phox in astrocytes affect tau hyperphosphorylation by activating astrocytes indirectly. Our results provide new insights into the role of NOX2 in AD and indicate that targeted inhibition of p47phox may be a new strategy for the treatment of AD.

Background Prognosis often differs between trial participants and nontrial (pragmatic) patients in similar clinical scenarios, raising a concern that results of trials may not represent those in real-world practice. Methods and Materials Individual patient data were extracted from three phase III randomized controlled trials and a big-data real-world database (n = 10,126). Patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy (CCRT [control]: 2438 vs. 519) or induction chemotherapy plus CCRT (experimental) were included. Propensity score matching and correspondence analysis were used for data mining. Results Compared with the real-world CCRT cohort, clinical trials preferred to include cases with T4 (25.3–43.3% vs. 18.8%) and N2 (44.4–60.7% vs. 38.9%) categories. Real-world patients were more likely to undergo shorter irradiation time (44 vs. 46–49 days), inadequate chemotherapy cycles (70.6% vs. 25.2–43.9%), other chemotherapy (36.4% vs. 0.0%), and flexible regimens (≥3 vs. 1). Although real-world patients had better survival than trial participants, the survival disparities disappeared in the matched cohorts, except for in one trial with the lowest pragmatism assessment caused by stringent eligibility criteria and low flexibility of delivery. Stage specification, year of treatment, and Epstein-Barr virus DNA were related to survival disparities (all P ≤ 0.034). The influence of pragmatic features on survival mainly affected the control (all P ≤ 0.043) rather than the experimental group. Conclusion Special attention should be paid to the control group when interpreting trial results. Assessing whether the pragmatic features of studies deviate from routine practice will lead to better conversion of trial findings into clinical guidelines.

Objective To compare survival effects of comprehensive neck dissection (CND) and selective neck dissection (SND) for patients with nasopharyngeal carcinoma (NPC) with only regional failure. Methods A total of 294 recurrent T0N1-3M0 NPC patients who underwent neck dissection in Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China, between January 1984 and February 2014, were enrolled in the survival and interaction analyses. Using propensity scores to adjust for potential prognostic factors, an additional well-balanced cohort of 210 patients was constructed by matching each patient who received SND with one patient who underwent CND (1:1); the differences were then compared between SND and CND in terms of overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS). Results Both univariate and multivariate analyses showed that SND was not inferior to CND (P > 0.05) but demonstrated that extracapsular spread (ECS) (hazard ratio [HR] 3.49, 95% confidence interval [CI] 2.30-5.29, P 0.05). Furthermore, no survival differences were found between SND and CND in the case-matched cohort in terms of OS, LRFS, RRFS, or DMFS (P = 0.550, 0.930, 0.214, and 0.146, respectively). Conclusion With a similar radical dissection extent around the tumor rather than dissection of extensive lymph region distal to the lesion, SND is not inferior to CND for patients with NPC with only cervical failure. ECS, rN stage, and positive margins were adverse independent prognostic factors for patients with NPC. Level of evidence 4 Laryngoscope, 129:387-395, 2019.

Background The purpose of this study was to verify 10-year results of survival and late toxicities and assess the ultimate therapeutic ratio of intensity-modulated radiotherapy (IMRT) versus two-dimensional radiotherapy (2DRT) in patients with nasopharyngeal carcinoma (NPC). Materials and Methods We retrospectively reviewed the data from 1,276 patients with nonmetastatic NPC who received IMRT or 2DRT from January 2003 to December 2006. Results Of the 1,276 patients, 512 were treated with IMRT and 764 with 2DRT. Median follow-up was 115 months. At 10 years, the IMRT group demonstrated significantly better results than the 2DRT group in local failure-free survival (L-FFS; 90% vs. 84%; hazard ratio [HR], 0.57, 95% confidence interval [CI], 0.40–0.81; p = .001), failure-free survival (FFS; 69% vs. 58%; HR, 0.69, 95% CI, 0.57–0.83; p Conclusion IMRT demonstrated an improved ultimate therapeutic ratio compared with 2DRT in patients with NPC after a 10-year follow-up, with significant improvement of L-FFS, FFS, and OS and decrease in most late toxicities. Implications for Practice The ultimate therapeutic ratio of intensity-modulated radiotherapy versus two-dimensional radiotherapy in patients with nasopharyngeal carcinoma is unclear. In this retrospective study of 1,276 patients with nonmetastatic nasopharyngeal carcinoma with a follow-up of 115 months, intensity-modulated radiotherapy demonstrated an improved ultimate therapeutic ratio compared with two-dimensional radiotherapy, with significant improvement of local failure-free survival, failure-free survival, and overall survival and decrease in most late toxicities and noncancer deaths. However, distant control remains insufficient with this treatment modality.

Purpose The purpose of this study was to investigate the effect of neutropenia during the first cycle of induction chemotherapy (IC-1) on survival in locoregionally advanced nasopharyngeal carcinoma (LANPC). Materials and methods Eligible patients (n=545) with LANPC receiving IC+concurrent chemoradiotherapy were included. Based on nadir neutrophil afterIC-1, all patientswere categorized into three groups: no/grade 1-2/grade 3-4 neutropenia. Five-year overall survival (OS) and disease-free survival (DFS) were compared between groups and subgroups stratified by IC regimen. We also explored the occurrence of IC-1-induced myelosuppression events and the minimal value of post-treatment neutrophil-to-lymphocyte ratio (post-NLRmin). Univariate/multivariate analyses were performed to investigate the effect of IC-1-induced neutropenia, timing of neutropenia, number of myelosuppression events, and high post-NLRmin on OS/DFS. Results Grade 1-2/grade 3-4 neutropeniawere associatedwith poorer OS/DFS than no neutropenia (all p l 0.05); OS/DFS were not significantly different between patients experiencing grade 1-2 vs. 3-4 neutropenia. Neutropenia had no significant effect on OS/DFS in patients receiving docetaxel-cisplatin-5-fluorouracil (TPF). Grade 1-2 (grade 3-4) neutropenia negatively influenced OS/DFS in patients receiving cisplatin-5-fluorouracil (PF) (PF and docetaxel-cisplatin [TP]; all p l 0.05). Neutropenia, two/three myelosuppression events, and high post-NLRmin (≥ 1.33) was most frequent on days 5-10, second and third week of IC-1, respectively. After adjustment for covariates, IC-1-induced neutropenia, two/three myelosuppression events, and post-NLRmin ≥ 1.33were validated as negative predictors of OS/DFS (all p l 0.05); timing of neutropenia had no significant effect. Conclusion Occurrence of neutropenia, number of myelosuppression events, and high post-NLRmin during PF/TP IC-1 have prognostic value for poor survival in LANPC.

Purpose: Because of the uneven geographic distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC + CCRT in locoregionally advanced NPC. Experimental Design: Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively. Results: Median follow-up was 5.0 years. The HR for PFS was 0.70 [95% confidence interval (CI), 0.56–0.86; P = 0.0009; 9.3% absolute benefit at 5 years] in favor of IC + CCRT versus CCRT alone. IC + CCRT also improved OS (HR = 0.75; 95% CI, 0.57–0.99; P = 0.04) and reduced distant failure (HR = 0.68; 95% CI, 0.51–0.90; P = 0.008). IC + CCRT had a tendency to improve locoregional control compared with CCRT alone (HR = 0.70; 95% CI, 0.48–1.01; P = 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected. Conclusions: This IPD pooled analysis demonstrates the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control. Clin Cancer Res; 24(8); 1824–33. ©2018 AACR.

Objectives To investigate the role of sequential chemoradiotherapy (SCRT; induction chemotherapy [IC] followed by intensity-modulated radiotherapy [IMRT]) in stage II and low-risk stage III–IV nasopharyngeal carcinoma (NPC). Materials and methods Four well-matched groups were individually generated using propensity score matching in patients (n = 689) with stage II (SCRT vs. concurrent chemoradiotherapy [CCRT], SCRT vs. IMRT alone) and low-risk stage III–IV NPC (SCRT vs. CCRT, SCRT vs. IC + CCRT). Five-year overall/disease-free/locoregional relapse-free/distant metastasis-free survival (OS/DFS/LRRFS/DMFS) and acute hematological toxicities were compared between groups. The value of SCRT was further investigated in multivariate analysis and subgroup analysis by adjusting for covariates and limiting IC-to-IMRT time interval, respectively. Results SCRT led to equivalent survival outcomes compared to CCRT/IMRT alone and CCRT/IC + CCRT in stage II and low-risk stage III–IV NPC, respectively (all P > .050). In multivariate analysis, patients with stage II NPC treated by SCRT obtained higher DMFS (AHR = 0.22, 95% CI = 0.05–1.00, P = .050), but not OS, DFS or LRRFS, compared to patients receiving CCRT; non-significant differences were observed between SCRT and other treatments. SCRT with short IC-to-IMRT time interval (≤70 days) achieved higher 5-year survival rates than IMRT alone (DMFS: P = .046), CCRT (stage II NPC; OS: P = .047; DMFS: P = .020) and IC + CCRT (DFS: P = .041). Moreover, SCRT was associated with higher, equivalent and lower frequencies of acute hematological toxicities than IMRT alone, CCRT and IC + CCRT, respectively. Conclusion SCRT is mainly beneficial in stage II NPC, leading to better DMFS and/or equivalent acute hematological toxicities compared to CCRT/IMRT alone. CCRT is still the best choice for low-risk stage III–IV NPC.

To clarify the optimal cumulative cisplatin dose (CCD) in locoregionally‐advanced nasopharyngel carcinoma (NPC) patients receiving induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT). Using the NPC‐specific database from the established big‐data intelligence platform at Sun Yat‐Sen University Cancer Center, 583 non‐disseminated, locoregionally‐advanced NPC patients receiving IC plus CCRT were enrolled. Propensity score matching (PSM) analysis was conducted to control for confounding factors. The median CCD was 160 mg/m2 after IC (range, 40‐300 mg/m2); only 74 patients (12.7%) achieved CCD >200 mg/m2. Patients receiving >200 mg/m2 CCD did not show significantly improved 5‐year overall survival (OS) (HR = 1.19; 95% confidence intervals [CI] 0.69‐2.06, P = .53) and progression‐free survival (PFS) (HR = 1.03; 95% CI: 0.63‐1.68, P = .92) compared with patients receiving 160 mg/m2 and CCD < 160 mg/m2 in both the original and PSM cohorts. In addition, subgroup analysis indicated a favorable PFS, but not OS, with higher cisplatin administration in patients with pretreatment Epstein–Barr virus deoxyribonucleic acid (EBV DNA)

Background: Anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), such as cetuximab and nimotuzumab have been used in the treatment of nasopharyngeal carcinoma (NPC), yet their efficacy and safety are undetermined. Materials and Methods: We performed two meta-analyses based on systematic searches of PubMed, EMBASE, the Cochrane Library and SinoMed: comparison 1 (standard therapy plus mAbs vs. standard therapy) and comparison 2 (radiotherapy plus concurrent mAbs vs. concurrent chemoradiotherapy) to explore the treatment value of anti-EGFR mAbs in NPC. Primary outcomes were overall survival (OS) and disease-free survival (DFS); secondary outcomes, locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and grade 3 and above acute adverse events. Results: Four randomized controlled trials and thirteen observational studies were eligible. Comparison 1 (twelve studies): adding mAbs to standard therapy (radiotherapy or chemoradiotherapy) significantly improved OS (HR, 0.51; 95% CI, 0.39-0.66) and DFS (HR, 0.68; 95% CI, 0.54-0.86), but increased the frequency of skin rashes and mucositis. Comparison 2 (six studies): OS (HR, 1.17; 95% CI, 0.81-1.70) and DFS (HR, 1.16; 95% CI, 0.86-1.57) were not significantly different when mAbs replaced conventional cytotoxic chemotherapy concurrently with radiotherapy, with fewer hematological, gastrointestinal and renal toxicities and more skin rashes in the mAb group. Conclusion: We recommend anti-EGFR mAbs enhance—but should not replace—current treatment paradigms for locoregionally advanced NPC. Further evidence from phase III clinical trials is required.

This study investigated the combined prognostic value of pretreatment anemia and cervical node necrosis (CNN) in patients with nasopharyngeal carcinoma (NPC). Retrospective review of 1302 patients with newly diagnosed nonmetastatic NPC treated with intensity‐modulated radiotherapy (IMRT) ± chemotherapy. Patients were classified into four groups according to anemia and CNN status. Survival was compared using the log‐rank test. Independent prognostic factors were identified using the Cox proportional hazards model. The primary end‐point was overall survival (OS); secondary end‐points were disease‐free survival (DFS), locoregional relapse‐free survival (LRRFS), and distant metastasis‐free survival (DMFS). Pretreatment anemia was an independent, adverse prognostic factor for DMFS; pretreatment CNN was an independent adverse prognostic factor for all end‐points. Five‐year survival for non‐anemia and non‐CNN, anemia, CNN, and anemia and CNN groups were: OS (93.1%, 87.2%, 82.9%, 76.3%, P

BACKGROUND: The effectiveness of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) over CCRT alone in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and chronic hepatitis B infection in the intensity-modulated radiotherapy (IMRT) era is unknown. PATIENTS AND METHODS: A total of 249 patients with stage T1-2 N2-3 or T3-4 N1-3 NPC and chronic hepatitis B infection treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) was employed to balance covariates; 140 patients were propensity-matched (1:1 basis). Survival outcomes in the IC+CCRT and CCRT groups were compared using the Kaplan–Meier method, log-rank test and Cox proportional hazards model. RESULTS : No significant survival differences were observed between IC+CCRT and CCRT (5-year overall survival, 88.3% vs. 82.2%; P =.484; disease-free survival, 73.9% vs. 75.2%; P =.643; distant metastasis-free survival, 84.1% vs. 85.1%; P =.781; and locoregional failure-free survival, 87.9% vs. 85.1%; P =.834). After adjusting for known prognostic factors in multivariate analysis, IC was not an independent prognostic factor for any outcome (all P >.05); subgroup analysis based on T category (T1-2/T3-4), N category (N0-1/N2-3), and overall stage (III/IV) confirmed these results. The incidence of hepatic function damage in the IC+CCRT and CCRT groups was not significantly different. CONCLUSION : IC+CCRT leads to comparable survival outcomes and hepatic function damage compared to CCRT alone in patients with locoregionally advanced NPC with chronic hepatitis B infection in the IMRT era. Further investigations are warranted.

The updated version of the National Comprehensive Cancer Network (NCCN) guidelines revised pretreatment workup for nasopharyngeal carcinoma (NPC) into “biopsy of the primary site or neck.” Despite provision of important diagnostic information, concerns regarding tumor cell dissemination limit the application of lymph node biopsy. This study aimed to investigate whether biopsy of the neck is associated with impaired survival in NPC. A propensity score-matched, population-based cohort identified from the Surveillance, Epidemiology, and End Results database was used to compare overall survival (OS) and disease-specific survival (DSS) of patients who underwent pretreatment cervical lymph node biopsy without subsequent neck dissection or removal of node compared with patients who did not undergo node biopsy. Of 2910 eligible patients, 416 (14.3%) underwent pretreatment lymph node biopsy. After use of control for patient, tumor, and demographic characteristics, biopsy was not associated with impaired OS (hazard ratio [HR], 1.15; 95% confidence interval [CI] 0.89–1.47; P = 0.29) or DSS (HR, 1.07; 95% CI 0.81–1.40; P = 0.63). Interestingly, in the subgroup analysis, the unfavorable effect of biopsy was observed for patients with differentiated non-keratinizing squamous cell carcinoma (but not other histologic types). Race did not positively alter the survival outcomes. The findings provide reference for clinical practice, showing that pretreatment cervical lymph node biopsy is not associated with impaired survival in NPC, except for patients with differentiated non-keratinizing squamous cell carcinoma. The recommended NCCN guidelines would be more specific by adding details to the general recommendation that neck biopsy is safe for all patients. Future prospective studies are needed to verify the study findings.

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

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.

Objectives To investigate the feasibility of contralateral lower neck sparing intensity modulation radiated therapy (IMRT) for nasopharyngeal carcinoma patients (NPC) with unilateral cervical lymph node metastasis. Materials and methods Retrospective review of 546 patients with unilateral cervical lymph node metastasis treated between November 2009 and February 2012 at one institution. All patients were staged using magnetic resonance imaging and received radical IMRT. Patients were classified into two groups: the inferior border of the negative neck irradiation field only covered Levels III to Va in Group 1; the inferior border covered entire neck down to Levels IV to Vb in Group 2. Results Median follow-up was 49.9 months (range, 1.3–69.2 months). Four-year overall survival (OS:89.3% vs. 88.9%, P = 0.91), disease-free survival (DFS:81.7% vs. 81.0%, P = 0.91), distant metastasis-free survival (DMFS:88.2% vs. 87.9%, P = 0.95), local relapse-free survival (LRFS:96.7% vs. 94.7%, P = 0.70) and nodal relapse-free survival (NRFS: 96.1% vs. 95.9%, P = 0.94) were not significantly different between Group 1 and Group 2. Twenty-two patients developed cervical lymph node relapse; of whom 20/22 (91.0%) developed unilateral relapse within pretreatment positive neck. Only one patient developed out-of-field relapse, though this patient also relapsed within the neck irradiation field (Level II). No clinicopathological feature tested had significant prognostic value for NRFS in multivariate analysis. Conclusions In the IMRT and MRI era, contralateral lower neck sparing IMRT seems to be feasible for NPC patients with unilateral cervical lymph node metastasis.