Search

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.

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

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.

The subgroups of patients with nasopharyngeal carcinoma (NPC) who benefit from induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) remain unclear.We established prognostic nomograms for overall survival (OS) and disease-free survival (DFS), and validated the nomograms in 1230 patients with NPC and subgroup of 923 patients with locoregionally advanced NPC (LANPC). Three well-matched risk groups (i.e., low, intermediate and high risk) were created via recursive partitioning and 1-to-1 propensity score matching; IC+CCRT was compared with CCRT in each risk group.Histological type, T category, N category, plasma Epstein-Barr virus deoxyribonucleic acid (and the same factors plus age and neutrophil-lymphocyte ratio) were included in the nomograms for DFS (and OS). Both nomograms had higher c-indexes than the 7th edition staging system in both NPC/LANPC (all P-values≤0.010). The nomogram for OS also had a higher c-index in LANPC than the 8th edition staging system (P-value=0.052). OS was significantly different between all three risk groups in the individualized risk stratification (all P-values0.001), while the 7th and 8th edition staging systems failed to clearly separate OS for stage II and III disease (P-value=0.415 and 0.347, respectively). IC+CCRT improved OS in intermediate and high risk patients with LANPC compared to CCRT alone (P-value0.001 and P-value=0.002, respectively).These prognostic nomograms could accurately guide treatment of individual patients with NPC. IC+CCRT could improve OS for patients with LANPC at intermediate to high risk.

The effect of socioeconomic factors on receipt of definitive treatment and survival outcomes in non‐metastatic head and neck squamous cell carcinoma (HNSCC) remains unclear. Eligible patients (n = 37 995) were identified from the United States Surveillance, Epidemiology and End Results (SEER) database between 2007 and 2012. Socioeconomic factors (i.e., median household income, education level, unemployment rate, insurance status, marital status and residence) were included in univariate/multivariate Cox regression analysis; validated factors were used to generate nomograms for cause‐specific survival (CSS) and overall survival (OS), and a prognostic score model for risk stratification. Low‐ and high‐risk groups were compared for all cancer subsites. Impact of race/ethnicity on survival was investigated in each risk group. Marital status, median household income and insurance status were included in the nomograms for CSS and OS, which had higher c‐indexes than the 6th edition TNM staging system (all P < 0.001). Based on three disadvantageous socioeconomic factors (i.e., unmarried status, uninsured status, median household income

Background: Given the distinct biological characteristics and regional distribution of nasopharyngeal carcinoma (NPC) compared with other head and neck cancers, and uncertainties regarding therapeutic strategies, physicians require high-quality clinical practice guidelines (CPGs) to provide transparent recommendations for NPC treatment. This study aimed to critically appraise the quality of NPC CPGs and assess the consistency of their recommendations. Methods: We identified CPGs that provided recommendations on the diagnosis and management of NPC published up to December 2015. Four investigators independently appraised CPG quality using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Key recommendations by CPGs were also evaluated. Results: A total of 7 CPGs were eligible for this study: 5 produced by professional organizations or governmental agencies and 2 were developed based on expert consensus. Of the 6 AGREE II domains, the applicability domain scored consistently low across CPGs (range, 13.5%-30.2%); no CPG achieved a score of >50% in all 6 domains. The scope and purpose domain (≥73.6% for 4 CPGs) and editorial independence domain (≥75.0% for 6 CPGs) scored highest. Of the 23 AGREE II items, 9 scored less than half of the points available in all 7 CPGs. The recommendations by CPGs were consistent in general; heterogeneity mainly existed among recommended therapeutic strategies. Conclusions: Variation exists in NPC CPG development processes and recommendations. Increased efforts are required to make comprehensive resources available to guide healthcare providers and enhance delivery of high-quality, evidence-based care for NPC. International collaboration is necessary to enable the development of high-quality and regionally relevant CPGs for NPC.

Background: The aim of this study is to evaluate the long-term therapeutic gain of induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (NPC) in the era of intensity-modulated radiotherapy (IMRT). Methods: Data on 957 patients with stage T1-2N2-3 or T3-4N1-3 NPC treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance influence of various covariates. Patient survival between IC and non-IC groups were compared. Results: For the 318 pairs selected from the original 957 patients by PSM, the median follow-up duration was 57.13 months (range, 1.27-78.1 months). The 5-year overall survival (OS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and locoregional relapse-free survival (LRRFS) rates for IC group vs. non-IC group were 87.2% vs. 80.8% (P = 0.023), 88.1% vs. 83.2% (P = 0.071), 80.7% vs. 71.4% (P = 0.011) and 92.1% vs. 86.7% (P = 0.081), respectively. Multivariate analysis identify IC as an independent prognostic factor for OS (HR, 0.595; 95% CI, 0.397-0.891; P = 0.012) and DFS (HR, 0.627; 95% CI, 0.451-0.872; P = 0.006). After excluding the patients not receiving concurrent chemotherapy, IC was found to be an independent prognostic factor for OS (HR, 0.566; 95% CI, 0.368-0.872; P = 0.01), DMFS (HR, 0.580; 95% CI, 0.367-0.916; P = 0.02) and DFS (HR, 0.633; 95% CI, 0.444-0.903; P = 0.012). Conclusions: IC is an effective treatment modality for patients with stage T1-2N2-3 and T3-4N1-3 NPC, and the incorporation of IC with standard CCRT could achieve the best therapeutic gain.

Background & Aims: We compared the efficacy of transcatheter arterial chemoembolization (TACE) in combination with CT-guided radiofrequency ablation (RFA) with that of surgical resection (SR) in patients with hepatocellular carcinoma (HCC) within the up-to-seven criteria. Methods: From January 2004 to December 2014, 420 multicenter consecutive patients with HCC who conformed to the up-to-seven criteria and initially received either TACE plus CT-guided RFA (TACE-RFA) or SR were enrolled. A matched cohort composed of 206 patients was selected after adjustment with propensity score matching. The overall survival (OS) of each patient was calculated with the Kaplan-Meier method and compared by the log-rank test. Results: The median OS and 1-, 3-, and 5-year survival rates were 56.0 months, 96.1%, 76.7% and 41.3% in the TACE-RFA group and 58.0 months, 96.1%, 86.4% and 46.2% in the SR group, respectively. There was no significant difference in OS between the two groups (P = 0.138). For patients with HCC beyond the Milan criteria, TACE-RFA provided a longer median OS than SR (52.0 vs 45.0 months, P = 0.023). Conclusions: Treatment by TACE-RFA conferred an OS rate comparable with that of SR in patients within the up-to-seven criteria. For patients with HCC between the Milan and the up-to-seven criteria, TACE-RFA might be superior to SR for survival prolongation.

Background: To explore the value of chemoradiotherapy (CRT) in stage II nasopharyngeal carcinoma (NPC) compared to radiotherapy (RT) alone which includes two-dimensional radiotherapy (2D-RT) and intensity-modulated radiotherapy (IMRT). Methods: All topic-related comparative articles were identified by a comprehensive search of public databases (MEDLINE, EMBASE, Cochrane Library and CBMdisc). The primary outcomes were overall survival (OS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS). Secondary outcomes were grade 3-4 acute toxicity events. We performed subgroup analysis of CRT versus 2D-RT/IMRT alone to investigate the optimal modality. Sensitivity analysis focused on CRT versus IMRT alone was used to assess stability of the study results. Results: Eleven comparative studies (2138 patients) were eligible. CRT had significantly higher OS (HR = 0.67, 95% CI = 0.45-0.98, P = 0.04) and LRRFS (HR = 0.61, 95% CI = 0.46-0.80, P = 0.0003) than RT alone, but no significant difference was observed in DMFS (HR = 0.83, 95% CI = 0.52-1.31, P = 0.41). Meanwhile, CRT was associated with higher frequencies of grade 3-4 leukopenia, mucositis and nausea (P = 0.005, 0.03, < 0.0001, respectively). Subgroup analysis showed that IMRT alone could achieve equivalent OS, LRRFS and DMFS compared to CRT (P = 0.14, 0.06, 0.89, respectively). Significant value was only observed in LRRFS for CRT compared to 2D-RT alone (P = 0.01). Sensitivity analysis for the comparison of CRT and IMRT alone demonstrated generally stable outcomes, in support of the final conclusions. Conclusions: In the treatment of patients with stage II NPC, CRT was better than 2D-RT alone with significant benefit in LRRFS. IMRT alone was superior to CRT with equivalent survival outcomes and fewer grade 3-4 acute toxicities.

In the war on cancer marked by personalized medicine, positron emission tomography (PET)-based theranostic strategy is playing an increasingly important role. Well-designed clinical trials are of great significance for validating the PET applications and ensuring evidence-based cancer care. This study aimed to provide a comprehensive landscape of the characteristics of PET clinical trials using the substantial resource of ClinicalTrials.gov database. We identified 25,599 oncology trials registered with ClinicalTrials.gov in the last ten-year period (October 2005-September 2015). They were systematically reviewed to validate classification into 519 PET trials and 25,080 other oncology trials used for comparison. We found that PET trials were predominantly phase 1-2 studies (86.2%) and were more likely to be single-arm (78.9% vs. 57.9%, P

Background The purpose of this study was to determine the predictive value of pretreatment serum uric acid (SUA) for metastasis in locally advanced nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy. Methods This retrospective study examined 1063 patients with locally advanced NPC. Multivariate survival analysis was used. Results High pretreatment SUA level (>353.4 μmol/L) independently predicted distant metastasis-free survival (p = .013) and was associated with high white blood cell (p = .005), lymphocyte counts (p < .001), and male sex (p < 0.001). In addition, SUA levels were significantly elevated in patients with T1 to T3 classification (p = .042). For patients with subsequent lung metastases after treatment, markedly higher pretreatment SUA levels were detected compared with patients who had other distant metastases (p =.012) and patients without distant metastasis (p = .024). Conclusion Pretreatment SUA may be a useful biomarker for evaluating treatment options for patients with locally advanced NPC. © 2016 Wiley Periodicals, Inc. Head Neck 39: 492–497, 2017

Objectives The aim of this study is to optimize the cycle for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) receiving neoadjuvant chemotherapy (NCT) in the era of intensity-modulated radiotherapy (IMRT). Materials and methods Data on 569 locoregionally advanced NPC patients treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance prognostic factors and match patients. Survival outcomes of matched patients between different NCT cycle groups were compared. Results The median cycle of NCT was 2 (range, 2–4 cycles) for the whole cohort, and patients were therefore stratified as low cycle (=2) and high cycle (>2) groups. In total, 247 pairs of NPC patients were selected by PSM. Univariate analysis found no significantly prognostic difference between the low cycle and high cycle groups, and multivariate analysis did not establish NCT cycle as an independent factor. However, stratified analysis revealed patients in the low cycle group had better OS than those of patients in the high cycle group (92.4% vs. 80.8%, P = 0.029), and NCT was identified as an independent prognostic factor for OS in patients with N2-3 category (HR, 2.252; 95% CI, 1.024–4.953; P = 0.043). Conclusion Two cycles of NCT may be enough and additional more cycles are not associated with improved survival outcomes for patients with locoregionally advanced NPC in the era of IMRT.

The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for nasopharyngeal carcinoma (NPC) merged T4N0–2 and T1–4N3 to create stage IVa. In the present study, we aimed to assess the difference in clinical outcomes and patterns of failure between 8th AJCC T4N0–2 and T1–4N3 NPC patients treated with intensity-modulated radiotherapy (IMRT). We included 3107 patients with stage IVa NPC disease (1871 with T4N0–2 and 1236 with T1–4N3) according to the 8th AJCC staging system. Overall survival (OS) was the primary endpoint. The clinical outcomes between T4N0–2 and T1–4N3 patients were compared. T1–4N3 patients had significantly worse 3-year OS (84.1% vs. 89.2%; p < 0.001) and distant metastasis–free survival (DMFS; 78.3% vs. 85.9%; p < 0.001), but better local relapse–free survival (LRFS; 94.9% vs. 92.2%; p = 0.003), as compared with T4N0–2 patients. Multivariate analysis showed that T1–4N3 was still an independent adverse prognostic factor for both DMFS (hazard ratio [HR] = 1.517, 95% confidence interval [CI] = 1.274–1.806, p < 0.001) and OS (HR = 1.315, 95% CI = 1.100–1.572, p = 0.003), whereas T4N0–2 was an independent adverse prognostic factor for LRFS (HR = 1.581, 95% CI = 1.158–2.158, p = 0.004). In terms of the OS, T4N0–2 patients had better prognosis compared with T1–4N3 patients, and the patterns of failure differed between T4N0–2 and T1–4N3 patients. We believe that future modifications of the AJCC/UICC staging system should separate T4N0–2 from T1–4N3. • In nasopharyngeal carcinoma, T4N0–2 patients tended to develop local relapse, whereas T1–4N3 patients were more likely to develop distant metastasis. • In terms of overall survival, T4N0–2 patients had better prognosis than T1–4N3 patients. • T4N0–2 should be separated from T1–4N3 in the UICC/AJCC staging system.

We performed comprehensive genomic analyses of the melatonergic system within the tumor microenvironment and their clinical relevance across a broad spectrum of solid tumors. RNA-seq data from The Cancer Genome Atlas (TCGA) of 14 solid tumors representing 6658 human samples were analyzed. The tumor melatonergic system was characterized by the rates of melatonin synthesis and metabolism using a two-gene expression model (melatonin synthesis/metabolism Index). We calculated three indexes according to different melatonin metabolism isoenzymes (Index-I [ASMT:CYP1A1], Index-II [ASMT:CYP1A2], and Index-III [ASMT:CYP1B1]). Samples of each cancer type were classified into two subgroups (high vs low) based on median values. Clinical outcomes, mutational burden, and neoepitope abundance were analyzed and compared. We found that the ability of the tumor microenvironment to synthesize and accumulate melatonin varied across cancer types and negatively correlated with tumor burden. Kaplan-Meier survival analyses and multivariable modeling showed that the three indexes played different roles across different cancers and harbored prognostic values in breast cancer (adjusted hazard ratio [AHR]Index-II = 0.65 [0.44-0.97]; P = 0.03), cervical cancer (AHRIndex-I = 0.62 [0.39-0.98]; P = 0.04), lung squamous cell carcinoma (AHRIndex-III = 0.75 [0.56-0.99]; P = 0.04), melanoma (AHRIndex-I = 0.74 [0.55-0.98]; P = 0.04), and stomach adenocarcinoma (AHRIndex-III = 0.68 [0.41-0.94]; P = 0.02). We further investigated its clinical relevance with tumor immunogenic features (mutational burden and neoantigen abundance), which may predict immunotherapy benefits. We observed significant negative correlations with mutational burden in the majority of tumors (P

Background Little is known about the extent of selective publication in contemporary oncology randomised controlled trials (RCTs) worldwide. This study aimed to evaluate the rates of publication and timely publication (within 24 months) for contemporary oncology RCTs from all over the world. We also investigated the trial characteristics associated with publication and timely publication. Patients and methods We identified all phase III oncology RCTs registered on ClinicalTrials.gov with a primary completion date between January 2008 and December 2012. We searched PubMed and EMBASE to identify publications. The final search date was 31 December 2015. Our primary outcome measure was the time to publication from the primary completion date to the date of primary publication in a peer-reviewed journal. Results We identified 598 completed oncology RCTs; overall, 398 (66.6%) had been published. For published trials, the median time to publication was 25 months (interquartile range, 16–37 months). Only 192 trials (32.1%) were published within 24 months. Timely publication was independently associated with trials completed late in 2012. Trials conducted in Asia and other regions were less likely to have timely publication, but trials conducted in different locations were all equally likely to be published. Industry- and NIH-funded trials were equally likely to be published timely or at any time after trial completion. Among 391 published trials with clear primary outcomes, there was a trend for timely publication of positive trials compared with negative trials. Conclusions Despite the ethical obligations and societal expectations of disclosing findings promptly, oncology RCTs performed poorly.

// Rui Guo 1,* , Yan-Ping Mao 1,* , Lei chen 1 , Ling-Long Tang 1 , Guan-Qun Zhou 1 , Li-Zhi Liu 2 , Li Tian 2 , Mu-Sheng Zeng 3 , Wei-Hua Jia 3 , Jian-Yong Shao 4 , Ai-Hua Lin 5 , and Jun Ma 1 1 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, People’s Republic of China 2 Imaging Diagnosis and Interventional Center, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, People’s Republic of China 3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, People’s Republic of China 4 Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, People’s Republic of China 5 Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Jun Ma, email: // Keywords : comorbidity, Initiation of chemotherapy, nasopharyngeal carcinoma, treatment outcome Received : September 11, 2015 Accepted : March 14, 2016 Published : April 06, 2016 Abstract Background: To assess the impact of comorbidity on the initiation of chemotherapy and its ultimate treatment outcomes in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Methods: Data on 1316 patients with NPC treated between February 2003 and January 2007 was retrospectively reviewed. Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) system. The association of various factors with chemotherapy was evaluated. And treatment outcomes of chemoradiotherapy regimes in patients with comorbidity were compared. Results: Comorbidity was present in 42.2% of patients; mild, moderate and severe comorbidity were observed in 33.6%, 8.1% and 0.5% of patients, respectively. Comorbidity (as indicated by ACE-27 score) was a negative prognostic factor for overall survival (OS) (hazard ratio HR=1.577; P 0), 5-year OS for the concomitant chemoradiotherapy group (CCRT) was 74.5% vs. 56.9% in the radiotherapy (RT) only group ( P = 0.008), the 5-year DFS rate was 64.0% in the CCRT group vs . 49.4% for RT only ( P = 0.015). Conclusions: Comorbidity should be assessed during treatment strategy decision-making to improve survival in NPC. Concomitant chemoradiotherapy is feasible and effective in patients with comorbidity in locoregionally advanced stages.

// Li Lin 1, * , Ji-Jin Yao 1, * , Guan-Qun Zhou 1 , Rui Guo 1 , Fan Zhang 1 , Yuan Zhang 1 , Lin Xu 1 , Lu-Lu Zhang 1 , Ai-Hua Lin 2 , Jun Ma 1 , Ying Sun 1 1 Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China 2 Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Ying Sun, e-mail: sunying@sysucc.org.cn Keywords: nasopharyngeal carcinoma, intensity modulated radiotherapy, individualized clinical target volume, clinical outcome, toxicities Received: October 10, 2015 Accepted: February 18, 2016 Published: March 09, 2016 ABSTRACT Background: To evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) using individualized clinical target volumes (CTVs) based on the loco-regional extension patterns of nasopharyngeal carcinoma (NPC). Methods: From December 2009 to February 2012, 220 patients with histologically-proven, non-disseminated NPC were prospectively treated with IMRT according to an individualized delineation protocol. CTV1 encompassed the gross tumor volume, entire nasopharyngeal mucosa and structures within the pharyngobasilar fascia with a margin. CTV2 encompassed bilateral high risk anatomic sites and downstream anatomic sites adjacent to primary tumor, bilateral retropharyngeal regions, levels II, III and Va, and prophylactic irradiation was gave to one or two levels beyond clinical lymph nodes involvement. Clinical outcomes and toxicities were evaluated. Results: Median follow-up was 50.8 (range, 1.3–68.0) months, four-year local relapse-free, regional relapse-free, distant metastasis-free, disease-free and overall survival rates were 94.7%, 97.0%, 91.7%, 87.2% and 91.9%, respectively. Acute severe (≥ grade 3) mucositis, dermatitis and xerostomia were observed in 27.6%, 3.6% and zero patients, respectively. At 1 year, xerostomia was mild, with frequencies of Grade 0, 1, 2 and 3 xerostomia of 27.9%, 63.3%, 8.3% and 0.5%, respectively. Conclusions: IMRT using individualized CTVs provided high rates of local and regional control and a favorable toxicity profile in NPC. Individualized CTV delineation strategy is a promising one that may effectively avoid unnecessary or missed irradiation, and deserve optimization to define more precise individualized CTVs.

// Jia-Wei Lv 1, * , Yu-Pei Chen 1, * , Guan-Qun Zhou 1, * , Ling-Long Tang 1 , Yan-Ping Mao 1 , Wen-Fei Li 1 , Rui Guo 1 , Ai-Hua Lin 2 , Jun Ma 1 , Ying Sun 1 1 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China 2 Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Ying Sun, e-mail: sunying@sysucc.org.cn Key words: baseline plasma EBV DNA, cigarette smoking, intensity-modulated radiation therapy, nasopharyngeal carcinoma, prognostication Received: December 12, 2015 Accepted: February 11, 2016 Published: February 23, 2016 ABSTRACT We evaluated the combined prognostic value of cigarette smoking and baseline plasma Epstein-Barr virus deoxyribonucleic acid (EBV DNA) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). Of consecutive patients, 1501 with complete data were eligible for retrospective analysis. Smoking index (SI; cigarette packs per day times smoking duration [years]), was used to evaluate the cumulative effect of smoking. Primary end-point was overall survival (OS); progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRFS) were secondary end-points. Both cigarette smoking and baseline plasma EBV DNA load were associated with poorer survival ( P

Background: The optimal treatment for early-stage nasopharyngeal carcinoma (NPC) remains controversial. Identification of prognostic factors for metastasis and tumor progression is urgently required to improve clinical decision-making for patients with American Joint Committee on Cancer (AJCC) 2009 stage II NPC from the endemic area. Methods: Consecutive newly-diagnosed patients (n=296) with non-disseminated, biopsy-proven stage II NPC were retrospectively reviewed; all patients received intensity-modulated radiotherapy and MRI follow-up. Plasma EBV DNA level, serum lactate dehydrogenase, serum albumin, serum globulin and leukocyte counts were measured before therapy. Survival rates were analyzed using the Kaplan-Meier method and log-rank test and multivariate Cox proportional hazards model. Results: Median follow-up was 50.2 months (range, 8-69.5 months). Multivariate analysis demonstrated a plasma Epstein-Barr virus (EBV) DNA level ≥ 4000 copies/mL, maximal axial diameter (MAD) of the cervical lymph nodes ≥ 30 mm and serum globulin level < 29.5 g/L were independent predictors of poor DMFS (P = 0.018; P = 0.019; P = 0.006, respectively). On the basis of these parameters, a prognostic model was developed as follows: 1) patients with no risk factors; 2) one risk factor; and 3) two or three risk factors. The 3-year distant metastasis-free survival rates for groups 1, 2 and 3 were 100%, 94.6% and 84.3%, respectively (P = 0.001). Conclusion: The prognostic model based on EBV DNA, serum globulin and nodal size may facilitate individualized treatment of patients with stage II NPC at high risk of distant metastasis.

Objectives Induction chemotherapy (IC) is gaining recognition for the treatment of nasopharyngeal carcinoma (NPC). We aimed to develop a model to predict benefit from additional IC to concurrent chemoradiotherapy (CCRT). Materials and methods From an NPC-specific database, 7413 patients with stage II–IVa disease who received CCRT with or without IC were included. Distant metastasis-free survival (DMFS) was the primary outcome and benefit from IC was evaluated by adjusted hazard ratio. Interaction terms between IC and other prognostic factors were identified in multivariate Cox model, and IC benefit score (ICBS) was calculated based on β coefficients from the Cox model. Results Nodal category, overall stage, and pre-treatment plasma Epstein–Barr virus DNA (log transformed as continuous variable) interacted with IC and determined ICBS. ICBS could discriminate patients who benefited differently from IC in terms of DMFS well, especially for patients with high and low ICBS. As for patients with medium ICBS, predictive performance of ICBS seemed reduced. Conclusions Based on the ICBS model, we proposed a decision-making process to help in clinical practice. Multi-institutional and prospective studies are warranted to further validate our findings.

PURPOSE The incidence, risk factors and survival impact of secondary primary malignancies (SPMs) among survivors of nasopharyngeal carcinoma (NPC) treated with definitive intensity-modulated radiation therapy (IMRT) with or without chemotherapy are poorly characterized. METHODS AND MATERIALS Consecutive patients (n=6,377) from the big-data intelligence platform at Sun Yat-sen University Cancer Center, China (in a high-incidence area) with newly diagnosed non-metastatic pathologically proven non-keratinizing undifferentiated NPC treated with IMRT±chemotherapy between January 2003 and June 2013 were retrospectively analyzed. Cumulative incidence of SPMs was calculated using the Kaplan-Meier method. Cox proportional hazards model was used to identify potential risk factors for SPMs and assess whether SPMs affect overall survival. RESULTS Of the 6,377 patients, 189 (3.0%) suffered SPMs (median follow-up, 62 months). One-, 2-, 3-, 4-, and 5-cumulative risks of SPMs were 0.4%, 0.9%, 1.6%, 2.2%, and 2.6%, respectively. Latency from start of IMRT to SPMs diagnosis was 37 months (range, 6 to 102 months). In patients with SPMs, 14.3% suffered SPMs within 1 year post-IMRT: 1-3 years, 38.1%; 3-5 years, 33.9%; and >5 years, 13.7%. Lung cancer was the most common SPM (50/6,377, 0.78%). Multivariate analysis demonstrated sex (male, 64% increase), age (≥50 years, 68% increase), and smoking history (41% increase) were significant risk factors for SPMs, and SPMs were associated with poorer overall survival. CONCLUSION This large cohort study confirms SPMs a dreadful complication for long-term survivors of NPC treated with IMRT. SPMs negatively impact overall survival in NPC. Close follow-up is recommended for older male survivors with a smoking history.

To compare survival effects of comprehensive neck dissection (CND) and selective neck dissection (SND) for patients with nasopharyngeal carcinoma (NPC) with only regional failure.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).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 0.001), recurrent N stage (rN stage) (HR 1.96, 95% CI 1.29-2.97, P = 0.002), and positive margins (HR 3.67, 95% CI 2.40-5.62, P 0.001) were independent poor prognostic factors for OS. The interaction effects between the dissection style and each independent factor were not significant for OS, LRFS, RRFS, or DMFS (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).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.4 Laryngoscope, 129:387-395, 2019.

Background To evaluate the incidence of neck muscle spasm in nasopharyngeal carcinoma (NPC) patients that received intensity-modulated radiotherapy (IMRT), and to analyse the patient- and treatment-related risk factors associated with neck muscle spasm. Methods A sample of 152 IMRT-treated, biopsy-proven, nondisseminated NPC patients were retrospectively analysed. All had documented IMRT treatment plans and had returned for follow-up review at 4 years post-radiotherapy. Spasm of the sternocleidomastoid (SCM) muscle was graded from 0 to 3 (absent to severe) and this grade served as the clinical endpoint. Risk factors were identified using logistic regression analysis. Results Within 4 years of radiotherapy, neck muscle spasm developed in 23.68% of the patients; Grades 0, 1, 2 and 3 were respectively assigned to 83.55, 7.57, 6.58 and 2.30% of assessed SCMs. Multivariate analysis indicated that gender, N stage, V60 (percentage of SCM volume that received >60 Gy) were independent prognostic variables, and that the optimal threshold for using V60 to predict neck muscle spasm was 61.92% (sensitivity = 0.900, specificity = 0.953). Conclusions Gender, N stage and V60 were independent predictive factors for post-radiotherapy neck muscle spasm, and a V60 of ≤61.92% in the SCM was relatively safe.

Background and purpose We used a literature-based meta-analysis to assess whether failure-free survival (FFS) or progression-free survival (PFS) could be reliable surrogate endpoints for overall survival (OS) in trials of combined chemotherapy and radiotherapy for nasopharyngeal carcinoma (NPC). Methods and materials We identified randomised trials that evaluated combined chemoradiotherapy strategies, and reported FFS or PFS and OS in NPC. We analysed the treatment effects on FFS or PFS, and OS. We used the coefficient of determination ( R 2 ), and the surrogate threshold effect (STE) to assess the trial-level correlation. Results Twenty-one trials (5212 patients), with sixteen treatment-control comparisons for FFS, and nine for PFS, were analysed. FFS was strongly correlated with OS ( R 2 =0.88, STE=0.84), as was PFS ( R 2 =0.90, STE=0.88). Moreover, FFS and PFS at 3years were still strongly correlated with 5-year OS ( R 2 =0.80, STE=0.83; R 2 =0.85, STE=0.84). Conclusions Both FFS and PFS could be valid surrogate endpoints for OS in trials of combined chemotherapy and radiotherapy for NPC; PFS may be a more acceptable surrogate endpoint compared with FFS.