Publications by authors named "Ji-Jin Yao"

32 Publications

Optimal cumulative cisplatin dose during concurrent chemoradiotherapy among children and adolescents with locoregionally advanced nasopharyngeal carcinoma: A real-world data study.

Radiother Oncol 2021 Aug 8;161:83-91. Epub 2021 Jun 8.

VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address:

Purpose: To identify an optimal cumulative cisplatin dose along with concurrent chemoradiotherapy (CC-CCD) for children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC) using real-world data.

Materials And Methods: Using an NPC-specific database at our center, 157 patients younger than 19 years old with non-disseminated CALANPC and receiving neoadjuvant chemotherapy (NAC) plus cisplatin-based concurrent chemoradiotherapy (CCRT) were enrolled. Confounding factors were controlled by conducting propensity score matching analysis. Primary endpoints include disease-free survival (DFS) and distant metastasis-free survival (DMFS).

Results: The optimal threshold for CC-CCD with respect to DFS was 160 mg/m based on recursive partitioning analyses (RPA). Therefore, a uniform threshold of 160 mg/m (≥160 vs. <160 mg/m) was selected to classify patients between high and low CC-CCD groups for survival analysis. Patients receiving low CC-CCD showed a significant decrease in 5-year DFS (76.6% vs 91.3%; P = 0.006) and DMFS (81.3% vs 93.5%; P = 0.009) compared to those receiving high CC-CCD. Multivariate analyses indicated that high CC-CCD as an favorable prognostic influence for DFS (P = 0.007) and DMFS (P = 0.008). Further matched analysis identified 65 pairs in both high and low CC-CCD groups. In the matched cohort, high CC-CCD was still identified as a favorable factor for prognosis in DFS (HR, 0.23; 95% CI, 0.08-0.70; P = 0.010) and DMFS (HR, 0.23; 95% CI, 0.06-0.82; P = 0.023).

Conclusion: CC-CCD exerts significant treatment effects and 160 mg/m CC-CCD may be adequate to provide antitumor effects for CALANPC receiving NAC plus CCRT.
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http://dx.doi.org/10.1016/j.radonc.2021.06.003DOI Listing
August 2021

A deep-learning-based prognostic nomogram integrating microscopic digital pathology and macroscopic magnetic resonance images in nasopharyngeal carcinoma: a multi-cohort study.

Ther Adv Med Oncol 2020 14;12:1758835920971416. Epub 2020 Dec 14.

Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, P. R. China.

Background: To explore the prognostic value of radiomics-based and digital pathology-based imaging biomarkers from macroscopic magnetic resonance imaging (MRI) and microscopic whole-slide images for patients with nasopharyngeal carcinoma (NPC).

Methods: We recruited 220 NPC patients and divided them into training ( = 132), internal test ( = 44), and external test ( = 44) cohorts. The primary endpoint was failure-free survival (FFS). Radiomic features were extracted from pretreatment MRI and selected and integrated into a radiomic signature. The histopathological signature was extracted from whole-slide images of biopsy specimens using an end-to-end deep-learning method. Incorporating two signatures and independent clinical factors, a multi-scale nomogram was constructed. We also tested the correlation between the key imaging features and genetic alternations in an independent cohort of 16 patients (biological test cohort).

Results: Both radiomic and histopathologic signatures presented significant associations with treatment failure in the three cohorts (C-index: 0.689-0.779, all  < 0.050). The multi-scale nomogram showed a consistent significant improvement for predicting treatment failure compared with the clinical model in the training (C-index: 0.817 0.730,  < 0.050), internal test (C-index: 0.828 0.602,  < 0.050) and external test (C-index: 0.834 0.679,  < 0.050) cohorts. Furthermore, patients were stratified successfully into two groups with distinguishable prognosis (log-rank  < 0.0010) using our nomogram. We also found that two texture features were related to the genetic alternations of chromatin remodeling pathways in another independent cohort.

Conclusion: The multi-scale imaging features showed a complementary value in prognostic prediction and may improve individualized treatment in NPC.
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http://dx.doi.org/10.1177/1758835920971416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739087PMC
December 2020

The effect of adding concurrent chemotherapy to radiotherapy for stage II nasopharyngeal carcinoma with undetectable pretreatment Epstein-Barr virus DNA: Retrospective analysis with a large institutional-based cohort.

Transl Oncol 2021 Feb 15;14(2):100990. Epub 2020 Dec 15.

VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong, China. Electronic address:

Little is known about the value of adding concurrent chemotherapy (CC) to radiotherapy for stage II nasopharyngeal carcinoma (NPC) with undetectable (0 copies/mL) pretreatment Epstein-Barr Virus (EBV) DNA in the intensity-modulated radiotherapy (IMRT) era. To address this question, the present study retrospectively reviewed 514 patients with newly diagnosed stage II NPC and undetectable pretreatment EBV DNA from Sun Yat-sen University Cancer Center between March 2008 and October 2016. Clinical characteristics and survival outcomes between concurrent chemoradiotherapy (CCRT) and IMRT alone groups were compared. Propensity score matching analysis was conducted to control for confounding factors. Although CCRT group had significantly higher proportions of stage N1 disease than IMRT alone group before matching (85% vs. 61%, p < 0.001), no statistically significant differences were noted for OS (97.8% vs. 98.1%, p = 0.700), DFS (93.4% vs. 94.5%, p = 0.846), DMFS (96.0% vs. 96.9%, p = 0.762), and LRFS (97.3% vs. 98.1%, p = 0.701). After 1:1 propensity-score matching, 177 pairs were identified. Patients in each group were found to be well balanced in baseline characteristics and risk factors (all P > 0.05). The five-year OS (96.9% vs. 98.2%, p = 0.302), DFS (92.0% vs. 95.2%, p = 0.777), DMFS (95.2% vs. 97.6%, p = 0.896), and LRFS (97.3% vs. 97.6%, p = 0.328) rates remain comparable for both CCRT and RT alone groups. Additionally, subgroup analysis still failed to observe any significant survival benefit for the addition of CC to IMRT for N1 disease (P>0.05 for all). Our results indicated that IMRT alone appeared to achieve comparable survival to CCRT for stage II NPC with undetectable pretreatment EBV DNA.
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http://dx.doi.org/10.1016/j.tranon.2020.100990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750417PMC
February 2021

Development and Validation of Web-Based Nomograms to Precisely Predict Survival Outcomes of Non-metastatic Nasopharyngeal Carcinoma in an Endemic Area.

Cancer Res Treat 2021 Jul 7;53(3):657-670. Epub 2020 Dec 7.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.

Purpose: This study aimed to develop web-based nomograms to precisely predict survival outcomes in patients with non-metastatic nasopharyngeal carcinoma (NPC) in an endemic area.

Materials And Methods: A total of 10,126 patients who underwent radical intensity-modulated radiotherapy at Sun Yat-sen University Cancer Center (SYSUCC) from 2009 to 2015 were analyzed. We assigned patients into a training cohort (SYSUCC-A, n=6,751) and an internal validation cohort (SYSUCC-B, n=3,375) based on computer-generated random numbers. Patients collected from Wuzhou Red Cross Hospital (WZRCH) between 2012 and 2015 were used as the independent external validation cohort (WZRCH, n=450). Concordance index (C-index) was used to determine predictive accuracy and discriminative ability for the nomogram. The web-based clinicopathologic prediction models for predicting survival were based on Cox regression.

Results: The C-indexes for SYSUCC-A, SYSUCC-B, and WZRCH cohorts for the established nomograms to predict 3-year overall survival (OS) was 0.736, 0.715, and 0.691. Additionally, C-indexes to predict 3-year distant metastasis-free survival (DMFS) was 0.717, 0.706, and 0.686, disease-free survival (DFS) was 0.713, 0.697, and 0.656, local relapse-free survival was 0.695, 0.684, and 0.652, and regional relapse-free survival was 0.672, 0.650, and 0.616. The calibration plots showed great agreement between nomogram-predicted 3-year survival outcomes and actual 3-year survival outcomes. Moreover, C-indexes of the nomograms for OS, DMFS, and DFS were significantly superior than TNM stage (p< 0.001 for all).

Conclusion: These user-friendly nomograms can precisely predict survival endpoints in patients with non-metastatic NPC. They may serve as a useful tool for providing patient counseling and help physicians to make individual follow-up plans.
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http://dx.doi.org/10.4143/crt.2020.899DOI Listing
July 2021

Development and validation of a novel MR imaging predictor of response to induction chemotherapy in locoregionally advanced nasopharyngeal cancer: a randomized controlled trial substudy (NCT01245959).

BMC Med 2019 10 23;17(1):190. Epub 2019 Oct 23.

Department of Radiation oncology, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.

Background: In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone.

Methods: All patients, including retrospective training (n = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts.

Results: Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25-0.74, p = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups (p = 0.063), with a significant treatment interaction (p <  0.001). This trend was also found in the validation cohort with high (n = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06-0.51, p <  0.001) and low ICTOS (n = 175, p = 0.31), with a significant treatment interaction (p = 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors.

Conclusion: An imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment.

Trial Registration: ClinicalTrials.gov , NCT01245959 . Registered 23 November 2010.
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http://dx.doi.org/10.1186/s12916-019-1422-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806559PMC
October 2019

Clinical features and survival outcomes between ascending and descending types of nasopharyngeal carcinoma in the intensity-modulated radiotherapy era: A big-data intelligence platform-based analysis.

Radiother Oncol 2019 08 15;137:137-144. Epub 2019 May 15.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, PR China. Electronic address:

Purpose: To compare clinical features and survival outcomes in patients with ascending type (type A) and descending type (type D) nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era.

Materials And Methods: A total of 5194 patients with type A and type D NPC treated at Sun Yat-sen University Cancer Center were randomly selected. Tumors that were mainly advanced local disease (T3-4 stage) with early stage cervical lymph node involvement (N0-1 stage) were determined as type A, while tumors with advanced lymph node disease (N2-3 stage) but early stage local invasion (T1-2 stage) were classified as type D NPC. Kaplan-Meier's analysis was used to evaluate survival rates, and log-rank test survival curves were used for comparison. In the multivariate analysis Cox proportional hazard models were developed.

Results: There was a larger proportion of type A tumors (82%) than type D tumors (18%). Compared to patients with type A tumors, those with type D tumors had increased likelihood of distant metastasis, regional recurrence, disease recurrence, and death (P < 0.001 for all), however, not for local recurrence (P < 0.001). The HR (hazard ratio) for death following recurrence of disease for type D tumors were 1.6 compared to type A tumors. Multivariate analysis revealed that elevated EBV DNA, elevated lactate dehydrogenase, alcohol consumption, and no family history of cancer attributed to the development of type D tumors. Annual hazard rate in type A patients increased, peaking at 12-18 months after initial treatment and downward thereafter. Similar trend also occurred in type D during the first 5 years following treatment. Notably, a minor peak was also observed 7-8 years post treatment.

Conclusions: In the IMRT era, recurrence patterns differed across tumor types. Type D NPC had a more aggressive clinical course and worse outcomes compared with type A NPC.
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http://dx.doi.org/10.1016/j.radonc.2019.04.025DOI Listing
August 2019

Pretreatment MRI radiomics analysis allows for reliable prediction of local recurrence in non-metastatic T4 nasopharyngeal carcinoma.

EBioMedicine 2019 Apr 27;42:270-280. Epub 2019 Mar 27.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, PR China. Electronic address:

Background: To identify a radiomics signature to predict local recurrence in patients with non-metastatic T4 nasopharyngeal carcinoma (NPC).

Methods: A total of 737 patients from Sun Yat-sen University Cancer Center (training cohort: n = 360; internal validation cohort: n = 120) and Wuzhou Red Cross Hospital (external validation cohort: n = 257) underwent feature extraction from the largest axial area of the tumor on pretreatment magnetic resonance imaging scans. Feature selection was based on the prognostic performance and feature stability in the training cohort. Radscores were generated using the Cox proportional hazards regression model with the selected features in the training cohort and then validated in the internal and external validation cohorts. We also constructed a nomogram for predicting local recurrence-free survival (LRFS).

Findings: Eleven features were selected to construct the Radscore, which was significantly associated with LRFS. For the training, internal validation, and external validation cohorts, the Radscore (C-index: 0.741 vs. 0.753 vs. 0.730) outperformed clinical prognostic variables (C-index for primary gross tumor volume: 0.665 vs. 0.672 vs. 0.577; C-index for age: 0.571 vs. 0.629 vs. 0.605) in predicting LRFS. The generated radiomics nomogram, which integrated the Radscore and clinical variables, exhibited a satisfactory prediction performance (C-index: 0.810 vs. 0.807 vs. 0.753). The nomogram-defined high-risk group had a shorter LRFS than did the low-risk group (5-year LRFS: 73.6% vs. 95.3%, P < .001; 79.6% vs 95.8%, P = .006; 85.7% vs 96.7%, P = .005).

Interpretation: The Radscore can reliably predict LRFS in patients with non-metastatic T4 NPC, which might guide individual treatment decisions. FUND: This study was funded by the Health & Medical Collaborative Innovation Project of Guangzhou City, China.
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http://dx.doi.org/10.1016/j.ebiom.2019.03.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491646PMC
April 2019

Do all patients with advanced N-stage nasopharyngeal carcinoma benefit from the addition of induction chemotherapy to concurrent chemoradiotherapy?

Ther Adv Med Oncol 2019 21;11:1758835919833863. Epub 2019 Mar 21.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, Guangdong Province, China.

Background: The aim of this study was to evaluate the benefits from the addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in N2-3 nasopharyngeal carcinoma (NPC).

Methods: A total of 3089 patients with nonmetastatic NPC, staged as N2-3 were retrospectively reviewed. IC contained cisplatin (80 mg/m) with 5-fluorouracil (800 mg/m/day over 120 h), or cisplatin (80 mg/m) with docetaxel (80 mg/m), or cisplatin (60 mg/m) with 5-fluorouracil (600 mg/m over 120 h), and docetaxel (60 mg/m) administered at 3-week intervals for two or three cycles. Concurrent chemotherapy consisted of cisplatin (80 or 100 mg/m) given in weeks 1, 4, and 7 of radiotherapy, or cisplatin (40 mg/m) given weekly during radiotherapy. Overall, three well-matched risk groups (low, intermediate, and high risk) were created using propensity score matching, and IC plus CCRT was compared with CCRT in each risk group. Our primary endpoint was distant metastasis-free survival (DMFS).

Results: A nomogram for DMFS was established with good prognostic accuracy (C-index, 0.69; 95% confidence interval, 0.64-0.73). The survival curves for low, intermediate, and high-risk groups stratified by the nomogram were significantly different between all three risk groups, with corresponding 5-year DMFS rates of 90.7%, 79.4%, and 64.9%, respectively ( < 0.001). IC plus CCRT was significantly associated with superior DMFS as compared with CCRT alone (69.5% 56.7%, = 0.004) in the high-risk group. However, no significant difference between IC plus CCRT and CCRT was observed ( = 0.831 and 0.608, respectively) in the intermediate and low-risk groups.

Conclusions: Our findings can help accurately guide the treatment of individual patients with advanced N-stage NPC.
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http://dx.doi.org/10.1177/1758835919833863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431774PMC
March 2019

Prognostic value of neutrophil-to-lymphocyte ratio in advanced nasopharyngeal carcinoma: a large institution-based cohort study from an endemic area.

BMC Cancer 2019 Jan 8;19(1):37. Epub 2019 Jan 8.

Department of Radiation Oncology, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong Province, People's Republic of China.

Background: Findings remain unclear whether neutrophil-to-lymphocyte ratio (NLR) detrimentally affects advanced nasopharyngeal carcinoma (NPC) prognosis. We aim to evaluate the prognostic value of NLR in patients with NPC based on a large-scale cohort from an endemic area.

Methods: We selected patients retrospectively from a cohort examining long-term cancer outcomes following diagnosis. Neutrophil counts and lymphocyte counts were assessed prior to treatment. Kaplan-Meier method and log-rank test were used to calculate and compare survival outcomes. Additionally, Cox proportional hazards model was utilized to carry out univariate and multivariate analyses.

Results: Between October 2009 and August 2012, we enrolled 1550 consecutive NPC patients staged II-IVB. The median value of NLR was 2.27 (interquartile range [IQR], 1.71-3.12). Determined by operating characteristic curve using overall survival (OS) as an endpoint, the cutoff value for NLR was 2.50. At 5 years, NLR > 2.50 was associated with inferior OS (90.3% vs 82.5%; P < 0.001), distant metastasis-free survival (DMFS, 89.4% vs 85.0%; P = 0.014), and progression-free survival (PFS, 80.9% vs 76.5%; P = 0.031) than NLR ≤2.50. In multivariate analysis, NLR was found to be a significant prognostic factor for OS (HR, 1.72; 95% CI, 131-2.24; P < 0.001), DMFS (HR, 1.45; 95% CI, 1.10-1.92; P = 0.009), and PFS (HR, 1.29; 95% CI, 1.04-1.59; P = 0.021).

Conclusion: Pretreatment NLR independently affects survival. Our findings suggest that NLR measurements will be of great clinical significance in the management of NPC.
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http://dx.doi.org/10.1186/s12885-018-5236-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325732PMC
January 2019

Efficacy and safety of primary surgery with postoperative radiotherapy in head and neck mucosal melanoma: a single-arm Phase II study.

Cancer Manag Res 2018 14;10:6985-6996. Epub 2018 Dec 14.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, Guangdong Province, People's Republic of China,

Background: There still remains no well-established treatment strategy for head and neck mucosal melanoma (HNMM). We aim to evaluate the effectiveness and safety of primary surgery with postoperative radiotherapy for this disease.

Patients And Methods: A single-arm, Phase II clinical trial was conducted at Sun Yat-Sen University Cancer Center. Patients with nonmetastatic, histologically proven HNMM were prospectively enrolled. Patients received primary surgery followed by intensity-modulated radiotherapy with an equivalent dose at 2 Gy per fraction of 65-70 Gy to CTV1 (high-risk regions including tumor bed) and 50-55 Gy to CTV2 (low-risk regions). Additional use of adjuvant chemotherapy (AC) depended on consultation from a multidisciplinary team. This trial is registered with ClinicalTrials.gov, number NCT03138642.

Results: A total of 33 patients were enrolled and analyzed between July 2010 and November 2016. There were 18 (54.5%) patients with T3 disease and 15 (45.5%) patients with T4a disease. The median age at diagnosis was 58 years (range 27-83 years), and 61% of the cohort were males. The overall median follow-up duration was 25.3 months (range 5.3-67.1 months). The 3-year overall survival (OS), local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were 44.4, 91.7, 78.1, and 41.7%, respectively. Patients with T4a disease showed significantly inferior OS (=0.049) and DMFS (=0.040) than those with T3 disease. Prophylactic neck radiation (PNR) was nearly associated with superior RRFS (=0.078). However, there was no significant difference in OS, LRFS, RRFS, and DMFS for patients treated with or without AC (>0.05 for all). Toxicities were generally mild to moderate.

Conclusion: Primary surgery with postoperative radiotherapy yielded excellent local control and acceptable toxicity profile for HNMM. Nevertheless, high rates of distant metastases resulted in limited survival.
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http://dx.doi.org/10.2147/CMAR.S185017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298389PMC
December 2018

Survival impact of radiotherapy interruption in nasopharyngeal carcinoma in the intensity-modulated radiotherapy era: A big-data intelligence platform-based analysis.

Radiother Oncol 2019 03 14;132:178-187. Epub 2018 Nov 14.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, PR China. Electronic address:

Purpose: To evaluate the effect of radiotherapy interruption (RTI) in patients with nasopharyngeal carcinoma (NPC) receiving intensity-modulated radiotherapy (IMRT).

Patients And Methods: A total of 7826 patients using the well-established big-data intelligence platform were identified. Computer-generated random numbers were used to assign these patients into a training cohort (n = 3913 patients) and an internal validation cohort (n = 3913 patients). RTI was defined as the difference between radiation treatment time and planned radiation time (assuming a Monday start). Survival analysis was performed using the Kaplan-Meier method for survival, and log-rank test to evaluate difference. Optimal RTI threshold was identified using the recursive partitioning analyses (RPAs). Multivariate analysis was performed using the Weibull model. The primary endpoint was overall survival (OS).

Results: The optimal threshold of RTI with respect to OS in the training cohort was 6.5 d based on RPAs. Therefore, a uniform threshold of 7 d (<7 vs. ≥7 d) was selected to classify both training and validation cohorts into high and low RTI groups for survival analysis. RTI of ≥7 d showed significant detrimental effects on OS in both training (5-y OS, 82.4% vs 86.5%; P = 0.001) and validation cohorts (5-y OS, 85.2% vs 86.7%; P = 0.013) than those patients with RTI of <7 d. Consistent with results of the univariate analysis, RTI of ≥7 d was found to be an independent unfavorable prognostic factor for OS in both training (HR, 1.49; 95% CI, 1.14-1.95; P = 0.003) and validation cohort (HR, 1.37; 95% CI, 1.07-1.65; P = 0.031). Subgroup analysis showed that RTI of ≥7 d had significant adverse effects on prognosis of NPC patients receiving IMRT, regardless of TNM stage and chemotherapy (P < 0.05 for all).

Conclusions: In the IMRT era, RTI independently influences survival. Raising RTI ≥ 7 d was consistently unfavorable for NPC survival. Medical practitioners must remind patients on the importance of minimizing RT interruptions.
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http://dx.doi.org/10.1016/j.radonc.2018.10.018DOI Listing
March 2019

Comparing treatment outcomes of concurrent chemoradiotherapy with or without nimotuzumab in patients with locoregionally advanced nasopharyngeal carcinoma.

Cancer Biol Ther 2018 6;19(12):1102-1107. Epub 2018 Aug 6.

a Department of Radiation Oncology, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy , Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology , Guangzhou , Guangdong Province , P.R. China.

: The benefits of additional use of nimotuzumab (NTZ) in the treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is largely unclear. We aim to compare LA-NPC treatment outcomes in patients that received CCRT with nimotuzumab (NTZ) to patients that received CCRT only. : Between October 2009 and January 2012, 31 previously untreated and newly diagnosed LA-NPC patients were administered CCRT (3 cycles of 100 mg/m cisplatin every third week with intensity-modulated radiotherapy) plus NTZ according to an IRB-approved institutional research protocol. A well-balanced cohort of 62 patients who received CCRT alone was created by matching each patient who received CCRT plus NTZ via propensity-matched analysis in a 2:1 ratio. : Compared with CCRT only, CCRT plus NTZ was significantly associated with superior overall survival (5-year OS; 96.8% vs. 82.3%; = 0.001), superior distant metastasis-free survival (5-year DMFS; 90.3% vs. 80.6%, = 0.012) and superior progression-free survival (5-year PFS; 83.9% vs. 71.0%, = 0.006). In multivariate analysis, the inclusion of NTZ to CCRT was confirmed to be a favorable factor for OS (HR, 0.31; 95% CI, 0.02-0.71; = 0.027), DMFS (HR, 0.45; 95% CI, 0.13-0.77; = 0.034), and PFS (HR, 0.38; 95% CI, 0.11-0.89; = 0.041). In addition, no significant differences in hematology parameters, dermatitis, nausea, vomiting, xerostomia, nephrotoxicity or neurotoxicity were found between the two arms (all  > 0.05). : The inclusion of NTZ to CCRT is more effective for long-term survival among LA-NPC patients than CCRT only.
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http://dx.doi.org/10.1080/15384047.2018.1491501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301798PMC
August 2018

The detrimental effects of radiotherapy interruption on local control after concurrent chemoradiotherapy for advanced T-stage nasopharyngeal carcinoma: an observational, prospective analysis.

BMC Cancer 2018 Jul 16;18(1):740. Epub 2018 Jul 16.

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, Guangdong Province, People's Republic of China.

Background: Previous studies have reported radiotherapy interruption (RTI) is associated with poor local control in two-dimensional radiotherapy (2DRT) era. However, it remains unclear whether RTI still affects local control for advanced T stage (T3-4) in the intensity-modulated radiation therapy (IMRT) era. We aim to evaluate whether RTI affects local control for T3-4 NPC treated with definitive IMRT.

Methods: In this observational prospective study, 447 T3-4 NPC patients treated with IMRT plus concurrent chemotherapy were included. All patients completed the planned radiotherapy course, and RTI was defined as the actual time taken to finish the prescribed course of radiotherapy minus the planned radiotherapy time. Receiver operating characteristic (ROC) curve was used for determined the cutoff point of RTI. The effects of RTI on local control were analyzed in multivariate analysis.

Results: At 5 years, the local relapse-free survival (LRFS) and overall survival (OS) rates were 93.7 and 85.7%, respectively. The cutoff RTI for LRFS was 5.5 days by ROC curve. Compared to patients with RTI >  5 days, patients with RTI ≤ 5 days had a significantly lower rate of LRFS (97% vs. 83%; P < 0.001). In multivariate analysis, RTI was a risk factor independently associated with LRFS (HR = 9.64, 95% CI, 4.10-22.65), but not for OS (HR = 1.09, 95% CI, 0.84-1.64).

Conclusions: The current analysis demonstrates a significant correlation between prolonged RTI and local control in NPC, even when concurrent chemotherapy is used. We consider that attention to RTI seems to be warranted for patients with advanced T-stage NPC in the era of IMRT.
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http://dx.doi.org/10.1186/s12885-018-4495-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048841PMC
July 2018

Prognostic Value of Circulating Lipoprotein in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma.

Cell Physiol Biochem 2018 16;48(1):285-292. Epub 2018 Jul 16.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.

Background/aims: Lipoproteins have been reported to be associated with prognosis in various cancers; however, the prognostic value of lipoproteins in patients with nasopharyngeal carcinoma (NPC) remains largely unknown. We aim to asses the role of circulating lipoproteins in locoregionally advanced NPC patients.

Methods: Between October 2009 and August 2012, a total of 1,081 patients with stage III-IVB NPC were included in the analysis. Circulating high-density lipoprotein (HDL) and low-density lipoprotein (LDL) are the two key lipoproteins, which were measured at baseline. Receiver operating characteristic (ROC) curve analysis was used to evaluate different cut-off points for lipoproteins. Actuarial rates were performed using Kaplan-Meier methods and the log-rank test.

Results: The cutoff points of HDL, LDL, and LDL/HDL ratio were 1.17 mmol/L, 3.75 mmol/L, and 2.73, respectively. At 5 years, high HDL (> 1.17 mmol/L) was significantly associated with better overall survival (OS, 86.6% vs. 78.9%; P=0.004), distant metastasis-free survival (DMFS, 86.9% vs. 80.8%; P=0.004), locoregional relapse-free survival (LRFS, 90.8% vs. 85.4%; P=0.010), and progression-free survival (PFS, 79.1% vs. 70.2%; P= 0.001) than low HDL (≤1.17 mmol/L). In contrast, high LDL (> 3.75 mmol/L) tend to be inferior OS (79.1% vs. 84.9%; P= 0.016) in compassion with low LDL (≤3.75 mmol/L). Likewise, patients with high LDL/HDL ratio (> 2.73) tend to be inferior OS (79.3% vs. 86.9%; P=0.001), DMFS (81.9% vs. 86.5%; P=0.030), and PFS (72.6% vs. 77.8%; P= 0.034) than those of low LDL/HDL ratio (≤2.73). In multivariate analysis, baseline HDL was found to be a significant prognostic factor for LRFS (HR= 0.65; 95% CI, 0.45-0.93; P= 0.019) and PFS (HR=0.75; 95% CI, 0.58-0.98; P= 0.034).

Conclusions: Circulating HDL is significantly associated with treatment outcomes in patients with locoregionally advanced NPC. We suggest that HDL measurements will be of great clinical significance in the management of NPC.
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http://dx.doi.org/10.1159/000491728DOI Listing
September 2018

Dose Escalation of Lobaplatin Concurrent with IMRT for the Treatment of Stage III-IVb NPC: A Phase I Clinical Trial.

Transl Oncol 2018 Aug 29;11(4):1007-1011. Epub 2018 Jun 29.

Department of Medical Oncology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519001, Guangdong Province, PR China. Electronic address:

The maximum tolerated dose (MTD) of lobaplatin as a single agent chemotherapy concurrent with intensity-modulated radiotherapy (IMRT) in Asian population with nasopharyngeal carcinoma (NPC) remains unclear. From June 2016 to December 2017, 17 patients diagnosed with stage III-IVb NPC from an Asian population were prospectively enrolled. Patients were administered lobaplatin with 25-50 mg/m escalation of dosage on day 1. Every 21 days (days 1, 22, and 43) during radiotherapy, cycles were repeated. We administered radiotherapy as 2.12-2.27 Gy per fraction with five daily fractions each week for 6 to 7 weeks. The evaluation of lobaplatin-related toxic effects was based on the Common Terminology Criteria for Adverse Events version 4.0. During the weekly treatment period, complete blood counts and biochemistry were performed. Dose-limiting toxicities (DLTs) were determined by the following events during any cycle in which lobaplatin was administered. Each dose group consisted of at least three cases. We proceeded to the subsequent dose group in the absence of DLT with a dose increment of 5 mg/m until DLT occurred. Periods from 1 week prior to the chemotherapy initiation to 3 weeks after the last chemotherapy were defined as DLT observation periods. MTD was determined by the dose that was immediately below the dose that produced DLT. After analysis, DLT occurred in three patients, including a group with two of three patients in 45 mg/m lobaplatin and another group with one of five patients in 40 mg/m lobaplatin. No grade 3-4 toxicity was observed in patients treated with lobaplatin <40 mg/m. The tumor response rate at 12 weeks after treatment was 100%. In summary, lobaplatin concurrent with IMRT was active in stage III-IVb NPC, and the MTD for the lobaplatin as single-agent chemotherapy was 40 mg/m when combined with IMRT in an Asian population. This trial is registered with ClinicalTrials.gov, number NCT03188497.
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http://dx.doi.org/10.1016/j.tranon.2018.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039884PMC
August 2018

Interobserver variations in the delineation of target volumes and organs at risk and their impact on dose distribution in intensity-modulated radiation therapy for nasopharyngeal carcinoma.

Oral Oncol 2018 07 3;82:1-7. Epub 2018 May 3.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, PR China. Electronic address:

Objective: This study aimed to (a) assess the differences in the delineation of target volumes and organs-at-risk (OARs) by different physicians designing an intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC) and (b) analyze the impact of these differences on the treatment plan optimization.

Materials And Methods: The planning target volumes (PTVs) and OARs for radiotherapy were manually delineated from computed tomography images of a patient with NPC, and a standard delineation was determined using the STAPLE algorithm of ABAS software. IMRT was designed using one standard plan and 10 individual plans based on the same constraints and field conditions. The maximum/minimum ratio (MMR) of the PTV and OAR volumes and the coefficient of variation (CV) for the different groups were evaluated and compared to the volume of the standard contour.

Results: Significant differences were seen in the PTVs of the nasopharynx (PTV), neck lymph node (PTV) and the OARs manually delineated by different physicians. Compared to the standard plan, the mean dose-related parameters of various OARs in different individual plans were not significantly different, while that of most organs in different individual plans were reduced. However, a significant difference in the dose at each organ was noted in different individual plans.

Conclusion: Significant differences were noted in the PTV and OAR delineations by different physicians in radiotherapy of NPC, and their dosimetric parameters were significantly different from the standard planned parameters. Therefore, multicenter trials should pay attention to the impact of these differences on the clinical evaluation.
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http://dx.doi.org/10.1016/j.oraloncology.2018.04.025DOI Listing
July 2018

Prognostic value of serum bilirubin in southern Chinese patients with advanced nasopharyngeal carcinoma.

Clin Chim Acta 2018 Sep 31;484:314-319. Epub 2018 May 31.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China.. Electronic address:

Background: We evaluated the prognostic value of serum bilirubin in advanced nasopharyngeal carcinoma (NPC) patients.

Methods: Seven-hundred fifty-nine advanced NPC patients treated with definitive chemoradiotherapy were retrospectively analyzed. Serum indirect bilirubin (IBIL) and direct bilirubin (DBIL) were measured before treatment. To evaluate different cutoff points for serum bilirubin, we utilized ROC curves. The Kaplan-Meier method and log-rank test were adopted to calculate and compare survival outcomes. Cox proportional hazard models were used to perform univariate and multivariate analyses.

Results: At 5 y, IBIL >7.15 μmol/l were significantly associated with superior progression-free survival (PFS, 83.6% vs 70.3%; P < .001), overall survival (OS, 88.6% vs 80.5%; P = .012), distant metastasis-free survival (DMFS, 90.3% vs 82.8%; P = .006), and locoregional relapse-free survival (LRFS, 92.1% vs 86.4%; P = .048) than IBIL ≤7.15 μmol/l. Similarly, patients with DBIL >2.65 μmol/l had better prognosis across all outcomes than those of patients with DBIL ≤2.65 μmol/l (all P < .05), except no difference was observed in LRFS (90.5% vs. 87.3%, P = .195). Multivariate analyses showed that IBIL >7.15 μmol/l was an independent protective prognostic factor for PFS (HR, 0.57; 95% CI, 0.40-0.81; P = .002), OS (HR, 0.67; 95% CI, 0.43-0.92; P = .041), and DMFS (HR, 0.63; 95% CI, 0.40-0.98; P = .034); while serum DBIL only remained significant for PFS (HR, 0.63; 95% CI, 0.44-0.89; P = .009).

Conclusions: Pretreatment IBIL and DBIL are potentially independent prognostic factors for patients with advanced NPC.
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http://dx.doi.org/10.1016/j.cca.2018.05.058DOI Listing
September 2018

Prognostic values of the integrated model incorporating the volume of metastatic regional cervical lymph node and pretreatment serum Epstein-Barr virus DNA copy number in predicting distant metastasis in patients with N1 nasopharyngeal carcinoma.

Chin J Cancer 2017 12 29;36(1):98. Epub 2017 Dec 29.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China.

Background: According to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system, over 50% of patients with nasopharyngeal carcinoma (NPC) have N1 disease at initial diagnosis. However, patients with N1 NPC are relatively under-researched, and the metastasis risk of this group is not well-stratified. This study aimed to evaluate the prognostic values of gross tumor volume of metastatic regional lymph node (GTVnd) and pretreatment serum copy number of Epstein-Barr virus (EBV) DNA in predicting distant metastasis of patients with N1 NPC, and to develop an integrated prognostic model that incorporates GTVnd and EBV DNA copy number for this group of patients.

Methods: The medical records of 787 newly diagnosed patients with nonmetastatic, histologically proven N1 NPC who were treated at Sun Yat-sen University Cancer Center between November 2009 and February 2012 were analyzed. Computed tomography-derived GTVnd was measured using the summation-of-area technique. Blood samples were collected before treatment to quantify plasma EBV DNA. The receiver operating characteristic (ROC) curve analysis was used to evaluate the cut-off point for GTVnd, and the area under the ROC curve was used to assess the predicted validity of GTVnd. The survival rates were assessed by Kaplan-Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model.

Results: The 5-year distant metastasis-free survival (DMFS) rates for patients with GTVnd > 18.9 vs. ≤ 18.9 mL were 82.2% vs. 93.2% (P < 0.001), and for patients with EBV DNA copy number > 4000 vs. ≤ 4000 copies/mL were 83.5% vs. 93.9% (P < 0.001). After adjusting for GTVnd, EBV DNA copy number, and T category in the Cox regression model, both GTVnd > 18.9 mL and EBV DNA copy number > 4000 copies/mL were significantly associated with poor prognosis (both P < 0.05). According to combination of GTVnd and EBV DNA copy number, all patients were divided into low-, moderate-, and high-risk groups, with the 5-year DMFS rates of 96.1, 87.4, and 73.8%, respectively (P < 0.001). Multivariate analysis confirmed the prognostic value of this model for distant metastatic risk stratification (hazard ratio [HR], 4.17; 95% confidence interval [CI] 2.34-7.59; P < 0.001).

Conclusions: GTVnd and serum EBV DNA copy number are independent prognostic factors for predicting distant metastasis in NPC patients with N1 disease. The prognostic model incorporating GTVnd and EBV DNA copy number may improve metastatic risk stratification for this group of patients.
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http://dx.doi.org/10.1186/s40880-017-0264-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747160PMC
December 2017

Prognostic value of primary gross tumor volume and standardized uptake value of F-FDG in PET/CT for distant metastasis in locoregionally advanced nasopharyngeal carcinoma.

Tumour Biol 2017 Jul;39(7):1010428317717843

2 Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.

Distant metastasis has become the predominant model of treatment failures in patients with locoregionally advanced nasopharyngeal carcinoma. Effort should therefore be made to stratify locoregionally advanced nasopharyngeal carcinoma patients into different groups based on the risk of metastasis to improve prognosis and tailor individualized treatments. This study aims to assess the value of primary gross tumor volume and the maximum standardized uptake value for predicting distant metastasis-free survival of patients with locoregionally advanced nasopharyngeal carcinoma. A total of 294 locoregionally advanced nasopharyngeal carcinoma patients who were identified from prospectively maintained database and underwent fluor-18-fluorodeoxyglucose positron emission tomography/computed tomography imaging before treatment were included. The maximum standardized uptake value was recorded for the primary tumor (SUVmax-P) and neck lymph nodes (SUVmax-N). Computed tomography-derived primary gross tumor volume was measured using the summation-of-area technique. At 5 years, the distant metastasis-free survival rate was 83.7%. The cut-off of the SUVmax-P, SUVmax-N, and primary gross tumor volume for distant metastasis-free survival was 8.95, 5.75, and 31.3 mL, respectively, by receiver operating characteristic curve. In univariate analysis, only SUVmax-N (hazard ratio: 7.01; 95% confidence interval: 1.70-28.87; p < 0.01) and clinical stage (hazard ratio: 3.03; 95% confidence interval: 1.67-5.47; p = 0.007) were confirmed as independent predictors of distant metastasis-free survival. A prognostic model was derived by SUVmax-N and clinical stage: low risk (SUVmax-N < 5.75 regardless of clinical stage), medium risk (stage III and SUVmax-N ≥ 5.75), and high risk (stage IV and SUVmax-N ≥ 5.75). Multivariate analysis revealed that SUVmax-N and the prognostic model remained independent prognostic factors for distant metastasis-free survival (p = 0.023 and p < 0.001, respectively), but the clinical stage became insignificant (p = 0.133). Furthermore, the adjusted hazard ratios for the prognostic model were higher than SUVmax-N (hazard ratio = 6.27 vs 5.21, respectively). In summary, compared with SUVmax-P, SUVmax-N may be a better predictor of distant metastasis-free survival for patients with locoregionally advanced nasopharyngeal carcinoma. Combining SUVmax-N with clinical stage gives a more precise picture in predicting distant metastasis.
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http://dx.doi.org/10.1177/1010428317717843DOI Listing
July 2017

Prognostic value of serum Epstein-Barr virus antibodies in patients with nasopharyngeal carcinoma and undetectable pretreatment Epstein-Barr virus DNA.

Cancer Sci 2017 Aug 13;108(8):1640-1647. Epub 2017 Jul 13.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC). Serum IgA antibodies against early antigen (EA-IgA) and viral capsid antigen (VCA-IgA) are the most commonly used to screen for NPC in endemic areas. However, the prognostic value of serum EA-IgA and VCA-IgA in patients with NPC is less clear. We hypothesize that serum EA-IgA and VCA-IgA levels have prognostic impact for survival outcomes in NPC patients with undetectable pretreatment EBV (pEBV) DNA. In this series, 334 patients with non-metastatic NPC and undetectable pEBV DNA were included. Serum EA-IgA and VCA-IgA were determined by ELISA. After analysis, serum EA-IgA and VCA-IgA loads correlated positively with T, N, and overall stage (all P < 0.05). Serum EA-IgA was not associated with survival outcome in univariable analyses. But patients with serum VCA-IgA >1:120 had significantly inferior 5-year progression-free survival (80.4% vs 89.6%, P = 0.025), distant metastasis-free survival (88.4% vs 94.8%, P = 0.050), and locoregional relapse-free survival (88.4% vs 95.6%, P = 0.023; log-rank test). Multivariable analyses revealed that N stage was the only independent prognostic factor (all P < 0.05), but the VCA-IgA became insignificant. Further analyses revealed that serum VCA-IgA was not an independent prognostic factor in early N (N0-1) or advanced N (N2-3) stage NPC. In summary, although both EA-IgA and VCA-IgA correlate strongly with TNM stage, our analyses do not suggest that these antibodies are prognostic biomarkers in patients with NPC and undetectable pEBV DNA.
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http://dx.doi.org/10.1111/cas.13296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543490PMC
August 2017

The Effect of Adding Neoadjuvant Chemotherapy to Concurrent Chemoradiotherapy in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma and Undetectable Pretreatment Epstein-Barr Virus DNA.

Transl Oncol 2017 Aug 29;10(4):527-534. Epub 2017 May 29.

State Key Laboratory of Oncology in South, China; Collaborative Innovation Center of Cancer Medicine; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P.R. China. Electronic address:

Purpose: To assess the effect of adding neoadjuvant chemotherapy (NACT) to concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and undetectable pretreatment Epstein-Barr virus (pEBV) DNA.

Materials And Methods: We enrolled 639 NPC patients with stage II to IVB and undetectable pEBV DNA to receive CCRT with or without NACT. Radiotherapy was 2.0 to 2.27 Gy per fraction with five daily fractions per week for 6 to 7 weeks to the primary tumor and 62 to 70 Gy to the involved neck area. NACT was cisplatin (80-100 mg/mday 1) and 5-fluorouracil (800-1000 mg/m, 120-hour continuous intravenous infusion) every 3 weeks for two or three cycles. CCRT was cisplatin (80-100 mg/mday 1) every 3 weeks for three cycles.

Results: For all patients, the 5-year overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) rates were 91.9%, 92.2%, 95.0%, and 86.4%, respectively. There was no significant difference in OS (5-year OS 90.8% [NACT + CCRT group] vs 92.7% [CCRT alone]; hazard ratio [HR] 1.24; P=.486), LRFS (HR 1.13, 95% confidence interval [CI] 0.59-2.14, P=.715), DMFS (HR 0.78, 95% CI 0.34-1.78, P=.554), or PFS (HR 1.21, 95% CI 0.75-1.95, P=.472).

Conclusion: CCRT with or without NACT produced a good treatment outcome in patients with locoregionally advanced NPC and undetectable pEBV DNA, but NACT before CCRT did not significantly improve survival rates.
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http://dx.doi.org/10.1016/j.tranon.2017.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453864PMC
August 2017

Is pretreatment Epstein-Barr virus DNA still associated with 6-year survival outcomes in locoregionally advanced nasopharyngeal carcinoma?

J Cancer 2017 12;8(6):976-982. Epub 2017 Mar 12.

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, Guangdong Province, People's Republic of China.

The objective of this study was to confirm the association between pretreatment Epstein-Barr virus (EBV) DNA (pre-DNA) load and survival outcomes after long-term follow-up in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Between November 2009 and February 2012, a total of 1036 patients with LA-NPC were enrolled. There were 762 patients in stage III and 274 in stage IVA-B. All patients were treated with radical radiotherapy with or without chemotherapy, and pre-DNA concentrations were quantified by a polymerase chain reaction assay. Patient outcomes were evaluated. The 5-year overall survival (OS), distant metastasis-free surviva (DMFS), locoregional relapse-free survival (LRFS), and progression-free survival (PFS) rates were 84.7%, 87.0%, 90.2%, and 77.1%, respectively. By using previously defined pre-DNA cutoff value (1500 copies/ml pretreatment), pre-DNA was an independent prognostic predictor for OS, DMFS, and PFS using log-rank test. Multivariate Cox analysis also confirmed these results. Subgroup analysis indicated that the 5-year OS, DMFS, and PFS rates in patients staged IVA-B with pre-DNA < 1500 copies/ml were similar to those patients staged III with pre-DNA ≥ 1500 copies/ml, whereas patients staged IVA-B patients with pre-DNA ≥ 1500 copies/ml predicted worse outcome. In this expanded study, the prognostic significance of pre-DNA was confirmed using predefined cutoff value in an independent patient group, and pre-DNA was identified as an independent prognostic marker for the risk stratification in LA-NPC.
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http://dx.doi.org/10.7150/jca.18124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436249PMC
March 2017

Critical Evaluation of the Quality and Recommendations of Clinical Practice Guidelines for Nasopharyngeal Carcinoma.

J Natl Compr Canc Netw 2017 03;15(3):336-344

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine

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. 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. 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. 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.
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http://dx.doi.org/10.6004/jnccn.2017.0033DOI Listing
March 2017

Radiotherapy with neoadjuvant chemotherapy versus concurrent chemoradiotherapy for ascending-type nasopharyngeal carcinoma: a retrospective comparison of toxicity and prognosis.

Chin J Cancer 2017 Mar 6;36(1):26. Epub 2017 Mar 6.

Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China.

Background: In the era of intensity-modulated radiotherapy (IMRT), the role of neoadjuvant chemotherapy (NACT) in treating ascending-type nasopharyngeal carcinoma (NPC) is under-evaluated. This study was to compare the efficacy of NACT followed by IMRT (NACT + RT) with the efficacy of concurrent chemoradiotherapy (CCRT) on ascending-type NPC.

Methods: Clinical data of 214 patients with ascending-type NPC treated with NACT + RT or CCRT between December 2009 and July 2011 were analyzed. Of the 214 patients, 98 were treated with NACT followed by IMRT, and 116 were treated with CCRT. The survival rates were assessed using Kaplan-Meier analysis, and the survival curves were compared using a log-rank test.

Results: The 4-year overall survival, locoregional failure-free survival, distant failure-free survival, and failure-free survival rates were not significantly different between the two groups (all P > 0.05). However, patients in the CCRT group exhibited more severe acute adverse events than did patients in the NACT + RT group during radiotherapy, including leukopenia (30.2% vs. 15.3%, P = 0.016), neutropenia (25.9% vs. 11.2%, P = 0.011), and mucositis (57.8% vs. 40.8%, P = 0.028). After radiotherapy, patients in the CCRT group exhibited significantly higher rates of xerostomia (21.6% vs. 10.2%, P = 0.041) and hearing loss (17.2% vs. 6.1%, P = 0.023).

Conclusions: The treatment outcomes of the NACT + RT and CCRT groups were similar; however, CCRT led to higher rates of acute and late toxicities. NACT + RT may therefore be a better treatment strategy for ascending-type NPC.
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http://dx.doi.org/10.1186/s40880-017-0195-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338080PMC
March 2017

The Impact of Clinical Stage on Radiation Doses to Organs at Risk Following Intensity-modulated Radiotherapy in Nasopharyngeal Carcinoma: A Prospective Analysis.

J Cancer 2016 25;7(14):2157-2164. Epub 2016 Oct 25.

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, Guangdong Province, People's Republic of China.

The development of intensity-modulated radiotherapy (IMRT) has revolutionized the management of nasopharyngeal carcinoma (NPC). The purpose of this study was to investigate the impact of clinical stage on radiation doses to organs at risk (OARs) in NPC. One hundred and forty-eight patients with newly diagnosed and untreated NPC were prospectively enrolled. Based on the anatomic definition and pathogenesis of radiation induced injury, a total of 28 OARs surrounding the nasopharynx were contoured on axial computed tomography (CT) planning images in each patient. Dose-volume histograms, as well as the mean and maximal doses for each structure, were calculated. Radiation doses to 15 OARs (including the brain stem, temporal lobe and eye) were positively correlated with T stage, the radiation doses to 13 OARs (including the brachial plexus, parotid and thyroid) increased significantly with N stage, and the radiation doses to the spinal cord and mandible had no association with T or N stage. Based on the characteristic of excess rates, 9 OARs (e.g. spinal cord, eye, trachea, and .) met tolerance doses easily in all stages, 9 OARs (e.g. brain stem, temporal lobe, brachial plexus, and .) easily in early stages but with difficulty in advanced stages, and 10 OARs (e.g. cochlea, parotid, thyroid, and .) with difficulty in all stages. The radiation doses to most of OARs are associated with T or N stage, and there are three kinds of patterns for them: 1) meet tolerance doses easily in all stages; 2) meet tolerance doses easily in early stages but with difficulty in advanced stages; and 3) meet tolerance doses with difficulty in all stages.
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http://dx.doi.org/10.7150/jca.16476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118681PMC
October 2016

Neoadjuvant and Concurrent Chemotherapy Have Varied Impacts on the Prognosis of Patients with the Ascending and Descending Types of Nasopharyngeal Carcinoma Treated with Intensity-Modulated Radiotherapy.

PLoS One 2016 26;11(10):e0161878. Epub 2016 Oct 26.

Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou 510060, Guangdong Province, People's Republic of China.

Purpose: To compare the outcomes of patients with ascending type (T4&N0-1) and descending type (T1-2&N3) of nasopharyngeal carcinoma (NPC) treated with concurrent chemoradiotherapy (CCRT), neoadjuvant chemotherapy (NACT) + intensity-modulated radiotherapy (RT) or NACT + CCRT.

Methods: Retrospective analysis of 839 patients with ascending or descending types of NPC treated at a single institution between October 2009 to February 2012. CCRT was delivered to 236 patients, NACT + RT to 302 patients, and NACT + CCRT to 301 patients.

Results: The 4-year overall survival rate, distant metastasis-free survival rate, local relapse-free survival rate, nodal relapse-free survival rate, loco-regional relapse-free survival rate, and progression free survival rate were 75.2% and 73.4% (P = 0.114), 85.7% and 74.1% (P = 0.008), 88.8% and 97.1% (P = 0.013), 96.9% and 94.1% (P = 0.122), 86.9% and 91.2% (P = 0.384), 73.7% and 66.2% (P = 0.063) in ascending type and descending type. Subgroup analyses indicated that NACT + RT significantly improved distant metastasis-free survival rate and progression-free survival rate when compared with CCRT in the ascending type, and there were no significant differences between the survival curves of NACT +RT and NACT + CCRT. For descending type, there were no significant differences among the survival curves of NACT +RT, CCRT, and NACT + CCRT groups, and the survival benefit mainly came from CCRT.

Conclusions: Compared with NACT + CCRT or CCRT, NACT + RT may be a reasonable approach for ascending type. Although concurrent chemotherapy was effective in descending type, NACT + CCRT may be a more appropriate strategy for descending type.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161878PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082619PMC
June 2017

The efficacy and toxicity of individualized intensity-modulated radiotherapy based on the tumor extension patterns of nasopharyngeal carcinoma.

Oncotarget 2016 Apr;7(15):20680-90

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.

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.
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http://dx.doi.org/10.18632/oncotarget.8004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991484PMC
April 2016

A prospective study on radiation doses to organs at risk (OARs) during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients.

Oncotarget 2016 Apr;7(16):21742-52

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, Guangdong Province, People's Republic of China.

This study is to investigate the dose distribution of organs at risk (OARs) in cases of nasopharyngeal carcinoma (NPC). From July 2013 to October 2014, a prospective cohort study involving 148 patients was carried out at our center. OARs surrounding the nasopharynx were contoured on axial CT planning images in all patients. Dose-volume histograms of OARs and gross tumor volumes (GTV) were calculated. Multivariate analysis showed that radiation dose to OARs was associated with T stage and, especially, GTV. Seven OARs, including the spinal cord, eye and mandible, easily tolerated radiation doses in all patients; six OARs including the brain stem, chiasm and temporal lobe easily tolerated radiation doses in patients with a small GTV, but with difficulty when GTV was large; and other nine OARs including the parotid gland, cochlea and tympanic cavity met tolerance doses with difficulty in all patients. According to the patterns of radiation doses to OARs, it may help us to further reduce subsequent complications by improving the efficiency of plan optimization and evaluation.
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http://dx.doi.org/10.18632/oncotarget.7826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008319PMC
April 2016

Predictors of Mastoiditis after Intensity-Modulated Radiotherapy in Nasopharyngeal Carcinoma: A Dose-Volume Analysis.

J Cancer 2016 8;7(3):276-82. Epub 2016 Jan 8.

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, Guangdong Province, People's Republic of China.

Background: To identify predictors for development of mastoiditis after intensity-modulated radiation therapy (IMRT) in nasopharyngeal carcinoma (NPC).

Methods: Data for 146 NPC patients treated with IMRT was retrospectively reviewed under institutional ethics committee approval. Clinical factors associated with mastoiditis were analyzed. Dose-volume histogram analysis was performed for the Eustachian tube, tympanic cavity, mastoid air cells, cochlea, internal auditory canal and vestibular apparatus to relate doses to radiographic changes in the mastoid. Mastoiditis was assessed using magnetic resonance imaging and was classified as Grade 0 (none), 1 (mild), 2 (moderate) or 3 (severe); Grade 3 mastoiditis was the study end-point.

Results: Eighty-eight ears (36%) had radiation-induced mastoiditis: 38/244 (15.6%) mastoid complexes had Grade 1-2 mastoiditis and 50/244 (20.5%) mastoid complexes had Grade 3 mastoiditis. Multivariate analysis revealed a mastoid mean dose > 35.93 Gy (odds ratio [OR]=4.22, P=.003), Eustachian tube mean dose > 53.43 Gy (OR=2.16, P=.034) and advanced T category (T3 and T4; OR=10.33, P=.032) were negative prognostic factors for Grade 3 mastoiditis.

Conclusions: Radiation-induced mastoiditis remains a common late toxicity in NPC after radiotherapy. The mean dose to the mastoid air cells and Eustachian tube should be limited to reduce the risk of radiation-induced mastoiditis.
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http://dx.doi.org/10.7150/jca.13183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747881PMC
February 2016

Dose-volume factors associated with ear disorders following intensity modulated radiotherapy in nasopharyngeal carcinoma.

Sci Rep 2015 Sep 1;5:13525. Epub 2015 Sep 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, Guangdong Province, People's Republic of China.

This study is to identify significant dosimetric parameters for ear disorders in nasopharyngeal carcinoma (NPC) patients treated with intensity modulated therapy only. Ninety-seven patients with NPC were retrospectively reviewed. Organs at risk (OARs) in the auditory apparatus were contoured. Dose-volume histogram parameters were generated for the Eustachian tube (ET), tympanic cavity (TC), mastoid air cells, vestibular apparatus, cochlea and internal auditory canal (IAC). Ear disorders were rated 0 (none), 1 (mild) or 2 (severe) by a clinician blinded to radiation doses; Grade 2 ear disorders was the study end-point. Multivariate analysis revealed ET.D30 (dose to 30% of ET volume) >52.75 Gy and M.D0.5CC (dose to 0.5 ml of mastoid volume) >41.04 Gy (OR = 3.77, P = 0.012 and OR = 1.27, P = 0.033, respectively) were associated with Grade 2 ear disorders. Our results demonstrated that post-irradiation ear disorders remain a common late toxicity in NPC after IMRT. ET.D30 and M.D0.5CC should be considered during IMRT treatment plan optimization, review and approval.
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http://dx.doi.org/10.1038/srep13525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642560PMC
September 2015
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