Refining the 8th edition TNM classification for EBV related nasopharyngeal carcinoma.

The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles.

Perioperative Nursing Informatics Relevant Data Standard Research in the Context of Medical Big Data: Improving Patients? Health Behavior.

Objectives: Our objective was to determine the progress of perioperative nursing informatics relevant data standard research in the context of medical big data. We also determine the moderating impact of big data in healthcare between standard data and perioperative nursing informatics. Methods: We used Smart PLS for structual equation modeling and reviewed some recent literature and briefly discussed the progress on perioperative nursing standardized data in five aspects. Results: Our findings demonstrate that the direct impact of standard data and big data in healthcare is positively confirmed on perioperative nursing informatics. The moderating impact of big data in healthcare between standard data and perioperative nursing informatics is also confirmed. Conclusions: Our model is novel in the literature. Big data can be used by the healthcare system to the advanced level for patient record-keeping according to their health behavior and improving the methods of treatment.

Construction of refined staging classification systems integrating FIGO/T-categories and corpus uterine invasion for non-metastatic cervical cancer.

BACKGROUND: To investigate the prognostic value of corpus uterine invasion (CUI) in cervical cancer (CC), and determine the necessity to incorporate it for staging. METHODS: A total of 809 cases of biopsy-proven, non-metastatic CC were identified from an academic cancer center. Recursive partitioning analysis (RPA) method was used to develop the refined staging systems with respect to overall survival (OS). Internal validation was performed by using calibration curve with 1000 bootstrap resampling. Performances of the RPA-refined stages were compared against the conventional FIGO 2018 and 9th edition TNM-stage classifications by the receiver operating characteristic curve (ROC) and decision curve analysis (DCA). RESULTS: We identified that CUI was independently prognostic for death and relapse in our cohort. RPA modeling using a two-tiered stratification by CUI (positive and negative) and FIGO/T-categories divided CC into three risk groupings (FIGO I'-III'/T1'-3'), with 5-year OS of 90.8%, 82.1%, and 68.5% for proposed FIGO stage I'-III', respectively (p ≤ 0.003 for all pairwise comparisons), and 89.7%, 78.8%, and 68.0% for proposed T1'-3', respectively (p < 0.001 for all pairwise comparisons). The RPA-refined staging systems were well validated with RPA-predicted OS rates showed optimal agreement with actual observed survivals. Additionally, the RPA-refined stages outperformed the conventional FIGO/TNM-stage with significantly higher accuracy of survival prediction (AUC: RPA-FIGO vs. FIGO, 0.663 [95% CI 0.629-0.695] vs. 0.638 [0.604-0.671], p = 0.047; RPA-T vs. T, 0.661 [0.627-0.694] vs. 0.627 [0.592-0.660], p = 0.036). CONCLUSION: CUI affects the survival outcomes in patients with CC. Disease extended to corpus uterine should be classified as stage III/T3.

Clinical utility of pretreatment serum squamous cell carcinoma antigen for prognostication and decision-making in patients with early-stage cervical cancer.

Background: To investigate the prognostic role of pretreatment squamous cell carcinoma antigen (SCCA) in early-stage cervical cancer (CC). Methods: We enrolled 487 cases of pathology-proven early-stage [International Federation of Gynecology and Obstetrics (FIGO) I/II] squamous or adenosquamous CC that were treated from 2012 to 2015. Restricted cubic splines (RCS) with a full Cox regression model were used to evaluate the association between SCCA levels and survival outcomes. Recursive partitioning analysis (RPA) was used to construct a risk stratification model for overall survival (OS). The performance of the RPA-based model was assessed using a receiver operating characteristic (ROC) curve. Results: RCS analysis revealed an association between SCCA and OS and disease-free survival (DFS); SCCA ⩾2.5 ng/mL was robust for risk discrimination in our cohort. SCCA had an interaction effect with FIGO classification: Patients with FIGO I and SCCA ⩾2.5 ng/mL overlapped with those with FIGO II and SCCA < 2.5 ng/mL for OS [hazard ratio, 1.04 (95% confidence interval (CI): 0.49-2.24), p = 0.903] and DFS [1.05 (0.56-1.98), p = 0.876]. RPA modeling incorporating SCCA (<2.5 ng/mL and ⩾2.5 ng/mL) and FIGO classification divided CC into three prognostic groups: RPA I, FIGO stage I, and SCCA < 2.5 ng/mL; RPA II, FIGO stage I, and SCCA ⩾ 2.5 ng/mL, or FIGO stage II and SCCA < 2.5 ng/mL; and RPA III, FIGO stage II, and SCCA ⩾ 2.5 ng/mL; with 5-year OS of 94.0%, 85.1%, and 73.5%, respectively (p < 0.001). ROC analysis confirmed that the RPA model outperformed the FIGO 2018 stage with significantly improved accuracy for survival prediction [area under the curve: RPA versus FIGO, 0.663 (95% CI: 0.619-0.705] versus 0.621 (0.576-0.664), p = 0.045]. Importantly, the RPA groupings were associated with the efficacy of treatment regimens. Surgery followed by adjuvant treatment had a higher OS (p < 0.01) and DFS (p = 0.024) than other treatments for RPA III, whereas outcomes were comparable among treatment regimens for RPA I-II. Conclusion: Herein, the role of SCCA for prognostication was confirmed, and a robust clinicomolecular risk stratification system that outperforms conventional FIGO classification in early-stage squamous and adenosquamous CC was presented. The model correlated with the efficacy of different treatment regimes.

Long-Term Evaluation and Normal Tissue Complication Probability (NTCP) Models for Predicting Radiation-Induced Optic Neuropathy after Intensity-Modulated Radiation Therapy (IMRT) for Nasopharyngeal Carcinoma: A Large Retrospective Study in China.

PURPOSE: To quantify the long-term evaluation of optic chiasma (OC) and/or optic nerve(s) (ONs) and to develop predictive models for radiation-induced optic neuropathy (RION) in nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: A total of 3,662 patients' OC/ONs with full visual acuity and dosimetry data between 2010 and 2015 were identified. Critical dosimetry predictors of RION were chosen by machine learning and penalized regression for survival. A nomogram containing dosimetry and clinical variables was generated for predicting RION-free survival. RESULTS: The median follow-up was 71.79 (2.63-120.9) months. Sixty-six eyes in 51 patients (1.39%) developed RION. Two patients were visual field deficient, and 49 patients had visual acuity of less than 0.1 (20/200). The median latency time was 36 (3-90) months. The 3-, 5-, and 8-year cumulative incidence of RION was 0.78%, 1.19%, and 1.97%, respectively. Dmax was the most critical dosimetry variable for RION (AUC: 0.9434, the optimal cutoff: 64.48 Gy). Patients with a Dmax ≥64.48 Gy had a significantly higher risk of RION (HR = 102.25; 95%CI, 24.86-420.59; P < 0.001). Age (>44 years) (HR = 2.234, 95% CI = 1.233-4.051, p = 0.008), advanced T stage (T3 vs. T1-2: HR = 7.516, 95% CI = 1.725-32.767, p=0.007; T4 vs. T1-2: HR = 37.189, 95% CI = 8.796-157.266, P < 0.001), and tumor infiltration/compression of the OC/ONs (HR = 4.572, 95% CI = 1.316-15.874, p=0.017) were significant clinical risk factors of RION. A nomogram comprising age, T stage, tumor infiltration/compression of the OC/ON, and Dmax significantly outperformed the model, with only Dmax predicting RION (C-index: 0.916 vs. 0.880, P < 0.001 in the training set; 0.899 vs. 0.874, P=0.038 in the test set). The nomogram-defined high-risk group had a worse 8-year RION-free survival. CONCLUSIONS: In the IMRT era, Dmax <60 Gy is safe and represents an acceptable dose constraint for most NPC patients receiving IMRT. A reasonable trade-off for selected patients with unsatisfactory tumor coverage due to proximity to the optic apparatus would be Dmax <65 Gy. Caution should be exercised when treating elderly and advanced T-stage patients or those with tumor infiltration/compression of the OC/ON. Our nomogram shows strong efficacy in predicting RION.

Development of a risk classification system combining TN-categories and circulating EBV DNA for non-metastatic NPC in 10,149 endemic cases.

BACKGROUND: The objective of this study was to construct a risk classification system integrating cell-free Epstein-Barr virus (cfEBV) DNA with T- and N- categories for better prognostication in nasopharyngeal carcinoma (NPC). METHODS: Clinical records of 10,149 biopsy-proven, non-metastatic NPC were identified from two cancer centers; this comprised a training (N = 9,259) and two validation cohorts (N = 890; including one randomized controlled phase 3 trial cohort). Adjusted hazard ratio (AHR) method using a two-tiered stratification by cfEBV DNA and TN-categories was applied to generate the risk model. Primary clinical endpoint was overall survival (OS). Performances of the models were compared against American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) 8th edition TNM-stage classification and two published recursive partitioning analysis (RPA) models, and were validated in the validation cohorts. RESULTS: We chose a cfEBV DNA cutoff of ⩾2,000 copies for optimal risk discretization of OS, disease-free survival (DFS) and distant metastasis-free survival (DMFS) in the training cohort. AHR modeling method divided NPC into six risk groups with significantly disparate survival (p < 0.001 for all): AHR1, T1N0; AHR2A, T1N1/T2-3N0 cfEBV DNA < 2,000 (EBVlow); AHR2B, T1N1/T2-3N0 cfEBV DNA ⩾ 2,000 (EBVhigh) and T1-2N2/T2-3N1 EBVlow; AHR3, T1-2N2/T2-3N1 EBVhigh and T3N2/T4N0 EBVlow; AHR4, T3N2/T4 N0-1 EBVhigh and T1-3N3/T4N1-3 EBVlow; AHR5, T1-3N3/T4 N2-3 EBVhigh. Our AHR model outperformed the published RPA models and TNM stage with better hazard consistency (1.35 versus 3.98-12.67), hazard discrimination (5.29 versus 6.69-13.35), explained variation (0.248 versus 0.164-0.225), balance (0.385 versus 0.438-0.749) and C-index (0.707 versus 0.662-0.700). In addition, our AHR model was superior to the TNM stage for risk stratification of OS in two validation cohorts (p < 0.001 for both). CONCLUSION: Herein, we developed and validated a risk classification system that combines the AJCC/UICC 8th edition TN-stage classification and cfEBV DNA for non-metastatic NPC. Our new clinicomolecular model provides improved OS prediction over the current staging system.

Liquid biopsy posttreatment surveillance in endemic nasopharyngeal carcinoma: a cost-effective strategy to integrate circulating cell-free Epstein-Barr virus DNA.

BACKGROUND: The optimal posttreatment surveillance strategy for nasopharyngeal carcinoma (NPC) remains unclear. Circulating cell-free Epstein-Barr virus (cfEBV) DNA has been recognized as a promising biomarker to facilitate early detection of NPC recurrence. Therefore, we aim to determine whether integrating circulating cfEBV DNA into NPC follow-up is cost-effective. METHODS: For each stage of asymptomatic nonmetastatic NPC patients after complete remission to primary NPC treatment, we developed a Markov model to compare the cost-effectiveness of the following surveillance strategies: routine follow-up strategy, i.e., (1) routine clinical physical examination; routine imaging strategies, including (2) routine magnetic resonance imaging plus computed tomography plus bone scintigraphy (MRI + CT + BS); and (3) routine 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT); cfEBV DNA-guided imaging strategies, including (4) cfEBV DNA-guided MRI + CT + BS and (5) cfEBV DNA-guided PET/CT. Clinical probabilities, utilities, and costs were derived from published studies or databases. Sensitivity analyses were performed. RESULTS: For all disease stages, cfEBV DNA-guided imaging strategies demonstrated similar survival benefits but were considerably more economical than routine imaging strategies. They only required approximately one quarter of the number of imaging studies compared with routine imaging strategies to detect one recurrence. Specifically, cfEBV DNA-guided MRI + CT + BS was most cost-effective for stage II (incremental cost-effectiveness ratio [ICER] $57,308/quality-adjusted life-year [QALY]) and stage III ($46,860/QALY) patients, while cfEBV DNA-guided PET/CT was most cost-effective for stage IV patients ($62,269/QALY). However, routine follow-up was adequate for stage I patients due to their low recurrence risk. CONCLUSIONS: The cfEBV DNA-guided imaging strategies are effective and cost-effective follow-up methods in NPC. These liquid biopsy-based strategies offer evidence-based, stage-specific surveillance modalities for clinicians and reduce disease burden for patients.

Circulating Epstein-Barr virus DNA level post induction chemotherapy contributes to prognostication in advanced-stage nasopharyngeal carcinoma.

BACKGROUND: To investigate the value of post-induction chemotherapy (IC) cell-free Epstein-Barr virus DNA (cfEBV DNApostIC) for prognostication in locally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: A total of 910 histologically proven LA-NPC undergoing radical IC + concurrent chemo-radiotherapy (CCRT) or targeted radiotherapy (CTRT) or both (CTCRT) were involved. The concentration of cfEBV DNA was measured by quantitative polymerase chain reaction pre-IC (cfEBV DNApreIC) and at IC completion. CfEBV DNApostIC was classified as undetectable (0 copy/ml) and detectable (>0 copy/ml). Recursive partitioning analysis (RPA) with respect to the overall survival (OS) was applied to construct a risk stratification system incorporating cfEBV DNApostIC and critical risk factors. RESULTS: We observed that 660 (72.5%) and 250 (27.5%) patients had cfEBV DNApostIC undetectable and detectable respectively. CfEBV DNApostIC positive was associated with a significant inferior 5-year OS (76.2% versus 85.9%), metastasis-free survival (DMFS, 71.7% versus 86.4%) and disease-free survival (DFS, 57.7% versus 80.1%) than cfEBV DNApostIC negative (P < 0.001 for all). Additionally, cfEBV DNApostIC was independently significant for OS (hazard ratio [HR] 1.90, 95% CI 1.40-2.59), DMFS (1.99, 1.45-2.71) and DFS (2.38, 1.86-3.06) in multivariate analyses (P < 0.001 for all). RPA modelling yielded three distinct risk groups: low-risk (N0-1 and undetectable cfEBV DNApostIC or N2-3 and pre-treatment cfEBV DNA [cfEBV DNApreIC] <7000), median-risk (N0-1 and detectable cfEBV DNApostIC or N2-3 and cfEBV DNApreIC ≥7000 with undetectable cfEBV DNApostIC) and high-risk (N2-3 and cfEBV DNApreIC ≥7000 with detectable cfEBV DNApostIC), with 5-year OS of 88.1%, 79.2% and 66.9%, respectively. Our risk stratification outperformed TNM classification for predicting death (AUC, 0.631 versus 0.562; P = 0.012) and distant metastasis (0.659 versus 0.562; P = 0.004). CONCLUSIONS: CfEBV DNApostIC represents an effective indicator of prognostication in LA-NPC. We developed a risk classification system that provides improved OS prediction over the current staging system by combining cfEBV DNApostIC, cfEBV DNApreIC and N-stage classification in LA-NPC.

Normal tissue complication probability (NTCP) models for predicting temporal lobe injury after intensity-modulated radiotherapy in nasopharyngeal carcinoma: A large registry-based retrospective study from China.

PURPOSE: To develop predictive models with dosimetric and clinical variables for temporal lobe injury (TLI) in nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Data of 8194 NPC patients who received IMRT-based treatment were retrospectively reviewed. TLI was diagnosed by magnetic resonance imaging. Dosimetric factors were selected by penalized regression and machine learning, with area under the receiver operating curve (AUC) calculated. Cox proportional hazards models containing the most predictive dosimetric factor with/without clinical variables were performed. A nomogram was generated as a visualization of Cox regression for predicting TLI-free survival. RESULTS: During median follow-up of 66.8 months (interquartile range [IQR] 54.2-82.2 months), 12.1% of patients (989/8194) developed TLI. Median latency from IMRT to TLI was 36 months (IQR 28-47 months). D0.5cc (dose delivered to 0.5-cm3 temporal-lobe volume) was the most predictive dosimetric factor (AUC: 0.799). Tolerance dose for 5% and 50% probabilities to develop TLI in 5 years were 65.06 Gy (95% confidence interval [CI]: 64.19-65.92) and 89.75 Gy (95% CI: 87.39-92.11), respectively. A nomogram comprising age, T stage, and D0.5cc significantly outperformed the model with only D0.5cc in predicting TLI (C-index: 0.78 vs. 0.737 in train set; 0.775 vs. 0.73 in test set; both P < 0.001). The nomogram-defined high-risk group had worse 5-year TLI-free survival. CONCLUSIONS: D0.5cc of 65.06 Gy was the tolerance dose of the temporal lobe. Reducing D0.5cc decreased risk of TLI, especially in older patients with advanced T stage. The nomogram could predict TLI precisely and allow individualized follow-up management.

Prognostic value of radiation interruption in different periods for nasopharyngeal carcinoma patients in the intensity-modulated radiation therapy era.

We aimed to investigate the prognostic value of radiation interruptions at different times on the overall survival (OS) and disease-free survival (DFS) of patients with nasopharyngeal carcinoma receiving intensity-modulated radiation therapy. Totally, 4510 patients were identified from a well-established big-data intelligence platform. Optimal interruption thresholds were identified using Recursive partitioning analyses. Actuarial rates were plotted using the Kaplan-Meier method and were compared using the log-rank test. Patients with preceding interruptions ≥1 d (5-year OS, 89.6% vs. 85.7%, p < 0.001; 5-year DFS, 81.4% vs. 76.4%, p < 0.001), or latter interruptions ≥4 d (88.4% vs. 82.3%, p < 0.001; 79.2% vs. 75.1%, p = 0.006) showed significant detrimental effects on OS and DFS than patients without those interruptions. However, no significant lower survival was identified in latter interruptions ≥1 d (5-year OS: 89.0% vs. 86.7%, p = 0.053; 5-year DFS, 80.2% vs. 77.8%, p = 0.080). Latter interruptions ≥4 d was an independent unfavorable prognostic factor for OS (HR, 1.404; 95% CI, 1.143-1.723, p = 0.001) and DFS (HR, 1.351; 95% CI, 1.105-1.652, p = 0.003) in multivariate analysis. Radiation interruptions longer than 3 days that occurred in the latter period of treatment with IMRT were independent factors in poorer survival. Efforts are needed to minimize radiation interruptions and improve the timely provision of treatment.

Development and validation of a web-based calculator to predict individualized conditional risk of site-specific recurrence in nasopharyngeal carcinoma: Analysis of 10,058 endemic cases.

BACKGROUND: Conditional survival (CS) provides dynamic prognostic estimates by considering the patients existing survival time. Since CS for endemic nasopharyngeal carcinoma (NPC) is lacking, we aimed to assess the CS of endemic NPC and establish a web-based calculator to predict individualized, conditional site-specific recurrence risk. METHODS: Using an NPC-specific database with a big-data intelligence platform, 10,058 endemic patients with non-metastatic stage I-IVA NPC receiving intensity-modulated radiotherapy with or without chemotherapy between April 2009 and December 2015 were investigated. Crude CS estimates of conditional overall survival (COS), conditional disease-free survival (CDFS), conditional locoregional relapse-free survival (CLRRFS), conditional distant metastasis-free survival (CDMFS), and conditional NPC-specific survival (CNPC-SS) were calculated. Covariate-adjusted CS estimates were generated using inverse probability weighting. A prediction model was established using competing risk models and was externally validated with an independent, non-metastatic stage I-IVA NPC cohort undergoing intensity-modulated radiotherapy with or without chemotherapy (n = 601) at another institution. RESULTS: The median follow-up of the primary cohort was 67.2 months. The 5-year COS, CDFS, CLRRFS, CDMFS, and CNPC-SS increased from 86.2%, 78.1%, 89.8%, 87.3%, and 87.6% at diagnosis to 87.3%, 87.7%, 94.4%, 96.0%, and 90.1%, respectively, for an existing survival time of 3 years since diagnosis. Differences in CS estimates between prognostic factor subgroups of each endpoint were noticeable at diagnosis but diminished with time, whereas an ever-increasing disparity in CS between different age subgroups was observed over time. Notably, the prognoses of patients that were poor at diagnosis improved greatly as patients survived longer. For individualized CS predictions, we developed a web-based model to estimate the conditional risk of local (C-index, 0.656), regional (0.667), bone (0.742), lung (0.681), and liver (0.711) recurrence, which significantly outperformed the current staging system (P < 0.001). The performance of this web-based model was further validated using an external validation cohort (median follow-up, 61.3 months), with C-indices of 0.672, 0.736, 0.754, 0.663, and 0.721, respectively. CONCLUSIONS: We characterized the CS of endemic NPC in the largest cohort to date. Moreover, we established a web-based calculator to predict the CS of site-specific recurrence, which may help to tailor individualized, risk-based, time-adapted follow-up strategies.

Role of Postoperative Radiotherapy in Nonmetastatic Head and Neck Adenoid Cystic Carcinoma.

BACKGROUND: Head and neck adenoid cystic carcinoma (ACC) is a rare malignant tumor that is prone to local recurrence. The NCCN Guidelines for Head and Neck Cancers recommend that all patients with ACC receive postoperative radiotherapy (PORT). However, whether PORT can improve local control and which patients can benefit from PORT are unknown. This study aimed to assess the role of PORT and provide individualized suggestions for postoperative therapy in patients with ACC. PATIENTS AND METHODS: We retrospectively reviewed patients with nonmetastatic head and neck ACC who underwent surgery with or without PORT. Recursive partitioning analysis (RPA) was performed to categorize the patients and predict local recurrence-free survival (LRFS). The survival outcome was compared between non-PORT and PORT groups. RESULTS: A total of 319 patients were included. PORT was identified as a prognostic factor for LRFS in univariate (P=.01) and multivariate analysis (P<.01). However, it did not improve distant metastasis-free survival, disease-free survival, or overall survival in univariate analysis. RPA categorized patients into 3 prognostic groups: low-risk (negative margin, T1-T2, primary location = major or minor salivary gland), intermediate-risk (negative margin, T1-T2, primary location = other locations instead of a major or minor salivary gland; negative margin, T3-T4; positive margin, without bone invasion), and high-risk (positive margin, with bone invasion). Significant LRFS improvements in the PORT group were observed among intermediate-risk (P<.01) and high-risk patients (P<.05). LRFS improvements among low-risk patients were relatively insignificant (P=.10). CONCLUSIONS: PORT was shown to be a positive prognostic factor for improved LRFS in ACC. Furthermore, PORT could significantly improve LRFS in intermediate-risk and high-risk patients with ACC, but whether low-risk patients could benefit from PORT needs further study.

Clinical Characteristics and Prognostic Factors of Early and Late Recurrence After Definitive Radiotherapy for Nasopharyngeal Carcinoma.

We investigated the clinical characteristics, prognostic factors, and post-recurrence prognostic factors of early- and late-recurrence patients for nasopharyngeal carcinoma (NPC) after definitive intensity-modulated radiation therapy (IMRT). This was a single-center retrospective analysis of patients in China from January 2010 to December 2015. The prognostic factors for overall survival (OS) and post-recurrence OS of early- and late-recurrence patients were identified using univariate and multivariate Cox regression analyses. Of the 9,468 patients included, 409 (4.3%), 325 (3.4%), and 182(1.9%) developed purely local recurrence, purely regional recurrence, and locoregional recurrence during follow-up, respectively. In the purely local recurrence group, 192 patients (46.9%) developed early local recurrence (ETR), and 217 patients (53.1%) developed late local recurrence (LTR). Of the 192 ETR patients, multivariate Cox regression analysis revealed that age and gender were independent risk factors of OS, and post-recurrence best supportive treatment (PRBST) was associated with poorer post-recurrence OS. Of the 217 LTR patients, the results revealed that baseline value of EBV-DNA was an independent risk factor for OS, while PRBST was associated with poorer post-recurrence OS. In the purely regional recurrence group, 183 patients (56.3%) developed early regional recurrence (ENR), and 142 patients (43.7%) developed late regional recurrence (LNR). Of the 183 ENR patients, multivariate Cox regression analysis revealed that alcohol abuse and TNM stage were independent risk factors of OS, while alcohol drinkers and PRBST were associated with poorer post-recurrence OS. Of the 142 LNR patients, PRBST was associated with poorer post-recurrence OS. In the locoregional recurrence group, 87 patients (47.8%) developed early locoregional recurrence (ELR), and 95 patients (52.2%) developed late locoregional recurrence (LLR). Of the 87 ELR patients, multivariate Cox regression analysis revealed that N stage and TNM stage were independent risk factors of OS, and N2/3 stage and PRBST were associated with poorer post-recurrence OS. Of the 95 LLR patients, the results revealed that T stage was an independent risk factor for OS, while T3/4 stage and PRBST were associated with poorer post-recurrence OS. Patients with LTR/LNR/LLR demonstrate significantly better OS compared with patients with ETR/ENR/ELR, Nevertheless, post-recurrence OS between patients with ETR/ENR/ELR and LTR/LNR/LLR was not significantly different.

An optimal posttreatment surveillance strategy for cancer survivors based on an individualized risk-based approach.

The optimal post-treatment surveillance strategy that can detect early recurrence of a cancer within limited visits remains unexplored. Here we adopt nasopharyngeal carcinoma as the study model to establish an approach to surveillance that balances the effectiveness of disease detection versus costs. A total of 7,043 newly-diagnosed patients are grouped according to a clinic-molecular risk grouping system. We use a random survival forest model to simulate the monthly probability of disease recurrence, and thereby establish risk-based surveillance arrangements that can maximize the efficacy of recurrence detection per visit. Markov decision-analytic models further validate that the risk-based surveillance outperforms the control strategies and is the most cost-effective. These results are confirmed in an external validation cohort. Finally, we recommend the risk-based surveillance arrangement which requires 10, 11, 13 and 14 visits for group I to IV. Our surveillance strategies might pave the way for individualized and economic surveillance for cancer survivors.

Individualized cumulative cisplatin dose for locoregionally-advanced nasopharyngeal carcinoma patients receiving induction chemotherapy and concurrent chemoradiotherapy.

OBJECTIVES: To screen subgroup potentially benefiting from cumulative cisplatin dose (CCD) ≥ 200 mg/m2 during concurrent chemoradiotherapy (CCRT) of patients with locoregionally-advanced nasopharyngeal carcinoma (LA-NPC) receiving induction chemotherapy (IC) and CCRT. MATERIALS AND METHODS: In total, 2 063 patients with non-disseminated LA-NPC diagnosed from 2009 to 2015 receiving IC plus CCRT were enrolled. Patients were restaged based on proposed stage groupings and risk groupings was established. After propensity score matching, survival outcomes were compared within different risk groupings with 200 mg/m2 CCD. Post-IC gross primary tumor (GTVp) and lymph node (GTVnd) volumes were calculated from planning computed tomography. The role of risk groupings and post-IC tumor volume to CCD was explored. RESULTS: Compared with the low-risk group, the high-risk group showed poor survival outcomes in terms of 5-year progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS). CCD ≥ 200 mg/m2 improved survival in terms of 5-year PFS, OS and DMFS in the high-risk group but not in the low-risk group. High-risk patients with unfavorable response to IC benefited from CCD ≥ 200 mg/m2 with respect to PFS and DMFS; while those in low-risk group or with favorable response to IC didn't. CONCLUSIONS: Risk groupings was effective for risk stratification. Combining risk groupings and post-IC tumor volume is a simple and useful method to guide individualized CCD treatment of CCRT for patients with LA-NPC receiving IC and CCRT. CCD ≥ 200 mg/m2 may be indicated for high-risk patients with unfavorable response to IC.

Prognostic potential of liquid biopsy tracking in the posttreatment surveillance of patients with nonmetastatic nasopharyngeal carcinoma.

BACKGROUND: The current study was performed to investigate whether circulating cell-free Epstein-Barr virus DNA (cfEBV DNA) would be useful for posttreatment surveillance in patients with nasopharyngeal carcinoma (NPC). METHODS: The authors identified a total of 1984 nondisseminated NPC patients from an institutional big-data research platform. Blood samples were collected within 3 months of the completion of radiotherapy and every 3 to 12 months thereafter for cfEBV DNA analysis. Patients were followed until disease recurrence was detected or for a median of 60 months. Diagnostic performance was assessed by calculating the sensitivity, specificity, and accuracy based on the clinical detection of disease recurrence by conventional surveillance modalities (imaging scans and pathological examination). RESULTS: During follow-up, a total of 767 patients (38.7%) had detectable cfEBV DNA. The recurrence rate among these patients was 63.8% (489 of 767 patients), which was significantly higher than that in patients with undetectable cfEBV DNA (8.6%; 105 of 1217 patients). cfEBV DNA sensitivity, specificity, and accuracy were 68.8%, 80.0%, and 78.2%, respectively, for local recurrence; 80.2%, 80.0%, and 85.9%, respectively, for regional recurrence; and 91.1%, 80.0%, and 92.8%, respectively, for distant metastasis. cfEBV DNA was found to have higher sensitivity for the detection of extrapulmonary metastases (94.9%-96.5%) compared with pulmonary metastases (78.4%). It is interesting to note that among the patients with disease recurrence with detectable cfEBV DNA, positive cfEBV DNA results preceded radiological and/or clinical evidence of disease recurrence by a median of 2.3 months (interquartile range, 0.1-9.5 months). In addition, of the 278 cfEBV DNA-positive patients who did not develop disease recurrence, 227 (81.7%) had transiently positive cfEBV DNA that fell to undetectable levels during long-term monitoring. CONCLUSIONS: Plasma cfEBV DNA in patients with NPC appears to be an early sign of tumor recurrence, especially extrapulmonary metastases.

Establishing M1 stage subdivisions by incorporating radiological features and Epstein-Barr virus DNA for metastatic nasopharyngeal carcinoma.

BACKGROUND: Significance of plasma Epstein-Barr virus deoxyribonucleic acid (EBV DNA)-a proven robust indicator for nasopharyngeal carcinoma (NPC)-is not yet clarified in risk stratification of metastatic NPC (mNPC). We aim to establish effective M1 stage subdivisions in mNPC by integrating radiological features and EBV DNA at diagnosis of metastasis (mEBV DNA). METHODS: The study comprised 1,007 mNPC patients, including 817 metachronous mNPC (mmNPC) patients randomized into training (n=613) and internal validation (n=204) cohorts, and 190 synchronous mNPC (smNPC) patients defined as smNPC validation cohort. Primary clinical end-point was overall survival (OS). Covariate inclusion to recursive partitioning analysis (RPA)-generated risk stratification was qualified by a multivariable two-sided P<0.05. Performances of different models were compared using area under ROC curve (AUC), Harrell's concordance index (c-index) and Akaike information criterion (AIC). RESULTS: Compared with other simply image-based models, the ultimate RPA-EBV-stage presented a best performance [c-index =0.68 (training), 0.70 (internal validation), 0.64 (smNPC validation); AUC =0.69 (training), 0.72 (internal validation), 0.70 (smNPC validation)]: M1a (low mEBV DNA + oligo lesion), M1b (low mEBV DNA + multiple lesions), M1c (high mEBV DNA + no liver involvement), and M1d (high mEBV DNA + liver involvement). Corresponding 3-year OS rates were 49.9%, 33.4%, 22.6%, and 6.7%, respectively (P<0.001). In mmNPC patients, compared with chemotherapy alone, addition of local treatment demonstrated superiority in M1a and M1b; systemic therapy combined with targeted therapy conferred benefit on patients of M1c and M1d (P<0.05). CONCLUSIONS: This RPA-EBV-stage provided favorable prognostic value for survival outcomes and could assist clinical and investigative management. Low-risk patients are considered suitable candidate for curative local treatment, and high-risk patients are recommended to undergo intensive systemic treatment.

Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment.

Alternative splicing (AS) has emerged as a key event in tumor development and microenvironment formation. However, comprehensive analysis of AS and its clinical significance in head and neck squamous cell carcinoma (HNSC) is urgently required. Methods: Genome-wide profiling of AS events using RNA-Seq data from The Cancer Genome Atlas (TCGA) program was performed in a cohort of 464 patients with HNSC. Cancer-associated AS events (CASEs) were identified between paired HNSC and adjacent normal tissues and evaluated in functional enrichment analysis. Splicing networks and prognostic models were constructed using bioinformatics tools. Unsupervised clustering of the CASEs identified was conducted and associations with clinical, molecular and immune features were analyzed. Results: We detected a total of 32,309 AS events and identified 473 CASEs in HNSC; among these, 91 were validated in an independent cohort (n = 15). Functional protein domains were frequently altered, especially by CASEs affecting cancer drivers, such as PCSK5. CASE parent genes were significantly enriched in pathways related to HNSC and the tumor immune microenvironment, such as the viral carcinogenesis (FDR < 0.001), Human Papillomavirus infection (FDR < 0.001), chemokine (FDR < 0.001) and T cell receptor (FDR < 0.001) signaling pathways. CASEs enriched in immune-related pathways were closely associated with immune cell infiltration and cytolytic activity. AS regulatory networks suggested a significant association between splicing factor (SF) expression and CASEs and might be regulated by SF methylation. Eighteen CASEs were identified as independent prognostic factors for overall and disease-free survival. Unsupervised clustering analysis revealed distinct correlations between AS-based clusters and prognosis, molecular characteristics and immune features. Immunogenic features and immune subgroups cooperatively depict the immune features of AS-based clusters. Conclusion: This comprehensive genome-wide analysis of the AS landscape in HNSC revealed novel AS events related to carcinogenesis and immune microenvironment, with implications for prognosis and therapeutic responses.

The Role of Post-Neoadjuvant Chemotherapy Tumor Volume for Prognostication and Treatment Guidance in Loco-Regionally Advanced Nasopharyngeal Carcinoma.

The value of post-neoadjuvant chemotherapy (NACT) tumor volume for prognostication in loco-regionally advanced nasopharyngeal carcinoma (LA-NPC) is unascertained. Here, we recruited 4109 histologically proven LA-NPC (stage III-IVA) that were treated with radical chemo-intensive-modulated radiotherapy (IMRT). Post-NACT gross primary tumor (GTVp) and lymph node (GTVnd) volumes of each patient were calculated from planning computed tomography (CT). We observed similar linear association between GTVp/GTVnd and overall survival (OS); thresholds of 52 cm3 for GTVp and 12 cm3 for GTVnd were consistent for risk discretization for OS, disease-free survival (DFS), distant metastasis-free survival (DMFS), and local relapse-free survival (LRFS). Recursive partitioning analysis (RPA) modelling incorporating T-/N-categories and GTVp/GTVnd yielded four T-N-volume (TNV) risk groupings with disparate OS (p < 0.001). TNV risk stratification outperformed GTVp/GTVnd and eighth edition TNM for predicting OS (AUC 0.643 vs. 0.541-0.591; p < 0.001), DFS (0.629 vs. 0.545-0.580; p < 0.001), and DMFS (0.652 vs. 0.522-0.621; p < 0.001). NACT + concurrent chemoradiotherapy (CCRT) over NACT + IMRT was not superior for low- and low-intermediate-risk groupings (p > 0.05 for both), but superior for intermediate- and high-risk groupings in terms of OS (HR 0.68 (95% CI 0.47-0.99) for intermediate risk, 0.73 (0.55-0.97) for high risk; both p < 0.05). Overall, GTVp/GTVnd represent effective indicators for prognostication and decision-making in LA-NPC after NACT.

Evolution and Dosimetric Analysis of Magnetic Resonance Imaging-Detected Brain Stem Injury After Intensity Modulated Radiation Therapy in Nasopharyngeal Carcinoma.

PURPOSE: To evaluate the evolution of radiation-induced brain stem injury (BSI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity modulated radiation therapy (IMRT) and to identify the critical dosimetric predictors of BSI. METHODS AND MATERIALS: A total of 6288 NPC patients treated with IMRT between 2009 and 2015 were retrospectively reviewed. Among these 6288 patients, 24 had radiation-induced BSI, which manifested as edematous lesions and contrast-enhanced lesions (CLs) on magnetic resonance imaging. Latency, symptoms, and evolution of BSI were assessed. Critical dosimetric predictors of BSI were identified using a penalized regression model with performance evaluated by receiver operating characteristic curve analysis. RESULTS: Median BSI latency was 14.5 months (range, 7.6-37.5 months), and 9 out of 24 patients (37.5%) were clinically symptomatic. Edematous lesions and CLs were both present in all patients. Necrosis was significantly more common in larger CLs (P = .007). After median follow-up of 12.5 months, 13 out of 24 patients (54.2%) had complete remission, and 5 out of 24 patients (20.8%) had partial remission. Remission was unaffected by whether or not symptomatic treatment was given. Maximum point dose (Dmax) was identified as the critical predictor of BSI (area under the receiver operating curve = 0.898), with the optimal cutoff equivalent dose in 2-Gy fractions (D2) being 67.4 Gy (sensitivity = 0.833, 20 out of 24; specificity = 0.835, 5234 out of 6264). Patients with Dmax ≥67.4 Gy (D2) were significantly more likely to develop BSI (odds ratio = 25.29; 95% CI, 8.63-74.14; P < .001) than those with Dmax <67.4 Gy (D2). CONCLUSIONS: In patients with NPC treated with IMRT, BSI generally tends to improve over time. Dmax = 67.4 Gy (D2) appears to be the dose constraint for brain stem, potentially providing clinicians with greater choice and flexibility when balancing the tumor target coverage and brain stem protection. Further studies are needed to validate our findings.