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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported significantly improved failure-free survival using gemcitabine plus cisplatin induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized trial, patients were assigned to be treated with concurrent chemoradiotherapy alone (standard therapy, n = 238) or gemcitabine and cisplatin induction chemotherapy before concurrent chemoradiotherapy (n = 242). With a median follow-up of 69.8 months, the induction chemotherapy group had a significantly higher 5-year OS (87.9% v 78.8%, hazard ratio, 0.51 [95% CI 0.34 to 0.78]; P = .001) and a comparable risk of late toxicities (≥ grade 3, 11.3% v 11.4%). Notably, the depth of the tumor response to induction chemotherapy correlated significantly and positively with survival (complete response v partial response v stable/progressive disease, 5-year OS, 100% v 88.4% v 61.5%, P = .005). Besides, patients with a low pretreatment cell-free Epstein-Barr virus DNA load (< 4,000 copies/mL) might not benefit from induction chemotherapy (5-year OS, 90.6% v 91.4%, P = .77). In conclusion, induction chemotherapy before concurrent chemoradiotherapy improved OS significantly in patients with locally advanced nasopharyngeal carcinoma, without increasing the risk of late toxicities. Tumor response to induction chemotherapy and pretreatment cell-free Epstein-Barr virus DNA might be useful to guide individualized treatment.

The aim of this trial was to address whether elective ipsilateral upper-neck irradiation (UNI) sparing the uninvolved lower neck provides similar regional relapse-free survival compared with standard whole-neck irradiation (WNI) in patients with nasopharyngeal carcinoma.This open-label, non-inferiority, randomised, controlled, phase 3 trial was done at three Chinese medical centres. Patients aged 18-65 years with untreated, non-keratinising, non-distant metastatic (M0) nasopharyngeal carcinoma; with N0-N1 disease (according to International Union Against Cancer-American Joint Committee on Cancer TNM classification, seventh edition); and a Karnofsky performance status score of 70 or higher were randomly assigned (1:1) to receive elective UNI or WNI of the uninvolved neck. Total radiation doses of 70 Gy (for the primary tumour volume and the enlarged retropharyngeal nodes), 66-70 Gy (for the involved cervical lymph nodes), 60-62 Gy (for the high-risk target volume), and 54-56 Gy (for the low-risk target volume) were administered in 30-33 fractions, five fractions per week. Patients with stage II-IVA disease were recommended to receive combined intravenous cisplatin-based chemotherapy (either induction chemotherapy followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy alone). Randomisation was done centrally by the Clinical Trials Centre of Sun Yat-sen University Cancer Centre by means of a computer-generated random number code with a block size of four. Patients were stratified according to treatment centre and nodal status. Investigators and patients were not masked to treatment allocation. The primary endpoint was regional relapse-free survival in the intention-to-treat population. Non-inferiority was indicated if the upper limit of the 95% CI of the difference in 3-year regional relapse-free survival between the UNI and WNI groups was within 8%. Adverse events were analysed in the safety population (defined as all patients who commenced the randomly assigned treatment). This study is registered with ClinicalTrials.gov, NCT02642107, and is closed.Between Jan 22, 2016, and May 23, 2018, 446 patients from 469 screened were randomly assigned to receive UNI (n=224) or WNI (n=222). Median follow-up was 53 months (IQR 46-59). 3-year regional relapse-free survival was similar in the UNI and WNI groups (97·7% [95% CI 95·7-99·7] in the UNI group vs 96·3% [93·8-98·8] in the WNI group; difference -1·4% [95% CI -4·6 to 1·8]; pElective UNI of the uninvolved neck provides similar regional control and results in less radiation toxicity compared with standard WNI in patients with N0-N1 nasopharyngeal carcinoma.Sun Yat-sen University Clinical Research 5010 Program, the Natural Science Foundation of Guangdong Province, and the Overseas Expertise Introduction Project for Discipline Innovation.For the Chinese translation of the abstract see Supplementary Materials section.

Studies are trying to add immunotherapy to gemcitabine and cisplatin (GP) induction chemotherapy, the standard therapy, in nasopharyngeal carcinoma (NPC) patients with locoregionally advanced disease. However, how the immune system responds to GP remains unknown.We examined the dynamic changes of circulating immune cells and plasma cytokines in NPC patients administered with GP.After GP administration, immunosuppressive myeloid cells, including CD11b+CD14+ monocytes, CD33+ myeloid cells, CD33+CD11+ myeloid cells, total MDSCs (CD33+CD11+HLA-DR-/low), monocytic MDSCs, and granulocytic MDSCs decreased significantly. The regulatory T cells and B cells, two important suppressive lymphocyte subpopulations, also decreased. On the other hand, the levels of CD3+ T cells, total B cells, central memory CD4+ T cells, and pro-inflammatory cytokines (including Interleukin [IL]-1β, IL-6, IL-2, IL-5, and IL-8) increased significantly after GP administration. Besides, GP chemotherapy did not weaken the cytotoxic activity and proliferative capacity of T cells.Our results showed the immune modulation effect of GP induction chemotherapy in locoregionally advanced NPC, providing a solid basis for its combination with immunotherapy.

Non-keratinizing nasopharyngeal carcinoma, the major subtype of nasopharyngeal carcinoma, is characterized by low differentiation and a close relation to Epstein-Barr virus infection, which indicates a link between Epstein-Barr virus oncogenesis and loss of differentiation, and raises our interest in investigating the involvement of Epstein-Barr virus in nasopharyngeal carcinoma dedifferentiation. Our previous study showed abundant expression of an Epstein-Barr virus-encoded microRNA, BART10-3p, in nasopharyngeal carcinoma tissues, but the association between BART10-3p and nasopharyngeal carcinoma differentiation remains unknown. Here, we examined the expression and prognostic value of BART10-3p, and undertook bioinformatics analysis and functional assays to investigate the influence of BART10-3p on nasopharyngeal carcinoma differentiation and proliferation and the underpinning mechanism. Microarray analysis identified BART10-3p as the most significantly upregulated Epstein-Barr virus-encoded microRNA in nasopharyngeal carcinoma tissues and the upregulation was confirmed in two public datasets. The expression of BART10-3p was an independent unfavorable prognosticator in nasopharyngeal carcinoma and its integration with the clinical stage showed improved prognosis predictive performance. Bioinformatics analysis suggested a potential role of BART10-3p in tumor differentiation and progression. Functional assays demonstrated that BART10-3p could promote nasopharyngeal carcinoma cell dedifferentiation, epithelial-mesenchymal transition, and proliferation in vitro, and tumorigenicity in vivo. Mechanistically, BART10-3p directly targeted the 3′UTR of ALK7 and suppressed its expression. Reconstitution of ALK7 rescued BART10-3p-induced malignant phenotypes. Overall, our study demonstrates that BART10-3p promotes dedifferentiation and proliferation of nasopharyngeal carcinoma by targeting ALK7, suggesting a promising therapeutic opportunity to reverse the malignant phenotypes of nasopharyngeal carcinoma.

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.

Increasing evidence has revealed the roles of long noncoding RNAs (lncRNAs) as tumor biomarkers. Here, we introduce an immune-associated nine-lncRNA signature for predicting distant metastasis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The nine lncRNAs are identified through microarray profiling, followed by RT–qPCR validation and selection using a machine learning method in the training cohort (n = 177). This nine-lncRNA signature classifies patients into high and low risk groups, which have significantly different distant metastasis-free survival. Validations in the Guangzhou internal (n = 177) and Guilin external (n = 150) cohorts yield similar results, confirming that the signature is an independent risk factor for distant metastasis and outperforms anatomy-based metrics in identifying patients with high metastatic risk. Integrative analyses show that this nine-lncRNA signature correlates with immune activity and lymphocyte infiltration, which is validated by digital pathology. Our results suggest that the immune-associated nine-lncRNA signature can serve as a promising biomarker for metastasis prediction in LA-NPC.

e15110 Background: Immune checkpoint inhibitors (ICIs) yield remarkable clinical efficacy in the treatment of cancer. With the increasing use of ICI therapies, the dissemination of immune-related adverse events (irAEs) data is essential. This study aimed to investigate the pattern of onset and resolution of ICI-induced irAEs in cancer. Methods: Phase II–III clinical trials with single or multiple arms studying ICI-based treatments in cancer published between January 2007 and December 2019 were included. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were analyzed based on irAE categories and severity grades using the metamedian package of the R software. Subgroup analyses were performed based on different ICI drugs, ICI doses, and cancer types. Results: Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. On average, irAEs occurred at 6.1 weeks (95% confidence interval [95% CI], 5.7–7.4) after the initial ICI-based treatment. The first four irAEs with the shortest PMT-O were hypersensitivity/infusion reaction (3.1 weeks), neurological (4.0 weeks), skin (4.1 weeks), and gastrointestinal (6.1 weeks) events. IrAEs were resolved within 4.5 weeks (95% CI, 4.0–6.1), with the shortest and longest PMT-R for hypersensitivity/infusion reaction (0.1 weeks) and endocrine events (28.7 weeks), respectively. The application of immune-modulation drugs prolonged the general resolution time to 5.9 weeks, with the shortest and longest PMT-IMR for hypersensitivity/infusion reaction (0.2 weeks) and endocrine events (56.6 weeks), respectively. Grade ≥ 3 irAEs showed a significantly longer PMT-O (7.9 vs. 6.1 weeks; P < 0.01) compared with all grade irAEs. Nivolumab + ipilimumab had a significantly shorter PMT-O than nivolumab alone (6.0 vs. 8.2 weeks; P < 0.01). A significantly shorter PMT-O was observed for lung cancer compared with that for melanoma (4.7 vs. 6.1 weeks; P = 0.02). Conclusions: This study revealed the pattern and kinetics of the time to onset and resolution of irAEs in pan-cancers, which will promote the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.

In this study, we developed a long noncoding RNA (lncRNA)‐based prognostic signature for stratification of patients with head a nd neck squamous cell carcinoma (HNSCC). In total, 493 HNSCC samples obtained from the Cancer Genome Atlas database were divided into training and testing cohorts (3:2 ratio). We identified 3913 immune‐related lncRNAs in the HNSCC training cohort by Pearson correlation analysis; only seven were independently associated with overall survival and were used to develop an immune‐related lncRNA prognostic signature (IRLPS) grouping of HNSCC patients into high‐ and low‐IRLPS subgroups. Univariate and multivariate Cox analyses revealed that low‐IRLPS patients had a better prognosis in all the cohorts, which was retained after stratification by sex, grade, and HPV status. Although the TNM stage was also an independent prognostic factor, the IRLPS had a better discriminability with higher AUC at the 3‐ and 5‐year follow‐ups in all cohorts. Low‐IRLPS samples had more immune cell infiltration and were enriched in immune‐related pathways, while high‐ IRLPS samples were enriched in metabolic pathways. A nomogram constructed including age, TNM stage, and IRLPS showed good calibration. Thus, IRLPS improves the prognostic prediction and also distinguishes different tumor microenvironment (TME) in HNSCC patients., We developed an immune‐related lncRNA signature for head and neck squamous cell carcinoma (HNSCC) patients, which could improve the prognostic prediction and distinguish different tumor microenvironments (TMEs) in HNSCC patients.

This cross‐sectional and longitudinal descriptive analysis aimed to track the evolving landscape of global immuno‐oncology (IO) trials and provide insight into the resolution of IO‐related controversies. Clinical trials (n = 4510) registered on ClinicalTrials.gov in 2007 to 2019 studying immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), cancer vaccines and immune modulators were included. Most of IO trials are Phase 2 and focus on ICIs and multiple IO therapies. The United States leads global IO research, with stable growth and the best methodological quality. Mainland China ranks first in the number of ACT trials but has the lowest article publication rate (6.2%). A multiple‐arm comparative design is often adopted in multiple IO therapies trials (44.0%). Trials studying ICIs and multiple IO therapies are likely to use early registration (80.0% and 86.6%) and stringent corticosteroid‐/infection‐related criteria. Hospitals have provided the most extensive and strongest support for all IO categories. Big pharma prefers to fund Phase 3‐4 ICI trials (6.98%), while small pharma has a wider sponsorship favoring Phase 1‐2 trials. The “partial‐use‐of‐corticosteroids” strategy is generally well accepted in ICI trials with a definitive trend (32.5%; P, What's new? In recent decades, immunotherapy has emerged and advanced to become a key part of cancer‐fighting strategies. The rapid growth of immuno‐oncology, however, has been accompanied by controversy in suitable interventions and trial design. In this cross‐sectional and longitudinal analysis, disparities in design were found to be common in immuno‐oncology trials, with differences influenced by factors such as cancer type and trial sponsor. Trials with strict limitations on corticosteroid use had significantly higher publications rates than trials permitting partial corticosteroid administration. The data further suggest that timely publication of immuno‐oncology trials is the third year after trial completion.

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.

We previously demonstrated that real-time monitoring of plasma Epstein-Barr virus DNA (EBV DNA) during chemoradiation therapy defined 4 distinct phenotypic clusters of nasopharyngeal carcinoma. In particular, the treatment-resistant group, defined as detectable EBV DNA at the end of radiation therapy, had the worst prognosis and is thought to have minimal residual disease.This is the first phase 2 trial to use a targeted agent, apatinib (an inhibitor of vascular endothelial growth factor receptor 2 tyrosine kinase), in the treatment-resistant group. Eligible patients had plasma EBV DNA0 copies/mL at the end of radiation therapy (±1 week). Patients received apatinib (500 mg, once daily) until disease progression, unacceptable toxicity, or for a maximum of 2 years. The primary endpoint was disease-free survival (DFS).Twenty-five patients were enrolled and 23 patients who received apatinib were included in the analyses. Three-year DFS was 47.8% and overall survival was 73.9%. Patients with plasma vascular endothelial growth factor-A ≤150 pg/mL at 28 days after the initiation of treatment had significantly better 3-year DFS (66.7% vs 14.3%; P = .041) and overall survival (88.9% vs 42.9%; P = .033). The most common adverse event of grade ≥3 was nasopharyngeal necrosis (26%), oral/pharyngeal pain (22%), and hand-foot syndrome (22%). Nineteen patients had serial EBV DNA data. Fourteen patients had plasma EBV DNA clearance (turn to 0), and 5 (36%) of these 14 patients had disease recurrence or death, whereas all 5 patients without EBV DNA clearance had disease recurrence or death (3-year DFS: 64.3% vs 0%; P = .001).The use of antiangiogenic agents shortly after radiation therapy might increase the risk of necrosis. This approach needs to be avoided until translational and preclinical studies reveal the underlying mechanism of interaction between radiation therapy and antiangiogenic agents.

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, Our findings suggest that 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.

Background. The classification criteria and staging groups for nasopharyngeal carcinoma described in the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system have been revised over time. This study assessed the proportion of patients whose staging and treatment strategy have changed due to revisions of the UICC/AJCC staging system over the past 10 years (ie, from the sixth edition to the eighth edition), to provide information for further refinement. Methods. We retrospectively reviewed 1901 patients with non-metastatic nasopharyngeal carcinoma treated in our cancer center between November 2009 and June 2012. The Akaike information criterion and Harrell concordance index were applied to evaluate the performance of the staging system. Results. In total, 25 (1.3%) of the 1901 patients who were staged as T2a according to the sixth edition system were downgraded to T1 in the eighth edition; 430 (22.6%) staged as N0 in the sixth edition were upgraded to N1 in the eighth edition; 106 (5.6%) staged as N1/2 in the sixth edition were upgraded to N3 in the eighth edition. In addition, 51 (2.7%) and 25 (1.3%) of the study population were upstaged from stage I to stage II and stage II to stage IVa, respectively; 10 (0.5%) was downgraded from stage II to stage I. The survival curves of adjacent N categories and staging groups defined by eighth classification system were well-separated. However, there was no significant difference in the locoregional failure-free survival (P = 0.730) and disease-free survival (P = 0.690) rates between the T2 and T3 categories in the eighth edition classification system. Conclusions. Modifications to the tumor-node-metastasis staging system over the past 10 years have resulted in N classification changes in numerous cases. Although the eighth edition tumor-node-metastasis staging system better predicts survival outcomes, the T classification could be simplified in future revisions.

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

Bacterial communities in the activated sludge (AS) determine the wastewater treatment performance in the municipal wastewater treatment plants (WWTPs). Aiming at identifying the affecting factors and the variation patterns of the bacterial assemblages in AS, a 2-year time-series AS samples were collected from two separated WWTPs and metagenomic sequencing was conducted. Obvious seasonal shift and succession of the bacterial community were observed in both WWTPs on the genus and species levels, especially for the persistent taxa, implying that temperature was a decisive factor for maintaining bacterial assemblage patterns in long-term period. Taxa abundance distribution (TAD) concerning occurrence frequency and average abundance were found fitting for exponential formulations, and the approximately equal total abundance of persistent taxa suggested that stable and high abundance (~ 90%) of core functional bacterial groups would help to maintain wastewater treatment performance. Drastic changes of environmental factors were found causing temporally significant bacterial structure variation, while the innate correlations between bacterial species could recover the community gradually and maintain relative stability of the AS system. Delayed correlations between environmental factors and abundant (persistent or intermittent) bacterial species were observed widely, while synchronous biotic interactions were identified more frequently. Besides, bacterial species with similar functions were prone to cluster together and shared the same seasonal variation pattern, implicating that the cooperation of functional correlated taxa played the most dominant role in shaping the bacterial assemblages. Furthermore, rare bacterial groups were to be explored for removing emerging pollutants with lower concentrations. The results of this study would assist dealing with operational defect and optimize the treatment system in WWTPs.

Rationale: Currently, for locoregionally advanced nasopharyngeal carcinoma (LA-NPC), there is no effective blood-based method to predict distant metastasis. We aimed to detect plasma protein profiles to identify biomarkers that could distinguish patients with NPC who are at high risk of posttreatment distant metastasis. Methods: A high-throughput antibody array was initially applied to detect 1000 proteins in pretreatment plasma from 16 matched LA-NPC patients with or without distant metastasis after radical treatment. Differentially expressed proteins were further examined using a low-throughput array to construct a plasma protein-based signature for distant metastasis (PSDM) in a cohort of 226 patients. Results: Fifty circulating proteins were differentially expressed between metastatic and non-metastatic patients and 18 were proven to be strongly correlated with distant metastasis-free survival (DMFS) in NPC. A PSDM signature consisting of five proteins (SLAMF5, ESM-1, MMP-8, INSR, and Serpin A5) was established to assign patients with NPC into a high-risk group and a low-risk group. Patients in the high-risk group had shorter DMFS (P < 0.001), disease-free survival (DFS) (P < 0.001) and overall survival (OS) (P < 0.001). Moreover, the PSDM performed better than N stage and Epstein-Barr virus (EBV) DNA load at effectively identifying patients with NPC at high risk of metastasis. For patients in the high-risk group, induction chemotherapy significantly improved DMFS, DFS, and OS. Conclusions: The PSDM could be a useful liquid biopsy tool to effectively predict distant metastasis and the benefit of induction chemotherapy in patients with LA-NPC.

Purpose Using real-world evidence, this study aimed to identify elderly nasopharyngeal carcinoma (NPC) patients who would benefit from chemotherapy. Methods and materials 1714 elderly NPC patients between April 2007 and December 2017 were identified. Recursive partitioning analysis (RPA) was used to generate risk-stratified outcomes. Prognostic factors were performed for individual comparisons of different risk groups to assess chemotherapy benefits. Results The median follow-up was 59.3 (0.39–170.09) months. Epstein Barr virus (EBV) DNA and T stage were included in the RPA-generated risk stratification, categorizing patients into a good-prognosis group (EBV DNA ≤ 4000 copies/mL & T1–2), and a poor-prognosis group (EBV DNA ≤ 4000 copies/mL & T3–4 and EBV DNA > 4000 copies/mL & any T). Overall survival (OS) was significantly higher in the good-prognosis group compared with the training set (HR = 0.309, 95% CI 0.184–0.517; P P = 0.002). In the poor-prognosis group, a significantly improved OS for chemoradiotherapy (CRT) compared with RT alone was observed (HR = 0.70, 95% CI 0.55–0.88; P = 0.003). Patients who received induction chemotherapy (IC) + concurrent chemoradiotherapy (CCRT) and CCRT had a significantly improved OS compared with RT alone (IC + CCRT vs. RT alone: P = 0.002; CCRT vs. RT alone: P = 0.008) but not in the IC + RT group (P = 0.306). The 5-year OS for CRT versus RT-alone with ACE-27 scores of 0, 1 and 2 were 76.0% versus 70.0% (P = 0.014), 80.5% versus 68.2% (P = 0.150) and 58.5% versus 62.2% (P = 0.490), respectively; for those aged 60–64, 65–70 and ≥ 70 years old they were 80.9% versus 75.9% (P = 0.068), 73.3% versus 63.4% (P = 0.270) and 64.8% versus 67.1% (P = 0.820), respectively. Conclusions For elderly NPC patients a simple screening cutoff for chemotherapy beneficiaries might be EBV DNA 70 years old and with an ACE-27 score > 1. IC + CCRT and CCRT were effective forms of chemotherapy.

Background The impact of radiotherapy interruption due to the Spring Festival holidays in China on the survival of patients with nasopharyngeal carcinoma (NPC) is unclear. Methods Nontrial patients with locoregionally advanced NPC receiving radiotherapy plus induction chemotherapy (IC) and/or concurrent chemotherapy (CC) were included (N = 5035) and divided into two groups based on the Spring Festival-induced radiotherapy interruption. Kaplan–Meier curves for overall survival (OS) and failure-free survival (FFS) were compared between rival groups. Impact of the timing of radiotherapy interruption (during or outside the Spring Festival) on survival was investigated in a propensity score-matched dataset. We adopted ordination correspondence analysis to determine the cut-off of radiotherapy prolongation for prognostic prediction, and accordingly performed subgroup analysis based on delayed days and chemotherapy details. Individual patient data of three phase III NPC trials (NCT00677118, NCT01245959, NCT01872962) were used for validation (N = 1465). Results Radiotherapy interruption was most frequently observed between December to January of the following year. Significantly lower OS and FFS were associated with the Spring Festival-induced interruption of radiotherapy (P = 0.009 and 0.033, respectively), but not that interruption of IC. In two matched comparison groups, the timing of radiotherapy interruption during the Spring Festival was more likely to lead to a decrease in FFS than outside the Spring Festival (P = 0.046), which was not observed in the validation using clinical trial data or in the subgroup analysis based on the 5-day delayed time. The absence of CC and the accumulated dose of cisplatin P = 0.002) and OS (P = 0.010), respectively. Conclusions The poor survival of patients with NPC is associated with the Spring Festival-induced interruption of radiotherapy. We recommend that these patients receive adequate doses of cisplatin concurrently with radiotherapy.

IMPORTANCE: Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT). OBJECTIVE: To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes

Background The psychometric properties of the simplified Chinese version of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) have not been assessed. Therefore, we aimed to assess its validity, reliability, and responsiveness. Patients and methods A Chinese version of the PRO-CTCAE and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30) were distributed to 1580 patients from four cancer hospitals in China. Validity assessments included construct validity, measured by Pearson’s correlations and confirmatory factor analysis (CFA), and known-groups validity, measured by t-tests. The assessment of reliability included internal consistency, measured by Cronbach’s ɑ, and test-retest reliability, measured by the intraclass correlation (ICC). Responsiveness was assessed by standardized response means (SRMs). Results Data from 1555 patients who completed the instruments were analyzed. The correlations were high between PRO-CTCAE items and parallel QLQ-C30 symptom scales (r > 0.60, p r = 0.49). Moreover, CFA showed the PRO-CTCAE structure was a good fit with the data (Root Mean Square Error of Approximation = 0.046). Known-groups validity was also confirmed. Cronbach’s ɑ of all item clusters were greater than 0.9 and the median test-retest reliability coefficients of the 38 items were 0.85 (range = 0.71–0.91). In addition, the SRMs of PRO-CTCAE items were greater than 0.8, indicating strong responsiveness. Conclusion The simplified Chinese version of the PRO-CTCAE showed good reliability, validity, and responsiveness.

Background Depression has been reported to be associated with some types of cancer in observational studies. However, the direction and magnitude of the causal relationships between depression and different types of cancer remain unclear. Methods We performed the two-sample bi-directional mendelian randomization with the publicly available GWAS summary statistics to investigate the causal relationship between the genetically predicted depression and the risk of multiple types of cancers, including ovarian cancer, breast cancer, lung cancer, glioma, pancreatic cancer, lymphoma, colorectal cancer, thyroid cancer, bladder cancer, and kidney cancer. The total sample size varies from 504,034 to 729,150. Causal estimate was calculated by inverse variance weighted method. We also performed additional sensitivity tests to evaluate the validity of the causal relationship. Results After correction for heterogeneity and horizontal pleiotropy, we only detected suggestive evidence for the causality of genetically predicted depression on breast cancer (OR = 1.09, 95% CI: 1.03–1.15, P = 0.0022). The causal effect of depression on breast cancer was consistent in direction and magnitude in the sensitivity analysis. No evidence of causal effects of depression on other types of cancer and reverse causality was detected. Conclusions The result of this study suggests a causative effect of genetically predicted depression on specific type of cancer. Our findings emphasize the importance of depression in the prevention and treatment of breast cancer.

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

Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials.In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety.A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group.Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

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

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

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

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

To report long-term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III-IVB (except T3-4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2 /d civ d1-5) every 3 weeks. Patients from both groups received intensity-modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow-up of 71.5 months, the IC plus CCRT group showed significantly better 5-year failure-free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure-free survival (88% vs. 79.8%, p = 0.030), and locoregional failure-free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein-Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long-term follow-up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.

Background: Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups. Patients and methods: A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation. Results: Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-gamma signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-beta signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P = 0.01). Conclusions: This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.

The purpose of this study was to explore the differences in interhemispheric functional connectivity in patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) based on a triple network model consisting of the default mode network (DMN), salience network (SN), and executive control network (ECN). The technique of voxel-mirrored homotopic connectivity (VMHC) analysis was applied to explore the aberrant connectivity of all patients. The results showed that: (1) the statistically significant connections of interhemispheric brain regions included DMN-related brain regions (i.e. precuneus, calcarine, fusiform, cuneus, lingual gyrus, temporal inferior gyrus, and hippocampus), SN-related brain regions (i.e. frontoinsular cortex), and ECN-related brain regions (i.e. frontal middle gyrus and frontal inferior); (2) the precuneus and frontal middle gyrus in the AD group exhibited lower VMHC values than those in the aMCI and healthy control (HC) groups, but no significant difference was observed between the aMCI and HC groups; and (3) significant correlations were found between peak VMHC results from the precuneus and Mini Mental State Examination (MMSE) and Montreal Cognitive Scale (MOCA) scores and their factor scores in the AD, aMCI, and AD plus aMCI groups, and between the results from the frontal middle gyrus and MOCA factor scores in the aMCI group. These findings indicated that impaired interhemispheric functional connectivity was observed in AD and could be a sensitive neuroimaging biomarker for AD. More specifically, the DMN was inhibited, while the SN and ECN were excited. VMHC results were correlated with MMSE and MOCA scores, highlighting that VMHC could be a sensitive neuroimaging biomarker for AD and the progression from aMCI to AD.

Purpose To estimate the clinical benefit and cost-effectiveness of routine head and neck magnetic resonance imaging (MRI) in the follow-up of patients with nasopharyngeal carcinoma after definitive intensity modulated radiation therapy. Patients and Methods Two Markov models were developed to compare the cost and effectiveness of 3 strategies: routine clinical surveillance without serial imaging and routine annual and biannual MRI surveillance in the first 5 years. Two hypothetical cohorts of patients with primary stage T1-2 or T3-4 nasopharyngeal carcinoma who achieved complete remission after radical treatment and remained asymptomatic were analyzed. Baseline probabilities, transition probabilities, utilities, and costs were derived from published studies. Markov models were used to calculate life-time costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Model robustness was addressed via univariable and probabilistic sensitivity analyses. Results In T1-2 patients, surveillance strategies utilizing routine MRI provided few QALYs compared with non-MRI clinical follow-up (annual MRI, 0.022 QALYs; biannual MRI, 0.035 QALYs), whereas the costs associated with MRI surveillance were considerable. Compared with clinical follow-up, the ICERs for annual and biannual MRI strategies were $328,389 and $403,857 per QALY. In T3-4 patients, annual and biannual MRI surveillance provided 0.052 and 0.088 incremental QALYs, with ICERs of $156,204 and $169,772 per QALY, respectively. Model conclusions were robust and remained stable in 1-way and probabilistic sensitivity analyses. Conclusions Routine MRI surveillance was not cost-effective owing to the high cost of MRI coupled with low rates of failure in T1-2 patients, whereas annual MRI surveillance was the dominant and possibly a cost-effective strategy for T3-4 patients, depending on the social willingness to pay.

Summary Background Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. Methods This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18–65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III–IVA, excluding T3–4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12–16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. Findings Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33–42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4–90·6]) than in the standard therapy group (75·7% [69·9–81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32–0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One ( Interpretation The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. Funding The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. Translation For the Chinese translation of the abstract see Supplementary Materials section.

To explore the prognostic value of different radiologic extranodal extension (rENE) grades and their potential improvement for the 8th edition N category in nasopharyngeal carcinoma (NPC).From 2009 to 2013, a cohort of 1887 patients with NPC was retrospectively enrolled and randomized to the training (n = 955) and validation (n = 932) groups. rENE was categorized as follows: grade 0, nodes without rENE; grade 1, nodes with rENE infiltrating the surrounding fat only; grade 2, matted nodes; grade 3, nodes with rENE infiltrating adjacent structures.The percentage of patients with MRI-positive cervical nodes was 66.5% (1254/1887), of whom grade 0, 1, 2 and 3 rENE cases accounted for 33.2% (416/1254), 14.9% (187/1254), 36.5% (458/1254) and 15.4% (193/1254), respectively. The kappa coefficients for the inter-rater and intra-rater assessments were 0.63, 0.51, 0.65 and 0.93, and 0.76, 0.69, 0.72 and 1.0 in grade 0, 1, 2 and 3 rENE, respectively. Grade 3 rENE rather than grades 0-2 rENE was an independent unfavorable predictor of overall survival and disease-free survival (P 0.001). Recursive partitioning analysis was applied to refine the N category: eN0 (N0), eN1 (N1 without grade 3), eN2 (N2 without grade 3), and eN3 (N1/N2 with grade 3, N3). Compared to the current system, the proposed N category performed better in hazard consistency, hazard discrimination, sample size balance and outcome prediction.Grade 3 rENE was an independent unfavorable indicator of NPC. Upstaging patients in N1-2 with grade 3 rENE to N3 led to a superior prognostic performance.

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 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.

BackgroundTumor-infiltrating lymphocytes have been reported as prognostic markers in tumors. We aimed to assess the prognostic value of total T cell (CD3+) density, cytotoxic T cell (CD8+) density and memory T cell (CD45RO+) density in patients with nasopharyngeal carcinoma (NPC).MethodsThe expression of CD3, CD8 and CD45RO was detected by immunohistochemistry in the training (n=221) and validation cohorts (n=115). The densities of these three markers were quantified by digital pathology both in the tumor and stroma. Then, we developed the immune score based on the density of these three markers and further analyzed its prognostic value.ResultsThe high density of CD3+, CD8+ and CD45RO+ T cells both in the tumor and/or stroma were significantly associated with the decrease in mortality in the training cohort, respectively. High immune score predicted a prolonged overall survival (OS) (HR 0.34, 95% CI 0.18 to 0.64, p=0.001, disease-free survival (DFS) (HR 0.44, 95% CI 0.25 to 0.78, p=0.005) and distant metastasis-free survival (DMFS) (HR 0.43, 95% CI 0.21 to 0.87, p=0.018) in NPC patients. The findings were confirmed in the validation cohort. Multivariate analysis revealed that immune score remained an independent prognostic indicator for OS, DFS and DMFS. In addition, we established a nomogram with the integration of all independent variables to predict individual risk of death.ConclusionsWe established an immune score model, which provides a reliable estimate of the risk of death, disease progress and distant metastasis in NPC patients.

Background and purpose In the intensity-modulated radiotherapy (IMRT) era, the role of concurrent chemoradiotherapy (CCRT) after induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LANPC) is undetermined, while concerns exist about CCRT-associated excessive toxicity. We aimed to combine tumor response and risk assessment to guide decisions about concurrent chemotherapy. Materials and methods From April 2009 to December 2015, 744 LANPC patients treated with CCRT/IMRT after IC were included. Matching techniques were performed for treatment effect evaluation. Tumor response to IC was used for patient stratification. A nomogram was built based on multivariable Cox regression analysis to predict overall survival (OS). Results After IC, 508 patients (68.3%) had favorable tumor response (complete or partial response), among whom IC + CCRT achieved significantly superior 5-year disease-free survival and OS than IC + IMRT (82.2% vs. 72.5%, P = 0.025; 89.2% vs. 79.9%, P = 0.025). However, no significant difference was found in patients with unfavorable response (both P > 0.05). For favorable responders, a nomogram was built integrating age, smoking, T category, N category, pretreatment Epstein-Barr virus DNA and treatment modality. The concordance index was 0.713 and calibration was good. The nomogram determined three risk groups with distinct OS. High-risk patients benefited from CCRT after IC regarding disease-free survival, OS and distant metastasis-free survival, whereas low- and intermediate-risk patients did not. Conclusions For LANPC patients with unfavorable response to IC, subsequent CCRT seems inadequate, rendering intensification necessary. For favorable responders with low risk, IC + IMRT represents a reasonable de-intensification approach, although confirmation by prospective data is needed.

Background Induction chemotherapy (IC) followed by concurrent chemoradiotherapy is the mainstay treatment for patients with locoregionally advanced nasopharyngeal carcinoma. However, some patients obtain little benefit and experience unnecessary toxicities from IC. We intended to develop a gene-expression signature that can identify beneficiaries of IC. Methods We screened chemosensitivity-related genes by comparing gene-expression profiles of patients with short-term tumor response or nonresponse to IC (n = 95) using microarray analysis. Chemosensitivity-related genes were quantified by digital expression profiling in a training cohort (n = 342) to obtain a gene signature. We then validated this gene signature in the clinical trial cohort (n = 187) and an external independent cohort (n = 240). Tests of statistical significance are 2-sided. Results We identified 43 chemosensitivity-related genes associated with the short-term tumor response to IC. In the training cohort, a 6-gene signature was developed that was highly accurate at predicting the short-term tumor response to IC (area under the curve [AUC] = 0.87, sensitivity = 87.5%, specificity = 75.6%). We further found that IC conferred failure-free survival benefits only in patients in the benefit group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.34 to 0.87; P = .01) and not on those in the no-benefit group (HR = 1.25, 95% CI = 0.62 to 2.51; P = .53). In the clinical trial cohort, the 6-gene signature was also highly accurate at predicting the tumor response (AUC = 0.82, sensitivity = 87.5%, specificity = 71.8%) and indicated failure-free survival benefits. In the external independent cohort, similar results were observed. Conclusions The 6-gene signature can help select beneficiaries of IC and lay a foundation for a more individualized therapeutic strategy for locoregionally advanced nasopharyngeal carcinoma patients.

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

Gene expression patterns can be used as prognostic biomarkers in various types of cancers. We aimed to identify a gene expression pattern for individual distant metastatic risk assessment in patients with locoregionally advanced nasopharyngeal carcinoma.In this multicentre, retrospective, cohort analysis, we included 937 patients with locoregionally advanced nasopharyngeal carcinoma from three Chinese hospitals: the Sun Yat-sen University Cancer Center (Guangzhou, China), the Affiliated Hospital of Guilin Medical University (Guilin, China), and the First People's Hospital of Foshan (Foshan, China). Using microarray analysis, we profiled mRNA gene expression between 24 paired locoregionally advanced nasopharyngeal carcinoma tumours from patients at Sun Yat-sen University Cancer Center with or without distant metastasis after radical treatment. Differentially expressed genes were examined using digital expression profiling in a training cohort (Guangzhou training cohort; n=410) to build a gene classifier using a penalised regression model. We validated the prognostic accuracy of this gene classifier in an internal validation cohort (Guangzhou internal validation cohort, n=204) and two external independent cohorts (Guilin cohort, n=165; Foshan cohort, n=158). The primary endpoint was distant metastasis-free survival. Secondary endpoints were disease-free survival and overall survival.We identified 137 differentially expressed genes between metastatic and non-metastatic locoregionally advanced nasopharyngeal carcinoma tissues. A distant metastasis gene signature for locoregionally advanced nasopharyngeal carcinoma (DMGN) that consisted of 13 genes was generated to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter distant metastasis-free survival (hazard ratio [HR] 4·93, 95% CI 2·99-8·16; p0·0001), disease-free survival (HR 3·51, 2·43-5·07; p0·0001), and overall survival (HR 3·22, 2·18-4·76; p0·0001) than patients with low-risk scores. The prognostic accuracy of DMGN was validated in the internal and external cohorts. Furthermore, among patients with low-risk scores in the combined training and internal cohorts, concurrent chemotherapy improved distant metastasis-free survival compared with those patients who did not receive concurrent chemotherapy (HR 0·40, 95% CI 0·19-0·83; p=0·011), whereas patients with high-risk scores did not benefit from concurrent chemotherapy (HR 1·03, 0·71-1·50; p=0·876). This was also validated in the two external cohorts combined. We developed a nomogram based on the DMGN and other variables that predicted an individual's risk of distant metastasis, which was strengthened by adding Epstein-Barr virus DNA status.The DMGN is a reliable prognostic tool for distant metastasis in patients with locoregionally advanced nasopharyngeal carcinoma and might be able to predict which patients benefit from concurrent chemotherapy. It has the potential to guide treatment decisions for patients at different risk of distant metastasis.The National Natural Science Foundation of China, the National ScienceTechnology Pillar Program during the Twelfth Five-year Plan Period, the Natural Science Foundation of Guang Dong Province, the National Key Research and Development Program of China, the Innovation Team Development Plan of the Ministry of Education, the HealthMedical Collaborative Innovation Project of Guangzhou City, China, and the Program of Introducing Talents of Discipline to Universities.

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

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

Long noncoding RNAs (lncRNAs) play an important role in the development and progression of cancers. However, the clinical significances of lncRNAs and their functions and mechanisms in nasopharyngeal carcinoma (NPC) remain largely unclear. Methods: Quantitative RT-PCR was used to determine DANCR expression and Kaplan-Meier curves were used to evaluate its prognostic value. RNA sequencing followed by bioinformatic analysis was performed to determine the potential function of DANCR. In vitro and in vivo experiments were conducted to investigate its biological effects. DANCR-interacting proteins were identified by RNA pull-down assay followed by mass spectrometry and western blotting, and then confirmed by RNA immunoprecipitation (RIP) assays. Results: Our previous microarray analysis identified a metastasis-associated lncRNA DANCR. Here, we found that DANCR was upregulated in NPC, especially in those with lymph lode metastasis, and its upregulation could predict poor survival. We then constructed a prognostic predictive model. RNA sequencing followed by bioinformatic analysis revealed that DANCR was responsible for NPC metastasis and hypoxia phenotype. Functional studies showed that DANCR promoted NPC cell invasion and metastasis in vitro and in vivo. Further investigation suggested that DANCR could increase HIF-1α mRNA stability through interacting with the NF90/NF45 complex. Additionally, overexpression of HIF-1α in DANCR knockdown cells restored its suppressive effects on NPC cell migration and invasion. Conclusions: Taken together, our results suggest that DANCR acts as a prognostic biomarker and increases HIF-1α mRNA stability by interacting with NF90/NF45, leading to metastasis and disease progression of NPC.

Background and purpose While parotid-sparing intensity modulated radiotherapy (IMRT) has demonstrated superiority to conventional RT in terms of observer-rated xerostomia, patient-reported outcome measures (PROMs) have only marginally improved. We investigated how sparing all salivary glands affects PROMs. Materials and methods Patients treated to the bilateral neck with all-gland-sparing IMRT answered xerostomia (XQ) and head-and-neck quality of life (HNQOL) questionnaires. Longitudinal regression was used to assess the relationship between questionnaire scores and mean bilateral parotid gland (bPG), contralateral submandibular gland (cSMG), and oral cavity (OC) doses. Marginal R 2 and Akaike information criterion (AIC) were used for model evaluation. Results 252 patients completed approximately 600 questionnaires. On univariate analysis, bPG, cSMG, and OC doses significantly correlated with XQ-summary, XQ-eating, and HNQOL-eating scores. On multivariate analysis, bPG and OC doses significantly correlated with XQ-summary, XQ-eating, and HNQOL-eating scores; and cSMG dose with HNQOL-summary. Combining doses to all three structures yielded the highest R 2 for XQ-summary, XQ-rest, XQ-eating, and HNQOL-eating. In the 147 patients who received a mean cSMG dose ≤39 Gy, there were no failures in contralateral level IB. Conclusions Reducing doses to all salivary glands maximizes PROMs. A cSMG dose constraint of ≤39 Gy does not increase failure risk.

Background Little is known about the nature of metastasis to small cervical lymph nodes (SCLNs) in the patients with nasopharyngeal carcinoma (NPC) examined by using 18-fluoro-2-deoxy-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). The present study aimed to evaluate the diagnostic values of PET/CT in identifying metastasis in SCLNs in NPC patients. Methods Magnetic resonance images (MRI) and PET/CT scans for 470 patients with newly diagnosed, non-distant metastatic NPC were analyzed. Metastatic rates of SCLNs were defined by the positive number of SCLNs on PET/CT scans and total number of SCLNs on MRI scans. Receiver operating characteristic curve was applied to compare PET/CT-determined stage with MRI-determined stage. Results In total, 2082 SCLNs were identified, with 808 (38.8%) ≥ 5 and

Background: The reporting quality of publications is of vital importance to ensure accurate evidence dissemination. This study aimed to compare the consistency of results reporting between the ClinicalTrials.gov results database and the respective matching publications. Methods: We identified 323 phase III/IV cancer drug trials with a randomized controlled design and searched PubMed for publications in a 50% random sample (n=160). Data were extracted independently from ClinicalTrials.gov and publications. A scoring system was applied to determine characteristics associated with reporting quality. Results: Of 117 reviewed trials with publications, result reporting was significantly more complete in ClinicalTrials.gov for efficacy measurement (92.3% vs 90.6%), serious adverse events (SAEs; 100% vs 43.6%), and other adverse events (OAEs; 100% vs 62.4%). For trials with both posted and published results for design information (n=117), efficacy measurements (n=98), SAEs (n=51), and OAEs (n=73), discrepancies were found in 16 (13.7%), 38 (38.8%), 26 (51.0%), and 54 (74.0%) trials, respectively. Overreporting of treatment effects (7 trials) and alteration of primary end points favoring statistically significant outcomes (11 trials) were the major discrepancies in efficacy reporting; incomplete (66 trials) and underreporting (20 trials) of SAEs were the predominant issues in benefit/risk reporting. Median quality score was 21 (range, 14-28). Trials that had parallel assignment, were phase IV, had primary funding by industry, were completed after 2009, and had earlier results posted possessed better reporting quality. Conclusions: Although most trials showed reasonable completeness and consistency, some discrepancies are prevalent and persistent, jeopardizing evidence-based decision-making. Our findings highlight the need to consult results systematically from both ClinicalTrials.gov and publications.

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

We performed a comprehensive immuno-genomic analysis of tumor microenvironment immune types (TMITs), which is classified into four groups based on PD-L1+CD8A or PD-L1+cytolytic activity (CYT) expression, across a broad spectrum of solid tumors in order to help identify patients who will benefit from anti- PD-1/PD-L1 therapy. The mRNA sequencing data from The Cancer Genome Atlas (TCGA) of 14 solid cancer types representing 6,685 tumor samples was analyzed. TMIT was classified only for those tumor types that both PD-L1 and CD8A/CYT could prefict mutation and/or neoantigen number. The mutational and neoepitope features of the tumor were compared according to the four TMITs. We found that PD-L1/CD8A/CYT subgroups could not distinguish different mutation and neoantigen numbers in certain tumor types such as glioblastoma multiforme, prostate adenocarcinoma, and head and neck and lung squamous cell carcinoma. For the remaining tumor types, compared with TIMT II (low PD-L1 and CD8A/CYT), TIMT I (high PD-L1 and CD8A/CYT) had a significantly higher number of mutations or neoantigens in bladder urothelial carcinoma, breast and cervical cancer, colorectal, stomach and lung adenocarcinoma, and melanoma. In contrast, TMIT I of kidney clear cell, liver hepatocellular, and thyroid carcinoma were negatively correlated with mutation burden or neoantigen numbers. Our findings show that the TMIT stratification proposed could serve as a favorable approach for tailoring optimal immunotherapeutic strategies in certain tumor types. Going forward, it will be important to test the clinical practicability of TMIT based on quantification of immune infiltrates using mRNA-seq to predict clinical response to these and other immunotherapeutic strategies in more different tumors.

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

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