RSPSSL: A novel high-fidelity Raman spectral preprocessing scheme to enhance biomedical applications and chemical resolution visualization.

Raman spectroscopy has tremendous potential for material analysis with its molecular fingerprinting capability in many branches of science and technology. It is also an emerging omics technique for metabolic profiling to shape precision medicine. However, precisely attributing vibration peaks coupled with specific environmental, instrumental, and specimen noise is problematic. Intelligent Raman spectral preprocessing to remove statistical bias noise and sample-related errors should provide a powerful tool for valuable information extraction. Here, we propose a novel Raman spectral preprocessing scheme based on self-supervised learning (RSPSSL) with high capacity and spectral fidelity. It can preprocess arbitrary Raman spectra without further training at a speed of ~1 900 spectra per second without human interference. The experimental data preprocessing trial demonstrated its excellent capacity and signal fidelity with an 88% reduction in root mean square error and a 60% reduction in infinite norm ([Formula: see text]) compared to established techniques. With this advantage, it remarkably enhanced various biomedical applications with a 400% accuracy elevation (ΔAUC) in cancer diagnosis, an average 38% (few-shot) and 242% accuracy improvement in paraquat concentration prediction, and unsealed the chemical resolution of biomedical hyperspectral images, especially in the spectral fingerprint region. It precisely preprocessed various Raman spectra from different spectroscopy devices, laboratories, and diverse applications. This scheme will enable biomedical mechanism screening with the label-free volumetric molecular imaging tool on organism and disease metabolomics profiling with a scenario of high throughput, cross-device, various analyte complexity, and diverse applications.

Camrelizumab and apatinib plus induction chemotherapy and concurrent chemoradiotherapy in stage N3 nasopharyngeal carcinoma: a phase 2 clinical trial.

The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Patients with N3 nasopharyngeal carcinoma have a high risk of distant metastasis, however, if the addition of immunotherapy to standard treatment could improve efficacy is unclear. In this phase II clinical trial (ChiCTR2000032317), 49 patients with stage TanyN3M0 nasopharyngeal carcinoma were enrolled and received the combination of three cycles of induction chemotherapy, camrelizumab and apatinib followed by chemoradiotherapy. Here we report on the primary outcome of distant metastasis-free survival and secondary end points of objective response rate, failure-free survival, locoregional recurrence-free survival, overall survival and toxicity profile. After induction therapy, all patients had objective response, including 13 patients (26.5%) with complete response. After a median follow-up of 28.7 months, the primary endpoint of 1-year distant metastasis-free survival was met for the cohort (1-year DMFS rate: 98%). Grade≥3 toxicity appeared in 32 (65.3%) patients, with the most common being mucositis (14[28.6%]) and nausea/vomiting (9[18.4%]). In this work, camrelizumab and apatinib in combination with induction chemotherapy show promising distant metastasis control with acceptable safety profile in patients with stage TanyN3M0 nasopharyngeal carcinoma.

Combination strategy exploration for prior treated recurrent or metastatic nasopharyngeal carcinoma in the era of immunotherapy.

To assess the efficacy and safety of the combination of immune checkpoint inhibitors (ICIs) and target therapy (anti-angiogenesis or EGFR inhibitors) as a second-line or subsequent treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M NPC), we conducted a retrospective study. In this study, previously treated R/M NPC patients were administered one of the following treatment: ICIs combined with target therapy and chemotherapy (ITC), ICIs combined with target therapy alone (IT), ICIs combined with chemotherapy (IC), or chemotherapy alone (C). The primary endpoint under consideration was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety measures. A total of 226 patients participated in this study, with 70 receiving the ITC regimen, 48 receiving IT, 48 treated with IC, and 60 undergoing C alone. The median PFS for the four cohorts was 20.67, 13.63, 12.47, and 7.93 months respectively. Notably, ITC regimen yielded the most favorable PFS among these cohorts. The ITC cohort exhibited a comparable tumor response and safety profile to the IT and IC cohorts (p > 0.05), but superior tumor response compared to the C cohort (p < 0.05). The ITC regimen also conferred a significant improvement in OS when comparing to C alone (HR 0.336, 95%CI 0.123-0.915, p = 0.033). The IT and IC regimens achieved a nearly identical PFS (HR 0.955, 95%CI 0.515-1.77, p = 0.884), although the IT regimen was associated with a lower occurrence of SAEs in contrast to the IC regimen (p < 0.05). In addition, the IT regimen demonstrated superior PFS (HR 0.583, 95%CI 0.345-0.985, p = 0.044) and fewer SAEs when compared to C alone (p < 0.05). These findings collectively support the notion that the combination of ICIs, target and chemotherapy exhibits robust antitumor activity in previously treated R/M NPC patients, without a significant increase in adverse events.

Efficacy and safety of sintilimab plus bevacizumab in metastatic nasopharyngeal carcinoma after failure of platinum-based chemotherapy: an open-label phase 2 study.

Background: There are limited treatment options for patients with metastatic nasopharyngeal carcinoma (mNPC) after failure of platinum-based chemotherapy. In this trial, we assessed the efficacy and safety of sintilimab plus bevacizumab in patients with mNPC where platinum-based chemotherapy has been ineffective. Methods: This was a single-centre, open-label, single-arm, phase 2 trial in Guangzhou, China for patients with mNPC progressed after at least one line of systemic therapy. Eligible patients were between 18 and 75 years old, were histologically confirmed differentiated or undifferentiated non-keratinized NPC, were ineffective after platinum-based chemotherapy, and they had at least one measurable metastatic lesion assessed with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST V.1.1) by investigators and unsuitable for local surgery or radiotherapy. Key exclusion criterion was previous treatment with anti-PD-1/PD-L1 antibodies plus anti-VEGF antibodies and high risk of hemorrhage or nasopharyngeal necrosis. Patients were enrolled and received sintilimab (200 mg) plus bevacizumab (7.5 mg/kg) intravenously every 3 weeks. Intention-to-treat population was included in primary endpoint analyses and safety analyses. The primary endpoint was objective response rate (ORR) assessed by investigators following the guidelines of RECIST V1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. This trial is registered with ClinicalTrials.gov (NCT04872582). Findings: Between July 29, 2021 and August 16, 2022, 33 patients were enrolled. Median age was 46 years (range, 18-64 years), and 63.6% of patients had previously received two or more lines of chemotherapy for metastatic disease. Median follow-up was 7.6 months (range, 4.1-17.5 months). ORR was 54.5% (95% CI, 36.4-71.9%) with 3 complete responses (9.1%) and 15 partial responses (45.5%). Median PFS was 6.8 months (95% CI, 5.2 months to not estimable). Median DOR was 7.2 months (95% CI, 4.4 months to not estimable). Median OS was not reached. The most common potential immune-related adverse event (AE) was Grade 1-2 hypothyroidism (42.4%). Treatment-related grade 3 or 4 AEs occurred in 7 patients (21.2%), including nasal necrosis (3/33), hypertension (1/33), pruritus (1/33), total bilirubin increased (1/33) and anaphylactic shock (1/33). No treatment-related deaths and severe epistaxis occurred. Interpretation: This phase 2 trial showed that sintilimab plus bevacizumab demonstrated promising antitumour activity and manageable toxicities in patients with mNPC after failure of platinum-based chemotherapy. Further trials are warranted, and the detailed mechanisms need to be elucidated. Funding: The Guangdong Basic and Applied Basic Research Foundation, the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, and the Science and Technology Planning Project of International Cooperation of Guangdong Province.

Anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR treatment beyond progression in recurrent/metastatic nasopharyngeal carcinoma patients.

We aim to evaluate the efficacy and safety of anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR treatment in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) patients who progressed to previous anti-PD1 therapy. Enrolled patients were divided into a combination group and a chemotherapy only group. A total of 145 patients were enrolled. The median progress-free survival (mPFS) was 7.9 months and 4.4 months, respectively for the two groups. The combination group exhibited significantly longer PFS (HR=0.363, p < 0.001), and better disease control ratio (DCR, p = 0.022) compared with the chemotherapy group. Among the combination group, longer PFS was found in those patients who received different PD1 inhibitor from prior therapy, reached object response rate (ORR) from prior anti-PD1 therapy, and EBV DNA ≤ 1500 copy/ml before therapy, comparing to the corresponding other patients. R/M NPC patients who progressed from prior anti-PD1 therapy could benefit from the anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR agents.

Effective of metastasis-directed therapy for de novo metastatic nasopharyngeal carcinoma: A propensity score matched analysis.

OBJECTIVE: Our objective was to establish a prognostic model for patients with de novo metastatic nasopharyngeal carcinoma (NPC) who received chemotherapy followed by locoregional radiotherapy (LRRT) to identify candidates for metastasis-directed therapy (MDT). METHODS: De novo metastatic NPC patients who received chemotherapy followed by LRRT were enrolled. Propensity score matching (PSM) method was used to compare overall survival (OS) for patients receiving LRRT alone and MDT plus LRRT. We developed a predictive model to predict survival and estimate the outcome of stratified therapy and identify suitable candidates for MDT. RESULTS: A total of 107 patients received MDT plus LRRT and 178 received LRRT alone were enrolled. PSM analysis identified 107 patients in each cohort and showed that MDT plus LRRT was associated with a significant survival benefit (HR: 0.640; 95% CI, 0.29-0.956; p = 0.027). Based on five independent prognostic factors, including metastases number, serum lactate dehydrogenase, liver metastasis, C-reactive protein, and tumor response, a prognostic model was established. All patients were stratified according to the prognostic score obtained by the prognostic model. In the low-risk group, MDT plus LRRT group revealed a significant improvement for OS compared with LRRT alone group (5-year OS, 69.9% vs. 57.8%, p = 0.020). However, no significant difference was observed between MDT plus LRRT group and LRRT alone in the high-risk group (p = 0.75). CONCLUSION: MDT plus LRRT was associated with improved OS in patients with de novo metastatic NPC, especially low-risk patients identified with a newly developed prognostic model.

Long noncoding RNA LINC00173 induces radioresistance in nasopharyngeal carcinoma via inhibiting CHK2/P53 pathway.

Radiotherapy is the backbone of nasopharyngeal carcinoma (NPC), nearly 11-17% NPC patients suffered local relapse and 18-37% suffered distant metastasis mainly due to radioresistance. Therefore, the key of improving patients' survivals is to investigate the mechanism of radioresistance. In this study, we revealed that the expression level of long intergenic nonprotein coding RNA 173 (LINC00173) was significantly increased in the radioresistant NPC patients' tumour tissues compared with the radiosensitive patients by RNA-sequencing, which also predict poor prognosis in NPC. Overexpression of LINC00173 induced radioresistance of NPC cells in vitro and in vivo. Mechanistically, LINC00173 bound with checkpoint kinase 2 (CHK2) in nucleus, and impaired the irradiation-induced CHK2 phosphorylation, then suppressed the activation of P53 signalling pathway, which eventually inhibiting apoptosis and leading to radioresistance in NPC cells. In summary, LINC00173 decreases the occurrence of apoptosis through inhibiting the CHK2/P53 pathway, leads to NPC radioresistance and could be considered as a novel predictor and therapeutic target in NPC.

Epstein-Barr virus DNA seropositivity links distinct tumoral heterogeneity and immune landscape in nasopharyngeal carcinoma.

Background: Epstein-Barr virus (EBV) DNA seronegative (Sero-) and seropositive (Sero+) nasopharyngeal carcinoma (NPC) are distinctly different disease subtypes. Patients with higher baseline EBV DNA titers seem to benefit less from anti-PD1 immunotherapy, but underlying mechanisms remain unclear. Tumor microenvironment (TME) characteristics could be the important factor affecting the efficacy of immunotherapy. Here, we illuminated the distinct multicellular ecosystems of EBV DNA Sero- and Sero+ NPCs from cellular compositional and functional perspectives at single-cell resolution. Method: We performed single-cell RNA sequencing analyses of 28,423 cells from ten NPC samples and one non-tumor nasopharyngeal tissue. The markers, function, and dynamics of related cells were analyzed. Results: We found that tumor cells from EBV DNA Sero+ samples exhibit low-differentiation potential, stronger stemness signature, and upregulated signaling pathways associated with cancer hallmarks than that of EBV DNA Sero- samples. Transcriptional heterogeneity and dynamics in T cells were associated with EBV DNA seropositivity status, indicating different immunoinhibitory mechanisms employed by malignant cells depending on EBV DNA seropositivity status. The low expression of classical immune checkpoints, early-triggered cytotoxic T-lymphocyte response, global activation of IFN-mediated signatures, and enhanced cell-cell interplays cooperatively tend to form a specific immune context in EBV DNA Sero+ NPC. Conclusions: Collectively, we illuminated the distinct multicellular ecosystems of EBV DNA Sero- and Sero+ NPCs from single-cell perspective. Our study provides insights into the altered tumor microenvironment of NPC associated with EBV DNA seropositivity, which will help direct the development of rational immunotherapy strategies.

Erratum: CHL1 suppresses tumor growth and metastasis in nasopharyngeal carcinoma by repressing PI3K/AKT signaling pathway via interaction with Integrin ß1 and Merlin: Erratum.

[This corrects the article DOI: 10.7150/ijbs.34785.].

Development of a prognostic model to identify the metastatic nasopharyngeal carcinoma patients who may benefit from chemotherapy combination PD-1 inhibitor.

Background: We aimed to establish a prognostic model to identify suitable candidates for chemotherapy combination PD-1 inhibitor in metastatic nasopharyngeal carcinoma (NPC) patients. Patients and methods: In this retrospective study, we included 524 patients (192 patients treated with chemotherapy combination PD-1 inhibitor and 332 received chemotherapy alone as first-line regimen) with metastatic NPC between January 2015 and March 2021. We developed a prognostic model to predict progression-free survival (PFS). A model-based trees approach was applied to estimate stratified treatment effects using prognostic scores and two well-matched risk groups (low-risk and high-risk) were created using propensity score matching. Results: A prognostic nomogram was established with good accuracy for predicting PFS (c-index values of 0.71; 95% confidence interval, 0.66-0.73). The survival curves were significantly different between low-risk and high-risk groups (median PFS: 9.8 vs. 22.8 months, P < 0.001, respectively). After propensity matching analysis, chemotherapy combination PD-1 inhibitor was significantly associated with superior PFS as compared with chemotherapy alone (median PFS, 10.6 versus 9.3 months, P = 0.016) in the high-risk group. However, no significant difference between chemotherapy combination PD-1 inhibitor and chemotherapy was observed (P = 0.840) in the low-risk groups. Conclusions: Our novel prognostic model was able to stratify patients with metastatic NPC into low-risk or high-risk groups and identify candidates for PD-1 inhibitor therapy. These results are expected to be confirmed by a prospective clinical trial.

Concurrent chemoradiotherapy combined with nimotuzumab in stage III-IVa nasopharyngeal carcinoma: a retrospective analysis.

PURPOSE: The efficacy and safety of nimotuzumab (NTZ) added to concurrent chemoradiotherapy (CCRT) were investigated in patients with stage III-IVa nasopharyngeal carcinoma (NPC). METHODS: Patients with stage III-IVa NPC treated with CCRT, with or without NTZ, were screened between January 2015 and December 2017. We compared patients' overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) between different therapeutic regimens. Propensity score matching (PSM) was applied to reduce the selection bias. Nomogram models were developed to predict the survival of CCRT with or without NTZ. RESULTS: Four hundred and twenty-six patients were included after PSM, with 213 patients in each regimen. Compared with NPC patients receiving CCRT alone, patients who received NTZ plus CCRT treatment had significantly better OS (5 year OS, 76.1 vs. 72.3%, P = 0.004), PFS (5 year PFS, 73.2 vs. 69.0%, P = 0.002), and LRFS (5 year LRFS, 73.2 vs. 69.0%, P = 0.028). A multivariate Cox regression analysis demonstrated that, compared with receiving CCRT alone, NTZ plus CCRT was an independently positive factor for OS, PFS, and LRFS. No significant difference was observed in the major toxicities between the two treatments (all P > 0.05). In addition, the nomogram presented good accuracy for predicting the prognosis of NPC patients. CONCLUSION: CCRT combined with NTZ presented favorable clinical outcomes for stage III-IVa NPC patients with good tolerance and similar toxicity compared to CCRT alone. A prospective, randomized clinical trial is essential to validate the current findings.

Adjuvant Capecitabine Following Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A Randomized Clinical Trial.

Importance: Induction or adjuvant chemotherapy with concurrent chemoradiotherapy (CCRT) are first-line treatment options for treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Adjuvant platinum regimens are, however, poorly tolerated, highlighting the unmet need for an efficacious, tolerable adjuvant regimen. Objective: To investigate the efficacy and safety of adjuvant capecitabine with CCRT for the treatment of patients with LA-NPC. Design, Setting, and Participants: This open-label randomized clinical trial recruited patients from March 31, 2014, to July 27, 2018, at 3 institutions in China, with at least 3 years of follow-up. The data collection cutoff date was February 9, 2022. Eligibility included stage III-IVb nasopharyngeal carcinoma and at least 1 of the following: T3-4N2 or T1-4N3; plasma Epstein-Barr virus DNA titer higher than 20 000 copies/mL; primary gross tumor volume larger than 30.0 cm3; fluorodeoxyglucose F 18 positron emission tomography/computed tomography maximum standard uptake value of the primary gross tumor volume larger than 10.0; or multiple nodal metastases and any larger than 4.0 cm. Interventions: Patients were randomly assigned 1:1 to receive either capecitabine (1000 mg/m2 twice daily for 14 days every 3 weeks for 8 cycles) or observation following CCRT (100 mg/m2 cisplatin every 3 weeks for 2 to 3 cycles, depending on duration of radiotherapy). Main Outcomes and Measures: Failure-free survival in the intention-to-treat cohort was assessed using Kaplan-Meier survival curves compared with the log-rank test. Unstratified Cox proportional hazards regression models were used to estimate hazard ratios, with corresponding 95% CIs based on the Wald test. Results: There were 180 patients enrolled (median [IQR] age, 47 [40-55] years; 143 [79.4%] men). Among 90 patients in the capecitabine group, 76 (84.4%) had at least 2 high-risk factors; among 90 patients in the control group, 80 (88.9%) had at least 2 high-risk factors. All patients completed CCRT, except 1 patient in the capecitabine group who received 1 cycle of cisplatin. Of the 90 patients in the capecitabine group, 85 (94.4%) received capecitabine, with 71 (78.9%) completing 8 cycles. With a median (IQR) follow-up of 58.0 (49.5-80.1) months, 18 events were recorded in the capecitabine group vs 31 events in the control group. Failure-free survival was improved with adjuvant capecitabine (3 years, 83.3% vs 72.2%; 5 years, 78.5% vs 65.9%; hazard ratio, 0.53 [95% CI, 0.30-0.94]; P = .03). The incidence of grade 3 treatment-related adverse events (TRAEs) was higher in the capecitabine group than in the control group (54 of 90 patients [60.0%] vs 46 of 90 patients [51.1%]). Treatment-related adverse events included xerostomia (17 [18.9%] vs 9 [10.0%] patients), mucositis (21 [23.3%] vs 15 [16.7%] patients), and anorexia (8 [8.9%] vs 4 [4.4%] patients). The incidence of grade 3 delayed treatment-related adverse events was comparable in both groups (9 of 83 [10.8%] vs 7 of 81 [8.6%] patients). Conclusions and Relevance: In this randomized clinical trial, adjuvant capecitabine at the full dose following CCRT was well tolerated and improved failure-free survival among patients with LA-NPC and high-risk factors. Further investigations assessing optimal dose and duration are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02143388.

Plasma Circulating Tumor Epstein-Barr Virus for the Surveillance of Cancer Progression in Bone-Only Metastatic Nasopharyngeal Carcinoma.

Background: Plasma Epstein-Barr virus DNA (EBV-DNA) is a sensitive and specific biomarker for nasopharyngeal carcinoma (NPC). We investigated whether longitudinal monitoring of EBV-DNA could accurately detect clinical disease progression in NPC patients with bone-only metastases. Methods: In this retrospective study, a total of 105 patients with bone-only metastatic NPC who were treated with platinum-based first-line chemotherapy were enrolled. Undetectable EBV-DNA after first-line chemotherapy was defined as a biochemical complete response (BCR). The correlation of the EBV-DNA dynamic status with overall survival (OS) and progression-free survival (PFS) was determined by Cox regression. The correlation between non-normalized EBV-DNA period and PFS period was determined. Results: After a median follow-up time of 53.4 months [Interquartile range (IQR): 42.8-80.6], 64 patients had disease progression. Thirty-nine of 105 patients (37.1%) had a BCR at all follow-up time points, and none of these 39 patients had disease progression, corresponding to a negative predictive value (NPV) of 100%. Sixty-six patients had a detectable EBV-DNA during surveillance, with 64 diagnosed as disease progression at the last follow-up, for a positive predictive value (PPV) of 97.0%. Actuarial 3-year OS rates were 45.0% for patients with detectable EBV-DNA during posttreatment surveillance and 100% for patients with undetectable EBV-DNA. Lastly, median lead time between non-normalized EBV-DNA and clinically proven progression was 5.87 ± 0.67 months. Conclusions: Taken together, EBV-DNA provided predictive value for the bone-only metastatic NPC patients. The results should be validated in prospective randomized studies.

Effect of Induction Chemotherapy With Paclitaxel, Cisplatin, and Capecitabine vs Cisplatin and Fluorouracil on Failure-Free Survival for Patients With Stage IVA to IVB Nasopharyngeal Carcinoma: A Multicenter Phase 3 Randomized Clinical Trial.

Importance: Induction chemotherapy added to concurrent chemoradiotherapy significantly improves survival for patients with locoregionally advanced nasopharyngeal carcinoma, but the optimal induction regimen remains unclear. Objective: To determine whether induction chemotherapy with paclitaxel, cisplatin, and capecitabine (TPC) improves survival vs cisplatin and fluorouracil (PF) prior to chemoradiotherapy for patients with stage IVA to IVB nasopharyngeal carcinoma. Design, Setting, and Participants: This randomized, open-label, phase 3 clinical trial recruited 238 patients at 4 hospitals in China from October 20, 2016, to August 29, 2019. Patients were 18 to 65 years of age with treatment-naive, nonkeratinizing stage IVA to IVB nasopharyngeal carcinoma and an Eastern Cooperative Oncology Group performance status of 0 to 1. Interventions: Patients were randomly assigned (1:1) to receive induction chemotherapy with two 21-day cycles of TPC (intravenous paclitaxel [150 mg/m2, day 1], intravenous cisplatin [60 mg/m2, day 1], and oral capecitabine [1000 mg/m2 orally twice daily, days 1-14]) or PF (intravenous cisplatin [100 mg/m2, day 1] and fluorouracil [800 mg/m2 daily, days 1-5]), followed by chemoradiotherapy. Main Outcomes and Measures: The primary end point was failure-free survival in the intention-to-treat population. Secondary end points included distant metastasis-free survival, locoregional relapse-free survival, overall survival, tumor response, and safety. Results: Overall, 238 eligible patients (187 men [78.6%]; median age, 45 years [range, 18-65 years]) were randomly assigned to receive TPC (n = 118) or PF (n = 120). The median follow-up duration was 48.4 months (IQR, 39.6-53.3 months). Failure-free survival at 3 years was 83.5% (95% CI, 77.0%-90.6%) in the TPC group and 68.9% (95% CI, 61.1%-77.8%) in the PF group (stratified hazard ratio [HR] for recurrence or death, 0.47; 95% CI, 0.28-0.79; P = .004). Induction with the TPC regimen resulted in a significant reduction in the risk of distant metastases (stratified HR, 0.49 [95% CI, 0.24-0.98]; P = .04) and locoregional recurrence (stratified HR, 0.40 [95% CI, 0.18-0.93]; P = .03) compared with the PF regimen. However, there was no effect on early overall survival (stratified HR, 0.45 [95% CI, 0.17-1.18]; P = .10). The incidences of grade 3 to 4 acute adverse events and late-onset toxicities were 57.6% (n = 68) and 13.6% (16 of 118), respectively, in the TPC group and 65.8% (n = 79) and 17.9% (21 of 117), respectively, in the PF group. One treatment-related death occurred in the PF group. Conclusions and Relevance: This randomized clinical trial found that induction chemotherapy with 2 cycles of TPC for patients with stage IVA to IVB nasopharyngeal carcinoma improved failure-free survival compared with 2 cycles of PF, with no increase in the toxicity profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02940925.

Effect of Capecitabine Maintenance Therapy Plus Best Supportive Care vs Best Supportive Care Alone on Progression-Free Survival Among Patients With Newly Diagnosed Metastatic Nasopharyngeal Carcinoma Who Had Received Induction Chemotherapy: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: Capecitabine maintenance therapy improves survival outcomes in various cancer types, but data are limited on the efficacy and safety of capecitabine maintenance therapy in metastatic nasopharyngeal carcinoma (NPC). OBJECTIVE: To investigate the efficacy and safety of capecitabine maintenance therapy in metastatic NPC. DESIGN, SETTING, AND PARTICIPANTS: This randomized phase 3 clinical trial was conducted at Sun Yat-sen University Cancer Center from May 16, 2015, to January 9, 2020, among 104 patients with newly diagnosed metastatic NPC who had achieved disease control after 4 to 6 cycles of induction chemotherapy with paclitaxel, cisplatin, and capecitabine. The final follow-up date was May 30, 2021. All efficacy analyses were conducted in the intention-to-treat population. INTERVENTIONS: Eligible patients were randomly assigned (1:1) to receive either capecitabine maintenance therapy (1000 mg/m2 orally twice daily on days 1-14) every 3 weeks plus best supportive care (BSC) (capecitabine maintenance group) or BSC alone after 4 to 6 cycles of induction chemotherapy. MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS). Secondary end points were objective response rate, duration of response, overall survival, and safety. RESULTS: This study included 104 patients (84 men [80.8%]; median age, 47 years [IQR, 38-54 years]), with 52 assigned to the capecitabine maintenance group and 52 assigned to the BSC group. After a median follow-up of 33.8 months (IQR, 22.9-50.7 months), there were 23 events (44.2%) of progression or death in the capecitabine maintenance group and 37 events (71.2%) of progression or death in the BSC group. Median PFS survival was significantly higher in the capecitabine maintenance group (35.9 months [95% CI, 20.5 months-not reached]) than in the BSC group (8.2 months [95% CI, 6.4-10.0 months]), with a hazard ratio of 0.44 (95% CI, 0.26-0.74; P = .002). Higher objective response rates and longer median duration of response were observed in the capecitabine maintenance group (25.0%; 40.0 months) compared with the BSC group (objective response rate, 25.0% [n = 13] vs 11.5% [n = 6]; and median duration of response, 40.0 months [95% CI, not reached-not reached] vs 13.2 months [95% CI, 9.9-16.5 months]). The most common grade 3 or 4 adverse events during maintenance therapy were anemia (6 of 50 [12.0%]), hand-foot syndrome (5 of 50 [10.0%]), nausea and vomiting (3 of 50 [6.0%]), fatigue (2 of 50 [4.0%]), and mucositis (2 of 50 [4.0%]). No deaths in the maintenance group were deemed treatment-related. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, capecitabine maintenance therapy significantly improved PFS for patients with newly diagnosed metastatic NPC who achieved disease control after capecitabine-containing induction chemotherapy. Capecitabine exhibited manageable toxic effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02460419.

Long-term Survivals, Toxicities and the Role of Chemotherapy in Early-Stage Nasopharyngeal Carcinoma Patients Treated with Intensity-Modulated Radiation Therapy: A Retrospective Study with 15-Year Follow-up.

PURPOSE: This study was aimed to investigate long-term survivals and toxicities of early-stage nasopharyngeal carcinoma (NPC) in endemic area, evaluating the role of chemotherapy in stage II patients. MATERIALS AND METHODS: Totally 187 patients with newly diagnosed NPC and restaged American Joint Committee on Cancer/International Union Against Cancer 8th T1-2N0-1M0 were retrospectively recruited. All received intensity-modulated radiotherapy (IMRT)±chemotherapy (CT) from 2001 to 2010. RESULTS: With 15.7-year median follow-up, 10-year locoregional recurrence-free survival, distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were 93.3%, 93.5%, 92.9% and 88.2%, respectively. Multivariable analyses showed cervical lymph nodes positive and pre-treatment prognostic nutritional index ≥ 52.0 could independently predict DMFS (p=0.036 and p=0.011), DSS (p=0.014 and p=0.026), and OS (p=0.002 and p < 0.001); Charlson comorbidity index < 3 points could predict DSS (p=0.011); age > 45 years (p=0.002) and pre-treatment lactate dehydrogenase ≥ 240 U/L (p < 0.001) predicted OS. No grade 4 late toxicity happened; grade 3 late toxicities included subcutaneous fibrosis (4.3%), deafness or otitis (4.8%), skin dystrophy (2.1%), and xerostomia (1.1%). No differences on survivals were shown between IMRT+CT vs. IMRT alone in stage II patients, even in T2N1M0 (p > 0.05). Unsurprising, patients in IMRT+CT had more acute gastrointestinal reaction, myelosuppression, mucositis, late ear toxicity, and cranial nerve injury (all p < 0.05) than IMRT alone group. CONCLUSION: Superior tumor control and satisfying long-term outcomes could be achieved with IMRT in early-stage NPC with mild late toxicities. As CT would bring more toxicities, it should be carefully performed to stage II patients.

Assessment of Survival Model Performance Following Inclusion of Epstein-Barr Virus DNA Status in Conventional TNM Staging Groups in Epstein-Barr Virus-Related Nasopharyngeal Carcinoma.

Importance: Nonanatomic prognostic factors complement the traditional anatomic staging system and could be incorporated into the tumor-node-metastasis (TNM) framework. Several diseases have incorporated nonanatomic prognostic factors into the determination of TNM staging groups. Objective: To refine TNM staging groups for Epstein-Barr virus (EBV)-related nonmetastatic nasopharyngeal carcinoma (NPC) by incorporating EBV DNA status. Design, Setting, and Participants: This multicenter prognostic study included patients with NPC treated with radiotherapy at 2 hospitals in China from January 2008 to December 2016. Progression-free survival and overall survival according to EBV DNA status and the TNM staging system were compared. Recursive partitioning analysis (RPA) combined with supervised clustering was applied to derive prognostic groupings, and then a refined RPA staging schema was developed, validated, and compared with existing staging schemes. Statistical analyses were conducted from October 1, 2020, to June 15, 2021. Exposures: Curative intensity-modulated radiotherapy with or without platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival. The performance of the staging system was assessed using the time-dependent area under the receiver operating characteristic curves and the TNM stage system's evaluation methodology. Results: A total of 2354 patients (1709 men [72.6%]; median [interquartile range] age, 45 [38-53] years) were split into training (1372 [58.3%]), internal validation (672 [28.5%]), and external validation (310 [13.2%]) cohorts. Pretreatment EBV DNA was detected in 1338 (56.8%) patients. EBV DNA status was an independent prognostic factor: lower survival probability by higher TNM stage was evident in EBV DNA-positive patients but not in those with EBV DNA-negative disease. After integrating EBV DNA status and TNM stage, nonmetastatic NPC cases were categorized into RPA-I (T1-3N0 or EBV DNA-negative T1-3N1 cancers), RPA-II (EBV DNA-positive T1-3N1-2 or EBV DNA-negative T1-3N2-3/T4N0-3 cancers), and RPA-III (EBV DNA-positive T4N0-3/T1-3N3 cancers) groups, each with distinctly different prognosis. This system of RPA staging outperformed the current TNM stage system and 2 reported RPA staging schemes. These results were internally and externally validated. Conclusions and Relevance: An RPA-based staging system for EBV-related NPC cases was associated with improved outcomes. This staging system may facilitate prognostic stratification and clinical trial designs.

Trajectories of EBV DNA and identifying the potential long-term survivors in metastatic nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is highly incident in southern China. Distant metastasis is the leading cause of death in NPC patients. However, the phenotypical feature of this patient population is largely undefined. The current study aimed to categorize metastatic NPC patients into novel subgroups based on their EBV DNA trajectories. In this retrospective study, 446 eligible patients with metastatic NPC treated at Sun Yat-Sen University Cancer Center between 2012 and 2016 were analyzed. Using a mixture model analysis, we identified distinct trajectories based on longitudinal EBV DNA measurements. We evaluated their associations with metastatic NPC mortality using Cox regression analysis. The two-class trajectory model provided the best fit, in which 272 patients were classified as non-sustained EBV DNA class and 174 patients as sustained EBV DNA class. After a median follow-up of 60.8 months, the median OS was 61.7 months in the sustained EBV DNA clearance class versus 20.0 months in the non-sustained EBV DNA clearance class (P<0.001). Compared with patients in the non-sustained EBV DNA clearance class, patients in the sustained EBV DNA clearance class demonstrated superior PFS (HR, 3.238; 95% CI, 2.601-4.032; P<0.001). Forty-three patients experienced disease-free for longer than 36 months, defined as long-term survivors (LTS). Notably, 41 patients were presented in the sustained EBV DNA clearance class (95.3%), along with only 2 patients in the non-sustained EBV DNA clearance class. Collectively, we identified two EBV DNA trajectory sub-phenotypes of patients with metastatic NPC, providing more reliable survival information for physicians and patients during their informed decision-making process.

Prognostic and Predictive Value of Circulating Inflammation Signature in Non-Metastatic Nasopharyngeal Carcinoma: Potential Role for Individualized Induction Chemotherapy.

PURPOSE: We sought to assess the prognostic and predictive value of a circulating inflammation signature (CISIG) and develop CISIG-based tools for predicting prognosis and guiding individualized induction chemotherapy (ICT) in non-metastatic nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: We retrospectively collected a candidate inflammatory biomarker panel from patients with NPC treated with definitive radiotherapy between 2012 and 2017. We developed the CISIG using candidate biomarkers identified by a least absolute shrinkage and selection operator (LASSO) Cox regression model. The Cox regression analyses were used to evaluate the CISIG prognostic value. A CISIG-based prediction model was constructed, validated, and assessed. Potential stratified ICT treatment effects were examined. RESULTS: A total of 1149 patients were analyzed. Nine biomarkers selected by LASSO regression in the training cohort were used to construct the CISIG, including hyaluronidase, laminin, procollagen III, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, high-density lipoprotein, lactate dehydrogenase, and C-reactive protein-to-albumin ratio. CISIG was an independent prognostic factor for disease-free survival (DFS; hazard ratio: 2.65, 95% confidence interval: 1.93-3.64; P < 0.001). High CISIG group (>-0.2) was associated with worse 3-year DFS than low CISIG group in both the training (67.5% vs 88.3%, P < 0.001) and validation cohorts (72.3% vs 85.1%, P < 0.001). We constructed and validated a CISIG-based nomogram, which showed better performance than the clinical stage and Epstein-Barr virus DNA classification methods. A significant interaction between CISIG and the ICT treatment effect was observed (P for interaction = 0.036). Patients with high CISIG values did not benefit from ICT, whereas patients with low CISIG values significantly benefited from ICT. CONCLUSION: The developed CISIG, based on a circulating inflammatory biomarker panel, adds prognostic information for patients with NPC. The proposed CISIG-based tools offer individualized risk estimation to facilitate suitable ICT candidate identification.