Induction Chemotherapy Followed by Radiotherapy vs Chemoradiotherapy in Nasopharyngeal Carcinoma: A Randomized Clinical Trial.

Importance: Induction chemotherapy plus concurrent chemoradiotherapy is recommended for locoregionally advanced nasopharyngeal carcinoma but is associated with higher rates of acute toxic effects and low compliance. Evidence on de-escalating treatment intensity after induction chemotherapy is limited. Objective: To assess if radiotherapy was noninferior to chemoradiotherapy after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma. Design, Setting, and Participants: From April 2015 to March 2018, a multicenter, open-label, randomized, noninferiority, phase 3 trial was conducted at 5 Chinese hospitals. A total of 383 patients aged 18 to 70 years with an untreated histologically confirmed nonkeratinizing tumor, Karnofsky performance status score not worse than 70, proper organ function, and stage III to IVB nasopharyngeal cancer were enrolled. Data were analyzed from April 2023 to June 2023. Interventions: Patients were assigned randomly. Both groups received 3 cycles of induction chemotherapy consisting of intravenous administration (on day 1) of cisplatin at 60 mg/m2 and docetaxel at 60 mg/m2 and continuous intravenous infusion (from day 1 to day 5) of daily fluorouracil (600 mg/m2), repeated every 21 days. Subsequently, the patients received radiotherapy alone (induction chemotherapy in combination with radiotherapy [IC-RT] group) or concomitant cisplatin (30 mg/m2/week) with radiotherapy for 6 to 7 weeks (induction chemotherapy combined with chemoradiotherapy [IC-CCRT] group). Main Outcomes and Measures: The primary end point was 3-year progression-free survival (time from the initiation of therapy until the first indication of disease progression or death), with a noninferiority margin of 10%. The secondary end points included overall survival, locoregional failure-free survival, distant metastasis-free survival, response rate, and toxic effects. Results: A total of 383 patients (median [range] age, 48 [19-70] years; 100 women [26%]). Median follow-up time was 76 months (IQR, 70-89 months). The 3-year progression-free survival was 76.2% and 76.8% in the IC-RT (n = 193) and IC-CCRT groups (n = 190), respectively, in the intention-to-treat population, showing a difference of 0.6% (95% CI, -7.9% to 9.1%; P = .01 for noninferiority). Identical outcomes were reported in the per-protocol population. The incidence of grade 3 to 4 short-term toxic effects in the IC-RT group was less than the IC-CCRT group. No differences were observed in late toxic effects. Conclusions and Relevance: The results of this randomized clinical trial suggest that after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma, radiotherapy alone was noninferior to chemoradiotherapy in terms of 3-year progression-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT02434614.

Intensity-modulated radiotherapy alone compared with intensity-modulated radiotherapy plus concurrent chemotherapy in intermediate-risk nasopharyngeal carcinoma : A prospective multicenter phase II trial.

BACKGROUND: This study aimed to investigate the clinical benefit of adding concurrent chemotherapy to intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) patients with an intermediate risk (stage II and T3N0M0). METHODS: A multicenter phase II randomized trial was conducted in intermediate-risk NPC patients. Enrolled patients were previously untreated and aged ranged from 18 to 70 years without severe coexisting diseases. Patients were randomly assigned to receive IMRT alone or IMRT+concurrent chemotherapy (CC; three cycles of 80 mg/m2 cisplatin every 3 weeks). Primary endpoint was defined as 3­year progression-free survival (PFS). The secondary endpoints were distant metastasis-free survival (DMFS), locoregional relapse-free survival (LRRFS), overall survival (OS), and treatment-associated toxicity. We registered this study with Chinese Clinical Trial Registry (CliCTR1800017132; registered July 13, 2018, study start July 13, 2018). RESULTS: From November 2015 to July 2019, 42 patients with stage II and T3N0M0 NPC were enrolled; 20 patients received IMRT alone while 22 patients received IMRT+CC. After a median of 58 months of follow-up, we estimated the 3­year PFS rates as 90% (IMRT group) and 86.4% (IMRT+CC group; hazard ratio 1.387, 95% confidence interval 0.240-8.014; P = 0.719). The 3­year PFS, OS, and cumulative DMFS and LRRFS showed no significant differences between the two groups (P > 0.05). However, the IMRT group displayed a lower incidence of nausea/vomiting, leucopenia, and dry mouth than the IMRT+CC group. CONCLUSION: Adding CC to IMRT provided no survival benefit but increased treatment-associated toxicities in patients with intermediate-risk NPC.

Development and validation of an individualized angiogenesis and tumor-infiltrating lymphocytes prognostic signature in nasopharyngeal carcinoma.

In recent years, targeted therapy and immunotherapy have become ideal choices for the treatment of advanced, metastatic, recurrent, and drug-resistant nasopharyngeal carcinoma (NPC), but the lack of understanding of the relationship and mechanism between TILs and angiogenic factors hinders therapeutic development and optimization. In this study, the expression of angiogenesis-related markers (VEGF-A,VEGFR-2) and TILs (CD4+T,CD8+T) was studied by using immunohistochemistry (IHC). Then we constructed an immunohistochemical scoring model for the co-expression of angiogenesis-related markers and TILs (COV+TIL score)in the training (n = 124) and validated the accuracy and reliability of the scoring system in the validation cohorts (n = 114), respectively We established the COV+TIL score model and stratified patients into different risk level in the training cohorts according to COV+TIL score (cut-off value=28). Patients in the high-risk group had worse prognosis in the training cohorts five-year overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) was lower than that of patients in the low-risk group, and this result was validated in the validation cohorts ( 5-year OS in the high-risk and the low-risk group 46.8% vs. 83.4%, HR: 3.42, 95%CI: 1.77-6.61, p < 0.001); ( 5-year PFS 45.9% vs. 81.2%, HR: 3.22, 95%CI: 1.71-6.06, p < 0.001); ( 5-year LRRFS 74.6% vs. 87.5%, HR: 3.22, 95%CI: 1.16-8.93, p = 0.027); and ( 5-year DMFS79.2% vs. 93.2%, HR: 2.22, 95%CI: 0.91-5.39, p = 0.086). Upon multivariable analysis, COV+TIL score emerged as an independent prognostic indicator for defining survival in the training cohorts and the validation cohorts. Combining the COV+TIL score and TNM stage improved the prediction ability of the survival. In conclusion, NPC patients with high COV+TIL score showed worse prognosis.

Effectiveness and safety of anlotinib with or without S-1 in the treatment of patients with advanced hepatocellular carcinoma in a Chinese population: a prospective, phase 2 study.

BACKGROUND: The aim of the study was to observe the safety and efficacy of anlotinib (ANL) alone or combined with S-1 in the first-line treatment of advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Fifty-four patients with untreated advanced HCC who could not be resected were randomly divided into the ANL group (n = 27) and ANL+S-1 group (n = 27). The ANL group was given 10 mg ANL orally once a day for 14 consecutive days, stopped for 1 week, and repeated every 21 days. The ANL+S-1 group was given 10 mg ANL once a day orally and 40 mg S-1 twice a day orally for 14 consecutive days, stopped for 1 week, repeated every 21 days. All patients were treated until the disease progressed or toxicity became unacceptable. For patients who could not tolerate adverse reactions, the ANL dose should be reduced to 8 mg per day. CT or MRI was reviewed every 6 weeks to evaluate the efficacy. RESULTS: A total of 44 patients were included in the results analysis, including 22 patients in the ANL group and 22 patients in the ANL+S-1 group. In the ANL group, the objective response rate (ORR) was 4.5% (1/22), the disease control rate (DCR) was 77.3% (17/22), the median progression-free survival (PFS) was 4.2 months (95% CI: 3.6-6.0) and the median overall survival (mOS) was 7.0 months (95% CI: 6.3-9.0). In the ANL+S-1 group, the ORR was 18.2% (4/22), the DCR was 59.1% (13/22), the median PFS was 4.0 months (95% CI: 3.6-5.4) and the mOS was 6.0 months (95% CI: 5.5-7.4). There was no significant difference in ORR (p = 0.345) or DCR (p = 0.195) between the two groups. Adverse reactions were mainly hypertension, anorexia, fatigue, liver transaminase heightened and hand and foot skin reaction. CONCLUSIONS: ANL monotherapy was effective in the treatment of advanced HCC, and adverse reactions have been able to tolerated.

Hypofractionated radiotherapy compared with conventionally fractionated radiotherapy to treat initial distant metastases in nasopharyngeal carcinoma: A multicenter, prospective, randomized, phase II trial.

BACKGROUND AND PURPOSE: To investigate the safety and efficacy of hypofractionated plus chemotherapy in patients with initially distant metastatic nasopharyngeal carcinoma (mNPC). MATERIALS AND METHODS: Between May 2014 and June 2020, 35 patients initially diagnosed with mNPC were enrolled on prospective trial. The enrolled patients were assigned randomly to receive either hypofractionated plus chemotherapy (HFRT) or conventionally fractionated radiotherapy plus chemotherapy (CFRT). 60 Gy over 25 fractions was administered to the HFRT group (n = 17) and 69.96 Gy over 33 fractions was administered to the CFRT group (n = 18), both groups five times each week.Progression free survival (PFS) comprised the primary endpoint. Overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and acute and late toxicity comprised the secondary endpoints. RESULTS: Twenty-eight patients (seven were excluded) were enrolled. The 2-year PFS was 33.3% (HFRT group) versus 30.0% (CFRT group) (stratified hazard ratio (HR):1.09; 95% confidence interval (CI): 0.45-2.65, P = 0.843). The 2-year OS was 66.7% (HFRT group) versus with 62.5% (CFRT group) (stratified HR, 0.88; 95% CI; 0.31-2.51, P = 0.806). All patients experienced acute grade 1 or 2, skin toxicity, oral mucositis, difficulty swallowing, xerostomia, but no acute grade 3 or 4 toxicities. All patients had grade 1 late xerostomia. Two patients experienced hearing loss in the HFRT group (one grade 1 and one grade 3), and three patients experienced grade 1 hearing loss in the CFRT group. One patient developed mucosal necrosis in the HFRT group. CONCLUSION: Improving the balance between severe late toxicities and local control by appropriately reducing the total dose but increasing the fractionated dose has marked clinical significance for those patients.

Apatinib combined with camrelizumab in the treatment of recurrent/metastatic nasopharyngeal carcinoma: a prospective multicenter phase II study.

Background: Preclinical studies demonstrated that immune checkpoint inhibitors combined with antiangiogenic drugs have a synergistic anti-tumor effect. This present phase II trial aimed to evaluate the efficacy and safety of apatinib combined with camrelizumab in patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC). Methods: Patients with RM-NPC were administered with apatinib at 250 mg orally once every day and with camrelizumab at 200 mg via intravenous infusion every 2 weeks until the disease progressed or toxicity became unacceptable. The objective response rate (ORR) was the primary endpoint, assessed using RECIST version 1.1. Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were the key secondary endpoints. This study was registered with ClinicalTrials.gov, NCT04350190. Results: This study enrolled 26 patients with RM-NPC between January 14, 2021 and September 15, 2021. At data cutoff (March 31, 2023), the median duration of follow-up was 16 months (ranging from 1 to 26 months). The ORR was 38.5% (10/26), the disease control rate (DCR) was 61.5% (16/26), and the median PFS was 6 months (IQR 3.0-20.0). The median OS was 14 months (IQR 6.0-21.25). Treatment-related grade 3 or 4 adverse events occurred in seven (26.9%) patients, and comprised anemia (7.7%), stomatitis (3.8%), headache (3.8%), pneumonia (7.7%), and myocarditis (3.8%). There were no serious treatment-related adverse events or treatment-related deaths. Conclusion: In patients with RM-NPC, apatinib plus camrelizumab showed promising antitumor activity and manageable toxicities.

Nomogram for distant metastasis-free survival in patients with locoregionally advanced nasopharyngeal carcinoma.

OBJECTIVE: To develop and validate a nomogram to predict distant metastasis-free survival of patients with locoregionally advanced nasopharyngeal carcinoma. METHODS: We collected the total clinical data of 820 nasopharyngeal carcinoma (NPC) patients, of whom 482 formed the training cohort from one hospital and 328 made up the validation cohort from another hospital. By analyzing the prognosis of all patients after intensity-modulated radiotherapy by univariate and multivariate Cox regression models, a nomogram related to DMFS was created in the training cohort. The discriminatory and calibration power of the nomogram was successively assessed in the training and validation cohorts by the C­index and calibration curve. The predictive ability for 3­year DMFS was compared between the nomogram and TNM stage using ROC curves. Patients were divided into different risk groups based on scores calculated from the nomogram. RESULTS: Age, lymph node gross tumor volume (GTVnd), and gross tumor volume of the nasopharynx (GTVnx) were the factors included in the nomogram. The C­index of the nomogram was 0.721 in the training cohort and 0.750 in the validation cohort. The calibration curves were satisfactory. Patients in the high-risk group were more likely to develop metastases. CONCLUSION: A nomogram incorporating age, GTVnd, and GTVnx showed good performance for predicting DMFS in patients with locoregionally advanced NPC.

A systematic review and meta-analysis of fluorescent-guided resection and therapy-based photodynamics on the survival of patients with glioma.

Glioma is the most common primary central nervous system tumor; many methods are currently being used to research and treat glioma. In recent years, fluorescent-guided resection (FGR) and photodynamic therapy (PDT) have become hot spots in the treatment of glioma. Based on the existing literatures regarding the FGR enhancing resection rate and regarding efficacy of PDT for the treatment of glioma, this paper made a systematic review of FGR for gross total resection of patients and the PDT for the survival of patients with glioma. Meta-analysis of eligible studies was performed to derive precise estimation of PDT on the prognosis of patients with glioma by searching all related literatures in PubMed, EMBASE, Cochrane, and Web of Science databases, and further to evaluate (GTR) under FGR and the efficacy of PDT therapy, including 1-year and 2-year survival rates, overall survival (OS), and progression-free survival (PFS). According to the inclusion and exclusion criteria, a total of 1294 patients with glioma were included in the final analysis of 31 articles, among which a 73.00% (95% CI, 68.00 ~ 79.00%, P < 0.01) rate of GTR in 27 groups included in 23 articles was reported for those receiving FGR. The OS was 17.78 months (95% CI, 8.89 ~ 26.67, P < 0.01) in 5 articles on PDT-treated patients with glioma, and the mean difference of OS was 6.18 (95% CI, 3.3 ~ 9.06, P < 0.01) between PDT treatment and conventional glioma surgery, showing a statistically significant difference (P < 0.01). The PFS was 10.82 months (95% CI, 7.04 ~ 14.61, P < 0.01) in 5 articles on PDT-treated patients with glioma. A 1-year survival rate of 59.00% (95% CI, 38.00 ~ 77.00%, P < 0.01) in 10 groups included in 8 articles and 2-year survival rate of 25.00% (95% CI, 15.00 ~ 36.00%, P < 0.01) in 7 groups included in 6 articles were reported for those with PDT. FGR and PDT are feasible for treatment of patients with glioma, because FGR can effectively increase the resection rate, at the same time, PDT can prolong the survival time. However, due to the limitation of small sample size in the existing studies, larger samples and randomized controlled clinical trials are needed to analyze the resection under FGR and efficacy of PDT in patients with glioma.

Impact of the weekday of the first intensity-modulated radiotherapy treatment on the survival outcomes of patients with nasopharyngeal carcinoma: A multicenter cohort study.

BACKGROUND: This study's purpose was to assess whether the weekday on which intensity-modulated radiotherapy (IMRT) is initiated influences survival outcomes in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: A total of 1440 patients with NPC who received IMRT were enrolled in this study between January 2010 and June 2016. The patients were divided into five groups according to the weekday of their first radiotherapy treatment. Group 1 (n = 322), Group 2 (n = 322), Group 3 (n = 286), Group 4 (n = 292) and Group 5 (n = 218) received first radiotherapy on Monday, Tuesday, Wednesday, Thursday and Friday respectively. Differences in the rates of overall survival (OS), disease-free survival (DFS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS) were compared among the five groups using the Kaplan-Meier method and Cox regression models. RESULTS: No significant differences were found in OS, DFS, LRRFS or DMFS among the five groups. The Cox regression analysis showed that the weekday on which the radiotherapy was initiated was not an independent predictor of OS (Hazard Ratio [HR], 1.056; 95%CI: 0.959-1.164, P = 0.268), DFS (HR, 1.067; 95% CI: 0.980-1.161, P = 0.137), LRRFS (HR, 1.069; 95% CI: 0.914-1.249, P = 0.404) and DMFS (HR, 1.027; 95% CI: 0.929-1.134, P = 0.607). The subgroup analysis showed no significant differences among the five groups. CONCLUSIONS: This study showed that the day of the week that patients with nasopharyngeal carcinoma begin radiotherapy has no effect on their survival outcomes.

Feasibility and efficiency of double-agent versus single-agent concurrent chemoradiotherapy in patients with nasopharyngeal carcinoma.

PURPOSE: Concurrent chemoradiotherapy (CCRT) is the mainstay of treatment for nasopharyngeal carcinoma (NPC) patients. It remains unclear whether double-agent CCRT (d-CCRT) is more effective than single-agent CCRT (s-CCRT). In this study, we compared the treatment efficiency and toxicity of d-CCRT with s-CCRT in NPC patients. METHODS AND MATERIALS: Patients with stage II-IV NPC treated with d-CCRT or s-CCRT were retrospectively reviewed. The d-CCRT group patients were compared with s-CCRT group patients for overall survival (OS), locoregional relapse-free survival (LRRFS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and toxicity. Differences in baseline characteristics were adjusted using the pair-matching method. RESULTS: In this study, 933 patients who received CCRT for NPC between 2011 and 2014 were pair-matched at a 1:2 ratio (n = 311 for d-CCRT; n = 622 for s-CCRT). The d-CCRT treated patients showed no significant advantages in terms of 4-year OS (87.2% vs. 85.5%), DFS (84.1% vs. 79.5%), LRRFS (94.6% vs. 91.8%), DMFS (87.5% vs. 85.5%) compared with s-CCRT treated patients (P = 0.450, 0.106, 0.203, 0.366, respectively). Multivariate analysis showed that CCRT regimen had no significant effects on survival. In the d-CCRT group, the incidence of grade 3-4 hematological toxicities was significantly higher. CONCLUSIONS: The d-CCRT regimen did not confer significant survival benefits compared with the s-CCRT regimen in the treatment of stage II-IV NPC patients. Furthermore, patients treated with the d-CCRT regimen experienced greater hematological toxicity.

Electrochemical sulfonylation of alkenes with sulfonyl hydrazides: a metal- and oxidant-free protocol for the synthesis of (E)-vinyl sulfones in water.

An efficient electrochemical transformation of a variety of alkenes and sulfonyl hydrazides into vinyl sulfones with a catalytic amount of tetrabutylammonium iodide in water is reported. The reaction proceeds smoothly to afford vinyl sulfones with good selectivities and yields at room temperature under air in an undivided cell. Cyclic voltammograms and control experiments have been performed to provide preliminary insight into the reaction mechanism. The key features of this reaction include using pure water as solvent, transition metal- and oxidant-free conditions, and being easily scaled up to gram-scale synthesis.

[Determination of the eliminating ratio of TCM polysaccharide to hydroxyl radical by kinetic fluorescent spectrophotometry].

OBJECTIVE: To explore reaction dynamic of hydroxyl radical (*OH) and salicylic acid,and to determine the elimination ratios of TCM polysaccharide to *OH by kinetic fluorescent analysis. METHODS: The impact dynamics factors of this reaction were studied by fluorescent, such as the reaction of concentration, reaction time and temperature. The dynamical equation was built, a kinetic fluorescent spectrophotometry based on the reaction was developed to determine the elimination ratio. Repetitiveness and reliability of this method were tested by vitamin C. RESULTS: The dynamical equation of reaction rate to salicylic acid was gamma = 0. 9818x -1. 1801 under the condition of lambda ex = 295 nm, lambda em = 411 nm at room temperature, r approximately 1. The 50% elimination ratio (IC50) of TCM polysaccharide of Tangerine peel and Ganoderma lucidum to *OH was 78.01 mg/L and 232.5 mg/L, respectively. The IC50 of vitamin C was 24.52 microg/L, RSD was 0.23% (n = 5). CONCLUSIONS: The method is sensitive and reliable, it can be used to determine the elimination ratio of TCM polysaccharide to *OH.

[Analysis on the volatile oil of Xinhui Pericarpium Citri Reticulatae in different years by GC/MS].

OBJECTIVE: To analyze the difference of the volatile oil of Xinhui Pericarpium Citri Reticulatae in different years. METHODS: The components and contents of the volatile oil of Xinhui Pericarpium Citri Reticulatae were analyzed in different years by GC/MS. RESULTS: The components and contents of the volatile oil of Xinhui Pericarpium Citri Reticulatae changed along with the years. CONCLUSION: With the years' extension, the components of the volatile oil changed slowly during 3 years but quickly after 3 years, a few new components appeared evenly, So there's relevance between using old Xinhui Pericarpium Citri Reticulatae and its component changing.

Dual fluorescence/contactless conductivity detection for microfluidic chip.

A new dual detection system for microchip is reported. Both fluorescence detector (FD) and contactless conductivity detector (CCD) were combined together and integrated on a microfluidic chip. They shared a common detection position and responded simultaneously. A blue light-emitting diode was used as excitation source and a small planar photodiode was used to collect the emitted fluorescence in fluorescence detection, which made the device more compact and portable. The coupling of the fluorescence and contactless conductivity modes at the same position of a single separation channel enhanced the detection characterization of sample and offered simultaneous detection information of both fluorescent and charged specimen. The detection conditions of the system were optimized. K(+), Na(+), fluorescein sodium, fluorescein isothiocyanate (FITC) and FITC-labeled amino acids were used to evaluate the performance of the dual detection system. The limits of detection (LOD) of FD for fluorescein Na(+), FITC, FITC-labeled arginine (Arg), glycine (Gly) and phenylalanine (Phe) were 0.02micromolL(-1), 0.05micromolL(-1), 0.16micromolL(-1), 0.15micromolL(-1), 0.12micromolL(-1) respectively, and the limits of detection (LOD) of CCD achieved 0.58micromolL(-1) and 0.39micromolL(-1) for K(+) and Na(+) respectively.