Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Adjuvant Apatinib in Nasopharyngeal Carcinoma With Residual Epstein-Barr Virus DNA After Radiation Therapy: A Biomarker-Driven, Phase 2 Trial.

PURPOSE: 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. METHODS AND MATERIALS: 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 DNA > 0 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). RESULTS: 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). CONCLUSIONS: 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.

Computed Tomography-Based Evaluation of Volume and Position Changes of the Target Region and Organs at Risk During Radiotherapy for Esophageal Cancer: A Pilot Study.

OBJECTIVE: To analyze changes in volume and position of target regions and organs at risk (OARs) during radiotherapy for esophageal cancer patients. METHODS: Overall, 16 esophageal cancer patients who underwent radiotherapy, including 10 cases of intensity-modulated radiation therapy (IMRT) and six of three-dimensional conformal radiotherapy (3D-CRT), were enrolled. The prescription doses for the planning target volumes (PTVs) were as follows: PTV1, 64 Gy/32 fractions; and PTV2, 46 Gy/23 fractions. Repeat computed tomography (CT) was performed for patients after the 5th, 10th, 15th, 20th, and 25th fractions. Delineation of the gross tumor volume (GTV) and OAR volume was determined using five repeat CTs performed by the same physician. The target and OAR volumes and centroid positions were recorded and used to analyze volume change ratio (VCR), center displacement (ΔD), and changes in the distance from the OAR centroid positions to the planned radiotherapy isocenter (distance to isocenter, DTI) during treatment. RESULTS: No patient showed significant changes in target volume (TV) after the first week of radiotherapy (five fractions). However, TV gradually decreased over the following weeks, with the rate slowing after the fourth week (40 Gy). The comparison of TV from baseline to 40 Gy (20 fractions) showed that average GTVs decreased from 130.7 ± 63.1 cc to 92.1 ± 47.2 cc, with a VCR of -29.21 ± 13.96% (p<0.01), while the clinical target volume (CTV1) decreased from 276.7 ± 98.2 cc to 246.7 ± 87.2 cc, with a VCR of -10.34 ± 7.58% (p<0.01). As TVs decreased, ΔD increased and DTI decreased. After the fourth week of radiotherapy (40 Gy), centroids of GTV, CTV1, and prophylactic CTV (CTV2) showed average deviations in ΔD of 7.6 ± 4.0, 6.9 ± 3.4, and 6.0 ± 3.0 mm, respectively. The average DTI of the heart decreased by 4.53 mm (from 15.61 ± 2.96 cm to 15.16 ± 2.27 cm). CONCLUSION: During radiotherapy for esophageal cancer, Targets and OARs change significantly in volume and position during the 2nd-4th weeks. Image-guidance and evaluation of dosimetric changes are recommended for these fractions of treatment to appropriate adjust treatment plans.

Development of a Comorbidity-Based Nomogram to Predict Survival After Salvage Reirradiation of Locally Recurrent Nasopharyngeal Carcinoma in the Intensity-Modulated Radiotherapy Era.

PURPOSE: To assess the impact of comorbidity on treatment outcomes in patients with locally recurrent nasopharyngeal carcinoma (lrNPC) using intensity-modulated radiotherapy (IMRT) and to develop a nomogram that combines prognostic factors to predict clinical outcome and guide individual treatment. METHODS: This was a retrospective analysis of patients with lrNPC who were reirradiated with IMRT between 2003 and 2014. Comorbidity was evaluated by Adult Comorbidity Evaluation-27 grading (ACE-27). The significant prognostic factors (P < 0.05) by multivariate analysis using the Cox regression model were adopted into the nomogram model. Harrell concordance index (C-index) calibration curves were applied to assess this model. RESULTS: Between 2003 and 2014, 469 lrNPC patients treated in our institution were enrolled. Significant comorbidity (moderate or severe grade) was present in 17.1% of patients by ACE-27. Patients with no or mild comorbidity had a 5-year overall survival (OS) rate of 36.2 versus 20.0% among those with comorbidity of moderate or severe grade (P < 0.0001). The chemotherapy used was not significantly different in patients with lrNPC (P > 0.05). For the rT3-4 patients, the 5-year OS rate in the chemotherapy + radiation therapy (RT) group was 30.0 versus 16.7% for RT only (P = 0.005). The rT3-4 patients with no or mild comorbidity were associated with a higher 5-year OS rate in the chemotherapy + RT group than in the RT only group (32.1 and 17.1%, respectively; P=0.003). However, for the rT3-4 patients with a comorbidity (moderate or severe grade), the 5-year OS rate in the chemotherapy + RT group vs. RT alone was not significantly different (15.7 vs. 15.0%, respectively; p > 0.05). Eight independent prognostic factors identified from multivariable analysis were fitted into a nomogram, including comorbidity. The C-index of the nomogram was 0.715. The area under curves (AUCs) for the prediction of 1-, 3-, and 5-year overall survival were 0.770, 0.764, and 0.780, respectively. CONCLUSION: Comorbidity is among eight important prognostic factors for patients undergoing reirradiation. We developed a nomogram for lrNPC patients to predict the probability of death after reirradiation and guide individualized management.

Retrospective dosimetry study of intensity-modulated radiation therapy for nasopharyngeal carcinoma: measurement-guided dose reconstruction and analysis.

BACKGROUND: Conventional phantom-based planar dosimetry (2D-PBD) quality assurance (QA) using gamma pass rate (GP (%)) is inadequate to reflect clinically relevant dose error in intensity-modulated radiation therapy (IMRT), owing to a lack of information regarding patient anatomy and volumetric dose distribution. This study aimed to evaluate the dose distribution accuracy of IMRT delivery for nasopharyngeal carcinoma (NPC), which passed the 2D-PBD verification, using a measurement-guided 3D dose reconstruction (3D-MGR) method. METHODS: Radiation treatment plans of 30 NPC cases and their pre-treatment 2D-PBD data were analyzed. 3D dose distribution was reconstructed on patient computed tomography (CT) images using the 3DVH software and compared to the treatment plans. Global and organ-specific dose GP (%), and dose-volume histogram (DVH) deviation of each structure was evaluated. Interdependency between GP (%) and the deviation of the volumetric dose was studied through correlation analysis. RESULTS: The 3D-MGR achieved global GP (%) similar to conventional 2D-PBD in the same criteria. However, structure-specific GP (%) significantly decreased under stricter criteria, including the planning target volume (PTV). The average deviation of all inspected dose volumes (DV) and volumetric dose (VD) parameters ranged from - 2.93% to 1.17%, with the largest negative deviation in V100% of the PTVnx of - 15.66% and positive deviation in D1cc of the spinal cord of 6.66%. There was no significant correlation between global GP (%) of 2D-PBD or 3D-MGR and the deviation of the most volumetric dosimetry parameters (DV or VD), when the Pearson's coefficient value of 0.8 was used for correlation evaluation. CONCLUSION: Even upon passing the pre-treatment phantom based dosimetric QA, there could still be risk of dose error like under-dose in PTVnx and overdose in critical structures. Measurement-guided 3D volumetric dosimetry QA is recommended as the more clinically efficient verification for the complicated NPC IMRT.

Correction to: Retrospective dosimetry study of intensity-modulated radiation therapy for nasopharyngeal carcinoma: measurement-guided dose reconstruction and analysis.

The original version of this article [1] unfortunately contained a mistake.

Dosimetric Effects of Head and Neck Immobilization Devices on Multi-field Intensity Modulated Radiation Therapy for Nasopharyngeal Carcinoma.

Background: In practice, the dose perturbation effect of head and neck immobilization devices is often overlooked in intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC). Purpose of this study is to verify and analyze the dosimetric effect of head and neck immobilization devices on NPC multi-field IMRT. Methods: Ten patients with nasopharyngeal carcinoma were randomly selected. Two sets of body contours were established for each patient. One set of body contours did not contain the immobilization device, and the other contour set included the immobilization device. For each patient, dose calculations were conducted for the two sets of contours using the same 9-field IMRT plan, which were recorded as Plan- and Plan+. The dose difference caused by the head and neck immobilization devices was assessed by comparing the dose-volume histogram (DVH) parameter results and by plan subtraction. The gafchromic EBT3 film and anthropomorphic phantom were used to verify the calculated doses. Results: The target coverage and average dose of Plan+ were lower than those of Plan- : the prescription dose coverage rates for PTVnx, PTVnd, PTV1 and PTV2 decreased by 2.4%, 9.9%, 1.5%, and 3.6%, respectively, and the mean doses were reduced by 0.9%, 1.9%, 1.1%, and 1.5%, respectively. Doses in the organs at risk showed no significant differences or slight reductions (the maximum reduction in mean dose was 1.7%). From the EBT3 measurements, the skin dose on the posterior neck was increased by approximately 53%. Conclusion: The attenuation and bolus effects of the head and neck immobilization device reduce dose coverage rate and average dose of the planning target volumes in nasopharyngeal carcinoma and lead to an increase in the skin dose. During treatment planning and dose calculation, the immobilization device should be included within body contour to account for the dose attenuation and skin dose increment.

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

Purpose: The benefits of additional use of nimotuzumab (NTZ) in the treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is largely unclear. We aim to compare LA-NPC treatment outcomes in patients that received CCRT with nimotuzumab (NTZ) to patients that received CCRT only. Materials and Methods: Between October 2009 and January 2012, 31 previously untreated and newly diagnosed LA-NPC patients were administered CCRT (3 cycles of 100 mg/m2 cisplatin every third week with intensity-modulated radiotherapy) plus NTZ according to an IRB-approved institutional research protocol. A well-balanced cohort of 62 patients who received CCRT alone was created by matching each patient who received CCRT plus NTZ via propensity-matched analysis in a 2:1 ratio. Results: Compared with CCRT only, CCRT plus NTZ was significantly associated with superior overall survival (5-year OS; 96.8% vs. 82.3%; P = 0.001), superior distant metastasis-free survival (5-year DMFS; 90.3% vs. 80.6%, P = 0.012) and superior progression-free survival (5-year PFS; 83.9% vs. 71.0%, P = 0.006). In multivariate analysis, the inclusion of NTZ to CCRT was confirmed to be a favorable factor for OS (HR, 0.31; 95% CI, 0.02-0.71; P = 0.027), DMFS (HR, 0.45; 95% CI, 0.13-0.77; P = 0.034), and PFS (HR, 0.38; 95% CI, 0.11-0.89; P = 0.041). In addition, no significant differences in hematology parameters, dermatitis, nausea, vomiting, xerostomia, nephrotoxicity or neurotoxicity were found between the two arms (all P > 0.05). Conclusion: The inclusion of NTZ to CCRT is more effective for long-term survival among LA-NPC patients than CCRT only.

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

OBJECTIVE: This study aimed to (a) assess the differences in the delineation of target volumes and organs-at-risk (OARs) by different physicians designing an intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC) and (b) analyze the impact of these differences on the treatment plan optimization. MATERIALS AND METHODS: The planning target volumes (PTVs) and OARs for radiotherapy were manually delineated from computed tomography images of a patient with NPC, and a standard delineation was determined using the STAPLE algorithm of ABAS software. IMRT was designed using one standard plan and 10 individual plans based on the same constraints and field conditions. The maximum/minimum ratio (MMR) of the PTV and OAR volumes and the coefficient of variation (CV) for the different groups were evaluated and compared to the volume of the standard contour. RESULTS: Significant differences were seen in the PTVs of the nasopharynx (PTVnx), neck lymph node (PTVnd) and the OARs manually delineated by different physicians. Compared to the standard plan, the mean dose-related parameters of various OARs in different individual plans were not significantly different, while that of most organs in different individual plans were reduced. However, a significant difference in the dose at each organ was noted in different individual plans. CONCLUSION: Significant differences were noted in the PTV and OAR delineations by different physicians in radiotherapy of NPC, and their dosimetric parameters were significantly different from the standard planned parameters. Therefore, multicenter trials should pay attention to the impact of these differences on the clinical evaluation.

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

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

[Genetic linkage between Atrn gene and microsatellite markers and the effects to some economic traits in pigs].

The genetic polymorphisms of Atrn gene, which were from 174 F0-F5 Danish resource family pigs (DRF) that has undergone five successive generations of inbreeding and 129 F9 Hunan yellow pigs (HY) that were developed by crossbreeding, were tested by PCR-RFLP method, and the effects to carcass and growth traits were also analyzed. The results showed that: (1) Three genotypes of AA, AB, BB were detected by Taq I-RFLP in the two pig breeds, and highly significant differences (P<0.01) in genotype frequencies were found between the two breeds; (2) Based on the linkage analysis of resource family pigs using CRI-MAP V2.4 software, Atrn gene loci in DRF was found to be linked with SW1031 loci on chromosome 17, the recombination frequency and LOD score for Atrn gene were 0.21 and 3.19 respectively; (3) With the least square analysis of multi-variable model, the significant differences among Atrn genotypes were found in ADSG and ABF traits in DRF and also in ADG, ABF and LMP traits in HY (P<0.05 or P<0.01), BB genotype pigs were superior to AA or AB genotype pigs. Based on the above mentioned results, B gene has favorable effects in important economic traits, and thus selection to BB genotype will get favorable effects in important economic traits. This will provide theory basis for Atrn gene being regarded as a candidate gene in pig carcass and growth traits.

[A search for chromosome 13 QTL in a complex pig family].

A search for chromosome 13 QTL was carried out in a pig family of complex pedigree. The results indicated that a significant QTL on chromosome 13 was segregating in pig family. The QTL significantly affected body weight and average daily gain (P < 0.05), but the effect on backfat thickness was not significant (P > 0.05). Interval mapping localized this QTL between SW1898 and SW398. The estimated linkage position of this QTL was 75.2 cM. The QTL variance estimated at the marker interval was 0.9037 for the body weight and 0.0010 for average daily gain, respectively. This was the region which flanked the PIT1 gene, an essential transcriptional regulatory factor of growth hormone, prolactin and thyrotropin beta subunit. The present result confirmed a previous suggestion of a QTL for early growth traits at the estimated PIT1 position, and further implied that the effect of PIT1 genes on growth and body weight remained for the whole period of individual growth and development. Aditional evidence was also found which suggested a backfat QTL on chromosome 13, at a location approximately 28.3-63.4 cM apart from the one for body weight and growth, but the level of significance was not consistent in different generations.

Mature miR-183, negatively regulated by transcription factor GATA3, promotes 3T3-L1 adipogenesis through inhibition of the canonical Wnt/ß-catenin signaling pathway by targeting LRP6.

Differentiation of preadipocytes into adipocytes and the formation of the subsequent adipose tissue are critical for mammalian growth and development. The molecular mechanism relating to preadipocyte differentiation and adipogenesis from the perspective of miRNAs is not yet completely understood. Here we investigated whether miR-183 functioned in the differentiation process. Both gain-of-function and loss-of-function assays demonstrated that miR-183 positively regulated 3T3-L1 differentiation by enhancing the expression of adipogenic marker genes such as CCAAT/enhancer binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), adiponectin and fatty acid synthase (FAS), as well as the triglyceride content and accumulation of lipid droplets. Meanwhile, low-density lipoprotein receptor-related protein 6 (LRP6) was known to impair the canonical Wnt/ß-catenin signaling pathway and thereafter reduce c-myc and nuclear ß-catenin protein. We showed that the inhibition of LRP6 by siRNA promoted 3T3-L1 adipogenic differentiation and adipogenesis. Further analysis showed that mouse miR-183 gene had its own transcription unit containing CpG islands, transcription start site (TSS), coding sequence (CDS) and polyA signal within the flanking sequences 2500 nt upstream and downstream of mouse miR-183 in genome. The core promoter of miR-183 gene was identified and transcription factor GATA3 (GATA binding protein 3) significantly inhibited the expression of mature miR-183 by binding to its core promoter in vivo, as indicated by the chromatin immunoprecipitation (ChIP) assay. These results suggest that miR-183, though negatively regulated by transcription factor GATA3, enhances 3T3-L1 preadipocyte differentiation and adipogenesis through the inhibition of the canonical Wnt/ß-catenin signaling pathway by targeting LRP6.