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Background Hepatocellular carcinoma (HCC) has a poor prognosis. Moreover, large HCCs have been commonly observed. We aimed to evaluate the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) combined with conventional transarterial chemoembolization (cTACE) for the treatment of patients with unresectable large (main tumor ≥5 cm in diameter) HCC compared to cTACE alone. Methods A retrospective matched cohort study was performed on consecutive patients with unresectable large HCC who underwent TACE as the initial treatment in our institution from May 2017 and March 2019. Fifty-five patients who underwent DEB-TACE combined with cTACE were compared with a case-matched control group of 110 patients who received cTACE alone. We compared the tumor response at 1 and 3 months after TACE, time to progression (TTP), and adverse events between the groups. Results The objective response rate (ORR) was higher for the DEB-TACE combined with cTACE group than for the cTACE alone group at 1(39/55[70.9%] vs 57/110[51.8%]，P=0.019) and 3 months (27/44 [61.4%] vs 31/71 [43.7%]，P=0.048) post-treatment. The DEB-TACE combined with cTACE group also had a significantly longer median TTP than that of the cTACE group (7.2vs 5.3 months, P= 0.039). Compared to cTACE group, occurrences of abdominal pain, nausea/vomiting and constipation were significantly more frequent in the DEB-TACE combined with cTACE group (P Conclusion Compared to cTACE alone, DEB-TACE combined with cTACE significantly increased the ORR at 1 and 3 months after the treatment of unresectable large HCCs, and had a longer TTP, without any significant increase in the number of severe complications. This article is protected by copyright. All rights reserved.

Background This study aimed to assess the effectiveness and cost-effectiveness of nimotuzumab in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Methods LA-NPC patients treated between October 2013 and December 2016 were retrospectively reviewed. A well-balanced cohort of patients who received nimotuzumab in addition to standard treatment (n = 50) and patients who did not receive nimotuzumab (n = 100) was selected using propensity score-matching method (1:2 ratio) for the cost-effectiveness analysis. Results Compared with concurrent chemoradiotherapy (CCRT) alone, addition of nimotuzumab to CCRT significantly improved the 3-year overall survival (OS) (98.00% vs. 91.00%, P = 0.032). On multivariate analysis, nimotuzumab (hazard ratio = 0.124, 95% confidence interval: 0.017–0.902, P = 0.039) showed prognostic significance for OS. No serious treatment-related adverse events were observed in the nimotuzumab group (P > 0.05). Cost-effectiveness analysis revealed that addition of nimotuzumab increased the average treatment costs by $14,364.63. The additional cost for every one percent increase in OS rate was $ 2,052.09. Conclusion Addition of nimotuzumab to CCRT for LA-NPC confers significant survival benefits; however, it is not cost-effective.

Background To assess the relationship between the level of clinical radiation oncologist and the prognosis of patients with nasopharyngeal carcinoma (NPC). To our knowledge, no previous study has explicitly assessed the relationship with cancer prognosis and clinical radiation oncologists level. The effect of physicians on the prognosis has been entirely ignored. Methods Clinical data were collected for 1140 patients with newly diagnosed NPC. Based on the 3-year overall survival, the treating physicians were classified into 3 grades: high-level group, medium-level group, and low-level group. Cox proportional hazards regression analysis was used to assess the independent significance of different prognostic factors. Propensity score matching (PSM) was used to minimize the influence of confounders so that difference in outcomes provides an unbiased estimate of the influence of physician. Interactive Risk Attributable Program (IRAP) was used to calculate the attribution risk of individual risk factors or a combination of multiple factors. Results The 3-year OS in the high-level, medium-level, and low-level groups was 92.9%, 87.7%, and 83.5%, respectively (p = 0.003). After propensity score matching, the 3-year OS was 92.4%, 87.4%, and 82.9%, respectively (p = 0.004). IRAP was used to calculate the attribution risk of mortality risk. After multivariable adjustment, patient-related factors including tumor accounted for 90.02% [95% confidence interval (CI), 73.43–96.84%) and physician factors accounted for 17.66% (95% CI, 5.39–44.65%) of the mortality risk. All related factors, including patient-related factors and physician factors accounted for 92.02% (95% CI, 77.83–97.43%). Conclusion Our study demonstrated obvious differences in the prognosis of patients treated by various clinical radiation oncologists. The largest share of prognosis risk was found to be at the patient level, while variation in prognosis was, in part, attributable to differences among physicians.

Introduction To identify the subset of patients with de novo nasopharyngeal carcinoma (NPC) for whom [18F] fluorodeoxyglucose positron emission tomography and computed tomography (18F-FDG PET/CT) should be recommended, and to determine whether PET/CT is a cost-effective decision for precise M staging in endemic areas. Materials and methods Retrospective analysis of data of 4469 patients diagnosed with de novo NPC between January 2014 and December 2019. The detection rate of distant metastasis was compared between different groups. Univariate and multiple logistic regression analysis was applied to identify the risk factors for distant metastasis. The cost-effectiveness of the diagnostic strategies was assessed. Results The detection rate of distant metastasis in the whole cohort was 5.46%. In multivariate analysis, male sex, T3-4 stage, N2-3 stage, and high plasma Epstein-Barr virus (EBV) DNA (≥ 14,650 copies/mL) were risk factors for distant metastases. NPC patients with T3-4 stage combined with N2-3 stage, high EBV DNA combined with male sex, or N2-3 stage combined with high EBV DNA were defined as recommended group with relatively higher tendency for metastasis. Distant metastasis incidence in recommended group and unrecommended group were 10.25% and 1.75%, respectively (P P = 0.005). Cost-effectiveness analysis revealed that additional cost for every one percent increase in distant metastasis detection rate was $22,785.58 in the recommended group ( Conclusions In patients with de novo NPC, the tendency for metastasis can be predicted based on clinical parameters. 18F-FDG PET/CT should be selectively recommended for the subset of patients with a relatively higher tendency for metastasis.

Background To explore the combined predictive value of serum uric acid (SUA) and tumor response to induction chemotherapy (IC) in locally advanced nasopharyngeal carcinoma (LANPC) patients receiving IC followed by concurrent chemoradiation therapy (CCRT). Methods A total of 341 LANPC patients treated with IC + CCRT were enrolled in this retrospective study. Overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) were compared by the Kaplan-Meier analysis and the log-rank test, and multivariable survival analysis was carried out to investigate the independent prognostic factors. Results Univariate analysis showed that a low SUA level and unsatisfactory tumor response to two cycles of IC both were negative predictors for OS, PFS, and DMFS in patients with LANPC. multivariable analysis demonstrated that the SUA level after two cycles of IC was an independent prognostic factor for OS (P = 0.012) but of borderline significance for PFS and DMFS (P = 0.055 and P = 0.067, respectively). Furthermore, tumor response to IC was of independent significance for predicting OS, PFS, and DMFS, respectively. Finally, LANPC patients with satisfactory tumor response and a high SUA level after two cycles of IC had a better OS, PFS, and DMFS than those with unsatisfactory tumor response and a low SUA level. Conclusion The SUA level and the tumor response to two cycles of IC had predictive value for LANPC patients treated with IC plus CCRT. However, more aggressive therapeutic strategies are recommended for those with a low SUA level and unsatisfactory tumor response to two cycles of IC.

Objective To investigate the relationship between absolute neutrophils count (ANC) in different periods of treatment and the outcomes of patients and assess effect of longitudinal neutrophils variation during radiotherapy (RT) on prognosis in patients with nasopharyngeal carcinoma (NPC). Methods A total of 1753 patients with newly diagnosed NPC were retrospectively analyzed. Complete blood counts of patients were obtained before treatment, before, during, and end of RT. The survival rate was calculated by Kaplan-Meier method and the result was compared by the log-rank test. The univariate and multivariate COX regression analyses were performed to investigate the association between the variation of ANC and survival for patients in different periods. Results Higher ANC pretreatment (>4 × 109/L) and pre-RT (>7 × 109/L) were correlated with poor OS (89.7% vs 85.6%, P = .009; 88.3% vs 77.3%, P = .002, respectively). An increase >5 × 109/L of ANC during RT was associated with adverse OS (87.9% vs 73.6%, P = .042). The multivariate Cox regression analysis showed that high ANC of pre-RT (>7 × 109/L) and a high increase (>5 × 109/L) of ANC during RT were independent prognostic factors of patients with NPC (P = .002, .044, respectively). Conclusion Our results demonstrated that ANC was an independent prognostic factor for survival in patients with NPC who received RT. Neutrophils may promote tumor resistance to radiotherapy in NPC. Level of evidence 2a.

Previous studies showed poorer survival in T4 disease with residual lesion. To evaluate the efficacy and toxicity of a boost dose for T4 nasopharyngeal carcinoma (NPC), patients with a residual primary lesion after intensity-modulated radiotherapy (IMRT). 398 T4 NPC patients with residual primary lesions after radical IMRT were retrospectively reviewed. An IMRT boost dose of 4–6.75 Gy was delivered to the residual lesions in 2–3 fractions. Propensity score matching (PSM) was applied to balance potential confounders between groups (ratio, 1:2). The presence of Epstein–Barr virus (EBV) DNA in plasma after IMRT was used for risk stratification. Patients who received boost radiation had significantly improved overall survival (OS) and local recurrence-free survival (LRFS) compared with those who did not (all P

Background: Although, in gastric cancer (GC), the presence of CD8 T cells and programmed cell death ligand-1(PD-L1) were considered as an inflamed marker for immunotherapy, the objective response rate was only 22% for this kind of patients. Herein, we comprehensively elucidate the gene mutation and expression, and functional enrichment pathways profile basing on CD8 and PD-L1 levels to better understand the immune pattern of inflamed GC and to interpretation the potential clinical treatment strategies to circumvent the obstacle of immunotherapy resistance for patients with different CD8 and PD-L1 levels. Methods: Histopathologic analysis was used to evaluate PD-L1/ CD8 expression in 186 tumor tissues from GC patients whose survival outcomes were recorded as well. Meanwhile, the gene expression and mutations of 289 GC samples in the Cancer Genome Atlas (TCGA) were computed using R 3.6.1 packages. Findings: The CD8/PD-L1 subtype were established with Types I (60.3%), II (11.8%), III (0%), and IV (27.9%) in 186 GC samples with survival outcomes related to CD8 T cells level. In 289 GC samples data from TCGA, all four CD8/PD-L1 subtypes had distinguishing molecular subtype with oncogenes and DNA damage repair-related (DDR) genes frequently altered in Type I, while TP53 mutations tend to be enriched in Type II and IV. Interpretation: We attempted to present a framework for distinguishing and conceptualizing the different signatures among GC with varied PD-L1/CD8 levels rely on histopathological data, gene mutation and expression to provide a new insight into the possibility of overcoming resistance of PD-1/PD-L1 inhibitors. Funding Statement: The work was supported by in part by Natural Science Foundation of Fujian Province (Grant No. 2017J01259, 2018J01267), Fujian provincial health and family planning research talent training program (Grant No. 2018-ZQN-13,2019-CX-4), Science and Technology Program of Fujian Province, China (Grant No. 2018Y2003, 2019L3018 and 2019YZ016006), Joint Funds for the innovation of science and Technology, Fujian province (Grant No. 2017Y9077，2018Y2003 and 2019YZ016006), Startup Fund for science research, Fujian Medical University (Grant No. 2019QH1196), and the National Clinical Key Specialty Construction Program. Declaration of Interests: None declared. Ethics Approval Statement: This study had been informed and approved by the ethics committee of the Fujian Medical University Cancer Hospital. All procedures in the study were conducted conformed to the standards set by the Declaration of Helsinki.

Chuanben Chen,1,2 Zhaodong Fei,1,2 Chaoxiong Huang,2 Jianming Ding,1,2 Lisha Chen1,2 1Department of Radiation Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, People’s Republic of China; 2Provincial Clinical College, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China Background: The prognostic value of primary tumor volume (TV) in nasopharyngeal carcinoma (NPC) has been confirmed. However, studies of the prognosis value of tumor burden, including TV and nodal volume (NV), have been relatively infrequent. Therefore, the aim of this study was to evaluate the prognostic value of tumor burden in NPC patients treated with intensity-modulated radiotherapy.Methods: Receiver operating characteristics curves were generated to determine rational cutoff points for TV and NV. The volumes identified included 12.5, 25.0, and 50.0mL, and 0, 12.5, and 25mL, respectively. According to these cutoff volumes, four subgroups were established for TV as TV1–TV4, and four subgroups were established for NV as NV0–NV3. Then, the entire cohort (992 NPC patients) was divided into 16 subgroups according to these four levels of TV and NV. Based on similarities in the 5-year overall survival (OS) rates for these 16 subgroups, four patient groups were established, G1–G4.Results: The mean TV and NV values for our cohort were 39.5±30.8mL and 16.5±17.6mL, respectively. The 5-year distant failure-free rate, the 5-year disease-free survival rate, and the 5-year OS rate for G3 and G4 were significantly lower than those for G1 and G2. In particular, the OS curves of the four patient groups were significantly separated. A multivariate analysis identified TV>50mL, T-stage (3–4), and N-stage (2–3) as adverse prognostic factors for OS.Conclusions: The results of this study demonstrate that tumor burden has a significant prognostic value for NPC patients treated with intensity-modulated radiotherapy. Hence, tumor burden, including TV and NV, should be incorporated into the current staging system for NPC to improve prognostic significance. Keywords: prognostic value, tumor burden, primary tumor volume , nodal volume, nasopharyngeal carcinoma

In patients with endometrial cancer, the expression and prognostic significance of calreticulin (CRT) remains to be fully elucidated. To investigate the role of CRT in endometrial cancer, the present study compared its expression status with clinicopathological characteristics and evaluated its prognostic significance. The expression of CRT, PKR-like endoplasmic reticulum kinase (PERK), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), and Ki67 were assessed by immunohistochemistry and/or western blotting in endometrial cancer patients. The association of the expression of CRT, p-eIF2α and Ki67 with patient survival rate was assessed by Kaplan-Meier and Cox regression analyses. Low levels of CRT and an overexpression of Ki67 were significantly associated with the stage, histology, and differentiation of the primary surgery without doxorubicin (DOX) neoadjuvant chemotherapy (NAC) patient group and were significantly correlated with a short progression-free survival and the overall survival. A multivariate analysis revealed that CRT and Ki67 expression were independent prognostic indicators for endometrioid endometrial cancer. Low CRT expression and an overexpression of Ki67 were significantly associated with DOX-NAC and the histology (P

Objectives: There are limited effective therapies for CC pts who have previously received multiple lines of chemotherapy. The combination of immune checkpoint inhibitors (ICIs) plus angiogenesis inhibitors has demonstrated significant anti-tumor activity in certain cancer. The goal of this study was to evaluate the efficacy and safety of sintilimab (a human programmed death-1 ICI) plus anlotinib (a multi-target tyrosine kinase inhibitor, inhibiting tumor angiogenesis and proliferative signaling) in persistent, recurrent or metastatic CC pts. Methods: Patients who have received at least once platinum-based systemic chemotherapy, recurrence or metastasis advanced cervical cancer (including squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma), more than 1% PD-L1 expression, ECOG 0-1 were considered eligible for enrollment. Sintilimab was administered intravenously (200mg once every 3weeks), and anlotinib was taken orally (10mg mg qd, d1-14, 21 days per cycle). The treatment was continued until disease progression, death or intolerant toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: From September 2019 to August 2020, 25 patients with FIGO stage I (8%), II (36%), III (44%), IV (4%) and undiagnosed (8%) were enrolled with a median age of 52 years old (range: 36-67). Among these patients, 17 patients were evaluable. The therapeutic evaluation showed the incidence of complete response, partial response, stable disease and progression disease was 11.8%, 58.8%, 29.4% and 0% respectively, yielding the ORR of 70.6% (95% CI: 44.0%-89.7%) and the DCR of 100% (95% CI: 80.5%-100.00%). The median PFS was not reached. Most of the occurring adverse events were grade 1 or 2, and >10% Grade 1 AEs included hyperlipemia (40.0%), hypothyroidism (20.0%), hypertension (16.0%), >10% Grade 2 AEs included hand-foot syndrome (12.0%). Intolerance was only observed in 1 patient. Conclusions: Sintilimab plus anlotinib showed a promising efficacy with a favorable toxicity profile for patients with persistent, recurrent or metastatic cervical cancer. We will report more data in the future.

Objective To analyze the correlation between relevant factors and radiation‐induced nasopharyngeal ulcer (RINU) in primary nasopharyngeal carcinoma (NPC) treated with intensity‐modulated radiation therapy (IMRT). Methods Clinical data were collected for 599 patients with newly diagnosed NPC who had completed IMRT. The entire cohort was randomly divided into two subgroups. The relationship between RINU and IMRT dose‐volume were statistically analyzed with ROC curves and the Chi‐square test. Nutritional status during and after treatment was compared between patients with vs without RINU. Results The results obtained showed that dose‐volume had no effect on the incidence of RINU (P > .05). Nutrition‐related parameters differed significantly between patients with vs without RINU (P

This cohort study examines the association of comutation of tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) genes with response to immune checkpoint inhibitor (ICI) treatment and overall survival among patients with non–small cell lung cancer (NSCLC)., Key Points Question What are the prevalence and association of tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) comutation with response to immune checkpoint inhibitors in patients with non–small cell lung cancer (NSCLC)? Findings In this multiple-cohort study, TP53 and ATM comutation sites were scattered throughout the genes analyzed. Comutation in TP53 and ATM was associated with a higher tumor mutation burden and better overall survival compared with sole mutations and no mutation. Meaning Patients with TP53 and ATM comutation compose a subgroup of patients with NSCLC associated with an increased tumor mutation burden and better response to immune checkpoint inhibitors; TP53 and ATM may be a clinically relevant biomarker in guiding immunotherapy treatment of NSCLC., Importance Immune checkpoint inhibitors (ICIs) can elicit durable antitumor responses in patients with non–small cell lung cancer (NSCLC), but only 20% to 25% of patients respond to treatment. As important genes in the DNA damage response pathway, comutation in the tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) genes may be associated with genomic instability and hypermutation. However, the prevalence of TP53 and ATM comutation and its association with response to ICIs are not fully understood. Objective To examine the prevalence of the TP53 and ATM comutation, the potential mechanism, and its association with response to ICIs among patients with NSCLC. Design, Setting, and Participants This multiple-cohort study included patients with NSCLC from the Geneplus Institute, the Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering Cancer Center (MSKCC) databases and from the POPLAR and OAK randomized controlled trials. Samples in the Geneplus cohort were collected and analyzed from April 30, 2015, through February 28, 2019. Data from TCGA, the MSKCC, and the POPLAR and OAK cohorts were obtained on January 1, 2019, and analyzed from January 1 to April 10, 2019. Next-generation sequencing assays were performed on tumor samples by the Geneplus Institute. Genomic, transcriptomic, and clinical data were obtained from TCGA and MSKCC databases. Exposures Comprehensive genetic profiling was performed to determine the prevalence of TP53 and ATM comutation and its association with prognosis and response to ICIs. Main Outcomes and Measures The main outcomes were TP53 and ATM comutation frequency, overall survival (OS), progression-free survival, gene set enrichment analysis, and immune profile in NSCLC. Results Patients with NSCLC analyzed in this study included 2020 patients in the Geneplus cohort (mean [SD] age, 59.5 [10.5] years; 1168 [57.8%] men), 1031 patients in TCGA cohort (mean [SD] age, 66.2 [9.5] years; 579 [56.2%] men), 1527 patients in the MSKCC cohort (662 [43.4%] men), 350 patients in the MSKCC cohort who were treated with ICIs (mean [SD] age, 61.4 [13.8] years; 170 [48.6%] men), and 853 patients in the POPLAR and OAK cohort (mean [SD] age, 63.0 [9.1] years; 527 [61.8%] men). Sites of TP53 and ATM comutation were found scattered throughout the genes, and no significant difference was observed in the frequency of TP53 and ATM comutation within the histologic subtypes and driver genes. In 5 independent cohorts of patients with NSCLC, TP53 and ATM comutation was associated with a significantly higher tumor mutation burden compared with the sole mutation and with no mutation (TCGA, MSKCC, Geneplus, and POPLAR and OAK cohort). Among patients treated with ICIs in the MSKCC cohort, TP53 and ATM comutation was associated with better OS than a single mutation and no mutation among patients with any cancer (median OS: TP53 and ATM comutation, not reached; TP53 mutation alone, 14.0 months; ATM mutation alone, 40.0 months; no mutation, 22.0 months; P = .001; NSCLC median OS: TP53 and ATM comutation, not reached; TP53 mutation alone, 11.0 months; ATM mutation alone, 16.0 months; no mutation, 14.0 months; P = .24). Similar results were found in the POPLAR and OAK cohort in which the disease control benefit rate, progression-free survival, and OS were all greater in patients with the TP53 and ATM comutation compared with the other 3 groups (median progression-free survival: TP53 and ATM comutation, 10.4 months; TP53 mutation, 1.6 months; ATM mutation, 3.5 months; no mutation, 2.8 months; P = .01; median OS: TP53 and ATM comutation, 22.1 months; TP53 mutation, 8.3 months; ATM mutation, 15.8 months; no mutation, 15.3 months; P = .002). Conclusions and Relevance This study’s findings suggest that the TP53 and ATM comutation occurs in a subgroup of patients with NSCLC and is associated with an increased tumor mutation burden and response to ICIs. This suggests that TP53 and ATM comutation may have implications as a biomarker for guiding ICI treatment.

e18003 Background: Treatment options for advanced cervical cancer (ACC) are limited and patients experiencing recurrence after first-line chemotherapy and bevacizumab have a poor prognosis. Checkpoint inhibitors targeting the PD-1/PD-L1 are promising treatment option. However, related genomic biomarker study is rare reported in ACC. Methods: We prospectively enrolled 102 pts with ACC. Tumor and plasma samples were obtained to analysis genomic profiles. DNA was sequenced by target-capture deep sequencing with the pan-cancer panel. TMB of tissue (tTMB) and blood (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion. PD-L1 expression was evaluated in tumor specimens by immunohistochemistry (IHC) using a combined-positive-score (CPS) cutoff of ≥1. Results: The median age of enrolled pts was 63 yrs, and most (84.3 %, 86/102 pts) weresquamous carcinoma. A total of 93 tissues and 96 plasma were collected from 102 pts. The most frequently mutated genes were PIK3CA (40.9%, 38/93 pts), KMT2D (35.5%, 33/93 pts), and KMT2C (28.0%, 26/93 pts) in tissues. 80% (77/96 pts) of plasma was detected positive, with PIK3CA (23.4%, 18/77 pts), KMT2D (20.8%, 16/77 pts), KMT2C (20.8%, 17/77 pts) mutant frequently. Among 87 pts with paired samples, at least a tumor-derived mutation was detected in 35 (40.2%)plasma. Median of tTMB was 11.9 mut/Mb, and 45% pts were TMB-H. Significant correlation was found between tTMB and bTMB (Pearson r = 0.39, P = 0.001). Higher tTMB was identified in KMT2D- or KMT2C-mut pts (P = 0.002 or P = 0.01, respectively). tTMB showed no relation with clinic characteristics, including pathological subtype, FIGO stage, and status of distant metastasis. PD-L1 expression (CPS≥1) was identified in 53 pts (93 %, 53/57) and mutually independent with TMB status. Conclusions: Molecular profiles and TMB in plama showed high consistence with that in tissue. Prospective clinical trial is ongoing to determine the genomic biomarkers and the PD-L1 expression as predictive factors for the ICI efficacy in ACC (ChiCTR1900023015).

e18533 Background: While the immune checkpoint blockades had demonstrated promising benefits in head and neck cancer (HNSC), its clinical efficacy is limited to a selected subset of less than 20% HNSC patients. Tumor mutation burden (TMB) has been reported as a predictor for ICBs in multiple tumors, including HNSC. However, the association of driver genes with TMB and outcomes in patients with HNSC has not yet been established. Methods: Somatic mutation landscape was characterized by interactively analyzed the sequencing data of 495 HNSC samples obtained from The Cancer Genome Atlas (TCGA) database and 185 samples from a Chinese cohort (Geneplus-database). Hybrid capture of a 1021 gene panel with potential clinical relevance was performed on tumor and paired Peripheral blood lymphocytes (PBLs) from 185 HNSC samples in a Chinese cohort. Results: In the Chinese cohort, patients harboring ≥5 muts/Mb (the top quartile of tTMB distribution) were classified as the TMB-H group; while ≥4.7 muts/Mb were classified as the TMB-M group. TMB -H was associated with better OS in the TCGA cohort. The rest were classified as TMB-L patients. Thirteen aberrant genes were significant correlation with TMB-H, including TSC2, POLE, CDK4, TSC1, MLH1, PTCH1, NF1, MSH3, RAD50, MSH2, CDH1, TNFRSF14, TERC. Among them,10 were further verified in the TCGA Head and Neck Cancer cohort, including TNFRSF14, MSH3, NF1, TSC2, RAD50, MSH2, PTCH1, POLE, MLH1, TSC1. Moreover, aberrant genes such as CDH1, MSH2 and RAD50 implicated better DFS (DFS:HR = .296, p = .034; HR = 0.128, p = .016; HR = .0422, p = .043) in HNSC of the TCGA cohort. Transcriptomic analysis in the TCGA Head and Neck Cancer cohort showed various degrees of immune upregulation in the tumor microenvironment (TME) in CDH1, MSH2, and RAD50 mutated population. Conclusions: These findings indicated that CDH1, MSH2, and RAD50 mutations may be associated with TMB-H, immuno-upregulation in TME and better survival outcomes. Combined with TMB, genes mentioned above may give us some insights into how ICB therapeutic strategies assist natural host immune responses against HNSC in Chinese population.

Background Copy number alterations in cyclin D1 (CCND1) relevant to malignant biological behavior exist in solid tumors, including head and neck squamous cell cancer (HNSCC). The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to immune checkpoint inhibitors (ICIs) therapy is unknown. Methods This was a three-cohort pooled study, 6904 samples from 6540 patients from the Geneplus Insitute, 10562 samples from the TCGA and 10614 samples from the MSKCC were statistically analyzed. Next-generation sequencing assays were performed in tumor samples at the Geneplus Institute. Genomic, transcriptomic, and clinical data were obtained from TCGA and MSKCC. Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and their correlation with the prognosis and the response to ICIs. Assessment of the CCND1 amplification frequency, overall survival (OS), gene set enrichment analysis (GSEA) and immune profile in solid tumors. Results In HNSCC, 7 cases (25.00%) were identified CCND1 amplification in the Chinese cohort, 120 cases (23.21%) in the TCGA cohort, and 5 cases (9.43%) in the MSKCC cohort. Survival analysis showed that CCND1 amplification was an independent prognostic factor for poor outcome in HNSCC as well as for pan-cancer in the TCGA and MSKCC populations. Furthermore, in the MSKCC cohort, patients receiving ICIs with CCND1 amplification had a shorter OS compared with neutral patients (HR, 1.63; 95%CI, 1.09–2.43; median OS, 11.0m vs. 18.0m; P = .0024), especial in the high-TMB subgroup (HR, 2.82; 95%CI, 1.11–7.20; median OS, 10.0m vs. 41.0m; P = .0003). Comparing the transcriptome between amplification and neutral groups in six solid tumors from the TCGA cohort showed various degrees of immunosuppression in the tumor microenvironment (TME), especially in HNSCC. The GSEA suggested that multiple aggressive, immunosuppressive and angiogenic hallmarks correlate with CCND1 amplification in HNSCC. Conclusions These findings indicate that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs. Legal entity responsible for the study Chuan Ben Chen. Funding Ministry of Health P.R.China (Grant No. WKJ2016-2-33). Disclosure All authors have declared no conflicts of interest.

Metastasis to lymph nodes is a key determinant of thoracic esophageal squamous cell carcinoma (TE-SCC) prognosis. We sought to identify factors linked with cervical lymph node metastasis, which could be used to inform the decision of surgical and definitive radiotherapy.We retrospectively reviewed records from 1715 patients who had had radical esophagectomy with three-field lymphadenectomy between January 1993 and March 2007 in our hospital. All patients included in the study had pathologically confirmed TE-SCC and no clinical evidence of cervical metastasis.Cervical node metastases were found in 547 patients (31.9%); rates of cervical-node positivity were 44.2% for those with upper-thoracic tumors, 31.5% for mid-thoracic tumors, and 14.4% for lower-thoracic tumors. Univariate analysis showed that cervical node metastasis was associated with tumor site, differentiation, and length, pathologic T status, and pN status (P0.05); however, only tumor site and pN status retained significance in multivariate analysis (P0.05). Positive cervical nodes were most often found in the paraesophageal region (72.3%), followed by supraclavicular (24.4%); involvement of deep cervical (2.4%) or retropharyngeal nodes (0.9%) was rare (P0.0001). Positive cervical nodes were most often associated with upper TE-SCCs (60.1%), followed by middle TE-SCCs (31.2%) and lower TE-SCCs (10.6%).Upper TE-SCC with multiple involved nodes at any site was associated with a high rate of cervical node metastasis. These findings provide critical information for clinical decision-making regarding the extent of nodal dissection or the size of radiation fields in definitive radiotherapy.

Background Results of the ADJUVANT trial established adjuvant gefitinib as an optimal choice for EGFR-mutated stage II-IIIA NSCLC patients. However, clinical benefit varied among patients. To investigate this heterogeneity, we performed comprehensive tumor genomic analyses on these patients. Here, we report the predictive MEDUSA model (Multiple-biomarker Evaluation to Determine the Utilization of Specific Adjuvant therapy) that can guide clinical decision of adjuvant therapy. Methods 171 baseline specimens from ADJUVANT (n = 95, gefitinib arm; n = 76, vinorelbine plus cisplatin [VP] arm) underwent targeted sequencing (Geneseeq 422-gene panel). Predictive biomarkers were identified by Cox regression with gene-by-treatment interactions, and a multi-gene composite score was developed to compare the benefits of these treatments. Results EGFR mutations were confirmed in all cases. TP53, NKX2-1, CDK4, MYC and RB1 were identified as predictive biomarkers. Specifically, gefitinib-favoring biomarkers include TP53 exon4/5 mutations (interaction HR [iHR] 0.33, 95% CI 0.12-0.93, p = 0.035), and copy number gain of NKX2-1 (iHR 0.26, 95% CI 0.098-0.68, p = 0.006), CDK4 (iHR 0.14, 95% CI 0.025-0.77, p = 0.024) and MYC (iHR 0.10, 95% CI 0.011-0.98, p = 0.048). RB1 alterations strongly favored VP (iHR 4.07, 95% CI 1.56-10.53, p = 0.004). The MEDUSA model was developed based on the above, and stratified patients into 3 groups: Strong Gefitinib-favoring (SG, n = 60), Moderate Gefitinib-favoring (MG, n = 87), and VP-favoring (VP, n = 24). Notably, the SG group demonstrated significant OS benefit with adjuvant gefitinib as well: HR of OS was 0.44 (95% CI 0.2-0.98, p = 0.04). Table: 1441PD . MEDUSA Score mDFS (m) 2y DFS(%) HR(95% CI) P SG ≤-0.5 34.5 vs 9.1 70.3 vs 11.0 0.21 (0.1-0.43) MG -0.5 to 0.5 32.8 vs 20.7 67.5 vs 41.0 0.61 (0.35-1.07) 0.08 VP ≥0.5 19.3 vs 34.2 41.6 vs 69.2 3.07 (0.98-9.52) 0.04 Conclusions Incorporating alterations in TP53, NKX2-1, CDK4, MYC and RB1, MEDUSA score could guide personalized adjuvant therapy for resected stage II-IIIA EGFR-mutant NSCLC patients. Clinical trial identification NCT01405079; Release at July 29. 2011. Legal entity responsible for the study Chinese Thoracic Oncology Group (CTONG). Funding AstraZeneca Roche. Disclosure Y. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. H. Bao: Full / Part-time employment: Geneseeq Technology Inc. Toronto. Y. Chen: Full / Part-time employment: Geneseeq Technology Inc. Nanjing. Y.W. Shao: Full / Part-time employment: Geneseeq Technology Inc. Nanjing. All other authors have declared no conflicts of interest.

Tumor-nodal-metastasis (TNM) is the most important survival predictor in nasopharyngeal carcinoma (NPC). Distant metastasis (DM) is the predominant failure pattern of NPC in the intensity-modulated radiotherapy (IMRT) era. The DM risk appears to be different for T-N subsets within the same clinical stage. Appropriately depicting DM risk has emerged as an important issue in tailoring individualized treatment and underpins the reason for this study.A total of 1616 non-metastatic (M0) NPC patients treated with IMRT were included. All were re-staged according to the 8th edition AJCC/UICC TNM (TNM-8). DM-free survival (DMFS) was calculated and compared among T-N subsets within each stage and DM risk groups were derived by Recursive-partitioning analysis (RPA) based on ordinal T and N categories.Significant heterogeneity in DM risk was evident among T-N subsets within cTNM-8 stages II-IV. The RPA algorithm classified patients into four DM risk groups: RPA-I (T1N0-1 and T2-3N0), RPA-II (T2-3N1), RPA-III (T4N0-1 and T1-3N2) and RPA-IV (T4N2 and T1-4N3), with 5-year DMFS of 93.4% (95% CI: 91.3-96.1), 84.3% (80.8-87.8), 78.9% (75.4-82.4) and 63.6% (56.3-70.9), respectively (p 0.001). Compared to cTNM-8 stage grouping, RPA grouping had a lower Akaike information criterion (AIC) and higher Harrell's concordance index (c-index) for DMFS.Significant heterogeneity in DM risk exists among T-N subsets within cTNM-8 stages. The RPA groups demonstrated improved intra-group hazard consistency compared to cTNM-8 stage groups. While further validation is warranted, these RPA prognostic groupings provide a strong anatomic foundation to augment DM prediction for optimal targeting in future clinical trials.

The aim of this study was to evaluate the treatment outcome and toxicities of radiation therapy alone for elderly patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Seventy-three patients of 70 years old or above treated at our institution between January 1995 and December 2008 for locoregionally advanced NPC (stage III–IVA) were reviewed and analyzed. All patients were treated in a uniform fashion using our institutional protocol with using conformal radiation therapy alone. Measured outcomes included 4-year overall survival (OS), tumor-specific survival (TSS), disease-free survival (DFS), local control (LC), regional relapse-free survival (RRFS), distant metastasis free survival (DMFS), as well as late toxicity. The median follow-up for all 73 patients at the time of this analysis was 45 months (range, 5–152 months). The 4-year OS, TSS, DFS, LC, RRFS, and DMFS were 51.0, 64.5, 54.7, 83.7, 80.6, and 63.5, respectively. Radiation therapy was well tolerated in this group of patients. Multivariate analyses revealed that clinical stage (P = 0.006) and comorbidities (P = 0.018) were significant prognosticators for OS, both N classification (P = 0.023) and comorbidities (P = 0.032) were significant prognosticators for DFS, N classification was the only independent prognostic factor for both TSS (P = 0.002) and DMFS (P = 0.004); and residual disease in the primary site was the only independent predictive factor for LC (P = 0.026). Radiation therapy alone can achieve a reasonable local and regional control in NPC patients with advanced age; however, distant metastasis remained the dominant failure pattern of our series. The presence of comorbidities was an important negative prognostic factor for treatment outcome.

The aim of this study was to evaluate the effect of the primary tumor volume on prognosis in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy.Between August 2003 and April 2005, 112 patients with Stage I-IVB nasopharyngeal carcinoma treated by intensity-modulated radiation therapy were included. Measurement of the primary tumor volume was based on contrast-enhanced computed tomography scans before treatment. A receiver operating characteristics curve was used to determine the best cut-off point of the primary tumor volume.The mean primary tumor volume for 112 patients with nasopharyngeal carcinoma was 33.9 ± 28.7 ml. Within the framework of UICC T-staging, all patients were divided into four groups according to the primary tumor volume. We call it the volume stage (V115.65 ml, V2 = 15.65-24.25 ml, V3 = 24.25-50.55 ml and V450.55 ml). The 5-year overall survival rates for V1, V2, V3 and V4 were 88.5, 83.3, 82.4 and 54.5% (P = 0.014), respectively. The cumulative survival curves for V1, V2 and V3 were very close, but clearly separated from V4. In addition, Cox proportional hazards regression model analysis showed that a primary tumor volume50 ml was an independent risk factor for radiotherapy (risk ratio = 3.485, P = 0.025).This study demonstrated that the primary tumor volume had significantly impacted on the prognosis of patients with nasopharyngeal carcinoma. We proposed that the primary tumor volume should be considered as an additional stage indicator in the new revision of the clinical stage of nasopharyngeal carcinoma.

To exam factors associated with overall survival (OS) in patients with nasopharyngeal carcinoma (NPC).This study is a retrospective study of a total of 1706 consecutive NPC patients from a single institution between January 1995 and December 1998. One thousand eighty-one patients were treated with radiotherapy (RT) alone and 625 with an intensive course of neoadjuvant chemotherapy followed by RT. Patient, tumor and treatment factors were analyzed for their significance on 5-year overall survival (OS).Younger age, female gender, absence of anemia pre-RT, early tumor stage, interruption of RT, and neoadjuvant chemotherapy were significantly associated with survival under multivariate analysis (all P0.05). The 5-year OS rates were 100%, 75.9% (95%CI 71.6-80.2%), 66.5% (95%CI 62.8-70.2%), and 49.3% (95%CI 45.0-53.6%) for stage I, II, III, and IV (P0.05); 68.9% (95%CI 66.2-71.5%) and 63.7% (95%CI 61.5-65.8%), for patients treated with or without neoadjuvant chemotherapy (P=0.0051), and 51.7% (95%CI 45.0-58.4%) and 69.5% (95%CI 67.2-71.7%) for patients with or without treatment break (P0.0001), respectively.Intensive neoadjuvant chemotherapy and absence of radiation break seem to be favorable factors associated with long-term survival in patients with NPC.

e18013Background: Emerging evidences have showed that immune checkpoint inhibitors lead to durable responses in a variety of advanced cancers, including recurrent/metastatic nasopharyngeal carcinom...

The purpose of this study was to compare the changing tendency of nutrition with 54 nasopharyngeal carcinoma patients during intensity-modulated radiation therapy (IMRT), and to investigate the correlation between comprehensive nutritional status and quality of life (QoL), which was assessed by the European Organization for Research and Treatment of Cancer Core Quality-of-Life Questionnaire. The nutritional index, including body mass index, ideal body weight percentage, usual body weight percentage, albumin, hemoglobin, and total lymphocyte count (TLC), was evaluated at 2 time points: within 48 h after admission (T1) and at the end of treatment with IMRT (T2). A statistically significant downgrade of every index was observed during IMRT. A comprehensive nutritional model was established by principal components analysis at T2. QoL scores of functional (P = 0.002) and the global QoL scales (P = 0.001) existed a positive correlation with comprehensive nutritional status. QoL scores of symptom scales (P = 0.002) and 6 single items (P = 0.005) had a negative correlation with it. The scores of global QoL scales in comprehensive nutrition of normal (20.4%), moderate (55.6%), and severe malnutrition (24.1%) were 69.70 ± 17.98, 48.33 ± 19.25, and 37.18 ± 24.67, respectively. Patients with different nutritional status had different QoL (B = 10.405, SE = 2.828, t = 3.680, P = 0.001). Multiaspect nutritional supports should be enhanced to improve patients' comprehensive nutritional status during treatment.

Our aim was to evaluate the volumetric and dosimetric changes of target volumes and organs at risk (OARs) during intensity-modulated radiation therapy (IMRT) for locoregionally advanced nasopharyngeal carcinoma (NPC) and the necessity of replanning. Twenty locoregionally advanced NPC patients treated by concurrent chemotherapy and IMRT were included. CT and MR images were acquired before treatment and at weeks 2, 3, 4, 5 and 6 during treatment. The target volumes and OARs were contoured based on the fused CT-MRI images and hybrid plans were generated. The changes of volume and dosimetry were measured by comparing original plan and hybrid plans. Significant volumetric changes of target volumes and parotid gland were observed. The primary nasopharyngeal tumor (GTVnx), CTV1, involved lymph nodes (GTVnd) and left and right parotid glands, shrank at a mean rate of 14.7, 11.56, 11.40, 6.54 and 6.78 % per treatment week, respectively. There were no significant dosimetric changes in GTVnx, GTVnd, CTV1, spinal cord and brain stem while the differences of dose to left and right parotid glands were significant (F = 6.73, P = 0.007; F = 7.43, P = 0.007). Remarkable volumetric changes were observed. However, the dosimetric changes were inconspicuous except for the parotid. Replanning might contribute to protect the parotid gland.

The aim of the present study was to evaluate the benefit of chemotherapy, combined with palliative radiotherapy (PRT) and other local treatments to the metastatic sites, for patients with metastatic nasopharyngeal carcinoma (NPC) who had a performance status 0–2. We conducted a retrospective review of available data from 197 biopsy-proven NPC patients who developed metastasis after their initial definitive treatment. These patients were grouped into three categories according to the different treatment paths that were followed: the best supportive care (64 patients), chemotherapy alone (55 patients), and multimodality treatment with chemotherapy combined with PRT and other local treatments to metastatic sites (78 patients). The 2-year metastatic survival rate of patients in the multimodality treatment group was 57.7%, which was significantly better than that of the patients in both the chemotherapy alone group and the best supportive care group (32.7% and 1.6%, respectively). The independent significant factors affecting survival were the disease-free interval prior to the detection of metastatic disease, the number of metastases, the number of chemotherapy cycles and the biological effective dose of PRT. In conclusion, multimodality treatment may improve survival of select patients with recurrent NPC with distant metastases.

BACKGROUND AND OBJECTIVE Radiotherapy is effective in treating nasopharyngeal carcinoma (NPC). This study evaluated the treatment efficacy, toxicity, and prognostic factors of intensity-modulated radiotherapy (IMRT) in the treatment NPC. METHODS Between September 2003 and September 2006, 305 patients with NPC were treated with IMRT in Fujian Provincial Cancer Hospital. IMRT was delivered as follows: gross tumor volume (GTV) received 66.0-69.8 Gy in 30-33 fractions, high-risk clinical target volume (CTV-1) received 60.0-66.65 Gy, low-risk clinical target volume (CTV-2) and clinical target volume of cervical lymph node regions (CTV-N) received 54.0-55.8 Gy. Patients with stages III or IV disease also received cisplatin-based chemotherapy. All patients were assessed for local-regional control, survival, and toxicity. RESULTS With a median follow-up of 35 months (range, 5-61 months), there were 16, 8, and 39 patients who had developed local, regional, and distant recurrence, respectively. The 3-year rates of local control, regional control, metastasis-free survival, disease-free survival, and overall survival were 94.3%, 97.7%, 86.1%, 80.3%, and 89.1%, respectively. Multivariate analyses revealed that T-classification had no predictive value for local control and survival, whereas N-classification was a significant prognostic factor for overall survival (P < 0.001), metastasis-free survival (P < 0.001), and disease-free survival (P = 0.003). For stages III-IV disease, concurrent and adjuvant chemotherapy did not influence prognosis. The most severe acute toxicities included Grade III mucositis in 14 patients (4.6%), Grade III skin desquamation in 90 (29.5%), and Grades III-IV leucocytopenia in 20 (6.5%). There were 7% patients with Grade II xerostomia after 2 years of IMRT, no Grades 3 or 4 xerostomia was detected. CONCLUSIONS IMRT provided favorable locoregional control and survival rates for patients with NPC, even in those with locally advanced disease. The acute and late toxicities were acceptable. N-classification was the main factor of prognosis. Further study is needed on chemotherapy for patients with NPC.