The TD(1) of TLI in patients with rNPC is 107.84 Gy in Lyman NTCP model. The nomogram model can accurately predict the risk of TLI for individual.

There is an unmet need for more effective treatments in recurrent/metastatic nasopharyngeal carcinoma (r/m NPC) after chemo- and immune-therapy. MRG003 is a novel ADC composed of a humanized anti-EGFR mAb conjugated to MMAE via a vc-linker. Here we report the primary dose finding study results of MRG003 in r/m NPC. This is a phase IIa study to evaluate the safety and efficacy of MRG003 in patients (pts) with pathologically documented r/m NPC, who had failed prior platinum and/or PD-(L)1 therapy. The study investigated two dose levels of MRG003 (2.0 or 2.3mg/kg, Q3W) to identify an optimal dose. The primary endpoint is objective response rate (ORR) per RECIST 1.1. Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) and safety. A total of 61 pts received at least 1 dose of MRG003, 30 pts at 2.0 mg/kg (DL1) and 31 pts at 2.3 mg/kg (DL2). Most pts (52/61) received ≥2 lines of prior treatment and 53 (86.9%) pts had prior platinum and PD-1/L1 therapy. By the cut-off date (March 15, 2023), 28 pts were evaluable in the DL1 cohort, the ORR and DCR were 39.3% and 71.4%, respectively. The ORR and DCR of 29 evaluable pts in the DL2 cohort were 55.2% and 86.2%, respectively. Median DoR (mDoR) was 6.8 months (95%CI: 5.7, 16.3) in DL1 and 6.8 months (95%CI: 2.9, 9.8) in DL2. The median PFS (mPFS) in DL1 cohort was 7.3 months (95%CI: 2.9, 9.7), while it was immature in DL2 cohorts. Most commonly reported treatment-related AEs (TRAEs) assessed by investigators were rash (49.2%), pruritus (41.0%), anemia (34.4%), and alopecia (31.1%); majority of TRAEs were grade 1 or 2 per CTCAE 5.0. The incidence of treatment related severe adverse event (SAE) was 11.5% (7/61). Dose reduction rate due to TRAEs were 13.1% (8/61) and 3 pts discontinued treatment (4.9%). No treatment related deaths were observed. MRG003 demonstrated promising antitumor activity in the late line r/m NPC patients, and with an acceptable tolerance and manageable safety profile. Based on numerically higher ORR and potentially better efficacy than 2.0 mg/kg group and well tolerated safety profile, 2.3mg/kg is the recommended dose for further pivotal study.

e18063 Background: Re-radiotherapy (re-RT) is the main treatment for locally recurrent nasopharyngeal carcinoma (lrNPC) patients, and commonly led to radiation-induced nasopharyngeal (NP) necrosis, which was lethal but rare study has focused on it. The aim of this study was to evaluate the cause and impact of radiation-induced NP necrosis in lrNPC patients who received re-RT. Methods: Totally 252 lrNPC patients who received re-RT between January 2013 and December 2020 were retrospectively collected. The inclusion criteria were as follows: (1) no NP necrosis before re-RT; (2) complete medical records, including treatment, clinical and dosimetric information; (3) conventional fractionated radiotherapy. All patients received intensity-modulated radiotherapy ± chemotherapy. Radiation-induced NP necrosis was diagnosed by magnetic resonance imaging and/or electronic nasopharyngoscopy. Dosimetric factors of the planning target volume of primary tumor (PTVp) were extracted from the dose-volume histogram (DVH), which was rescaled to an equivalent dose of 2 Gy per fraction (EQD 2 Gy) using a linear quadratic model. Logistic regression was used to identify the independent prognostic factors for generating the nomogram. Results: With a median follow-up of 44.63 months (inter-quartile range [IQR], 27.70 – 69.20 months), 47.6% of patients (120/252) occurred radiation-induced NP necrosis, which mostly happened within 1 year post re-RT (median [IQR], 5.83 [3.37 – 11.57] months). The 3-year overall survival was 83.0% vs 39.7% ( P＜0.001) in lrNPC patients with or without radiation-induced NP necrosis. Except for the fractionated dose, other dosimetric factors of PTVp were not significantly different between two groups, including D 98 (dose to 98% of PTVp), D 50 , D 2 and homogeneity index (Table). Furthermore, multivariate analysis showed that continuous variable age (HR [95%CI]: 1.04 [1.02 – 1.07], P = 0.003) and tumor volume (HR [95%CI]: 1.02 [1.01 – 1.03], P＜0.001), and fractionated dose > 2.22 Gy (HR [95%CI]: 2.36 [1.32 – 4.21], P = 0.004) were independent factors in predicting radiation-induced NP necrosis, which yielded a C-index of 0.742 (95% CI, 0.682 - 0.803) for OS in the nomogram. Conclusions: The incidence of radiation-induced NP necrosis was high in lrNPC patients who received re-RT. Patients with older age, larger tumor volume or receiving fractionated dose over 2.22 Gy were more easily to suffer NP necrosis, which need to explore novel treatment strategies to improve patients’ survivals. [Table: see text]

Gemcitabine plus cisplatin (GP) prior to concurrent chemoradiotherapy (CCRT) has favorable survival outcomes with acceptable toxicity in patients with locoregionally advanced nasopharyngeal carcinoma (LANPC). Immune checkpoint blockade therapy plus GP has been shown to improve the survival in recurrent or metastatic NPC. We aim to evaluate the efficacy and safety of envafolimab (PD-L1) with curative chemoradiotherapy in previously untreated LANPC. In this single-arm, phase 2 study, eligible patients were of age 18-65, diagnosed with staged TxN2-3M0 or T4N1M0(AJCC 8th) non-keratinizing LANPC. Enrolled patients received 3 cycles of intravenous gemcitabine (1000 mg/m2, d1/8, Q3W)+cisplatin (80 mg/m2, d1, Q3W), in combination with subcutaneous envafolimab injections (300mg, d1, Q3W) for induction chemotherapy, followed by CCRT, during which, every patient would receive 2 cycles of DDP (100 mg/m2, d1, Q3W)+envafolimab (300mg, d1, Q3W). Then patients would receive envafolimab (300mg, d1, Q3W) for maintenance treatment for a year, until disease progression or intolerance of treatment. The primary endpoint was 3-year progress-free survival, the secondary endpoints included objective response rate (ORR), the disease control rate (DCR), locoregional failure-free survival, distant metastasis-free survival, and toxicity. All enrolled patients have finished induction chemotherapy treatment, the study is ongoing. From June 14th 2022 to December 13th, 2022, a total of 36 patients (median age 44y, 63.9% male) were enrolled at Sun Yat-sen University Cancer Center. As of May 4th, 2023, the median follow-up is 7.38 months. The ORR and DCR rate were 94.4%(95%CI: 81.3%, 99.3%) and 97.2%(95%CI: 85.5%, 99.9%).Compared to standard regimen, in combination with envafolimab did not increase the incidence of hematological toxicity events., and no irAEs for grade 3/4 were observed.. Long-term efficacy is awaited. Envafolimab plus chemoradiotherapy was effective and safety in the treatment of LANPC. Further follow-up is needed to confirm the long-term efficacy.

This study showed that nodal tumour-stroma ratio (NTSR) is an independent prognostic factor for overall and disease-free survival of patients with gastric cancer. Both relative stroma-rich primary tumour-stroma ratio (PTSR) and NTSR were independent negative prognostic factors for overall survival in gastric cancer. This study supports assessment of tumour-stroma ratio in the routine pathological diagnosis of gastric cancer. validated in node-positive disease

Background: We conducted a single-arm phase II trial to evaluate the efficacy and adverse effects (AEs) of an anti-epidermal growth factor receptor monoclonal antibody, nimotuzumab, combined with cisplatin and 5-fluorouracil (PF) as first-line treatment in recurrent metastatic nasopharyngeal carcinoma after radical radiotherapy. Methods: Patients who met the eligibility criteria were recruited from ten institutions (ClinicalTrials.gov; NCT01616849). A Simon optimal two-stage design was used to calculate the sample size. All patients received weekly nimotuzumab (200 mg) added to cisplatin (100 mg/m(2) D1) and 5-fluorouracil (4 g/m(2) continuous infusion D1-4) every 3-weekly for a maximum of six cycles. Primary end point was objective response rate (ORR). Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and AEs. Results: A total of 35 patients were enrolled (13 in stage 1 and 22 in stage 2). Overall ORR and DCR were 71.4% (25/35) and 85.7% (30/35), respectively. Median PFS and OS were 7.0 (95% CI 5.8-8.2) months and 16.3 (95% CI 11.4-21.3) months, respectively. Unplanned exploratory analyses suggest that patients who received >= 2400 mg nimotuzumab and >= 4 cycles of PF had superior ORR, PFS and OS than those who did not (88.9% versus 12.5%, P < 0.001; 7.4 versus 2.7 months, P = 0.081; 17.0 versus 8.0 months, P = 0.202). Favourable subgroups included patients with lung metastasis [HROS 0.324 (95% CI 0.146-0.717),P = 0.008] and disease-free interval of >12 months [HROS 0.307 (95% CI 0.131-0.724), P = 0.004], but no difference was observed for metastatic burden. The only major grade 3/4 AE was leukopenia (62.9%). Conclusion: Combination nimotuzumab-PF chemotherapy demonstrates potential efficacy, and is well tolerated as first-line chemotherapy regimen in recurrent metastatic nasopharyngeal carcinoma.

Fibulin-3 (FBLN3) levels vary among different types of cancers.We found that fibulin-3 was downregulated in colorectal cancer (CRC) cells, particularly in the SW480 cell line.However, transfecting SW480 cells with a lentivirus overexpressing fibulin-3 RNA inhibited proliferation, induced G1/S arrest, and promoted apoptosis.Fibulin-3 overexpression also suppressed CRC invasion and metastasis.These effects were regulated through the AKT/mTOR signaling pathway.

Background Intensity modulated radiation therapy (IMRT) is the standard of care for nasopharyngeal carcinoma (NPC). Part of the IMRT quality assurance process involves accurate target volume delineation, which is crucial for local control and survival. Current practice utilizes a uniform contouring method for clinical target volume (CTV) for all stages of NPC. Here, we conducted a single-arm phase 2 trial investigating the tumor control rates of reduced CTV margins and corresponding doses in low-risk, early-stage NPC. Methods Patients with biopsy-proven stage I-IIb (6th UICC/AJCC) NPC were enrolled. All patients were treated with IMRT alone. Two CTVs (CTV1 [high risk] and CTV2 [low risk]) were outlined; CTV1 was defined by grossly identified tumour (on MRI or CT) plus 5-mm margin (3-mm posteriorly); CTV2 was CTV1 plus 5-mm margin (3-mm posteriorly). 60 Gy and 50–54 Gy in 30 fractions were prescribed to CTV1 and CTV2, respectively. Primary end-point was locoregional recurrence free survival (LRRFS). Results From May 2001 to August 2006, 103 patients were recruited; all patients completed IMRT as planned (time duration 39-61 days). At a median follow-up of 12.6 years, five patients developed locoregional failures; of which one was in-field, and four were regional recurrence (two in-field and two marginal). 10-year LRRFS, distant metastasis free survival (DMFS), disease specific survival (DSS) and overall survival (OS) were 95.0% and 94.1%, 94.0% and 91.1%, respectively. The most common grade 1-2 late toxicities included subcutaneous fibrosis (79.6%), hearing loss (53.4%) and skin dystrophy (43.2%); grade 3 included subcutaneous fibrosis (2.9%) and hearing loss (2.9%); and no grade 4 late toxicity. Conclusions Reduced CTV margins and corresponding doses results in optimal long-term tumour control, with minimal late adverse events. Clinical trial identification NCT03839602. Legal entity responsible for the study Chong Zhao. Funding National Natural Science Foundation of China [No. 81872469]; Science and Technology Project of Guangdong Province [No. 2014A020212433]. Disclosure M.L.K. Chua: Honoraria (institution), Advisory / Consultancy: Janssen, Astellas, Varian, Ferring Singapore and AstraZeneca; Research grant / Funding (institution), Structured research agreement/Research funding - Ferring Singapore, GenomeDx Biosciences, Varian, MedLever.: Ferring Singapore, GenomeDx Biosciences, Varian, MedLever. All other authors have declared no conflicts of interest.

The vascular damage plays an important role in the response of tumors to high-dose hypofractionated radiation such as stereotactic body radiotherapy (SBRT). Non-invasive diagnostic imaging is an essential element in the evaluation and quantification of radiation-induced vascular damage in tumors. The primary aim of our study was to assess the potential of a combination of two novel imaging modalities together (the fluorescence imaging in the second near-infrared window (NIR-II, 1000 - 1700 nm) and photoacoustic (PA) imaging) for direct morphological and functional measurement of the head and neck tumors response to SBRT. Novel donor-acceptor chromophore-based nanoprobes (DAPs) with an absorption in NIR-I window and a fluorescence peak in NIR-II region were developed as contrast agents for both PA and NIR-II imaging in this study. We used a xenograft mouse model of human head & neck squamous carcinoma (SAS). Radiation therapy was performed using a 225 kVp image-guided small animal cabinet X-ray irradiator. The mice for conventional radiation therapy (CRT) were irradiated with 20 Gy in 5 fractions in 5 days, while the SBRT group was irradiated with 20 Gy in a single dose. Both PA and NIR-II imaging were performed one day before and 8 days after the radiation therapy after SAS tumor bearing mice were intravenously injected with DAPs. The DAPs show the unique ability to combine both PA and NIR-II modalities for tumor vasculature imaging. To repeatedly and non-invasively imaging the tumor area, we developed the principal component analysis (PCA) method to analyze the dynamic contrast enhanced images to differentiate the neovasculature from normal blood vessels and monitor the functional abnormalities of blood vessels. In the SAS tumors treated with CRT, the morphology and function of the vasculature was preserved during the treatment, but the irradiation with SBRT dramatically induced severe vascular damage to the tumors. The morphology and density of tumor blood vessels were evaluated using PA and NIR imaging. The result confirmed that severe vascular damage resulted in reduced blood perfusion. Although inhibition of tumor growth after CRT was observed, the regrowth of irradiated tumors appeared to be followed by neovascularization. There was a significant correlation between the extent of vascular density and survival rate of tumor mice. Our study provided a direct proof that the tumor vessel density is related to underlying effects of SBRT. To the best of our knowledge, it is the first time to use dual PA and NIR-II imaging modalities to evaluate the responses of blood vessels to SBRT. Noninvasive measures of vessel density and function using PA and NIR-II imaging successfully detected vascular damage, which plays a critical role in the response of tumors to SBRT. With advances of dual modality imaging technology and availability of imaging probes, our approach could enable optimal scheduling of radiation therapy with improved therapeutic outcome.

The purpose of this study was to investigate the significance of the prognostic nutritional index (PNI) in predicting the prognosis and guiding the treatment choices for nasopharyngeal carcinoma (NPC) patients treated by intensity-modulated radiotherapy (IMRT). Five hundred thirty-nine patients with newly diagnosis stage I-IV NPC who received radical IMRT with or without chemotherapy were retrospectively analyzed. The PNI was calculated as 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (per mm3). All patients were split randomly into a training set (n = 239) and a testing set (n = 300) for analysis. The receiver operating characteristic (ROC) curves were calculated to identify the cut-off value of PNI and tested its prognostic validity. Survival curves were calculated by the Kaplan-Meier method and differences were compared with a log-rank test. Univariate and multivariate analysis were applied to identify the prognostic factors. Of the 539 patients, 63.8% patients received concurrent chemoradiotherapy (CCRT) with or without neoadjuvant/adjuvant chemotherapy. The median follow-up time was 101.3 months. The five-year loco-regional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) of the whole cohort was 90.7%, 85.8%, 85.3%, and 83.1%, respectively. The cut-off value of PNI was 52.0 in the training set, which was significant in predicting DMFS, DSS, and OS in testing set and all patients (all P < 0.05). Multivariate analysis showed PNI was an independent prognostic factor on DMFS (P = 0.004), DSS (P < 0.001), and OS (P < 0.001) in the whole cohort. In order to explore the role of CCRT in the different PNI subclassifications of patients with stage II-IV, 220 patients who received CCRT alone were analyzed. In these 220 patients, 62 patients were in PNI ≤52.0, and 158 patients were in PNI >52.0. The 5-year DMFS, DSS, OS in patients with PNI ≤52.0 were significant worse than those with PNI >52.0 (76.0% vs. 86.4%, P = 0.039; 71.8% vs. 87.8%, P = 0.008; 67.7% vs. 84.8%, P = 0.008). Our results suggest that PNI is a reliable independent prognostic factor in NPC patients treated with IMRT. For locoregionally intermediate and advanced NPC patients with PNI≤52.0, CCRT alone could not achieve satisfactory treatment outcome, and further studies on treatment optimization are needed.

The value of adding concurrent chemotherapy to radiation therapy is unknown in patients with stage IVC nasopharyngeal carcinoma (NPC). We retrospectively evaluated the role of concurrent chemotherapy in this group of patients who were treated with palliative chemotherapy followed by definitive radiation therapy to primary tumor as first-line treatment. A total of 172 patients with newly diagnosed NPC and distant metastasis between January 2008 and December 2011 were analyzed. Patients were treated with few cycles of platinum-based palliative chemotherapy followed by definitive radiation therapy to the primary head and neck region with concurrent chemotherapy (CRT group) or without concurrent chemotherapy (RT group). There were 73 patients in CRT group and 99 patients in RT group. Overall survival (OS) was calculated with the Kaplan-Meier method, and differences were compared by using the log-rank test. Multivariate analysis was performed by using the Cox proportional hazards model. The median OS time for the entire cohort was 46.9 months (range, 2-79 months), and the 1-year, 2-year, 3-year, 5-year OS rates were 90.9%, 70.8%, 60.0% and 36.9%. No additional survival benefit was found in CRT group compared with RT group. The 1-year, 2-year, 3-year and 5-year OS rates of the CRT group and RT group were 91.4% and 90.6%, 68.6% and 72.4%, 62.5% and 58.3%, 39.1% and 35.1%, respectively (P = 0.382). Subgroup analysis of different locations of metastases demonstrated that concurrent chemoradiation therapy had a tendency towards an improved survival rate for patients with solitary lung metastasis, with median OS time of 65.7 months (range, 8-77 months) in CRT group and 42.7 months (range, 2-66 months) in RT group. Multivariate analysis showed that serum lactate dehydrogenase level and Epstein-Barr virus-DNA load were significant prognostic factors. The use of palliative chemotherapy followed by concurrent chemoradiation therapy to primary tumor could achieve better survival in NPC patients with solitary lung metastasis at initial diagnosis. Further randomized prospective study is necessary to find the optimal treatment strategy.

Comparative studies on triweekly and weekly cisplatin in locally advanced nasopharyngeal carcinoma (NPC) were all based on small sample size, and no definitive conclusion has been reached. The aim of this study was to compare the outcomes of concurrent chemoradiotherapy (CCRT) using two different schedules of cisplatin in patients with locally advanced NPC. From January 2007 to December 2011, 1582 patients with stage II-IVb NPC, treated with CCRT alone were reviewed. Eight hundred and two patients received triweekly cisplatin (80-100 mg/m2 every three weeks, two to three cycles) and 780 patients received weekly cisplatin (30-40 mg/m2 every week, over five cycles). Clinical characteristics and treatment factors were well balanced in two groups. Overall survival (OS), disease–free survival (DFS), locoregional recurrence–free survival (LRRFS), distant metastasis-free survival (DMFS) and acute toxicity profiles were calculated. Median follow-up time was 64 months (range, 4–194 months). For the entire cohort, the distant metastasis risk was decreased by 30% in the triweekly group than weekly group (hazard ratio [HR] = 0.70; 95% confidence interval [CI]: 0.49-0.99). Subgroup analysis revealed that triweekly cisplatin could further improve patients' 5-year DMFS (92.6% vs. 85.8%, P < 0.001, respectively) and DFS (82.6% vs. 77.6%, P = 0.016, respectively) compared with the weekly group, for patients treated with intensity-modulated radiotherapy (IMRT). Furthermore, the 5-year DMFS rates were significantly improved by using triweekly cisplatin in patients with N3 diseases (HR = 0.37; 95% CI: 0.14-0.94) and stage IV diseases (HR = 0.52; 95% CI: 0.29-0.93). Grade 3-4 acute toxicities were similar in two groups. Triweekly cisplatin treatment is more effective than weekly cisplatin regimen in reducing distant metastases in patients with locally advanced NPC, especially for those with N3 or stage IV diseases and who were treated with IMRT.

No consensus is available for delineation of the target volumes after neoadjuvant chemotherapy (NACT) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The aim of current study was to evaluate the long-term results and loco-regional failure patterns in delineation of the target volumes according to the shrunken gross tumor volumes (GTVs) after NACT in LA-NPC treated with NACT followed by intensity-modulated radiation therapy and concurrent chemotherapy (CCRT). Previously untreated LA-NPC patients were recruited. All patients received two cycles of NACT followed by CCRT. The gross tumor volumes of the primary site and the neck nodes (GTVnx and GTVnd) were defined according to the MR images which obtained two weeks after the last cycle of NACT. The first clinical target volume (CTV1) was defined as the GTVnx plus a 5–10mm margin (2 to 3mm margin posteriorly) to encompass the high-risk sites of microscopic extension, the whole nasopharynx, and the location and extent of the primary tumor before NACT. The second clinical target volume (CTV2) was defined as the CTV1 plus a 5-10mm margin (2 to 3mm margin posteriorly) to encompass the low-risk sites of microscopic extension, the level of the lymph node located before NACT, and the elective neck area. The prescribed dose to GTVnx, GTVnd, CTV1 and CTV2 were 68Gy/30f, 62-66Gy/30f, 60Gy/30f and 54Gy/30f, respectively. All loco-regional recurrences were transferred to the pretreatment planning computer tomography for dosimetry analysis. One hundred and twelve patients were enrolled in current study. With the median follow-up of 92.3 months, there have been 8 local and 6 regional recurrences in twelve patients. The 5-year local relapse-free, regional relapse-free, distant metastasis-free and overall survival rates were 92.7%, 94.3%, 86.3% and 80.4%, respectively. Dosimetry analysis showed that all of the 8 local recurrences were in-field. Of the 6 regional recurrences, 4 were in-field, one was marginal, and the remaining one was outside. The most common late toxicities were grade 1-2 skin dystrophy, subcutaneous fibrosis, hearing lost and xerostomia. No grade 4 late toxicities were noted. Delineation of the target volumes according to the shrunken GTVs after NACT could obtain excellent loco-regional control with fewer marginal or outside recurrences and milder late toxicities in LA-NPC treated with NACT followed by CCRT. A further phase III study is warranted.

Objectives: To explore metabolic symbiosis in gastric cancer and its relationship with cancer prognosis.Patients and methods: Immunohistochemistry was used to detect MCT4 and TOMM20 expression in 113 gastric cancer patient specimens. The correlations of MCT4 and TOMM20 expression with gastric cancer clinicopathological features and survival were studied.Results: Stromal MCT4 expression was closely associated with the pathological (p) TNM stage and TOMM20 expression. We also assessed the predictive value of epithelial MCT4 expression. However, no correlation with patient clinical outcome was evident. TOMM20 expression was closely associated with tumor size and stromal MCT4 expression. Further, stromal MCT4 and mitochondrial TOMM20 were positively correlated, and Kaplan-Meier analysis showed that high stromal MCT4 expression and high mitochondrial TOMM20 expression were associated with reduced overall survival and disease-free survival. Both univariate and multivariate analyses revealed that stromal MCT4 expression and mitochondrial TOMM20 expression were independent prognostic factors in gastric cancer patients.Conclusions: Our findings directly support the existence of metabolic symbiosis in gastric cancer. Stromal MCT4 and mitochondrial TOMM20 could be promising biomarkers for predicting the prognosis of patients with gastric cancer. These proteins might also serve as novel therapeutic targets in gastric cancer treatment. (C) 2014 Elsevier Ltd. All rights reserved.