Recurrent Metastatic Nasopharyngeal Carcinoma Research Articles

356O Construction of an immune-related adverse events prediction model for teripulimab in the treatment of recurrent metastatic nasopharyngeal carcinoma and its analysis with survival prognosis

356O Construction of an immune-related adverse events prediction model for teripulimab in the treatment of recurrent metastatic nasopharyngeal carcinoma and its analysis with survival prognosis

Gemcitabine combined with apatinib and toripalimab in recurrent or metastatic nasopharyngeal carcinoma

The role of a triple combination of gemcitabine (chemotherapy) plus apatinib (anti-vascular endothelial growth factor [VEGFR]) and toripalimab (anti-PD-1) (GAT) in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) is unclear. Between August 2019 and April 2020, 41 patients with RM-NPC were enrolled and received GAT for up to 6 cycles followed by apatinib and toripalimab. The primary endpoint was the safety. The secondary endpoints included the objective response rate (ORR) and progression-free survival (PFS). Integrated genomic and transcriptional analyses were conducted to identify the patients who benefited in response to this novel combination therapy. As of April 1, 2022, treatment-related grade 3 or 4 adverse events (AEs) occurred in 23 of 41 patients (56.1%, 95% confidence interval [CI] 41%-70.1%). G3-4 nasopharyngeal necrosis was observed in 9 (9/41, 21.9%) patients. High-risk factors for necrosis included repeated radiotherapy and an interval of less than 12months from the last radiotherapy. The ORR was 90.2% (95% CI: 76.9%-97.2%). The median PFS was 25.8months (95% CI: not reached (NR)-NR), and the 24-month PFS rate was 50.7% (95% CI: 34.0%-67.4%). MAS-related GPR family member F (MRGPRF) high expression in tumors correlated with poor PFS from the GAT therapy, characterized by high epithelial mesenchymal transition signatures. Serial circulating tumor DNA (ctDNA) sequencing could predict PFS outcomes to combination therapy. GAT therapy exhibits a promising antitumor activity and manageable toxicities in patients with RM-NPC. Patients with repeated radiotherapy and an interval of less than 12months from the last radiotherapy should be carefully selected for antiangiogenic therapies. MRGPRF expression and serial ctDNA monitoring could identify patients that derive benefits from the combination therapy. ClinicalTrials.gov: NCT04073784. This research was funded by the National Natural Science Foundation of China (nos. 81772895 and 82002857), the Key-Area Research and Development of Guangdong Province (2020B1111190001), the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project (202103010001), and the National "Ten Thousand TalentsProgram" Science and Technology Innovation Leading Talents (84000-41180005).

A phase 1b/2 study of nanatinostat and valganciclovir in patients with advanced Epstein-Barr virus positive (EBV+) solid tumors and in combination with pembrolizumab in patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC).

TPS6107 Background: Epstein-Barr virus (EBV) is linked to the development and pathogenesis of nasopharyngeal carcinoma (NPC). Most patients present with advanced stage disease at diagnosis (Li 2014); first-line chemoradiation is commonly followed by recurrence and poor prognosis emphasizing the need for new treatment options. Targeting EBV in NPC represents a novel therapeutic approach. EBV is predominantly latent in NPC; pre-clinical studies demonstrated that induction of the viral lytic phase by histone deacetylase inhibitors (HDACi) renders EBV+ tumor cells susceptible to the cytotoxic activity of ganciclovir (GCV) (Hui 2016). Nanatinostat (Nstat), a potent Class-I HDACi, induces the expression of the lytic BGLF4 protein kinase in EBV+ tumor cells, which activates the nucleoside analog GCV via phosphorylation. Phosphorylated GCV becomes incorporated into the cellular DNA causing chain termination and apoptosis. The all-oral combination of Nstat and valganciclovir (VGCV), a pro-drug of GCV, has demonstrated favorable safety and preliminary efficacy in a phase 1/2 study in patients with recurrent EBV+ lymphoma (NCT03397706). This phase 1b/2, open-label, multicenter study will evaluate the safety, tolerability, pharmacokinetics, and preliminary activity of Nstat + VGCV in patients with advanced EBV+ solid tumors. Additionally, the combination of pembrolizumab together with Nstat + VGCV will be evaluated in recurrent/metastatic NPC (RM-NPC) patients. NPC frequently exhibits high PD-L1 expression levels; however, PD-1 inhibitors resulted in limited response rates ranging from 20-30% in the RM-NPC setting. Methods: Phase 1b utilizes a 3+3 dose escalation design to determine the recommended Phase 2 dose (RP2D) of Nstat + VGCV in patients with EBV+ RM-NPC. In Phase 2, up to 60 patients with EBV+ RM-NPC will be randomized 1:1 to receive Nstat + VGCV at the RP2D with or without pembrolizumab to evaluate safety, tolerability, overall response rate, and potential pharmacodynamic markers of drug activity, including plasma EBV DNA levels. Additionally, patients with EBV+ solid tumors other than RM-NPC will receive Nstat + VGCV at the RP2D in a separate Phase 1b dose expansion cohort. Patients eligible for the phase 1b dose escalation and phase 2 will have EBV+ RM-NPC with 1-3 prior lines of platinum-based chemotherapy and no available curative therapies. Patients with advanced EBV+ non-NPC solid tumors (gastric cancer, lymphoepithelioma-like carcinoma, leiomyosarcoma) and no curative therapies are eligible for the phase 1b expansion cohort. All patients must have measurable disease per RECIST v1.1 and adequate bone marrow, liver, and renal function. Enrollment began in January 2022. Clinical trial information: NCT05166577.

Cover Image, Volume 42, Issue 1

The cover image is based on the Discussion of Paper JUPITER-02 trial: advancing survival for recurrent metastatic nasopharyngeal carcinoma and next steps by Melvin Chua et al., https://doi.org/10.1002/cac2.12248.

Successful management of a recurrent hepatosplenic metastatic nasopharyngeal carcinoma in an adolescent boy: case report and review of literature

Nasopharyngeal carcinoma (NPC) is a rare tumor in pediatric age group and adolescents are the commonly affected age group. It generally presents as locoregionally advanced disease and 15-30% of them develop a recurrence or distant metastatic disease. The outcome of patients with recurrent metastatic nasopharyngeal carcinoma has been reported to be very poor, with a median overall survival of about 20 months. We present a case of adolescent boy who presented initially with locally advanced nasopharyngeal carcinoma, treated with local radiotherapy and cisplatin, 5 flurouracil and later presented with a recurrent metastatic disease in liver and spleen, within 2 months of completing treatment. He was managed with total splenectomy and paclitaxel and gemcitabine and he remains disease free for more than 18 months now. The case highlights that long term remission could be attained with conventional chemotherapy, combined with surgery in relapsed metastatic NPC even in a resource limited settings.

Lactate dehydrogenase kinetics predict chemotherapy response in recurrent metastatic nasopharyngeal carcinoma.

Background:Lactate dehydrogenase (LDH) is a known prognostic biomarker for the endemic variant of nasopharyngeal carcinoma (NPC). Here, we investigate whether serial changes in LDH level between chemotherapy (CT) cycles are associated with tumour response to CT.Methods:Patients with biopsy-proven, recurrent or treatment-naïve metastatic NPC (mNPC) were recruited. All patients had received at least two cycles of platinum-based doublet or triplet CT, with serial assessment of LDH prior to every cycle of chemotherapy (CT1–6). Patients harbouring conditions that affect LDH levels (IU/L) were excluded. Tumour response was assessed after every two cycles of CT by RECIST v1.1.Results:A total of 158 patients were analysed, including 77 with recurrent and 81 with treatment-naïve mNPC. High pre-CT LDH was associated with an inferior overall survival [hazard ratio 1.93 for ⩾240 versus <240 (1.34–2.77), p < 0.001], which is consistent with published literature. We found that both absolute LDH levels and LDH ratios (LDHCTn: LDHCTn–1) were associated with tumour response [partial response versus progressive disease: median value across CT1–6 = 168–190 versus 222–398 (absolute); 0.738–0.988 versus 1.039–1.406 (ratio)], albeit LDH ratio had a tighter variance between patients. Finally, we showed that an LDH ratio cut-off of 1.0 at CT1, CT3 and CT5 was predictive of progressive disease at CT2, CT4, CT6 [area under the curve of 0.73 (0.65–0.80)].Conclusion:Herein, we characterised the longitudinal variation of LDH in response to CT in mNPC. Our findings suggest the potential utility of interval LDH ratio to predict subsequent tumour response to CT.

Successful treatment of recurrent metastatic nasopharyngeal carcinoma with nivolumab: a case report

The study objective is to report a case of successful treatment of disseminated nasopharyngeal carcinoma with nivolumab. Materials and methods . A 22-year-old male patient was admitted to N.N. Blokhin National Medical Research Center of Oncology with a diagnosis of T3N3M1 stage IV nasopharyngeal carcinoma with bone metastasis. After a course of radical chemoradiotherapy, the patient was found to have cancer progression. Between September 2016 and July 2017, the patient received chemotherapy with 3 lines of drugs, but with no effect. We decided to initiate treatment with PD-1 inhibitors. The patient received nivolumab 3 mg/kg every 2 weeks between July 2017 and March 2018. Results. Positron emission tomography (September 2018) demonstrated no increased uptake of [18F]-fluorodeoxyglucose in earlier identified cancer foci. Since September 2018, the patient has been in persistent remission without any therapy. Conclusion. This case report demonstrates high efficacy of PD-1 inhibitors in the treatment of disseminated recurrent nasopharyngeal squamous cell carcinoma, resistant to standard radiotherapy and chemotherapy.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibody combined with cisplatin and 5-fluorouracil in patients with metastatic nasopharyngeal carcinoma after radical radiotherapy: a multicentre, open-label, phase II clinical trial

BackgroundWe 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. MethodsPatients 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 (200mg) added to cisplatin (100mg/m2 D1) and 5-fluorouracil (4g/m2 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. ResultsA 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 ≥2400mg 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 2.7months, P=0.081; 17.0 versus 8.0months, 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 >12months [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%). ConclusionCombination nimotuzumab-PF chemotherapy demonstrates potential efficacy, and is well tolerated as first-line chemotherapy regimen in recurrent metastatic nasopharyngeal carcinoma.

Evaluation of stem-like side population cells in a recurrent nasopharyngeal carcinoma cell line.

BackgroundSide population (SP) assay identifies cells with dye/drug extrusion ability, a characteristic of stem cells. Here, we determined if SP cells exist in a verified cell line originating from recurrent nasopharyngeal carcinoma (NPC) and a xenograft established from recurrent metastatic NPC. These cells were evaluated for stem-like properties via functional assays as well as for tumourigenicity.MethodsWe used Hoechst 33342 to identify the SP from non-SP (NSP) cells in HK1 NPC cell line and xeno-284 NPC xenograft. The cells were assayed for in vitro characteristics of cancer stem cells (CSC), gene expression and tumourigenicity ability. Student’s t test was used to test for significance.ResultsFive to ten percent and less than 0.5% of HK1 and xeno-284 NPC cells, respectively, were SP cells. Fumitremorgin C (FTC), as opposed to verapamil, was effective in causing the cells to retain Hoechst 33342 dye. HK1 SP cells formed more holoclones, had more aldehyde dehydrogenase (ALDH) activity, divided asymmetrically and contained slow-proliferating cells. ABCG2, SOX2, TERT, MYC, Hedgehog, Notch, TGFβ and Wnt signalling pathway genes were significantly upregulated in the SP cells. However, despite these differences in vitro, both HK1 SP and NSP cells had an overall similar tumourigenic potential in vivo.ConclusionsHK1 SP cells were ABCG2-specific as confirmed by FTC inhibition and gene expression data. Despite data from in vitro and gene expression experiments suggesting stem-like features, there was no significant difference in tumourigenic potential between SP and NSP cells. We conclude that SP assay alone is not sufficient to identify CSCs in HK1 cells. Our work also suggests the presence of a stem-cell like population among NPC cells which do not display increased tumourigenicity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-014-0101-0) contains supplementary material, which is available to authorized users.

Radiological, pathological and DNA remission in recurrent metastatic nasopharyngeal carcinoma

BackgroundCirculating plasma Epstein Barr Virus DNA (EBV-DNA) is a sensitive and specific marker of nasopharyngeal carcinoma (NPC). The mainstay of treatment of metastatic NPC is systemic chemotherapy and resection for solitary metastasis. Despite high response rate to chemotherapy, complete remission is uncommonly seen.Case PresentationWe report a case of recurrent metastatic NPC in a 43-year-old man, who achieved complete remission three times with chemotherapy and surgery. Serial plasma EBV-DNA levels were measured during the course of disease. The patient had three episodes of recurrences of NPC manifested as distant metastasis. Both time, rise in the plasma EBV-DNA level preceded detection of recurrences by imaging. Following systemic chemotherapy, he achieved complete remission each time, of which was confirmed by 18-flourodeoxyglucose positron emission tomography and hepatectomy pathology. The plasma EBV-DNA level dropped to zero copy/ml at the time of each remission.ConclusionThis case highlights the high chemosensitivity of NPC by illustrating a rare occurrence of complete response of metastatic NPC to chemotherapy. This case also underscores the usefulness of EBV-DNA as a useful tool in monitoring NPC by its ability to detect early recurrence and excellent correlation with treatment response.

Salvage neck dissection for cervical recurrence of nasopharyngeal carcinoma.

To evaluate the effectiveness of salvage neck dissection as part of a multidisciplinary treatment approach in persistent or recurrent metastatic nasopharyngeal carcinoma, after failure of initial radiotherapy at the regional site. A retrospective study of 31 patients treated during a 14-year period from March 1981 through May 1995, with a maximum follow-up of 152 months. Factors evaluated include patients' sex, age, and initial stage of tumor, mobility and number of nodal recurrences, surgical and pathological findings, and postoperative irradiation. Academic tertiary referral center. Twenty-six men and 5 women were studied; one patient had neck dissection to both sides of the neck on separate occasions, for a total of 32 operations. All patients had pathologically proved nasopharyngeal carcinoma and had been previously treated at the primary site and both sides of the neck with definitive radiotherapy. Patients underwent a radical, modified radical, or level I-sparing radical neck dissection. Surgical morbidity, time to recurrence at the regional site, and survival time. Clinically, there was a disease predilection of 81% at levels II and V. Surgical morbidity was minimal. Regional control was achieved in 20 (65%) of the patients, and the overall 5-year survival was 67%. Tumor involvement of the posterior triangle musculature and spinal accessory nerve was associated with failure to control neck disease. Extracapsular nodal extension correlated with a poor survival outcome. Control of regional disease by salvage neck dissection when radiotherapy has failed is both safe and effective in properly selected patients.