Relapse Of Nasopharyngeal Carcinoma Research Articles

Phase 1/2 study of PRO1160, a CD70-directed antibody-drug conjugate, in patients with advanced solid tumors and hematologic malignancies

Abstract Background: PRO1160 is a novel antibody-drug conjugate (ADC) directed to CD70, an antigen mediating immuno-suppression that is overexpressed in multiple solid tumors and hematologic malignancies, with limited distribution in normal tissues. PRO1160 comprises (1) a human monoclonal antibody specific for CD70, (2) a protease-cleavable proprietary hydrophilic linker, and (3) exatecan, a topoisomerase 1 inhibitor. Comprehensive prior work demonstrated that the hydrophilic linker confers excellent physicochemical properties and pharmacokinetics (PK) across a range of payload mechanisms and is superior to conventional linkers on these critical parameters for ADCs. In addition, exatecan is broadly active in many tumor types, is membrane permeable, and is not a substrate of multidrug resistance pumps, thus likely lending strong bystander effects and durable treatment responses. PRO1160 is highly potent in cell-derived xenograft models of renal cell carcinoma (RCC), non-Hodgkin lymphoma (NHL), and nasopharyngeal carcinoma (NPC). PRO1160 also demonstrates marked antitumor activity in patient-derived xenograft models of diverse tumor sites, histologies, molecular subtypes, target expression levels, and Epstein Barr Virus status. PRO1160 is stable in circulation and displays PK characteristics indistinguishable from the parent antibody in rats. In a GLP toxicity study in cynomolgus monkeys, the primary PRO1160-related toxicity resided in the thymus and bone marrow, was consistent with exatecan toxicities, and was reversible. PRO1160-001 is an ongoing, open-label Phase 1/2 study to evaluate the safety, tolerability, PK, and antitumor activity of PRO1160 in patients with metastatic RCC, metastatic or relapsed NPC, or advanced relapsed/refractory NHL. Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or the Lugano Classification for NHL. Patients must also have previously received therapies known to confer clinical benefit unless considered ineligible, refused by the patient, or not available in the region. PRO1160 is given by intravenous infusion on Day 1 of a 21-day cycle and treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to evaluate the safety and tolerability of PRO1160 and to identify the maximum tolerated dose, if reached, and recommended phase 2 dose (RP2D). This study consists of 2 parts, Part A: dose-escalation and dose-level expansion, and Part B: 3 tumor-specific expansion cohorts (metastatic RCC, metastatic or relapsed NPC, or advanced relapsed/refractory NHL) treated at the RP2D. PK, immunogenicity, and antitumor activity will also be evaluated. The study is currently enrolling at sites in the US, with future enrollment in China planned (Clinicaltrials.gov: NCT05721222).

Local and Lymph Node Relapse of Nasopharyngeal Carcinoma: A Single-Center Experience.

The study aimed to investigate the epidemiological and clinical characteristics as well as the therapeutic results in patients with locoregional (LR) relapse after treatment of nasopharyngeal carcinoma (NPC). We retrospectively reviewed the medical records of patients with local and/or regional recurrent NPC over 13 years (2003-2015). Twenty-five patients were treated for local or/and local-regional recurrence of NPC. The rate of LR relapse was 7.2%. The mean age of the patients was 46 ± 13.9 years. The median time to relapse was 25 months. The recurrence was nasopharyngeal in 17 patients, nasopharyngeal and neck lymph nodes in 7 patients, and neck lymph nodes in 1 patient. Fifteen relapsed patients had a locally advanced disease (rT3-rT4). Patients who had initially T1 or T2 tumor had a locally advanced relapsed disease (rT3rT4) in 27.3% and patients whose disease was initially classified as T3 or T4 had a locally advanced relapsed disease (rT3T4) in 85.7% (P = .005, Fisher test). Twelve patients had chemotherapy after relapse. Chemotherapy was followed by concurrent chemoradiotherapy in 3 patients and by radiotherapy (RT) in 4 patients. Nine patients had concurrent chemoradiotherapy and 1 patient had exclusive RT. The overall survival (OS) at 1 year, 3 years, and 5 years was, respectively, 58%, 18%, and 10%. The OS was significantly higher in patients with good performance status at the time of relapse (World Health Organization = 1; P = .01) and in patients with late relapse (after 2 years; P = .03). Locoregional relapse rate in our study was 7.2%. Locoregional reirradiation was the mainstay treatment modality in relapsed NPC. Relapsed NPC had a poor prognosis with a 5-year survival rate of 18%. The OS was significantly higher in patients with good performance status and in patients with late relapse (after 2 years).

Perspective: Contribution of Epstein-Barr virus (EBV) Reactivation to the Carcinogenicity of Nasopharyngeal Cancer Cells.

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma derived from the epithelium of the post-nasal cavity, with a unique geographic and ethnic distribution. Epstein–Barr virus (EBV) is an etiological agent of NPC, but how it contributes to carcinogenesis is not completely clear. Although it is thought that EBV latency participates in the development of NPC, increasing evidence reveals that the lytic cycle also plays an important role in the carcinogenic process. In this review, we summarize our recent studies on how EBV reactivation causes genomic instability and accelerates tumorigenesis in epithelial cells. The roles of three lytic genes, namely, BRLF1, BGLF5 and BALF3, in this process are also introduced. Moreover, blocking EBV reactivation using natural compounds may help delay the progression of NPC tumorigenesis. These studies provide a new insight into NPC carcinogenesis and raise the possibility that inhibition of EBV reactivation may be a novel approach to prevent the relapse of NPC.

Epstein-Barr virus BRLF1 induces genomic instability and progressive malignancy in nasopharyngeal carcinoma cells.

Nasopharyngeal carcinoma (NPC) is a serious health problem in China and Southeast Asia. Relapse is the major cause of mortality, but mechanisms of relapse are mysterious. Epstein–Barr virus (EBV) reactivation and host genomic instability (GI) have correlated with NPC development. Previously, we reported that lytic early genes DNase and BALF3 induce genetic alterations and progressive malignancy in NPC cells, implying lytic proteins may be required for NPC relapse. In this study, we show that immediate early gene BRLF1 induces chromosome mis-segregation and genomic instability in the NPC cells. Similar phenomenon was also demonstrated in 293 and zebrafish embryonic cells. BRLF1 nuclear localization signal (NLS) mutant still induced genomic instability and inhibitor experiments revealed that BRLF1 interferes with chromosome segregation and induces genomic instability by activating Erk signaling. Furthermore, the chromosome aberrations and tumorigenic features of NPC cells were significantly increased with the rounds of BRLF1 expression, and these cells developed into larger tumor nodules in mice. Therefore, BRLF1 may be the important factor contributing to NPC relapse and targeting BRLF1 may benefit patients.

Promoting tumorigenesis in nasopharyngeal carcinoma, NEDD8 serves as a potential theranostic target

Nasopharyngeal carcinoma (NPC), is one of the most common human malignancies in south China, it has the highest recurrence rate and treatment resistance. The underlying molecular mechanisms of NPC relapse and treatment tolerance are not fully understood. In this study, the effects of NEDD8 and NEDD8-activating enzyme inhibitor (MLN4924) on NPC were studied both in vitro and in vivo. Immunohistochemical staining of 197 NPC tissues revealed an elevated NEDD8 expression as an unfavorable independent factor in overall survival and disease-free survival rates. NEDD8 expression was positively correlated with a high risk of death and positivity of lymph node metastasis. Depleted NEDD8 expression by shRNA and inhibited by specific inhibitor MLN4924 dramatically suppressed cell proliferation, cell apoptosis, cell cycle arrest, while ectopic NEDD8 exhibited opposing effects. NEDD8 affected cancer stem cell phenotypes of NPC as assessed in vitro using the cell number of side population (SP) by flow cytometry analysis, colony formation assay, sphere formation assay, and tumor initiation ability in vivo. Downregulation of NEDD8 enhanced the susceptibility of NPC cells to cisplatin and radiation. Moreover, we found that MLN4924 suppressed c-Jun degradation in human NPC cells. Taken together, this report revealed that NEDD8 may act as a novel prognostic marker and MLN4924 may serve as a promising therapeutic target for patients with NPC.

Relapse status as a prognostic factor in patients receiving salvage surgery for recurrent or residual nasopharyngeal cancer after definitive treatment.

The purpose of this study was to determine the prognostic value of relapse status (recurrent vs residual disease) in patients receiving surgical salvage for nasopharyngeal carcinoma (NPC). Retrospective review was conducted on 52 patients who underwent salvage surgery for locoregional relapse of NPC. Univariate and multivariate analyses were used to investigate the prognostic value of relapse status. Median follow-up duration was 44.4 months. Mean overall survival (OS) and disease-free survival (DFS) for patients with NPC with residual and recurrent disease after surgical salvage were 107.4 and 54.4 months, and 83.6 and 34.6 months, respectively (p < .001). This improved survival was demonstrated regardless whether the relapse was at the primary or nodal site. Multivariate analysis revealed that recurrent disease status and nodal disease relapse were independent poor prognostic factors for survival in patients receiving salvage surgery for NPC. In patients undergoing surgical salvage for NPC relapse, residual disease carries a better prognosis than recurrent disease. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1393-1400, 2016.

EBV reactivation as a target of luteolin to repress NPC tumorigenesis.

Nasopharyngeal carcinoma (NPC) is a malignancy derived from the epithelial cells of the nasopharynx. Although a combination of radiotherapy with chemotherapy is effective for therapy, relapse and metastasis after remission remain major causes of mortality. Epstein-Barr virus (EBV) is believed to be one of causes of NPC development. We demonstrated previously that EBV reactivation is important for the carcinogenesis of NPC. We sought, therefore, to determine whether EBV reactivation can be a target for retardation of relapse of NPC. After screening, we found luteolin is able to inhibit EBV reactivation. It inhibited EBV lytic protein expression and repressed the promoter activities of two major immediate-early genes, Zta and Rta. Furthermore, luteolin was shown to reduce genomic instability induced by recurrent EBV reactivation in NPC cells. EBV reactivation-induced NPC cell proliferation and migration, as well as matrigel invasiveness, were also repressed by luteolin treatment. Tumorigenicity in mice, induced by EBV reactivation, was decreased profoundly following luteolin administration. Together, these results suggest that inhibition of EBV reactivation is a novel approach to prevent the relapse of NPC.

Levels of plasma Epstein-Barr virus DNA prior and subsequent to treatment predicts the prognosis of nasopharyngeal carcinoma.

The level of Epstein-Barr virus DNA (EBV-DNA) in the plasma prior and subsequent to treatment is a reliable biomarker for the screening, diagnosis, monitoring and prognosis of nasopharyngeal carcinoma (NPC). The present retrospective study aimed to determine whether pre- and post-treatment levels of plasma EBV-DNA were predictive of survival in a large sample of patients with NPC. The level of plasma EBV-DNA in 637 NPC patients prior and subsequent to treatment was determined by quantitative polymerase chain reaction. The value of pre- and post-treatment plasma EBV-DNA in predicting the survival of NPC patients was then analyzed. The results revealed that pre-treatment plasma EBV-DNA loads were significantly higher in patients with NPC than those in healthy controls (P<0.001). The percentage of patients with positive plasma EBV-DNA was markedly higher prior to treatment (70.64%; median, 1150 copies/ml; range, 0-9.75×106 copies/ml) than following treatment (25.99%; median, 0 copies/ml; range, 0-3.83×106 copies/ml) (P<0.001). Patients with a high plasma EBV-DNA load presented with a higher clinical tumor classification, lymph node status, metastatic status and overall cancer stage. The risk of NPC relapse and mortality was higher in patients with pre-treatment plasma EBV-DNA levels of ≥1,500 copies/ml than that in patients with <1,500 copies/ml. Furthermore, the risk of relapse and mortality was higher in patients with positive post-treatment plasma EBV-DNA than in patients with negative post-treatment plasma EBV-DNA. Detectable post-treatment plasma EBV-DNA was the most significant prognostic factor to affect relapse-free survival, whilst metastasis was the prognostic factor with the greatest effect on overall survival. These data indicated that pre- and post-treatment levels of plasma EBV-DNA were able to predict the prognosis of NPC. This finding may provide novel references for research and clinical practice.

Epstein-Barr virus BALF3 mediates genomic instability and progressive malignancy in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer prevalent throughout Southern China and Southeast Asia. Patient death following relapse after primary treatment remains all too common but the cause of NPC relapse is unclear. Clinical and epidemiological studies have revealed the high correlation among NPC development, Epstein-Barr virus (EBV) reactivation and host genomic instability. Previously, recurrent EBV reactivation was shown to cause massive genetic alterations and enhancement of tumor progression in NPC cells and these may be required for NPC relapse. Here, EBV BALF3 has the ability to induce micronuclei and DNA strand breaks. After recurrent expression of BALF3 in NPC cells, genomic copy number aberrations, determined by array-based comparative genomic hybridization, had accumulated to a significant extent and tumorigenic features, such as cell migration, cell invasion and spheroid formation, increased with the rounds of induction. In parallel experiments, cells after highly recurrent induction developed into larger tumor nodules than control cells when inoculated into NOD/SCID mice. Furthermore, RNA microarrays showed that differential expression of multiple cancer capability-related genes and oncogenes increased with recurrent BALF3 expression and these changes correlated with genetic aberrations. Therefore, EBV BALF3 is a potential factor that mediates the impact of EBV on NPC relapse.

Treatment outcome of docetaxel, capecitabine and cisplatin regimen for patients with refractory and relapsed nasopharyngeal carcinoma who failed previous platinum-based chemotherapy

Objective: Although cisplatin combined with 5-fluorouracil is a common first-line regimen for advanced nasopharyngeal carcinoma (NPC), there are no standard regimens for refractory or relapsed patients. A study of DXD regimen [cisplatin (D), capecitabine (X) and docetaxel (D)] was conducted to evaluate the efficacy and toxicity for patients with refractory or relapsed NPC.Methods: The regimen was administered as follows: 50 mg/m2 docetaxel and 50 mg/m2 cisplatin on day 1 and 800 mg/m² capecitabine on days 1 – 14, repeated every 3 – 4 weeks.Results: Thirty patients were enrolled. The overall response and complete remission rate was 46.4 and 21.4%. Median follow-up was 24 months; median overall survival (OS) and progression-free survival (PFS) were 14.0 and 8.0 months. Five-year OS and PFS rates were 14.8 and 13.3%, respectively. Four patients achieved long-term tumor-free survival (range, 53.8 – 125.3 months). Multivariate analysis demonstrated that Epstein–Barr virus DNA status (p = 0.003) and therapeutic effect (p < 0.001) were significant independent factors for OS and PFS. The main grade 3/4 toxicities included neutropenia (26.6%), anemia (13.3%) and thrombocytopenia (10.0%). There were no chemotherapy-related deaths.Conclusion: The DXD regimen appeared to be effective and well tolerated by patients with refractory or relapsed NPC. Further investigation is warranted.

Nasolacrimal relapse of nasopharyngeal carcinoma

To describe three rare cases of nasolacrimal relapse of nasopharyngeal carcinoma, and to discuss the route of tumour spread from nasopharynx to lacrimal system as well as the relevant computed tomography findings. We report three cases of nasolacrimal relapse in patients with previously treated nasopharyngeal carcinoma. The common initial presentations in these cases were epiphora and medial canthal swelling. The tumour spread from the nasopharynx to the lacrimal sac along the lateral nasal wall and nasolacrimal canal. Computed tomography demonstrated nasolacrimal canal invasion and osteomeatal complex obliteration by the tumour. Distant metastasis was detected in two cases. More targeted radiotherapy should be delivered to prevent under-treatment of nasopharyngeal carcinoma. Nasolacrimal relapse of nasopharyngeal carcinoma is an advanced disease with a poor prognosis.

The results and prognosis of different treatment modalities for solitary metastatic lung tumor from nasopharyngeal carcinoma: a retrospective study of 105 cases

Nasopharyngeal carcinoma (NPC) is known for its propensity for distant metastases. Lung metastasis is one of the most important causes of death for patients with NPC. Solitary metastatic lung tumor from NPC is a distinctive group associated with a better survival. This study was to find a more effective treatment modality and prognostic factors for the group. Clinical data of 105 cases of solitary metastatic lung tumor from NPC were retrospectively analyzed. Survival rate was calculated by the Kaplan-Meier method. The difference of survival between the patients treated by different modalities was evaluated by the log-rank test. The Cox univariate and multivariate analyses of gender, age, pathologic type, stage, adjuvant chemotherapy, evaluation of treatment for NPC, disease-free interval, size of metastatic tumor, pulmonary hilar and/or mediastinal lymph node metastasis, treatment modalities, recurrent distant metastases and/or relapse of NPC were conducted. The local control rate was 53.8% in chemotherapy group, 88.0% in radiotherapy ± chemotherapy group, and 96.4% in operation ± chemotherapy group (P < 0.01). The most promising progression-free survival (PFS) and overall survival (OS) were obtained with operation ± chemotherapy and followed by radiotherapy ± chemotherapy. Both of them showed much better efficacy than chemotherapy (P < 0.001). The Cox multivariate analysis showed that recurrent distant metastases and/or relapse of NPC affected the survival (OR = 2.087, 95% CI = 1.277-3.410, P = 0.003). The T stage of NPC, size of metastatic tumor, hilar and/or mediastinal lymph node metastasis, and the treatment modality were independent prognostic factors. Operation ± chemotherapy and radiotherapy ± chemotherapy are better treatment of solitary metastatic lung tumor from NPC, which could improve the local control and prolong the PFS and OS. Chemotherapy is recommended for patients with higher T stage of NPC, size of metastatic tumor ≥ 3 cm, pulmonary hilar and/or mediastinal lymph node metastasis.

Prognostic factors of locoregionally recurrent nasopharyngeal carcinoma--a retrospective review of 182 cases.

Locoregional relapse is the major cause of failure of nasopharyngeal carcinoma (NPC) after radical radiation therapy. The prognosis of such patients is dismal, and the factors related to the outcome are not well identified. Between January 1983 and December 1989, 1,168 new patients with biopsy-proven NPC were seen at this hospital. Eight hundred and eighty-three of these patients were treated uniformly with radical external irradiation and intracavitary treatment with or without chemotherapy. The clinical courses, retreatment outcomes, and prognostic factors for locoregional relapse and subsequent distant metastasis were analyzed. During the follow-up period of 3-10 years or until death, 182 patients (20.6%) developed locoregional relapses without distant metastasis initially. T stage and age were significant prognostic factors for locoregional recurrence. In contrast, histopathologic subtype, N stage, sex, and systemic chemotherapy were not. There were 36 patients (19.8%) who developed subsequent distant metastasis with or without retreatment. The median time from locoregional relapses to distant metastasis was 6 months in this study, and bone was the most frequent and the earliest site of distant metastasis. The N stage at diagnosis, the initial disease-free interval, the presence of neck nodal disease at relapse, and age were the significant factors for predicting the subsequent distant metastasis in locoregionally recurrent NPC patients. We recommend that additional systemic chemotherapy should be considered for retreatment of locoregional relapsed NPC, not only for enhancement of local control but also for eradicating microscopic metastasis as anticipated.

105 Head and neck: Treatment of primary and relapsed nasopharyngeal carcinoma

105 Head and neck: Treatment of primary and relapsed nasopharyngeal carcinoma

105 Head and neck: Treatment of primary and relapsed nasopharyngeal carcinoma

105 Head and neck: Treatment of primary and relapsed nasopharyngeal carcinoma

Head and neck: Treatment of primary and relapsed nasopharyngeal carcinoma

Head and neck: Treatment of primary and relapsed nasopharyngeal carcinoma

Head and neck: Treatment of primary and relapsed nasopharyngeal carcinoma

Head and neck: Treatment of primary and relapsed nasopharyngeal carcinoma

Head and neck: Treatment of primary and relapsed nasopharyngeal carcinoma

Head and neck: Treatment of primary and relapsed nasopharyngeal carcinoma

Head and neck: treatment of primary and relapsed nasopharyngeal carcinoma

Head and neck: treatment of primary and relapsed nasopharyngeal carcinoma