Locoregional Nasopharyngeal Carcinoma Research Articles

Efficacy of Cetuximab in Nasopharyngeal Carcinoma Patients Receiving Concurrent Cisplatin-Radiotherapy: A Meta-Analysis.

Background Nasopharyngeal carcinoma (NPC) is a malignant neoplasm of the nasopharyngeal epithelium. Concurrent chemoradiotherapy has been established as a standard treatment for locoregional NPC, and cisplatin is a common agent in NPC treatment. Cetuximab is a monoclonal antibody against epidermal growth factor receptor. This meta-analysis was performed to evaluate the curative effectiveness and survival outcomes of cetuximab in NPC patients who received concurrent cisplatin-radiotherapy. Methods PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Wan Fang, and China Biology Medicine disc (CBM) were used to search publications studying on concurrent chemoradiotherapy and/or cetuximab in NPC. The qualities of included RCTs were assessed by the Newcastle-Ottawa Scale. STATA 14.0 was used to conduct the statistical analysis. Results In total, 17 trials with 2066 patients were included in this meta-analysis. The results from this study show that cetuximab improved the therapy efficacy in NPC patients who received concurrent cisplatin-radiotherapy. Cetuximab cotreatment improved the complete response (RR = 1.92, 95% CI [1.61, 2.30]), and reduced stable disease (RR = 0.67, 95% CI [0.51, 0.88]) as well as progression disease (RR = 0.24, 95% CI [0.15, 0.40]). Besides, it also improved the overall survival (RR = 1.10, 95% CI [1.02, 1.18]), disease-free survival (RR = 1.09, 95% CI [1.03, 1.15]), metastasis-free survival (RR = 1.06, 95% CI [1.01, 1.11]), and relapse-free survival (RR = 1.04, 95% CI [1.01, 1.07]) in NPC patients. Conclusions Cetuximab could improve the curative efficacy and survival outcomes of NPC patients who underwent concurrent cisplatin-radiotherapy. However, all the trials included were conducted in China; thus, the quality of the trials in this study remains doubtful. More high-quality RCTs should be included in further relevant studies.

Multimodal Treatment of Nasopharyngeal Carcinoma in Children, Adolescents and Young Adults-Extended Follow-Up of the NPC-2003-GPOH Study Cohort and Patients of the Interim Cohort.

Simple SummaryMultimodal treatment of nasopharyngeal carcinoma (NPC) in children and young adults with induction chemotherapy, followed by radiochemotherapy and interferon-β (IFN-β) maintenance, has been successfully applied in studies NPC-91 and NPC-2003 of the German Society of Pediatric Oncology and Hematology (GPOH). We, here, present updated survival rates of the NPC-2003 study cohort after longer follow-up and include 21 additional patients recruited after closure of the study and treated as per the NPC-2003 study protocol (interim cohort) in our survival analysis. Survival rates remain high after extended follow-up and in the larger cohort with EFS and OS of 94% and 97%, respectively, reinforcing the high antitumor efficacy of this multimodal treatment concept. Seven patients with CR after induction therapy received a reduced radiation dose of 54 Gy, and none of them relapsed. Thus, the reduction of radiation dose seems feasible and has the potential to reduce treatment-related late effects in this vulnerable population.Nasopharyngeal carcinoma (NPC) in children and young adults has been treated within two consecutive prospective trials in Germany, the NPC-91 and the NPC-2003 study of the German Society of Pediatric Oncology and Hematology (GPOH). In these studies, multimodal treatment with induction chemotherapy, followed by radio (chemo)therapy and interferon-beta maintenance, yielded promising survival rates even after adapting total radiation doses to tumor response. The outcome of 45 patients in the NPC-2003 study was reassessed after a median follow-up of 85 months. In addition, we analyzed 21 further patients after closure of the NPC-2003 study, recruited between 2011 and 2017, and treated as per the NPC-2003 study protocol. The EFS and OS of 66 patients with locoregionally advanced NPC were 93.6% and 96.7%, respectively, after a median follow-up of 73 months. Seven patients with CR after induction therapy received a reduced radiation dose of 54 Gy; none relapsed. In young patients with advanced locoregional NPC, excellent long-term survival rates can be achieved by multimodal treatment, including interferon-beta. Radiation doses may be reduced in patients with complete remission after induction chemotherapy and may limit radiogenic late effects.

Multimodality Therapy for Locoregional Nasopharyngeal Carcinoma—A Decision Tool for Treatment Optimization

Multimodality Therapy for Locoregional Nasopharyngeal Carcinoma—A Decision Tool for Treatment Optimization

The efficacy and safety of induction chemotherapy combined with concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in nasopharyngeal carcinoma patients: a systematic review and meta-analysis

BackgroundInduction chemotherapy (IC) combined with concurrent chemoradiotherapy (CCRT) has been recommended as the first-line therapy for locoregional nasopharyngeal carcinoma (NPC). Due to the different chemotherapeutic drugs used in the IC and CCRT, the results remain controversial.MethodsPubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically retrieved to search potentially eligible clinical trials up to Sep 11, 2019. Eligible studies were registered and prospective randomized controlled clinical trials.ResultsFrom 526 records, nine articles including seven randomized controlled clinical trials were eligible, with a total of 2311 locoregional advanced NPC patients. IC + CCRT had significantly lower risks of death (3-year hazard ratio [HR]: 0.70, 95% confidence interval [CI] 0.55–0.89, p = 0.003; 5-year HR: 0.77, 95% CI 0.62–0.94, p = 0.01), disease progression (3-year HR: 0.67, 95% CI 0.55–0.80, p < 0.001; 5-year HR: 0.70, 95% CI 0.58–0.83, p < 0.0001), distant metastasis (3-year HR: 0.58, 95% CI 0.45–0.74, p < 0.0001; 5-year HR: 0.69, 95% CI 0.55–0.87, p = 0.001) and locoregional relapse (3-year HR: 0.69, 95% CI 0.50–0.95, p = 0.02; 5-year HR: 0.66, 95% CI 0.51–0.86, p = 0.002) than CCRT. Compared with CCRT, IC + CCRT showed higher relative risks of grade 3 or more neutropenia, thrombocytopenia, nausea, vomiting and hepatotoxicity throughout the course of treatment, and higher relative risks of grade ≥ 3 thrombocytopenia and vomiting during CCRT.ConclusionIC combined with CCRT significantly improved the survival in locoregional advanced NPC patients. Moreover, toxicities were well tolerated during IC and CCRT. Further clinical trials are warranted to confirm the optimal induction chemotherapeutic regimen in the future.

Concurrent-Adjuvant Chemoradiation Therapy for Stage III-IVB Nasopharyngeal Carcinoma—Exploration for Achieving Optimal 10-Year Therapeutic Ratio

This is an updated combined analysis of 2 randomized studies (NPC-9901 and NPC-9902 trials) to evaluate the 10-year outcome attributed to the addition ofconcurrent-adjuvant chemotherapy for advanced locoregional nasopharyngeal carcinoma (NPC). Eligible patients with stage III-IVB nonkeratinizing NPCwere randomly assigned to radiation therapy alone (RT: 218 patients) or chemoradiation therapy (CRT: 223 patients) using 3 cycles of cisplatin (100mg/m2) concurrent with RT, followed by 3 cycles of cisplatin (80mg/m2) and fluorouracil (1000mg/m2/day for 4days). All of the patients were irradiated with conventional fractionation to ≥66Gy. The median follow-up was 13.9years. Intention-to-treat analysis confirmed that the CRT group achieved significant improvement in 10-year failure-free rate (FFR: 62% vs 52%, P=.016), progression-free survival rate (PFS: 56% vs 44%, P=.008), and overall survival rate (OS: 60% vs 50%, P=.044). There was no significant increase in overall late toxicity rate (51% vs 48%, P=.34) or noncancer deaths (19% vs 16%, P=.52). Exploratory studies showed no difference in disease control between 2 or 3 cycles of concurrent cisplatin; however, patients given 3 concurrentcycles had a significant increase in hearing impairment (40% vs 24%, P=.017). Only those who continued to receive 2 or more cycles of adjuvant cisplatin-fluorouracil achieved significant improvement in distant control (73% vs 65%, P=.037) and maximal survival gain. The addition of concurrent cisplatin plus adjuvant cisplatin-fluorouracil could significantly improve overall survival and disease control without incurring a significant increase in late toxicity or noncancer deaths. Exploratory analyses suggested that both the concurrent and the adjuvant phases contributed to tumor control. Furthermore, the number of concurrent cycles could be reduced from 3 to 2 cycles in order to achieve a similar survival benefit without incurring an excessive increase inhearing impairment. This is a useful hypothesis that warrants further validation.

Diagnosis and Treatment of Nasopharyngeal Carcinoma in Children and Adolescents - Recommendations of the GPOH-NPC Study Group.

Nasopharyngeal carcinoma (NPC) is a rare malignant tumor arising from epithelial cells of the nasopharynx. Its incidence is highest in Southeast Asia. Age distribution of NPC is bimodal, with one peak in young adolescents and another in patients 55-59 years of age. EBV appears to be the primary etiologic agent in the pathogenesis, environmental factors such as nitrosamines and genetic factors are contributory. NPC is most commonly diagnosed in locally advanced stages, with lymph node metastases occurring in up to 90% of patients. About 5-10% of patients present with distant metastases. Diagnosis of NPC is made histologically, supported by an abnormal anti-EBV-VCA IgA titer and elevated plasma EBV-DNA load. Superior results in children and adolescents with advanced locoregional NPC, with overall and event-free survival rates>90%, have been achieved by neoadjuvant chemotherapy with 5-fluoruracil and cisplatin, followed by synchronous radiochemotherapy and subsequent maintenance therapy with interferon-ß as demonstrated by the 2 prospective studies GPOH-NPC-91 and -2003. Response to therapy can be assessed by PET-imaging and in patients with complete remission after neoadjuvant chemotherapy, the radiation dose to the primary tumor can be safely reduced from 59.4 to 54.4 Gy. Since the majority of long term sequalae such as xerostomia, skin and tissue fibrosis are caused by high radiation dosages, radiotherapy modalities such as intensity-modulated radiotherapy should be used to efficiently spare non-tumorous tissue. For patients with metastatic disease and relapse, survival chances are low. New treatment strategies, such as the application of EBV-specific T-lymphocytes should be considered for these patients.

Expression of pAkt affects p53 codon 72 polymorphism-based prediction of response to radiotherapy in nasopharyngeal carcinoma

BackgroundCodon 72 (Arg/Pro), the most frequently studied single nucleotide polymorphism (SNP) of p53 to date, is associated with the ability of the gene to induce cell apoptosis. The PI3K/Akt pathway plays an essential role in the transcriptional activation function of p53, and is an important factor in radiotherapy resistance. The present study was designed to evaluate the prediction of response to radiotherapy based on p53 codon 72 SNP and pAkt expression in biopsy specimens of locoregional nasopharyngeal carcinoma (NPC) before treatment.Materials and methodsIn total, 75 consecutive patients with locoregional NPC were enrolled. The p53 codon 72 SNP was identified from retrospectively collected paraffin-embedded biopsy specimens using Sanger sequencing. Expression patterns of p53, p21, 14-3-3σ, and pAkt proteins were investigated using immunohistochemical analyses. The effects of genetic polymorphisms and protein expression on progression-free survival (PFS) were evaluated using the Cox proportional hazards model, Kaplan–Meier method, and log-rank test.ResultsThe p53 codon 72 Pro/Pro carriers showed lower risk of disease progression (local recurrence and distant metastases) (HR: 0.300; 95% CI: 0.092–0.983; p=0.047). However, this association between the p53 codon 72 polymorphism and PFS was not significant in the pAkt-positive subgroup. No association was observed between protein expression of p53, p21 or 14-3-3σ and p53 codon72 polymorphisms. Notably, positive expression of p53 protein appeared to be correlated with poorer PFS among patients diagnosed as local regional lymph node metastasis (N+) before treatment (p=0.032).ConclusionsThe p53 codon 72 Pro/Pro genotype may be an effective independent prognostic marker for better outcome in patients with locoregional NPC. Based on the current findings, we hypothesize that pAkt weakens the predictive value of p53 codon 72 SNP in NPC. A combination of positive p53 protein expression and local regional lymph node metastasis may additionally be predictive of high risk of disease progression.

Application of induction PF chemotherapy plus concurrent chemo-radiotherapy in patients with Iocoregional advanced nasopharyngeal carcinoma

Objective To investigate the efficacy and safety of induction chemotherapy(DDP + 5-FU)followed by concurrent chemo-radiotherapy(CCRT)in patients with locoregional advanced nasopharyngeal carcinoma (NPC).Methods 42 patients with locoregional NPC were enrolled in the study.Before CCRT,patients were assigned to receive two cycles of chemotherapy(DDP 20mg/m2 d1～5 ;5-FU 750mg/m2 d1～5)every three weeks.Then the same chemotherapy was given from the first day of standard radiotherapy.Results All patients completed planned treatment and were eligible for toxicity and response analysis.After induction chemotherapy,9 patients achieved complete response in nasopharynx and 12 patients achieved CR in regional nodes;Three months after radiotherapy,41 patients achieved CR in nasopharynx and 34 patients achieved CR in regional nodes.Induction PF was well tolerated and the most common acute high-graded toxicity of CCRT was grade Ⅲ mucositis(35.7％)and grade Ⅲ vomiting (16.7％).At median follow-up of 15 months,the overall survival rate was 100％,two-year cumulative local recurrence rate was 4.8％ and distant metastasis rate was 2.4％.Conclusion Induction PF chemotherapy plus concurrent chemo-radiotherapy was tolerable and satisfactory for patients with locoregional NPC. Key words: Nasopharyngeal carcinoma; Induction chemotherapy; Concurrent chemo-radiotherapy; Cisplatin; 5-Fluorouracil

Adoptive Transfer of EBV-specific T Cells Results in Sustained Clinical Responses in Patients With Locoregional Nasopharyngeal Carcinoma

Patients with recurrent or refractory Epstein Barr Virus (EBV)-positive nasopharyngeal carcinoma (NPC) continue to have poor outcomes. Our earlier Phase I dose escalation clinical study of 10 NPC patients showed that infusion of EBV-specific cytotoxic T cells (EBV-CTLs) was safe and had antitumor activity. To better define the overall response rate and discover whether disease status, EBV-antigen specificity, and/or in vivo expansion of infused EBV-CTLs predicted outcome, we treated 13 additional NPC patients with EBV-CTLs in a fixed-dose, Phase II component of the study. We assessed toxicity, efficacy, specificity, and expansion of infused CTLs for all 23 recurrent/refractory NPC patients treated on this Phase I/II clinical study. At the time of CTL infusion, 8 relapsed NPC patients were in remission and 15 had active disease. No significant toxicity was observed. Of the relapsed patients treated in their second or subsequent remission, 62% (5/8) remain disease free (at 17 to 75 mo), whereas 48.7% (7/15) of those with active disease had a CR/CRu (33.3%) or PR (15.4%). In contrast to locoregional disease, metastatic disease was associated with an increased risk of disease progression (HR: 3.91, P=0.015) and decreased overall survival (HR: 5.55, P=0.022). Neither the specificity of the infused CTLs for particular EBV antigens nor their measurable in vivo expansion discernibly influenced outcome. In conclusion, treatment of patients with relapsed/refractory EBV-positive NPC with EBV-CTLs is safe and can be associated with significant, long-term clinical benefit, particularly for patients with locoregional disease.

Plasma Osteopontin, Hypoxia, and Response to Radiotherapy in Nasopharyngeal Cancer

Recent studies have suggested that osteopontin is induced by hypoxia in head and neck cancer cell lines and its plasma level may serve as a surrogate marker for tumor hypoxia and treatment outcome in head and neck cancer. We investigated the response of osteopontin to in vitro hypoxia in nasopharyngeal carcinoma cell lines, and determined plasma osteopontin levels in nasopharyngeal carcinoma patients, nonnasopharyngeal carcinoma head and neck cancer patients, and healthy controls. We explored the relationship of plasma osteopontin and response to radiotherapy in nasopharyngeal carcinoma. Nasopharyngeal carcinoma cell lines HK1, HONE-1, C666-1, and CNE-2 were treated with 0 to 48 hours of hypoxia or normoxia, +/- reoxygenation. Osteopontin secretion in the supernatant was measured by ELISA assay. Cellular osteopontin protein and mRNA were detected by Western blotting and reverse transcription-PCR, respectively. Plasma osteopontin levels in patients (n=66; 44 nasopharyngeal carcinoma, 22 head and neck cancer) and controls (n=29) were measured by ELISA. Hypoxia has no effect on osteopontin protein and mRNA level in nasopharyngeal carcinoma cells. Only CNE-2 secreted osteopontin, and there was no significant induction by hypoxia. Plasma osteopontin levels in patients of metastatic nasopharyngeal carcinoma and head and neck cancer, but not in locoregional nasopharyngeal carcinoma, were significantly higher than in controls. In patients with locoregional nasopharyngeal carcinoma receiving curative radiotherapy (n=31), a high (>median) pretreatment plasma osteopontin level was a significant predictor of poor response to radiotherapy (complete response rate, 40% versus 88%; P=0.009), which remained significant in multivariate analysis. Our results suggested that the pretreatment plasma osteopontin level may be a useful biomarker of response to radiotherapy in nasopharyngeal carcinoma.

Comparison of Contrast-enhanced Magnetization Transfer Imaging and Contrast-enhanced Fat Saturation T1-weighted Imaging in Nasopharyngeal Carcinoma

The objective of this study was to evaluate the efficacy of contrast-enhanced magnetization transfer (CEMT) imaging in the study of nasopharyngeal carcinoma (NPC). The contrast-to-noise ratio (CNR) of CEMT images was compared with the CNR of contrast-enhanced fat-saturation (CEFS) T1-weighted images in locoregional tumors and adenopathies of 50 patients with pathologically proven NPC. The CEMT images showed higher CNRs than CEFS images of local nasopharyngeal regions. The mean CNRs of the precontrast T1-weighted, CEFS, and CEMT images were 4.9, 15.4, and 21.2, respectively. There was a statistically significant difference (p < 0.01) in the CNRs of CEFS and CEMT images. In considering images of nodal metastasis, the mean values in these three groups were 0.7, 16.8, and 19.7, respectively, with the difference (p < 0.05) between CEFS and CEMT being statistically significant. The CEMT image with a larger CNR is superior to the CEFS image in detecting locoregional NPC. CEMT can be useful in imaging patients with possible small tumors and local recurrences.

T classification and clivus margin as risk factors for determining locoregional control by radiotherapy of nasopharyngeal carcinoma.

The purpose of this study was to determine risk factors that affect locoregional control of nasopharyngeal carcinoma (NPC) after radiotherapy. Computed tomography (CT) is utilized for radiotherapy planning and for identifying high risk anatomic areas. Between April 1990 and December 1993, 40 consecutive patients (1 in Stage I, 3 in Stage II, 5 in Stage III, and 31 in Stage IV) who had locoregional NPC were given definitive radiotherapy at the Koo Foundation Sun Yat-Sen Cancer Center in Taipei, Taiwan. All patients had individualized CT treatment planning. The dimension of each tumor as shown on the treatment planning CT were mapped on conventional simulation films. The extent of each tumor was further affirmed by magnetic resonance imaging (MRI) and the tumor map revised as necessary. The primary radiation fields were designed to include the primary tumor and potential spread areas with appropriate margins. Concurrent chemotherapy was also given to 35 patients (87.5%) who had positive cervical lymph nodes or primary tumors extending beyond the nasopharynx. By the end of December 1995, after a median follow-up of 42 months and minimal follow-up of 24 months, the locoregional control rate at 4 years was 84.8% (95% confidence interval [CI], 72.3-97.3), disease free survival 68.4% (95% CI, 52. 1-84.7), and overall survival 76.7% (95% CI, 63.4-90.0). The radiation field margin near the sphenoid sinus averaged 1.9 cm, the clivus margin 1.1 cm, the pterygoid fossa margin 2.0 cm, and the oral cavity margin 1.7 cm. Risk factor analysis revealed that T classification and the radiation field margin at the clivus were the most important factors for locoregional control of the tumor. The locoregional control rates were 92.6% (25/27) for T1-T3 patients and 76.9% (10/13) for T4 patients (P = 0.03). The locoregional control rates were 71.4% (5/7) for patients with a clivus margin < 1 cm and 90.6% (29/32) for patients with a clivus margin > or = 1 cm (P = 0.08). The excellent locoregional control observed in this series may be attributed to the concurrent chemotherapy and radiotherapy as well as meticulous treatment planning with CT and MRI. The precise delineation of the involved area with the aid of CT, which is taken while the patient is in the position for irradiation, serves to define the necessary safety margin of the radiation field. T classification and clivus margin are the most important factors in determining locoregional control of radiotherapy of NPC. The statistical trend observed in this study indicated that the clivus margin should be adequate to reduce the failure around the clivus, as all local recurrences were observed in this area.

Induction chemotherapy followed by radiotherapy versus radiotherapy alone in patients with advanced nasopharyngeal carcinoma

Prospective randomized and retrospective studies on adjunctive chemotherapy in patients with advanced locoregional nasopharyngeal carcinoma have yielded conflicting results and the role of chemotherapy in this disease had not been clearly defined. The authors report the results of a single institution, matched cohort study comparing a group of 61 patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy followed by radiation therapy with a matched group treated with radiotherapy alone. Between 1985 and 1992, 61 patients with advanced locoregional nasopharyngeal carcinoma received induction chemotherapy (cisplatin, 100 mg/m2 on Day 1 and 5-fluorouracil [5-FU], 1000 mg/m2, on Days 1-5) for 3 cycles followed by definitive radiation therapy (CT/RT group). This group was matched with a group of 61 patients from a population of 378 patients who received radiation therapy alone (RT group). Matching characteristics were T classification, N classification, histology, and level of cervical lymph node metastases. These characteristics were found to be significant determinants of distant metastasis (DM) and/or survival in a multivariate analysis that was performed in the entire radiotherapy group. Radiation therapy consisted of 66-72 gray in 6.5 to 7 weeks in both groups. Fifty-nine patients (97%) in both groups had Stage IV disease. Fifteen patients (25%) in both groups had lower cervical lymph node metastases. The tumor histologic types also had similar distribution in both groups. Median follow-up time among surviving patients of the CT/RT group was 4.9 years (range, 1.3-9.8 years). The 5-year cumulative incidence of DM was 19 +/- 5% for the CT/RT group and 34 +/- 6% for the RT alone group (P = 0.019; log rank test). This reduction in distant failure was more prominent in patients with intermediate (N2-N3 disease; upper or midcervical lymph nodes), or high risk (N2-N3 disease; lower cervical lymph nodes) of DM. This reduction in DM translated into improvement in disease free survival (DFS) and overall survival (OS). The 5-year actuarial DFS rates were 64 +/- 6% for the CT/RT group compared with 42 +/- 7% for the RT group (P = 0.015). The 5-year actuarial OS rates were 69 +/- 6% (CT/RT group) and 48 +/- 7% (RT group), respectively (P = 0.012). The incidence of locoregional failure was slightly lower in the CT/RT group, but this difference did not reach statistical significance. There was no significant difference in the incidence and severity of acute mucositis between the two groups during radiotherapy. The 5-year cumulative incidence of Grade 3 or higher late complications was also similar in both groups (5 +/- 3% in the CT/RT group and 8 +/- 3% in the RT group; P = 0.721). This matched cohort study provides additional evidence that induction cisplatin-5-FU chemotherapy prior to definitive radiation improves freedom from distant metastasis, DFS, and OS for patients with locoregional Stage IV nasopharyngeal carcinoma without increasing treatment-related morbidity.