Significant value of 18F-FDG-PET/CT in diagnosing small cervical lymph node metastases in patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy

Background: Little is known about the nature of metaistasis to small cervical lymph nodes(SCLNS) in the patients with nasopharyngeal carcinoma(NPC)examined by using 18-fluoro-2-deoxy-glucose(^(18)F-FDG) positron emission tomography/computed tomography(PET/CT).The present study aimed to evaluate the diagnostic values of PET/CT in identifying metastasis in SCLNs in NPC patients.Methods: Magnetic resonance images(MRI) and PET/CT scans for 470 patients with newly diagnosed, non-distant metastatic NPC were analyzed. Metastatic rates of SCLNs were defined by the positive number of SCLNs on PET/CT scans and total number of SCLNs on MRI scans. Receiver operating characteristic curve was applied to compare PET/CT-determined stage with MRI-determined stage.Results: In total, 2082 SCLNs were identified, with 808(38.8%) ≥ 5 and < 6 mm in diameter(group A), 526(25.3%)≥ 6 and < 7 mm in diameter(group B),374(18.0%)≥ 7 and < 8 mm in diameter(group C), 237(11.4%) ≥8 and<9 mm in diameter(group D),and 137(6.5%) ≥ 9 and <10 mm in diameter(group E).The overall metastatic rates examined by using PET/CT for groups A, B,C,D, and E were 3.5%, 8.0%, 31.3%, 60.0%, and 83.9%, respectively(P< 0.001). In level IV/Vb, the metastatic rate for nodes ≥ 8 mm was 84.6%. PET/CT examination resulted in modification of N category and overall stage for 135(28.7%) and 46(9.8%) patients, respectively. The areas under curve of MRIdetermined and PET/CT-determined overall stage were 0.659 and 0.704 for predicting overall survival, 0.661 and 0.711 for predicting distant metastasis-free survival, and 0.636 and 0.663 for predicting disease-free survival.Conclusions: PET/CT was more effective than MRI in identifying metastatic SCLNs, and the radiologic diagnostic criteria for metastatic lymph nodes in level IV/Vb should be re-defined.

Prognostic factors and failure patterns in non-metastatic nasopharyngeal carcinoma after intensity-modulated radiotherapy

Background: The prognostic values of staging parameters require continual re?assessment amid changes in diag?nostic and therapeutic methods. This study aimed to identify the prognostic factors and failure patterns of non?meta?static nasopharyngeal carcinoma(NPC) in the intensity?modulated radiotherapy(IMRT) era.Methods: We reviewed the data from 749 patients with newly diagnosed, biopsy?proven, non?metastatic NPC in our cancer center(South China, an NPC endemic area) between January 2003 and December 2007. All patients under?went magnetic resonance imaging(MRI) before receiving IMRT. The actuarial survival rates were estimated using the Kaplan–Meier method, and survival curves were compared using the log?rank test. Multivariate analyses with the Cox proportional hazards model were used to test for the independent prognostic factors by backward eliminating insigniicant explanatory variables.Results: The 5?year occurrence rates of local failure, regional failure, locoregional failure, and distant failure were 5.4, 3.0, 7.4, and 17.4%, respectively. The 5?year survival rates were as follows: local relapse?free survival, 94.6%; nodal relapse?free survival, 97.0%; distant metastasis?free survival, 82.6%; disease?free survival, 75.1%; and overall survival, 82.0%. Multivariate Cox regression analysis revealed that orbit involvement was the only signiicant prognostic fac?tor for local failure(P = 0.011). Parapharyngeal tumor extension, retropharyngeal lymph node involvement, and the laterality, longest diameter, and Ho's location of the cervical lymph nodes were signiicant prognostic factors for both distant failure and disease failure(all P < 0.05). Intracranial extension had signiicant prognostic value for distant failure(P = 0.040).Conclusions: The key failure pattern for NPC was distant metastasis in the IMRT era. With changes in diagnostic and therapeutic technologies as well as treatment modalities, the signiicant prognostic parameters for local control have also been altered substantially.

Locoregional extension patterns of nasopharyngeal carcinoma and suggestions for clinical target volume delineation

Clinical target volume (CTV) delineation is crucial for tumor control and normal tissue protection. This study aimed to define the locoregional extension patterns of nasopharyngeal carcinoma (NPC) and to improve CTV delineation. Magnetic resonance imaging scans of 2366 newly diagnosed NPC patients were reviewed. According to incidence rates of tumor invasion, the anatomic sites surrounding the nasopharynx were classified into high-risk (>30%), medium-risk (5%-30%), and low-risk (<5%) groups. The lymph node (LN) level was determined according to the Radiation Therapy Oncology Group guidelines, which were further categorized into the upper neck (retropharyngeal region and level Ⅱ), middle neck (levels Ⅲ and Va), and lower neck (levels Ⅳ and Vb and the supraclavicular fossa). The high-risk anatomic sites were adjacent to the nasopharynx, whereas those at medium- or low-risk were separated from the nasopharynx. If the high-risk anatomic sites were involved, the rates of tumor invasion into the adjacent medium-risk sites increased; if not, the rates were significantly lower (P < 0.01). Among the 1920 (81.1%) patients with positive LN, the incidence rates of LN metastasis in the upper, middle, and lower neck were 99.6% , 30.2%, and 7.2%, respectively, and skip metastasis happened in only 1.2% of patients. In the 929 patients who had unilateral upper neck involvement, the rates of contralateral middle neck and lower neck involvement were 1.8% and 0.4%, respectively. Thus, local disease spreads stepwise from proximal sites to distal sites, and LN metastasis spreads from the upper neck to the lower neck. Individualized CTV delineation for NPC may be feasible.

Radiotherapy with neoadjuvant chemotherapy versus concurrent chemoradiotherapy for ascending-type nasopharyngeal carcinoma:a retrospective comparison of toxicity and prognosis

Background:In the era of intensity?modulated radiotherapy(IMRT),the role of neoadjuvant chemotherapy(NACT)in treating ascending?type nasopharyngeal carcinoma(NPC)is under?evaluated.This study was to compare the efficacy of NACT followed by IMRT(NACT+RT)with the efficacy of concurrent chemoradiotherapy(CCRT)on ascending?type NPC.Methods:Clinical data of 214 patients with ascending?type NPC treated with NACT+RT or CCRT between Decem?ber 2009 and July 2011 were analyzed.Of the 214 patients,98 were treated with NACT followed by IMRT,and 116 were treated with CCRT.The survival rates were assessed using Kaplan–Meier analysis,and the survival curves were compared using a log?rank test.Results:The 4?year overall survival,locoregional failure?free survival,distant failure?free survival,and failure?free sur?vival rates were not significantly different between the two groups(all P>0.05).However,patients in the CCRT group exhibited more severe acute adverse events than did patients in the NACT+RT group during radiotherapy,includ?ing leukopenia(30.2%vs.15.3%,P=0.016),neutropenia(25.9%vs.11.2%,P=0.011),and mucositis(57.8%vs.40.8%,P=0.028).After radiotherapy,patients in the CCRT group exhibited significantly higher rates of xerostomia(21.6%vs.Conclusions:The treatment outcomes of the NACT+RT and CCRT groups were similar;however,CCRT led to higher rates of acute and late toxicities.NACT+RT may therefore be a better treatment strategy for ascending?type NPC.

Long-term outcome and late toxicities of simultaneous integrated boost-intensity modulated radiotherapy in pediatric and adolescent nasopharyngeal carcinoma

The application of simultaneous integrated boost-intensity modulated radiotherapy(SIB-IMRT)in pediatric and adolescent nasopharyngeal carcinoma(NPC)is underevaluated.This study aimed to evaluate long-term outcome and late toxicities in pediatric and adolescent NPC after SIB-IMRT combined with chemotherapy.Thirty-four patients(aged 8–20 years)with histologically proven,non-disseminated NPC treated with SIB-IMRT were enrolled in this retrospective study.The disease stage distribution was as follows:stage I,1(2.9%);stage III,14(41.2%);and stage IV,19(55.9%).All patients underwent SIBIMRT and 30 patients also underwent cisplatin-based chemotherapy.The prescribed dose of IMRT was64–68 Gy in 29–31 fractions to the nasopharyngeal gross target volume.Within the median follow-up of 52months(range,9–111 months),1 patient(2.9%)experienced local recurrence and 4(11.8%)developed distant metastasis(to the lung in 3 cases and to multiple organs in 1 case).Four patients(11.8%)died due to recurrence or metastasis.The 5-year locoregional relapse–free survival,distant metastasis–free survival,disease-free survival,and overall survival rates were 97.1%,88.2%,85.3%,and 88.2%,respectively.The most common acute toxicities were grades 3–4 hematologic toxicities and stomatitis.Of the 24 patients who survived for more than 2 years,16(66.7%)and 15(62.5%)developed grades 1–2 xerostomia and ototoxicity,respectively.Two patients(8.3%)developed grade 3 ototoxicity;no grade 4 toxicities were observed.SIB-IMRT combined with chemotherapy achieves excellent long-term locoregional control in pediatric and adolescent NPC,with mild incidence of late toxicities.Distant metastasis is the predominant mode of failure.

Prognostic scoring system for locoregional control among the patients with nasopharyngeal carcinoma treated by intensity-modulated radiotherapy

The prognostic value of T category for locoregional control in patients with nasopharyngeal carcinoma(NPC)has decreased with the extensive use of intensity-modulated radiotherapy(IMRT).We aimed to develop a prognostic scoring system(PSS)that incorporated tumor extension and clinical characteristics for locoregional control in NPC patients treated with IMRT.The magnetic resonance imaging scans and medical records of 717 patients with nonmetastatic NPC treated with IMRT at Sun Yat-sen University Cancer Center between January 2003 and January 2008 were reviewed.Age,pathologic classification,primary tumor extension,primary gross tumor volume(GTV-p),T and N categories,and baseline lactate dehydrogenase(LDH)level were analyzed.Hierarchical cluster analysis as well as univariate and multivariate analyses were used to develop the PSS.Independent prognostic factors for locoregional relapse included N2–3 stage,GTV-p≥26.8 mL,and involvement of one or more structures within cluster3.We calculated a risk score derived from the regression coefficient of each factor and classified patients into four groups:low risk(score 0),intermediate risk(score>0 and≤1),high risk(score>1 and≤2),and extremely high risk(score>2).The 5-year locoregional control rates for these groups were 97.4%,93.6%,85.2%,and 78.6%,respectively(P<0.001).We have developed a PSS that can help identify NPC patients who are at high risk for locoregional relapse and can guide individualized treatments for NPC patients.

Dosimetric benefit to organs at risk following margin reductions in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy

Introduction:It is important to decrease the radiation exposure of normal tissue in intensity-modulated radiation therapy(IMRT).Minimizing planning target volume(PTV) margins with more precise target localization techniques can achieve this goal.This study aimed to quantify the extent to which organs at risk(OARs) are spared when using reduced margins in the treatment of nasopharyngeal carcinoma(NPC).Methods:Two IMRT plans were regenerated for 40 patients with NPC based on two PTV margins,which were reduced or unchanged following cone beam computed tomography online correction.The reduced-margin plan was optimized based on maximal dose reduction to OARs without compromising target coverage.Dosimetric comparisons were evaluated in terms of target coverage and OAR sparing.Results:Improvements in target coverage occurred with margin reduction,and significant improvements in dosimetric parameters were observed for all OARs(P<0.05) except for the right optic nerve,chiasm,and lens.Doses to OARs decreased at a rate of 1.5%to 7.7%.Sparing of the left parotid and right parotid,where the mean dose(D_(mean)) decreased at a rate of 7.1%and 7.7%,respectively,was greater than the sparing of other OARs.Conclusions:Significant improvements in OAR sparing were observed with margin reduction,in addition to improvement in target coverage.The parotids benefited most from the online imaging-guided approach.

18F-FDG-PET/CT在诊断接受调强放射治疗的鼻咽癌患者颈部小淋巴结转移中的重要价值

背景与目的 18-氟-2-脱氧-葡萄糖正电子发射断层扫描/计算机断层扫描(positron emission tomography/computed tomography,PET/CT)在检测鼻咽癌(nasopharyngeal carcinoma,NPC)颈部小淋巴结(small cervical lymph nodes,SCLNs)转移方面的特性目前知之甚少。本研究旨在评价PET/CT在诊断鼻咽癌SCLN转移中的价值。方法本研究分析了470例新诊断的无远处转移的NPC患者的磁共振成像(magnetic resonance images,MRI)和PET/CT扫描图像。通过PET/CT扫描上的阳性SCLNs数和MRI扫描上的总SCLN数来确定SCLN转移率。受试者工作特征曲线用来比较PET/CT确定的分期和MRI确定的分期。结果共鉴定出2082个SCLN,其中808个(38.8%)直径≥5 mm且<6 mm(A组),526个(25.3%)直径≥6 mm且<7 mm(B组),374个(18.0%)直径≥7 mm且<8 mm(C组),237个(11.4%)直径≥8 mm且<9 mm(D组),137个(6.5%)直径≥9 mm且<10 mm(E组)。PET/CT检查的总转移率在A、B、C、D和E组分别为3.5%、8.0%、31.3%、60.0%和83.9%(P<0.001)。在IV/Vb区,直径≥8 mm的淋巴结转移率为84.6%。PET/CT检查分别修正了135例(28.7%)患者的N分期和46例(9.8%)患者的总分期。用MRI和PET/CT确定的总分期预测患者总生存的曲线下面积为0.659和0.704,预测无远处转移生存的曲线下面积为0.661和0.711,预测无病生存的曲线下面积为0.636和0.663。结论PET/CT比MRI在识别转移性SCLN方面更有效,IV/Vb区转移淋巴结的影像学诊断标准应重新定义。

N0期鼻咽癌颈部淋巴结肿大患者调强放疗的临床治疗思考

背景与目的鼻咽癌(nasopharyngeal carcinoma,NPC)有较高比例的淋巴结转移,淋巴结阳性的治疗指南已经制订。但对于不符合放射标准的淋巴结阳性直径大于10 mm的颈部淋巴结肿大(enlarged neck lymph nodes,ENLNs)患者,还没有给出放射治疗指南。本研究旨在探讨调强放疗(intensity-modulated radiotherapy,IMRT)治疗N0期ENLNs的NPC患者的预后疗效和放射剂量。方法回顾251例接受IMRT治疗的非转移性N0期NPC患者的临床资料。应用受试者工作特征曲线计算预测失败的ENLN直径临界值,计算ENLNs的生物等效剂量(biological equivalent dose,BED)。比较小型和大型ENLN组患者的生存率。应用Cox比例风险回归模型确定独立的预后因素。结果 ENLNs≥5.5 mm组患者4年区域无复发生存率高于ENLNs<5.5 mm组患者(100%vs. 98.8%,P=0.049),而两组的无病生存率、总体生存率和无远处转移生存率无显著性差异。经调整多种因素后,ENLN直径不是独立的预后因素(所有生存率P>0.05)。在亚组分析中,无论是小型ENLN组还是大型ENLN组,接受BED≥72 Gy的患者与接受BED<72 Gy的患者的预后无显著性差异。多因素分析也证实BED≥72 Gy对N0期NPC患者的预后无明显改善作用。结论对ENLNs给予72 Gy的BED足以使N0期NPC患者临床获益。还有必要进行前瞻性研究来验证本研究中的发现。

新辅助化疗联合放疗与同期放化疗对上行型鼻咽癌疗效的比较:毒性和预后的回顾性分析

背景与目的在调强放射治疗(intensity?modulated radiotherapy, IMRT)的时代,新辅助化疗(neoadjuvant chemotherapy, NACT)在治疗上行型鼻咽癌(nasopharyngeal carcinoma, NPC)中的作用被低估了。本研究旨在比较NACT结合IMRT(NACT+RT)与同期放化疗(concurrent chemoradiotherapy,CCRT)对治疗上行型鼻咽癌的疗效。方法分析2009年12月至2011年7月期间用NACT+RT或CCRT治疗的214例上行型鼻咽癌患者的临床数据。在214例患者中,98例接受了NACT+RT治疗,116例接受了CCRT治疗。用Kaplan?Meier法分析存活率,并用log?rank检验比较存活曲线。结果两组患者在4年总生存率、局部区域无复发生存率、无远处转移生存率和无进展生存率均没有显著差异(均P> 0.05)。然而,CCRT组患者在放疗期间比NACT+RT组患者表现出更严重的急性不良反应,包括白细胞减少(30.2%vs. 15.3%, P=0.016)、中性粒细胞减少(25.9%vs.11.2%, P=0.011)和黏膜炎(57.8%vs.40.8%, P=0.028)。放疗结束后,CCRT组患者表现出较高比例的口腔干燥症(21.6%vs. 10.2%, P=0.041)和听力损失(17.2%vs. 6.1%,P=0.023)。结论 NACT+RT和CCRT两组的治疗结果相似。然而,CCRT组会导致更高比例的急性和迟发性毒性。因此,NACT+RT可能是治疗上行型鼻咽癌更好的方法。

基于三网络模式的阿尔茨海默病和遗忘型轻度认知功能障碍的半球间功能连接研究（英文）

目的:探讨阿尔茨海默病(AD)和遗忘型轻度认知功能障碍(aMCI)在默认脑网络(DMN)、突显网络(SN)和执行控制网络(ECN)这三个脑网络中的半球间脑功能连接的差异性。创新点:利用体素镜像同伦功能连接(VMHC)来观察AD和aMCI在多个脑网络基础上的半球间功能连接特点。方法:该研究纳入了浙江省人民医院就诊的30例AD患者、14例aMCI患者和18例老年健康对照者,均给予静息态功能磁共振扫描,利用VMHC进行数据分析,联合简易智力状态检查量表(MMSE)和蒙特利尔认知评估量表(MOCA)进行相关分析。结论:(1)位于三个脑网络的异常半球功能连接主要存在于AD组,可以作为AD诊断的一个敏感性指标;(2)VMHC值可以作为预测AD进展包括aMCI发展为AD的一个敏感性指标。

Development and validation of a web-based calculator to predict individualized conditional risk of site-specific recurrence in nasopharyngeal carcinoma: Analysis of 10,058 endemic cases

Background:Conditional survival(CS)provides dynamic prognostic estimates by considering the patients existing survival time.Since CS for endemic nasopharyngeal carcinoma(NPC)is lacking,we aimed to assess the CS of endemic NPC and establish a web-based calculator to predict individualized,conditional sitespecific recurrence risk.Methods:Using an NPC-specific database with a big-data intelligence platform,10,058 endemic patients with non-metastatic stage I–IVA NPC receiving intensity-modulated radiotherapy with or without chemotherapy between April 2009 and December 2015 were investigated.Crude CS estimates of conditional overall survival(COS),conditional disease-free survival(CDFS),conditional locoregional relapse-free survival(CLRRFS),conditional distant metastasis-free survival(CDMFS),and conditional NPC-specific survival(CNPC-SS)were calculated.Covariate-adjusted CS estimates were generated using inverse probability weighting.A prediction model was established using competing risk models and was externally validated with an independent,non-metastatic stage I–IVA NPC cohort undergoing intensity-modulated radiotherapy with or without chemotherapy(n=601)at another institution.Results:The median follow-up of the primary cohort was 67.2 months.The 5-year COS,CDFS,CLRRFS,CDMFS,and CNPC-SS increased from 86.2%,78.1%,89.8%,87.3%,and 87.6%at diagnosis to 87.3%,87.7%,94.4%,96.0%,and 90.1%,respectively,for an existing survival time of 3 years since diagnosis.Differences in CS estimates between prognostic factor subgroups of each endpoint were noticeable at diagnosis but diminished with time,whereas an ever-increasing disparity in CS between different age subgroups was observed over time.Notably,the prognoses of patients that were poor at diagnosis improved greatly as patients survived longer.For individualized CS predictions,we developed a web-based model to estimate the conditional risk of local(C-index,0.656),regional(0.667),bone(0.742),lung(0.681),and liver(0.711)recurrence,which significantly outperformed the current staging system(P<0.001).The performance of this webbased model was further validated using an external validation cohort(median follow-up,61.3 months),with C-indices of 0.672,0.736,0.754,0.663,and 0.721,respectively.Conclusions:We characterized the CS of endemic NPC in the largest cohort to date.Moreover,we established a web-based calculator to predict the CS of sitespecific recurrence,which may help to tailor individualized,risk-based,timeadapted follow-up strategies.

Comparative role of real-world study and traditional randomized controlled trials in head and neck cancer:a literature-based analysis

To the Editor:In the era of evidence-based medicine,the traditional randomized controlled trials(RCT)is on the top of the pyramid of evidence hierarchy.With well-controlled inclusion and exclusion criteria,randomization,and strict intervention protocol,traditional RCT construct the ideal medical circumstance,under which the causal relationship between the outcome and intervention can be better interpreted.However,it will also make the external validity and generalizability of traditional RCT limited.

The evolution of the nasopharyngeal carcinoma staging system over a 10-year period:implications for future revisions

Background:The classification criteria and staging groups for nasopharyngeal carcinoma described in the Union for International Cancer Control/American Joint Committee on Cancer(UICC/AJCC)staging system have been revised over time.This study assessed the proportion of patients whose staging and treatment strategy have changed due to revisions of the UICC/AJCC staging system over the past 10 years(ie,from the sixth edition to the eighth edition),to provide information for further refinement.Methods:We retrospectively reviewed 1901 patients with non-metastatic nasopharyngeal carcinoma treated in our cancer center between November 2009 and June 2012.The Akaike information criterion and Harrell concordance index were applied to evaluate the performance of the staging system.Results:In total,25(1.3%)of the 1901 patients who were staged as T2a according to the sixth edition system were downgraded to T1 in the eighth edition;430(22.6%)staged as N0 in the sixth edition were upgraded to N1 in the eighth edition;106(5.6%)staged as N1/2 in the sixth edition were upgraded to N3 in the eighth edition.In addition,51(2.7%)and 25(1.3%)of the study population were upstaged from stage Ⅰ to stage Ⅱ and stage Ⅱ to stage IVa,respectively;10(0.5%)was downgraded from stage Ⅱ to stage Ⅰ.The survival curves of adjacent N categories and staging groups defined by eighth classification system were well-separated.However,there was no significant difference in the locoregional failure-free survival(P=0.730)and disease-free survival(P=0.690)rates between the T2 and T3 categories in the eighth edition classification system.Conclusions:Modifications to the tumor-node-metastasis staging system over the past 10 years have resulted in N classification changes in numerous cases.Although the eighth edition tumor-node-metastasis staging system better predicts survival outcomes,the T classification could be simplified in future revisions.