Significance of radiologic extranodal extension in locoregionally advanced nasopharyngeal carcinoma with lymph node metastasis: a comprehensive nomogram.

OBJECTIVE: We aimed to assess the significance of rENE and creat a predictive tool (nomogram) for estimating Overall Survival (OS) in locoregionally advanced Nasopharyngeal Carcinoma (NPC) patients with Lymph Node Metastasis (LNM) based on their clinical characteristics and Radiologic Extranodal Extension (rENE). METHODS: Five hundred and sixty-nine NPC patients with LNM were randomly divided into training and validation groups. Significant factors were identified using univariate and multivariate analyses in the training cohort. Then, the nomogram based on the screening results was established to predict the Overall Survival (OS). Calibration curves and the Concordance index (C-index) gauged predictive accuracy and discrimination. Receiver Operating Characteristic (ROC) analysis assessed risk stratification, and clinical utility was measured using Decision Curve Analysis (DCA). The nomogram's performance was validated for discrimination and calibration in an independent validation cohort. RESULTS: A total of 360 (63.2%) patients were present with radiologic extranodal extension at initial diagnosis. Patients with rENE had significantly lower OS than other patients. Multivariate analysis identified the five factors, including rENE, for the nomogram model. The C-index was 0.75 (0.71-0.78) in the training cohort and 0.76 (0.69-0.83) in the validation cohort. Notably, the nomogram outperformed the 8th TNM staging system, as evident from the higher AUC values (0.77 vs. 0.60 for 2year and 0.75 vs. 0.65 for 3year) and well-calibrated calibration curves. Decision curve analysis indicated improved Net Benefit (NB) with the nomogram for predicting OS. The log-rank test confirmed significant survival distinctions between risk groups in both training and validation cohorts. CONCLUSIONS: We demonstrated the prognostic value of rENE in nasopharyngeal carcinoma and developed a nomogram based on rENE and other factors to provide individual prediction of OS for locoregionally advanced nasopharyngeal carcinoma with lymph node metastasis. LEVEL OF EVIDENCE: III.

Radiomics-clinical nomogram based on pretreatment 18F-FDG PET-CT radiomics features for individualized prediction of local failure in nasopharyngeal carcinoma.

To explore the prognostic significance of PET/CT-based radiomics signatures and clinical features for local recurrence-free survival (LRFS) in nasopharyngeal carcinoma (NPC). We retrospectively reviewed 726 patients who underwent pretreatment PET/CT at our center. Least absolute shrinkage and selection operator (LASSO) regression and the Cox proportional hazards model were applied to construct Rad-score, which represented the radiomics features of PET-CT images. Univariate and multivariate analyses were used to establish a nomogram model. The concordance index (C-index) and calibration curve were used to evaluate the predictive accuracy and discriminative ability. Receiver operating characteristic analysis was performed to stratify the local recurrence risk of patients. The nomogram was validated by evaluating its discrimination ability and calibration in the validation cohort. A total of eight features were selected to construct Rad-score. A radiomics-clinical nomogram was built after the selection of univariate and multivariable Cox regression analyses, including the Rad-score and maximum standardized uptake value (SUVmax). The C-index was 0.71 (0.67-0.74) in the training cohort and 0.70 (0.64-0.76) in the validation cohort. The nomogram also performed far better than the 8th T-staging system with an area under the receiver operating characteristic curve (AUC) of 0.75 vs. 0.60 for 2 years and 0.71 vs. 0.60 for 3 years. The calibration curves show that the nomogram indicated accurate predictions. Decision curve analysis (DCA) revealed significantly better net benefits with this nomogram model. The log-rank test results revealed a distinct difference in prognosis between the two risk groups. The PET/CT-based radiomics nomogram showed good performance in predicting LRFS and showed potential to identify patients at high-risk of developing NPC.

Do all patients at the initial stage of nasopharyngeal carcinoma need bone metastasis screening? A retrospective study.

BACKGROUND: To identify patients at low risk of synchronous bone metastasis who should not receive bone scans when initially diagnosed with nasopharyngeal carcinoma (NPC). METHODS: In total, 6652 patients were enrolled in the training cohort and 1919 patients in the multicenter external validation cohort. Logistic regression analyses were performed to assess independent predictors of synchronous bone metastasis for the nomogram model. RESULTS: After risk stratification, 46.3% (3081/6652) patients were separated into the low-risk group with an incidence of 0.71% for synchronous bone metastasis. The odds ratio of the intermediate and high-risk groups was 5.61 and 23.82 times that of the low-risk group, respectively. For patients with high EBV DNA, we recommend routine screening for N2-3 female patients, but that all male subgroups are screened. CONCLUSIONS: Bone scans should not be routine. Patients in the low-risk group should not be screened, which would avoid excessive radiation and economize iatrical resource.

PET/CT standardized uptake value and EGFR expression predicts treatment failure in nasopharyngeal carcinoma.

OBJECTIVE: This study inventively combines epidermal growth factor receptor (EGFR) expression of the primary lesion and standardized uptake value (SUV) of positron emission tomography and computed tomography (PET/CT) to predict the prognosis of nasopharyngeal carcinoma (NPC). This study aimed to evaluate the predictive efficacy of maximum standard uptake value (SUVmax) and EGFR for treatment failure in patients with NPC. METHODS: This retrospective study reviewed the results of EGFR expression and pretreatment 18F-FDG PET/CT of 313 patients with NPC. Time-dependent receiver operator characteristics was used for analyzing results and selecting the optimal cutoff values. Cox regression was used to screen out multiple risk factors. Cumulative survival rate was calculated by Kaplan-Meier. RESULTS: The selected cutoff value of SUVmax-T was 8.5. The patients were categorized into four groups according to EGFR expression and SUVmax-T. There were significant differences in the 3-year local recurrence-free survival (LRFS) (p = 0.0083), locoregional relapse-free survival (LRRFS) (p = 0.0077), distant metastasis-free survival (DMFS) (p = 0.013), and progression-free survival (PFS) (p = 0.0018) among the four groups. Patients in the EGFR-positive and SUVmax-T > 8.5 group had the worst survival, while patients in the EGFR-negative and SUVmax-T ≤ 8.5 group had the best prognosis. Subsequently, patients with only positive EGFR expression or high SUVmax-T were classified as the middle-risk group. There were also a significant difference in 3-year overall survival among the three risk groups (p = 0.034). SUVmax-T was associated with regional recurrence-free survival and LRRFS in multivariate analysis, whereas EGFR was an independent prognostic factor for LRRFS, DMFS, and PFS. CONCLUSION: The combination of SUVmax-T and EGFR expression can refine prognosis and indicate clinical therapy.

Analysis of risk characteristics for metachronous metastasis in different period of nasopharyngeal carcinoma.

OBJECTIVE: To identify the main risk factors for metachronous metastatic nasopharyngeal carcinoma (NPC) in different periods after radiotherapy and estimate the weight of various factors in the early or late metachronous metastasis (EMM/LMM) groups. METHODS: This retrospective registry consists of 4434 patients with newly diagnosed NPC. Cox regression analysis was used to assess the independent significance of various risk factors. The Interactive Risk Attributable Program (IRAP) was used to calculate the attributable risks (ARs) for metastatic patients during different periods. RESULTS: Among 514 metastatic patients, 346 (67.32%) patients diagnosed with metastasis within 2 years after treatment were classified into the EMM group, while other 168 patients were classified into the LMM group. The ARs of T-stage, N-stage, pre-Epstein-Barr virus (EBV) DNA, post-EBV DNA, age, sex, pre-neutrophil-to-lymphocyte ratio, pre-platelet-to-lymphocyte ratio, pre-hemoglobin (HB), and post-HB were 20.19, 67.25, 2.81, 14.28, 18.50, - 11.17%, 14.54, 9.60, 3.74% and - 9.79%, respectively, in the EMM group. In the LMM group, the corresponding ARs were 3.68, 49.11, - 18.04%, 2.19, 6.11, 0.36, 4.62, 19.77, 9.57 and 7.76%, respectively. After multivariable adjustment, the total AR for tumor-related factors was 78.19%, and that for patient-related factors was 26.07% in the EMM group. In the LMM group, the total AR of tumor-related factors was 43.85%, while the weights of patient-related factors was 39.97%. In addition, except for these identified tumor- and patient-related factors, other unevaluated factors played a more important role in patients with late metastasis, with the weight increasing by 15.77%, from 17.76% in the EMM group to 33.53% in the LMM group. CONCLUSION: Most metachronous metastatic NPC cases occurred in the first 2 years after treatment. Early metastasis was mainly affected by tumor-related factors, which accounted for a declining percentage in the LMM group.

Biological target volume based on fluorine-18-fluorode-oxyglucose positron emission tomography/computed tomography imaging: a spurious proposition?

PURPOSE: To assess whether the high metabolic region of fluorine-18-fluorode-oxyglucose (18F-FDG) in the primary lesion is the crux for recurrence in patients with nasopharyngeal carcinoma (NPC), to assess the feasibility and rationale for use of biological target volume (BTV) based on 18F-FDG positron emission tomography/computed tomography (18F-FDG-PET/CT). METHODS: The retrospective study included 33 patients with NPC who underwent 18F-FDG-PET/CT at the time of initial diagnosis as well as the time of diagnosis of local recurrence. Paired 18F-FDG-PET/CT images for primary and recurrent lesion were matched by deformation coregistration method to determine the cross-failure rate between two lesions. RESULTS: The median volume of the Vpri (primary tumor volume using the SUV thresholds of 2.5), the Vhigh (the volume of high FDG uptake using the SUV50%max isocontour), and the Vrecur (the recurrent tumor volume using the SUV thresholds of 2.5) were 22.85, 5.57, and 9.98 cm3, respectively. The cross-failure rate of Vrecur∩high showed that 82.82% (27/33) of local recurrent lesions had < 50% overlap volume with the region of high FDG uptake. The cross-failure rate of Vrecur∩pri showed that 96.97% (32/33) of local recurrent lesions had > 20% overlap volume with the primary tumor lesions and the median cross rate was up to 71.74%. CONCLUSION: 18F-FDG-PET/CT may be a powerful tool for automatic target volume delineation, but it may not be the optimal imaging modality for dose escalation radiotherapy based on applicable isocontour. The combination of other functional imaging could delineate the BTV more accurately.

Recommendation for imaging follow-up strategy based on time-specific disease failure for nasopharyngeal carcinoma.

BACKGROUND: To develop a common follow-up strategy for appropriate imaging examination at an appropriate time for nasopharyngeal carcinoma (NPC). METHODS: Independent prognostic factors were identified by Cox regression analysis, and a nomogram model was developed. Random survival forest (RSF) model was constructed to depict probability of disease failure during a 5-year follow-up and establish a reasonable risk-based follow-up strategy. RESULTS: The nomogram model finally categorized the patients into three risk groups. RSF model demonstrated distribution trends for local and regional recurrences, bone metastasis, liver metastasis, and lung metastasis of NPC. Adequate imaging at follow-up should be considered between 10 and 21 months for patients at moderate-risk of recurrence or metastasis and 7-36 months for those at high-risk. CONCLUSIONS: The temporal distribution of incidence rates of recurrence or metastasis varied among different risk groups. We recommend implementing a focused and targeted imaging surveillance intervention at appropriate times to improve its efficiency and reduce costs.

Abnormal variation and prognostic significance of circulating immune cells in patients with nasopharyngeal carcinoma treated with chemoradiotherapy: a prospective cohort study.

Background: Circulating immune cells are associated with tumor development and poor prognosis in multiple solid tumors. However, the circulating immune-cell profile of nasopharyngeal carcinoma (NPC) remains largely unknown. Therefore, we aimed to determine the changes in immune status and the prognostic significance of circulating immune cells before and after chemoradiotherapy (CRT) in patients, which can provide clinicians with valuable insights to optimize treatment strategies, monitor immune function, and personalize interventions, ultimately improving patient outcomes. Methods: Circulating immune cells before and after CRT in 77 patients with NPC and in 30 healthy controls were measured with flow cytometry. A thorough follow-up was conducted to assess prognosis outcomes, including local failure-free rate (LFFR), distant failure-free rate (DFFR), disease-free survival (DFS), and overall survival (OS). The differences of the subpopulation distribution in the two groups were determined by t-tests or Mann-Whitney tests. The paired t-test or Wilcoxon matched-pairs signed rank test was used to compare differences in lymphocyte subsets before and after CRT. The prognostic significance of lymphocyte subsets was evaluated by Kaplan-Meier analysis and Cox proportional hazards model. Results: Compared with the control group, the NPC group showed significant decreases in the proportions of CD3+ cells, CD4+ T cells, CD8+CD28+ T cells, and CD19+ B cells as well as the CD4+:CD8+ ratio (P<0.05) but a significant increase in the proportion of natural killer (NK) cells (P<0.05). After CRT, the proportions of CD4+ cells, CD8+CD28+ T cells, and CD19+ B cells as well as the CD4+:CD8+ ratio were markedly decreased (P<0.05), while the proportions of CD8+ T cells and NK cells were significantly increased (P<0.05). Multivariate analysis showed that a lower percentage of CD19+ B cells [hazard ratio (HR) 6.550, 95% CI: 1.661-25.831; P=0.007] and a positive test for Epstein-Barr virus (EBV) DNA (HR 0.261, 95% CI: 0.074-0.926; P=0.038) before treatment independently predicted worse 5-year OS (P<0.05). Conclusions: The disproportion of circulating immune cells was observed in patients with NPC before treatment. CRT further aggravated immune dysfunction. Notably, a lower percentage of CD19+ B cells and EBV DNA-positive status before treatment were independent predictors of a worse prognosis. Thus, the measurement of circulating immune cells may help elucidate immune function status and predict the outcomes of patients with NPC.

Reflecting on the utility of standardized uptake values on 18F-FDG PET in nasopharyngeal carcinoma.

BACKGROUND: To rethink the clinical significance of standardized uptake values (SUVs) of nasopharyngeal carcinoma (NPC) on 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET). METHODS: We retrospectively reviewed 369 NPC patients who underwent pretreatment 18F-FDG PET. The predictive value of the SUVmax of the primary tumor (SUVmax-t) and regional lymph nodes (SUVmax-n) was evaluated using probability density functions. Receiver operating characteristic curves were used to determine optimal cutoffs for the SUVmax-n/SUVmax-t ratio (NTR). Kaplan-Meier and Cox regression analyses were used to assess survival. RESULTS: The optimal SUVmax-t and SUVmax-n cutoffs were 7.5 and 6.9, respectively. High SUVmax-t and SUVmax-n were related to local and regional recurrence, respectively. Patients with low SUVmax had better 3-year overall survival (OS). To avoid cross-sensitization of cutoff points, we stratified patients with high SUVmax into the low and high NTR groups. The 3-year distant metastasis-free survival (DMFS; 92.3 vs. 80.6%, P = 0.009), progression-free survival (PFS; 84.0 vs. 67.7%, P = 0.011), and OS (95.9 vs. 89.2%, P = 0.002) significantly differed between the high vs. low NTR groups for patients with high SUVmax. Multivariable analysis showed that NTR was an independent prognostic factor for DMFS (hazard ratio [HR]: 2.037, 95% CI: 1.039-3.992, P = 0.038), PFS (HR: 1.636, 95% CI: 1.021-2.621, P = 0.041), and OS (HR: 2.543, 95% CI: 1.214-5.325, P = 0.013). CONCLUSION: High SUVmax was associated with NPC recurrence. NTR is a potential prognosticator for DMFS, suggesting that heterogeneity in the pretreatment 18F-FDG uptake between the primary tumor and lymph nodes is associated with high invasion and metastatic potential.

Selectively recommend 18F-FDG PET/CT for patients with de novo nasopharyngeal carcinoma in endemic areas.

INTRODUCTION: To identify the subset of patients with de novo nasopharyngeal carcinoma (NPC) for whom [18F] fluorodeoxyglucose positron emission tomography and computed tomography (18F-FDG PET/CT) should be recommended, and to determine whether PET/CT is a cost-effective decision for precise M staging in endemic areas. MATERIALS AND METHODS: Retrospective analysis of data of 4469 patients diagnosed with de novo NPC between January 2014 and December 2019. The detection rate of distant metastasis was compared between different groups. Univariate and multiple logistic regression analysis was applied to identify the risk factors for distant metastasis. The cost-effectiveness of the diagnostic strategies was assessed. RESULTS: The detection rate of distant metastasis in the whole cohort was 5.46%. In multivariate analysis, male sex, T3-4 stage, N2-3 stage, and high plasma Epstein-Barr virus (EBV) DNA (≥ 14,650 copies/mL) were risk factors for distant metastases. NPC patients with T3-4 stage combined with N2-3 stage, high EBV DNA combined with male sex, or N2-3 stage combined with high EBV DNA were defined as recommended group with relatively higher tendency for metastasis. Distant metastasis incidence in recommended group and unrecommended group were 10.25% and 1.75%, respectively (P < 0.001). In the recommended group, PET/CT significantly improved the detection rate of distant metastasis (13.25% vs 9.02%, P = 0.005). Cost-effectiveness analysis revealed that additional cost for every one percent increase in distant metastasis detection rate was $22,785.58 in the recommended group (< Willingness-to-pay (WTP) threshold of $32,700.00) and $310,912.90 in the unrecommended group. CONCLUSIONS: In patients with de novo NPC, the tendency for metastasis can be predicted based on clinical parameters. 18F-FDG PET/CT should be selectively recommended for the subset of patients with a relatively higher tendency for metastasis.

Significance of boost dose for T4 nasopharyngeal carcinoma with residual primary lesion after intensity-modulated radiotherapy.

BACKGROUND: Previous studies showed poorer survival in T4 disease with residual lesion. To evaluate the efficacy and toxicity of a boost dose for T4 nasopharyngeal carcinoma (NPC), patients with a residual primary lesion after intensity-modulated radiotherapy (IMRT). METHODS: 398 T4 NPC patients with residual primary lesions after radical IMRT were retrospectively reviewed. An IMRT boost dose of 4-6.75 Gy was delivered to the residual lesions in 2-3 fractions. Propensity score matching (PSM) was applied to balance potential confounders between groups (ratio, 1:2). The presence of Epstein-Barr virus (EBV) DNA in plasma after IMRT was used for risk stratification. RESULTS: Patients who received boost radiation had significantly improved overall survival (OS) and local recurrence-free survival (LRFS) compared with those who did not (all P < 0.05). In the matched cohort, 3-year OS was 86.6% in the boost radiation group and 72.7% in the non-boost group (P = 0.022). Three-year LRFS was 93.4% in the boost radiation group and 83.5% in the non-boost group (P = 0.022). In the subgroup analysis, boost dose was shown to significantly improve 3-year OS (88.0% vs. 74.1%, P = 0.021) in the low-risk group (with undetectable plasma EBV DNA after IMRT). The administration of a boost dose also improved 3-year OS in the high-risk group (with detectable plasma EBV DNA after IMRT) (66.7% vs. 60.0%, P = 0.375). Multivariate analysis demonstrated that boost dose was the only protective prognostic factor. CONCLUSION: The addition of a boost dose for T4 NPC patients with residual primary lesion after radical IMRT provides satisfactory tumor control and clinical benefit. Additional timely and effective strengthening treatments are recommended for patients with detectable levels of plasma EBV DNA after radiotherapy.

Selection of a high-level physician may help improve outcomes of nasopharyngeal carcinoma.

BACKGROUND: To assess the relationship between the level of clinical radiation oncologist and the prognosis of patients with nasopharyngeal carcinoma (NPC). To our knowledge, no previous study has explicitly assessed the relationship with cancer prognosis and clinical radiation oncologists level. The effect of physicians on the prognosis has been entirely ignored. METHODS: Clinical data were collected for 1140 patients with newly diagnosed NPC. Based on the 3-year overall survival, the treating physicians were classified into 3 grades: high-level group, medium-level group, and low-level group. Cox proportional hazards regression analysis was used to assess the independent significance of different prognostic factors. Propensity score matching (PSM) was used to minimize the influence of confounders so that difference in outcomes provides an unbiased estimate of the influence of physician. Interactive Risk Attributable Program (IRAP) was used to calculate the attribution risk of individual risk factors or a combination of multiple factors. RESULTS: The 3-year OS in the high-level, medium-level, and low-level groups was 92.9%, 87.7%, and 83.5%, respectively (p = 0.003). After propensity score matching, the 3-year OS was 92.4%, 87.4%, and 82.9%, respectively (p = 0.004). IRAP was used to calculate the attribution risk of mortality risk. After multivariable adjustment, patient-related factors including tumor accounted for 90.02% [95% confidence interval (CI), 73.43-96.84%) and physician factors accounted for 17.66% (95% CI, 5.39-44.65%) of the mortalityrisk. All related factors, including patient-related factors and physician factors accounted for 92.02% (95% CI, 77.83-97.43%). CONCLUSION: Our study demonstrated obvious differences in the prognosis of patients treated by various clinical radiation oncologists. The largest share of prognosis risk was found to be at the patient level, while variation in prognosis was, in part, attributable to differences among physicians.

Prognostic value of tumor burden in nasopharyngeal carcinoma.

BACKGROUND: The prognostic value of primary tumor volume (TV) in nasopharyngeal carcinoma (NPC) has been confirmed. However, studies of the prognosis value of tumor burden, including TV and nodal volume (NV), have been relatively infrequent. Therefore, the aim of this study was to evaluate the prognostic value of tumor burden in NPC patients treated with intensity-modulated radiotherapy. METHODS: Receiver operating characteristics curves were generated to determine rational cutoff points for TV and NV. The volumes identified included 12.5, 25.0, and 50.0 mL, and 0, 12.5, and 25 mL, respectively. According to these cutoff volumes, four subgroups were established for TV as TV1-TV4, and four subgroups were established for NV as NV0-NV3. Then, the entire cohort (992 NPC patients) was divided into 16 subgroups according to these four levels of TV and NV. Based on similarities in the 5-year overall survival (OS) rates for these 16 subgroups, four patient groups were established, G1-G4. RESULTS: The mean TV and NV values for our cohort were 39.5±30.8 mL and 16.5±17.6 mL, respectively. The 5-year distant failure-free rate, the 5-year disease-free survival rate, and the 5-year OS rate for G3 and G4 were significantly lower than those for G1 and G2. In particular, the OS curves of the four patient groups were significantly separated. A multivariate analysis identified TV >50 mL, T-stage (3-4), and N-stage (2-3) as adverse prognostic factors for OS. CONCLUSIONS: The results of this study demonstrate that tumor burden has a significant prognostic value for NPC patients treated with intensity-modulated radiotherapy. Hence, tumor burden, including TV and NV, should be incorporated into the current staging system for NPC to improve prognostic significance.

Experience of weekly cisplatin concurrent with intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma patients with resistance to neoadjuvant chemotherapy.

Nasopharyngeal carcinoma (NPC) is highly sensitive to radiotherapy. Locally advanced NPC has a relatively poor prognosis if treated with radiotherapy alone. Several studies have demonstrated that chemoradiotherapy confers survival benefit in locally advanced NPC. However, a small proportion of patients are resistant to chemotherapy based on cisplatin. So, it is important to make a valuable and inexpensive schedule for these patients. After 2 cycles of neoadjuvant chemotherapy that consisted of gemcitabine and cisplatin (80 mg/m, every 3 weeks) or paclitaxel and cisplatin (80 mg/m, every 3 weeks), magnetic resonance imaging (MRI) was used to evaluate efficacy. A total of 13 patients with extensive nodal disease or/and bulky tumors volume were determined with a stable disease (SD) and enrolled in this study. Cisplatin at a dose of 30 mg/m administered weekly concurrent with intensity-modulated radiotherapy (IMRT) was used to treat these patients resistant to neoadjuvant chemotherapy. The efficacy was evaluated by tumor response and the change of tumor volume. After the completion of concurrent chemoradiotherapy (CCRT), the overall tumor response was a complete response (CR) for 4 of 13 (30.8%) patients and partial response (PR) for 9 of 13 (69.2%) patients. The mean primary tumor volume was reduced by 59.7% and 89.8% at the 24th fraction of IMRT and after the completion of IMRT, respectively. The mean nodal volume was reduced by 63.8% and 93.5% at the 24th fraction of IMRT and after completion of IMRT, respectively. The study showed that weekly cisplatin concurrent with IMRT improved the treatment parameters for locally advanced NPC with resistance to neoadjuvant chemotherapy based on cisplatin. It was a valuable and relatively inexpensive schedule to improve the prognosis for these patients.