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OBJECTIVES Cranial neuropathy is a common presenting symptom of advanced T4 nasopharyngeal carcinoma (NPC). Data on neurological outcomes after modern intensity-modulated radiotherapy (IMRT) and chemotherapy are scarce. MATERIALS AND METHODS Case records of consecutive T4 NPC patients who received definitive IMRT in two tertiary oncology centers in 2004-2019 were reviewed. Patterns of cranial neuropathies at disease presentation were recorded. Time to neurological recovery and the rate of subsequent re-palsy were estimated by the Kaplan-Meier method. Clinical predictors were analyzed using multivariable Cox regression. RESULTS During the study period, 257 T4 NPC patients presented with 504 individual cranial neuropathies. The median time from neuropathy onset to NPC diagnosis was two months (IQR, 1-4 months). Cranial nerves (CN) VI (56.4%), V2 (47.9%), and V3 (29.2%) were most frequently involved. At a median follow-up of 6.4 years, the crude partial and full recovery rates of neuropathies were 111 (22%) and 289 (57.3%), respectively. CN III, IV, and VI had the highest 5-year full recovery rate (72.7%), followed by CN V1-3 (60.3%), XII (48.6%), and II (18.2%) (p

Background Stereotactic body radiation therapy (SBRT) using flattening filter free (FFF) has been commonly used, however, its outcomes and predictive factors in lung tumors are limiting. Thus, we aim to assess the clinical outcomes of this approach and identify factors associated with outcomes in patients with early stage non-small cell lung cancer (NSCLC) and oligometastatic/oligoprogressive lung tumor (OLT). Methods Patients who underwent lung SBRT with FFF were retrospectively reviewed. All patients were delivered using volumetric modulated arc therapy (VMAT) technique. The primary outcome was local control (LC). The secondary outcomes were overall survival (OS) and toxicities. We assessed the association between LC and various factors in OLT. Results From February 2014 to July 2019, ninety-four patients and 129 lesions with median follow-up time of 30 months were included in the analysis. Twenty-six patients with 26 lesions were early NSCLC, while 68 patients with 103 lesions were OLT, 41.7% of which were from colorectal cancers (CRC) and 18.5% were from primary lung cancers. Two-year LC was 88.9% and 85.7% for early NSCLC and OLT, respectively. Two-year OS was significantly higher for early NSCLC than OLT (83.3% vs. 68.7%, P=0.035). In the multivariate analysis for OLT, CRC origin (hazard ratio, HR 10.59, 95% CI: 2.29–48.95, P=0.003) and gross tumor volume (GTV) mean BED10 ≤147 Gy (HR 5.16, 95% CI: 1.13–23.59, P=0.034) were significantly associated with higher local failure (LF). Most of the acute grade 1–2 toxicities were radiation pneumonitis (26.5%). No grade 3–5 event was observed. Conclusions This study confirmed the clinical efficacy and safety of lung SBRT using FFF-technique. Our findings support the role of using a high BED10 regimen to achieve good LC for OLT and the potential role for dose escalation for primary CRC.

PurposeWe aimed to construct predictive models for the overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) for nasopharyngeal carcinoma (NPC) patients by using CT-based radiomics.Materials and MethodsWe collected data from 197 NPC patients. For each patient, radiomic features were extracted from the CT image acquired at pretreatment via PyRadiomics. Feature selection was performed in two steps. First, features with high inter-observer variability based on multiple tumor delineations were excluded. Then, stratified bootstrappings were performed to identify feature combinations that most frequently achieved the highest (i) area under the receiver operating characteristic curve (AUC) for predicting 3-year OS, PFS, and DMFS or (ii) Harrell’s C-index for predicting time to event. Finally, regularized logistic regression and Cox proportional hazard models with the most frequently selected feature combinations as input were tuned using cross-validation. Additionally, we examined the robustness of the constructed model to variation in tumor delineation by simulating 100 realizations of radiomic feature values to mimic features extracted from different tumor boundaries.ResultsThe combined model that used both radiomics and clinical features yielded significantly higher AUC and Harrell’s C-index than models using either feature set alone for all outcomes (p < 0.05). The AUCs and Harrell’s C-indices of the clinical-only and radiomics-only models ranged from 0.758 ± 0.091 to 0.789 ± 0.082 and from 0.747 ± 0.062 to 0.767 ± 0.074, respectively. In comparison, the combined models achieved AUC of 0.801 ± 0.075 to 0.813 ± 0.078 and Harrell’s C-indices of 0.779 ± 0.066 to 0.796 ± 0.069. The results showed that our models were robust to variation in tumor delineation with the coefficient of variation ranging from 4.8% to 6.4% and from 6.7% to 9.3% for AUC and Harrell’s C-index, respectively.ConclusionOur results demonstrated that using CT-based radiomic features together with clinical features provided superior NPC prognostic prediction than using either clinical or radiomic features alone.

Purpose With improved technology, more patients with nasopharyngeal cancer (NPC) are receiving definitive treatment with proton therapy, which allows greater sparing of dose to normal tissues without compromising efficacy. As there is no randomized data, the purpose of this study was to systematically review the available literature on proton therapy in this setting, focusing on the toxicity endpoints. Materials and Methods A systematic search using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was conducted in 5 databases: PubMed, Embase, SCOPUS, Web of Science, and the Cochrane Central Register of Controlled Trials. A total of 491 studies were found on the topic of NPC and proton therapy. Following independent study selection by 2 investigators, 9 studies were found to have sufficient focus and relevance to be incorporated into the systematic review. Results All 9 studies were retrospective and examined only NPC patients except for one that also included paranasal sinus cancer. One study was a reirradiation study. Four studies used 3D or double scatter technique, while all others used intensity-modulated proton therapy. Oncologic outcomes were similar to intensity-modulated radiation therapy (IMRT) rates, with 2-year local and regional progression-free survival (LRFS) ranging from 84% to 100%, 2-year progression-free survival (PFS) ranging from 75% to 88.9%, and 2-year overall survival (OS) ranging from 88% to 95% in the up-front setting. Four comparison studies with IMRT found significantly lower feeding tube rates (20% versus 65%, P = .015; and 14% versus 85%, P Conclusions NPC patients receiving proton therapy maintain good outcomes with improved toxicity profile, likely due to sparing of dose to normal structures. Prospective studies are ongoing to better quantify the magnitude.

Background Plasma EBV DNA concentrations at the time of diagnosis (pre-EBV) and post treatment (post-EBV) have significant value for predicting the clinical outcome of nasopharyngeal cancer (NPC) patients. However, the prognostic value of the EBV concentration during radiation therapy (mid-EBV) has not been vigorously studied. Patients and methods This was a post hoc analysis of 105 detectable pre-EBV NPC patients from a phase II/III study comparing sequential (SEQ) versus simultaneous integrated boost (SIB) intensity-modulated radiation therapy (IMRT). Plasma EBV DNA concentrations were measured by PCR before commencement of IMRT, at the 5th week of radiation therapy and 3 months after the completion of IMRT. The objective was to identify the prognostic value of mid-EBV to predict overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). Results A median pre-EBV was 6880 copies/ml. Mid-EBV and post-EBV were detectable in 14.3% and 6.7% of the patients, respectively. The median follow-up time was 45.3 months. The 3-year OS, PFS and DMFS rates were 86.0% vs. 66.7% (p = 0.043), 81.5% vs. 52.5% (p = 0.006), 86.1% vs. 76.6% (p = 0.150), respectively, for those with undetectable mid-EBV vs. persistently detectable mid-EBV. However, in the multivariate analysis, only persistently detectable post-EBV was significantly associated with a worse OS (hazard ratio (HR) = 6.881, 95% confident interval (CI) 1.699-27.867, p = 0.007), PFS (HR = 5.117, 95% CI 1.562–16.768, p = 0.007) and DMFS (HR = 129.071, 95%CI 19.031–875.364, p < 0.001). Conclusions Detectable post-EBV was the most powerful adverse prognostic factor for OS, PFS and DMFS; however, detectable mid-EBV was associated with worse OS, PFS especially Local-PFS (LPFS) and may facilitate adaptive treatment during the radiation treatment period.

This study was performed to compare the acute and late toxicities between sequential (SEQ) and simultaneous integrated boost (SIB) intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC). Stage I-IVB NPC patients were randomized to receive SEQ-IMRT or SIB-IMRT. SEQ-IMRT consisted of two plans: 2 Gy × 25 fractions to low-risk planning target volume (PTV) followed by a sequential boost (2 Gy × 10 fractions) to high-risk PTV, while SIB-IMRT treated low- and high-risk PTVs with doses of 56 and 70 Gy in 33 fractions. Toxicities and survival outcomes were analyzed. Between October 2010 and September 2015, of the 209 patients who completed treatment, 102 in the SEQ and 107 in the SIB arm were analyzed. The majority had undifferentiated squamous cell carcinoma (82%). Mucositis and dysphagia were the most common grade 3–5 acute toxicities. There were no statistically significant differences in the cumulative incidence of grade 3–4 acute toxicities between the two arms (59.8% in SEQ vs. 58.9% in SIB; P = 0.892). Common grade 3–4 late toxicities for SEQ and SIB included hearing loss (2.9 vs. 8.4%), temporal lobe injury (2.9 vs. 0.9%), cranial nerve injury (0 vs. 2.8%), and xerostomia (2 vs. 0.9%). With the median follow-up of 41 months, 3‑year progression-free and overall survival rates were 72.7 vs. 73.4% (P = 0.488) and 86.3 vs. 83.6% (P = 0.938), respectively. SEQ and SIB provide excellent survival outcomes with few late toxicities. According to our study, SIB with a satisfactory dose–volume constraint to nearby critical organs is the technique of choice for NPC treatment due to its convenience.

PURPOSE/OBJECTIVE(S) Cranial neuropathy is a common presenting symptom of advanced T4 nasopharyngeal carcinoma (NPC). Data on neurological outcomes after modern intensity-modulated radiotherapy (IMRT) and chemotherapy are scarce. This study sets to evaluate the prognostic factors and recovery pattern of cranial neuropathies, using longitudinal clinical data from two tertiary oncology centers in endemic areas. MATERIALS/METHODS Case records of consecutive T4 NPC patients who received definitive IMRT in 2004-2019 were reviewed. Distribution of cranial neuropathies at disease presentation were recorded. Time to partial and full neurological recovery, time from neurological recovery to re-palsy, relapse-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Predictors for neurological recovery were analyzed using multivariable Cox regression. RESULTS During the study period, 257 T4 NPC patients presented with 504 individual cranial neuropathies. The median time from neuropathy onset to NPC diagnosis was 2 months (IQR, 1-4 months). All patients completed definitive IMRT, and 94% of patients received chemotherapy. The 5-year RFS and OS of the combined cohort were 50.8% and 60.1% respectively. Median RFS of patients with single versus multiple neuropathies were 5.8 years and 4.2 years (P = 0.62). Cranial nerves (CN) VI (56.4%), V2 (47.9%) and V3 (29.2%) were most frequently involved. Over a median follow-up of 6.4 years, 111 (22%) and 289 (57.3%) neuropathies attained partial and full recovery respectively, and 86% of the recoveries occurred within the first year after definitive radiotherapy. CN III, IV, VI had the highest 5-year full recovery rate (72.7%), followed by CN V1-3 (60.3%), CN XII (48.6%), and CN II (18.2%) (P < 0.001). Positive smoking history, optic nerve involvement, and long duration of neuropathy were independent negative predictors for neurological recovery. After full recovery, re-palsy was observed in 6.9% (20/289) of the nerves, 60% of which co-occurred with local NPC recurrences at the base of skull. CONCLUSION Rate and durability of cranial neuropathy recovery in this contemporary NPC cohort compared favorably with data from the 2D radiotherapy era. Both patient and disease factors affected the chance of nerve recovery. Re-palsy of recovered nerves should prompt careful evaluation for local recurrence.

Key Points Question Is intensity-modulated proton therapy (IMPT) associated with fewer treatment-related adverse events and comparable oncologic outcomes for patients with nonmetastatic nasopharyngeal carcinoma (NPC) compared with patients treated with intensity-modulated radiation therapy (IMRT)? Findings In this cohort study of 77 patients with nonmetastatic NPC treated with curative-intent radiotherapy, IMPT treatment was associated with significantly fewer acute adverse events compared with standard-of-care IMRT, with rare late complications. Propensity score–matched analysis demonstrated equally excellent oncologic outcomes in both groups, including 100% locoregional control rate at 2 years in the IMPT group. Meaning These findings suggest that IMPT should be discussed with patients as the potential primary radiotherapy modality for nonmetastatic NPC when it is available because it was associated with less acute toxicity burden compared with IMRT, with potential oncologic benefit in locoregional control., This cohort study compares toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic nasopharyngeal carcinoma (NPC) when treated with intensity-modulated proton therapy (IMPT) vs intensity-modulated radiation therapy (IMRT) with or without chemotherapy., Importance Patients with nonmetastatic nasopharyngeal carcinoma (NPC) are primarily treated by radiotherapy with curative intent with or without chemotherapy and often experience substantial treatment-related toxic effects even with modern radiation techniques, such as intensity-modulated radiation therapy (IMRT). Intensity-modulated proton therapy (IMPT) may improve the toxicity profile; however, there is a paucity of data given the limited availability of IMPT in regions with endemic NPC. Objective To compare toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic NPC when treated with IMPT vs IMRT with or without chemotherapy. Design, Setting, and Participants This retrospective cohort study included 77 patients with newly diagnosed nonmetastatic NPC who received curative-intent radiotherapy with IMPT or IMRT at a tertiary academic cancer center from January 1, 2016, to December 31, 2019. Forty-eight patients with Epstein-Barr virus (EBV)–positive tumors were included in a 1:1 propensity score–matched analysis for survival outcomes. The end of the follow-up period was March 31, 2021. Exposures IMPT vs IMRT with or without chemotherapy. Main Outcomes and Measures The main outcomes were the incidence of acute and chronic treatment-related adverse events (AEs) and oncologic outcomes, including locoregional failure-free survival (LRFS), progression-free survival (PFS), and overall survival (OS). Results We identified 77 patients (25 [32.5%] women; 52 [67.5%] men; median [interquartile range] age, 48.7 [42.2-60.3] years), among whom 28 (36.4%) were treated with IMPT and 49 (63.6%) were treated with IMRT. Median (interquartile range) follow-up was 30.3 (17.9-41.5) months. On multivariable logistic regression analyses, IMPT was associated with lower likelihood of developing grade 2 or higher acute AEs compared with IMRT (odds ratio [OR], 0.15; 95% CI, 0.03-0.60; P = .01). Only 1 case (3.8%) of a chronic grade 3 or higher AE occurred in the IMPT group compared with 8 cases (16.3%) in the IMRT group (OR, 0.21; 95% CI, 0.01-1.21; P = .15). Propensity score matching generated a balanced cohort of 48 patients (24 IMPT vs 24 IMRT) and found similar PFS in the IMPT and IMRT groups (2-year PFS, 95.7% [95% CI, 87.7%-100%] vs 76.7% [95% CI, 60.7%-97.0%]; hazard ratio [HR], 0.31; 95% CI, 0.07-1.47; P = .14). No locoregional recurrence or death was observed in the IMPT group from the matched cohort. Two-year LRFS was 100% (95% CI, 100%-100%) in the IMPT group and 86.2% (95% CI, 72.8%-100%) in the IMRT group (P = .08). Three-year OS was 100% (95% CI, 100%-100%) in the IMPT group and 94.1% (95% CI, 83.6%-100%) in the IMRT group (P = .42). Smoking history was the only clinical factor significantly associated with both poor LRFS (HR, 63.37; 95% CI, 3.25-1236.13; P = .006) and poor PFS (HR, 6.33; 95% CI, 1.16-34.57; P = .03) on multivariable analyses. Conclusions and Relevance In this study, curative-intent radiotherapy with IMPT for nonmetastatic NPC was associated with significantly reduced acute toxicity burden in comparison with IMRT, with rare late complications and excellent oncologic outcomes, including 100% locoregional control at 2 years. Prospective trials are warranted to direct the optimal patient selection for IMPT as the primary radiotherapy modality for nonmetastatic NPC.

OBJECTIVE To validate the eighth edition of the AJCC/UICC staging system in nasopharyngeal cancer (NPC) patients who were uniformly treated in a prospective randomized study using intensity-modulated radiation therapy and to investigate the prognostic value of plasma Epstein-Barr virus (EBV) DNA level when incorporated into the TNM staging. METHODS Between October 2010 and September 2015, non-metastatic NPC patients were treated with concurrent chemoradiation followed by adjuvant chemotherapy. Pretreatment images of 205 patients were reviewed by two radiologists to determine the TNM classification according to the seventh and eighth editions of the AJCC/UICC staging system. Overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated. Harrell's C concordance index (C-index) and Akaike information criterion (AIC) were used to compare the staging models. Recursive partitioning analysis (RPA) was conducted and incorporated with plasma EBV DNA. RESULTS Overall, the eighth edition showed higher C-indexes and lower AIC values in nodal classification and stage groups, indicating a better discrimination performance and better goodness of fit, but showed similar separation for T classification compared with the seventh edition. The integration of pretreatment EBV values (

Objective Plasma Epstein-Barr virus (EBV) DNA concentration at the time of diagnosis (pre-EBV) can be used to stratify risk for nasopharyngeal cancer (NPC) patients. However, pre-EBV cut-off values vary among studies. Methods This was a post hoc analysis of 208 NPC patients from a phase II/III study comparing sequential (SEQ) vs. simultaneous integrated boost (SIB) intensity modulated radiation therapy. The objective was to identify the optimal pre-EBV cut-off value to predict overall survival (OS), progression free survival (PFS) and distant metastatic free survival (DMFS) rates. Results The pre-EBV and post-treatment EBV DNA (post-EBV) were detectable in 59.1% and 3.8% of the patients, respectively. A new pre-EBV cut-off value of 2300 copies/ml was identified by the receiver operating characteristics analysis. This cut-off value showed 82% sensitivity, 59% specificity and 31.7% positive and 93.5% negative predictive values in predicting OS. The 3-year OS, PFS and DMFS were 95.6 vs. 73.8%, 89.8 vs. 55.3% and 93 vs. 70.1% for pre-EBV < vs. ≥2300 copies/ml, respectively. Older age group (≥45 years), high pre-EBV and detectable post-EBV concentration were independent predictors for OS, PFS and DMFS in a multivariate analysis. When the stage grouping and pre-EBV value were combined, a subgroup of patients with stage II-III and pre-EBV values