International recommendations for plasma Epstein-Barr virus DNA measurement in nasopharyngeal carcinoma in resource-constrained settings: lessons from the COVID-19 pandemic.

The effects of the COVID-19 pandemic continue to constrain health-care staff and resources worldwide, despite the availability of effective vaccines. Aerosol-generating procedures such as endoscopy, a common investigation tool for nasopharyngeal carcinoma, are recognised as a likely cause of SARS-CoV-2 spread in hospitals. Plasma Epstein-Barr virus (EBV) DNA is considered the most accurate biomarker for the routine management of nasopharyngeal carcinoma. A consensus statement on whether plasma EBV DNA can minimise the need for or replace aerosol-generating procedures, imaging methods, and face-to-face consultations in managing nasopharyngeal carcinoma is urgently needed amid the current pandemic and potentially for future highly contagious airborne diseases or natural disasters. We completed a modified Delphi consensus process of three rounds with 33 international experts in otorhinolaryngology or head and neck surgery, radiation oncology, medical oncology, and clinical oncology with vast experience in managing nasopharyngeal carcinoma, representing 51 international professional societies and national clinical trial groups. These consensus recommendations aim to enhance consistency in clinical practice, reduce ambiguity in delivering care, and offer advice for clinicians worldwide who work in endemic and non-endemic regions of nasopharyngeal carcinoma, in the context of COVID-19 and other airborne pandemics, and in future unexpected settings of severe resource constraints and insufficiency of personal protective equipment.

Comparison between the seventh and eighth edition of the AJCC/UICC staging system for nasopharyngeal cancer integrated with pretreatment plasma Epstein-Barr virus DNA level in a non-Chinese population: secondary analysis from a prospective randomized trial.

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 (<2300 vs ≥2300 copies/ml) to the eighth edition AJCC/UICC staging system allowed the classification of patients into three RPA categories and further lowered the AIC value and increased the C-index for OS. CONCLUSION: The eighth edition of the AJCC/UICC staging system had higher prognostic values in terms of OS, PFS and DMFS than the previous edition. An integration of pretreatment plasma EBV DNA into the next AJCC/UICC staging could improve the outcome prediction especially in poor risk groups who might benefit from treatment intensification.

A randomized phase III study between sequential versus simultaneous integrated boost intensity-modulated radiation therapy in nasopharyngeal carcinoma.

PURPOSE: 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). MATERIALS AND METHODS: 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. RESULTS: 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, 3­year 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. CONCLUSION: 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.

Optimal plasma pretreatment EBV DNA cut-off point for nasopharyngeal cancer patients treated with intensity modulated radiation therapy.

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 <2300 copies/ml. had the best survival outcomes, while the worst survival subgroup was the patients with stage III-IVb with pre-EBV values ≥2300 copies/ml. CONCLUSIONS: Pre-EBV cut-off of 2300 copies/ml is an optimal value predicting OS, PFS and DMFS.

Randomized control trial of benzydamine HCl versus sodium bicarbonate for prophylaxis of concurrent chemoradiation-induced oral mucositis.

PURPOSE: The purpose of the study is to compare the efficacy of benzydamine HCl with sodium bicarbonate in the prevention of concurrent chemoradiation-induced oral mucositis in head and neck cancer patients. METHODS: Sixty locally advanced head and neck cancer patients treated with high-dose radiotherapy concurrently with platinum-based chemotherapy were randomly assigned to receive either benzydamine HCl or sodium bicarbonate from the first day of treatment to 2 weeks after the completion of treatment. The total score for mucositis, based on the Oral Mucositis Assessment Scale (OMAS), was used for the assessment, conducted weekly during the treatment period and at the fourth week of the follow-up. Pain score, all prescribed medications, and tube feeding needs were also recorded and compared. RESULTS: The median of total OMAS score was statistically significant lower in patients who received benzydamine HCl during concurrent chemo-radiotherapy (CCRT) than in those who received sodium bicarbonate, (p value < 0.001). There was no difference in median pain score, (p value = 0.52). Nineteen percent of patients in sodium bicarbonate arm needed oral antifungal agents whereas none in the benzydamine HCl arm required such medications, (p value = 0.06). Tube feeding needs and the compliance of CCRT were not different between the two study arms. CONCLUSIONS: For patients undergoing high-dose radiotherapy concurrently with platinum-based chemotherapy, using benzydamine HCl mouthwash as a preventive approach was superior to basic oral care using sodium bicarbonate mouthwash in terms of reducing the severity of oral mucositis and encouraging trend for the less need of oral antifungal drugs.

Prognostic Value of Plasma EBV DNA for Nasopharyngeal Cancer Patients during Treatment with Intensity-modulated Radiation Therapy and Concurrent Chemotherapy.

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.

Efficacy of intensity-modulated radiotherapy with concurrent carboplatin in nasopharyngeal carcinoma.

BACKGROUND: The aim of the prospective phase II study was to evaluate the efficacy and toxicities of concurrent carboplatin with intensity-modulated radiotherapy (IMRT) in the treatment of nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Between October 2005 and November 2011, 73 stage II-IVB NPC patients received IMRT 70 Gy concurrently with three cycles of carboplatin (AUC 5) every three weeks, followed by three cycles of adjuvant carboplatin (AUC 5) and 5-FU (1,000 mg/m(2)/day for four days) every four weeks. All patients were evaluated for tumour response using response evaluation criteria in solid tumour (RECIST) criteria, survival analysis using Kaplan-Meier methods, and toxicities according to common terminology criteria for adverse events (CTCAE) version 4.0. RESULTS: At three months after chemoradiation, 82.2% and 17.8% of patients achieved complete and partial response, respectively. With a median follow-up of 48.1 months (1.3-97.8 months), 9.6% and 17.8% had local recurrence and distant metastasis, respectively. The median survival was not reached. A three-year overall survival was 83.6% and a progression-free survival was 65.3%. Regarding treatment compliance, 97.2%, 68.5% and 69.8% completed radiation treatment, concurrent carboplatin and adjuvant chemotherapy, respectively. Grade 3-4 acute toxicities were oral mucositis (16.4%), dysphagia (16.4%), xerostomia (15.1%) and haematotoxicity (6.8%). CONCLUSIONS: Carboplatin concurrently with IMRT provided excellent tumour response, manageable toxicities and good compliance. This should be considered as an alternative treatment for NPC patients.

Multimodality radiomics for tumor prognosis in nasopharyngeal carcinoma.

BACKGROUND: The prognosis of nasopharyngeal carcinoma (NPC) is challenging due to late-stage identification and frequently undetectable Epstein-Barr virus (EBV) DNA. Incorporating radiomic features, which quantify tumor characteristics from imaging, may enhance prognosis assessment. PURPOSE: To investigate the predictive power of radiomic features on overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) in NPC. MATERIALS AND METHODS: A retrospective analysis of 183 NPC patients treated with chemoradiotherapy from 2010 to 2019 was conducted. All patients were followed for at least three years. The pretreatment CT images with contrast medium, MR images (T1W and T2W), as well as gross tumor volume (GTV) contours, were used to extract radiomic features using PyRadiomics v.2.0. Robust and efficient radiomic features were chosen using the intraclass correlation test and univariate Cox proportional hazard regression analysis. They were then combined with clinical data including age, gender, tumor stage, and EBV DNA level for prognostic evaluation using Cox proportional hazard regression models with recursive feature elimination (RFE) and were optimized using 20 repetitions of a five-fold cross-validation scheme. RESULTS: Integrating radiomics with clinical data significantly enhanced the predictive power, yielding a C-index of 0.788 ± 0.066 to 0.848 ± 0.079 for the combined model versus 0.745 ± 0.082 to 0.766 ± 0.083 for clinical data alone (p<0.05). Multimodality radiomics combined with clinical data offered the highest performance. Despite the absence of EBV DNA, radiomics integration significantly improved survival predictions (C-index ranging from 0.770 ± 0.070 to 0.831 ± 0.083 in combined model versus 0.727 ± 0.084 to 0.734 ± 0.088 in clinical model, p<0.05). CONCLUSIONS: The combination of multimodality radiomic features from CT and MR images could offer superior predictive performance for OS, PFS, and DMFS compared to relying on conventional clinical data alone.

A multivariable normal tissue complication probability model for predicting radiation-induced hypothyroidism in nasopharyngeal carcinoma patients in the modern radiotherapy era.

Radiation-induced hypothyroidism (RHT) is a common long-term complication for nasopharyngeal carcinoma (NPC) survivors. A model using clinical and dosimetric factors for predicting risk of RHT could suggest a proper dose-volume parameters for the treatment planning in an individual level. We aim to develop a multivariable normal tissue complication probability (NTCP) model for RHT in NPC patients after intensity-modulated radiotherapy or volumetric modulated arc therapy. The model was developed using retrospective clinical data and dose-volume data of the thyroid and pituitary gland based on a standard backward stepwise multivariable logistic regression analysis and was then internally validated using 10-fold cross-validation. The final NTCP model consisted of age, pretreatment thyroid-stimulating hormone and mean thyroid dose. The model performance was good with an area under the receiver operating characteristic curve of 0.749 on an internal (200 patients) and 0.812 on an external (25 patients) validation. The mean thyroid dose at ≤45 Gy was suggested for treatment plan, owing to an RHT incidence of 2% versus 61% in the >45 Gy group.

A prospective randomized study comparing the efficacy between povidone-iodine gargling and benzydamine hydrochloride for mucositis prevention in head and neck cancer patients receiving concurrent chemoradiotherapy.

Background: Concurrent chemoradiation (CCRT) has been the standard treatment for organ preservation or locally advanced head and neck cancer (LAHNC). Radiation-induced oral mucositis (RIOM) is an important treatment-limiting toxicity. Benzydamine hydrochloride was recommended to prevent oral mucositis. Povidone-iodine had also been adopted to use as an oral rinse to prevent mucositis. Objective: This study compared the efficacy between benzydamine hydrochloride and 0.1% povidone-iodine to prevent RIOM in HNC patients who received concurrent chemoradiotherapy. Methods: We conducted a randomized control study in HNC patients receiving CCRT with curative intent. The stratification factors were primary site of disease, treatment modality, chemotherapy regimen, and schedule. The primary outcome was RIOM assessed by Oral Mucositis Assessment Scale (OMAS). Secondary outcomes included RIOM assessed by NCI-CTCAE, use of analgesic, antibiotics and anti-fungal drugs, hospitalization, and participant satisfaction. Results: There were 83 participants recruited for this study with 71 completing the trial. Demographic characteristics were well-balanced between both arms. The univariate regression analysis revealed that povidone-iodine correlated with less RIOM compared to benzydamine hydrochloride (coefficient -2.25, 95% CI -4.37 to -0.012, p-value 0.03). The incidence of grade III-IV CTCAE RIOM during the study period was 51.4% with benzydamine hydrochloride compared to 26.5% with 0.1% povidone iodine (p-value 0.032). The peak incidence of grade III-IV CTCAE RIOM occurred in the 7th week of treatment (40.5% vs. 11.8%, p-value 0.01). This indicated the efficacy of povidone-iodine to prevent severe RIOM which usually most severity in the last week of CCRT treatment. The multivariate analysis revealed that the CCRT setting (definitive vs. adjuvant) and gargling agents (povidone-iodine vs. benzydamine hydrochloride were the factors associated with RIOM. Conclusion: This study demonstrated higher efficacy of 0.1% povidone-iodine gargle than benzydamine hydrochloride in mucositis prevention.

Improved prediction of radiation-induced hypothyroidism in nasopharyngeal carcinoma using pre-treatment CT radiomics.

When planning radiation therapy, late effects due to the treatment should be considered. One of the most common complications of head and neck radiation therapy is hypothyroidism. Although clinical and dosimetric data are routinely used to assess the risk of hypothyroidism after radiation, the outcome is still unsatisfactory. Medical imaging can provide additional information that improves the prediction of hypothyroidism. In this study, pre-treatment computed tomography (CT) radiomics features of the thyroid gland were combined with clinical and dosimetric data from 220 participants to predict the occurrence of hypothyroidism within 2 years after radiation therapy. The findings demonstrated that the addition of CT radiomics consistently and significantly improves upon conventional model, achieving the highest area under the receiver operating characteristic curve (AUCs) of 0.81 ± 0.06 with a random forest model. Hence, pre-treatment thyroid CT imaging provides useful information that have the potential to improve the ability to predict hypothyroidism after nasopharyngeal radiation therapy.

Comparison of intensity modulated proton therapy beam configurations for treating thoracic esophageal cancer.

Background and purpose: Specific proton-beam configurations are needed to spare organs at risk (OARs), including lungs, heart, and spinal cord, when treating esophageal squamous cell carcinoma (ESCC) in the thoracic region. This study aimed to propose new intensity-modulated proton therapy (IMPT) beam configurations and to demonstrate the benefit of IMPT compared with intensity-modulated x-ray therapy (IMXT) for treating ESCC. Material and methods: IMPT plans with three different beam angle configurations were generated on CT datasets of 25 ESCC patients that were treated with IMXT. The IMPT beam designs were two commonly-used beam configurations (anteroposterior and posterior oblique) and a recently proposed beam configuration (anterosuperior with posteroinferior). The target doses were 50-54 Gy(RBE) and 60-64 Gy(RBE) to the low-risk and high-risk target volumes, respectively. Robust optimization was applied for the IMPT plans. The differences in the dose-volume parameters between the IMXT and IMPT plans were compared. Results: With target coverage comparable to standard IMXT, IMPT had significantly lower mean doses to the OARs. IMPT with an anteroposterior opposing beam generated the lowest lung dose (mean = 7.1 Gy(RBE), V20 = 14.1%) and the anterosuperior with posteroinferior beam resulted in the lowest heart dose (mean = 12.8 Gy(RBE), V30 = 15.7%) and liver dose (mean = 3.9 Gy(RBE), V30 = 5.9%). For the subgroup of patients with an inferior tumor location (PTVs overlapping a part of the contoured heart), the novel beam demonstrated the optimal OARs sparing. Conclusion: Compared with IMXT, the IMPT plans significantly reduced the radiation dose to the surrounding organs when treating ESCC. IMPT beam configuration selection depends on the tumor location relative to the heart.

Tumor Prognostic Prediction of Nasopharyngeal Carcinoma Using CT-Based Radiomics in Non-Chinese Patients.

PURPOSE: We 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 METHODS: We 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. RESULTS: The 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. CONCLUSION: Our 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.

High-dose Intensity-modulated proton therapy versus Standard-dose Intensity-modulated RadIation therapy for esophageal squamous cell carcinoma (HI-SIRI): study protocol for a randomized controlled clinical trial.

BACKGROUND: Chemoradiotherapy is the standard of care for esophageal cancer as a neoadjuvant treatment before surgery, or as a definitive treatment for unresectable disease. Intensity-modulated radiotherapy (IMRT) has been considered the standard radiation technique. However, patients suffer from treatment-related toxicities, and most die from disease progression or recurrence. With emerging technological advancement, proton therapy has theoretical advantages over IMRT because it offers apparent dosimetric benefits to allow dose escalation to the target while better sparing surrounding tissues such as the lungs, heart, liver, and spinal cord. The purpose of this study protocol is to investigate the survival benefit of proton therapy using modern intensity-modulated proton therapy (IMPT) compared to standard IMRT for esophageal cancer. METHODS: This is a two-arm open phase II/III multi-institution randomized controlled trial. Eligible patients will have histologically confirmed squamous cell carcinoma of the thoracic esophagus with no evidence of tracheoesophageal/esophagobronchial fistula or distant metastasis. After stratification according to resectability status (resectable vs. borderline resectable/unresectable), a total of 232 patients will be randomized to receive IMPT or IMRT using a 1:1 allocation ratio. In resectable cases, surgical resection following concurrent chemoradiation will be attempted for the patients who are medically fit at the time of surgery. In those with initially borderline resectable/unresectable disease, definitive concurrent chemoradiation will be performed. The phase II study will assess safety (toxicity and postoperative complications) and feasibility (recruitment rate and chemoradiation dose modification) in 40 patients into each arm. The study will then continue into phase III, further recruit 76 patients into each arm, and compare progression-free survival between IMPT vs IMRT groups. The secondary endpoints will be overall survival, local and distant control, toxicities, health-related quality of life, and cost-utility. This protocol describes a detailed radiotherapy and chemotherapy. DISCUSSION: This randomized clinical trial will demonstrate the clinical benefit of IMPT in esophageal cancer treatment in terms of survival and toxicity outcomes which will further establish high-level evidence for radiation modality in squamous cell carcinoma of the thoracic esophagus. TRIAL REGISTRATION: TCTR20200310006 . Registered 10 March 2020.

Neutrophil-to-lymphocyte ratio trend: A novel prognostic predictor in patients with nasopharyngeal carcinoma receiving radiotherapy.

BACKGROUND: Peripheral neutrophil-lymphocyte ratio (NLR), reflecting immune-inflammation status, shows great potential for tumor progression and outcome. Pre-treatment NLR does not fully reflect the immune-inflammatory response to treatment. This study aimed to introduce the NLR trend as a new indicator and to investigate its prognostic value in patients with nasopharyngeal carcinoma receiving radiotherapy. METHODS: This retrospective study evaluated patients with nasopharyngeal carcinoma treated with radiotherapy. The NLR trend value was calculated from the fitted line gradient via the NLRs before, during (at least once), and after each patient's first radiotherapy. The Kaplan-Meier curve and log-rank test were used to calculate and compare survival outcomes of different pretreatment NLRs and NLR trends for progression-free survival, locoregional recurrence-free survival (LRFS), and overall survival at 3 and 5 years. Multivariate Cox regression analyses were performed to assess the association between the NLR trend plus 3- and 5-year overall survival. RESULTS: The study included 528 patients. A lower NLR trend predicted worse progression-free survival, LRFS, plus 3- and 5-year overall survival. Multivariate Cox regression analysis showed that the NLR trend independently predicted 3- and 5-year overall survival. Sub-group analysis showed that the prognosis of patients with a low pretreatment NLR and a high NLR trend were superior to those of other groups. CONCLUSION: The NLR trend independently predicted the prognosis of patients with nasopharyngeal carcinoma receiving radiotherapy. The NLR trend and the pretreatment NLR combination is more precise than pretreatment NLR in predicting prognosis. A high NLR trend may be evidence of a positive immune response to radiotherapy in patients with nasopharyngeal carcinoma.

Flattening filter free stereotactic body radiation therapy for lung tumors: outcomes and predictive factors.

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.

Cranial neuropathies in advanced nasopharyngeal carcinoma: Neurological recovery after modern radiotherapy and systemic chemotherapy.

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 < 0.001). Positive smoking history, optic nerve involvement, and longer 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. CONCLUSION: Durable recovery of most cranial neuropathies in advanced T4 NPC was observed in the era of modern IMRT and effective systemic chemotherapy. Both patient and disease factors affected the chance of neurological recovery. Re-palsy of recovered nerves should prompt careful evaluation for local recurrence.

A predictive model of radiation-related fibrosis based on the radiomic features of magnetic resonance imaging and computed tomography.

BACKGROUND: To establish a predictive model for the fibrotic level of neck muscles after radiotherapy by using radiomic features extracted from the magnetic resonance imaging (MRI) before and after radiotherapy and planning computed tomography (CT) in nasopharyngeal carcinoma patients. METHODS: A total of one hundred and eighty-six patients were finally enrolled in this study. According to the specific standard, all patients were divided into three different fibrosis groups. Regions of interests (ROI), including sternocleidomastoids (SCMs), trapezius (T), levator scapulae (LS), and scalenus muscles (S), were delineated manually and used for features extraction on IBEX. XGBoost, a machine learning algorithm, was used for the establishment of the prediction model. First, the patients were divided into training cohort (80%) and testing cohort (20%) randomly. Then the image features of CT or delta changes calculated from pre- and post-radiotherapy MRI images on each cohort constituted training and testing datasets. Then, based on the training dataset, a well-trained prediction model was produced. We used five-fold cross-validation to validate the predictive models. Afterward, the model performance was assessed on the 'testing' set and reported in terms of area under the receiver operating characteristic curve (AUC) under five scenarios: (I) only T1 sequence, (II) only T2 sequence, (III) only T1 post-contrast (T1 + C) sequence, (IV) Combination of all MRI sequences, (V) only CT. RESULTS: Most of the patients enrolled are male (73.1%), mean age was 47 years, receiving concurrent chemo-radiotherapy as the primary treatment (90.9%). By the end of the final follow-up, most of the patients were rated as mild fibrosis (60.8%). We found the prediction model based on the CT image features outperform all MRI features with an AUC of 0.69 and accuracy of 0.65. Contrarily, the model based on features from all MRI sequence showed lower AUC less than 0.5 and lower accuracy less than 0.6. CONCLUSIONS: The prediction model based on CT radiomics features has better performance in the prediction of the grade of post-radiotherapy neck fibrosis. This might help guide radiotherapy treatment planning to achieve a better quality of life.

Validation of previously reported predictors for radiation-induced hypothyroidism in nasopharyngeal cancer patients treated with intensity-modulated radiation therapy, a post hoc analysis from a Phase III randomized trial.

This study aimed to validate previously reported dosimetric parameters, including thyroid volume, mean dose, and percentage thyroid volume, receiving at least 40, 45 and 50 Gy (V40, V45 and V50), absolute thyroid volume spared (VS) from 45, 50 and 60 Gy (VS45, VS50 and VS60), and clinical factors affecting the development of radiation-induced hypothyroidism (RHT). A post hoc analysis was performed in 178 euthyroid nasopharyngeal cancer (NPC) patients from a Phase III study comparing sequential versus simultaneous-integrated boost intensity-modulated radiation therapy. RHT was determined by increased thyroid-stimulating hormone (TSH) with or without reduced free thyroxin, regardless of symptoms. The median follow-up time was 42.5 months. The 1-, 2- and 3-year freedom from RHT rates were 78.4%, 56.4% and 43.4%, respectively. The median latency period was 21 months. The thyroid gland received a median mean dose of 53.5 Gy. Female gender, smaller thyroid volume, higher pretreatment TSH level (≥1.55 µU/ml) and VS60 < 10 cm3 were significantly associated with RHT in univariate analyses. Only pretreatment TSH ≥ 1.55 µU/ml and VS60 < 10 cm3 were significant predictors in multivariate analysis. Our results suggested that patients with pretreatment TSH ≥ 1.55 µU/ml should be cautious about the risk of RHT. The VS60 ≥ 10 cm3 is recommended for treatment planning.

Prevalence and significance of plasma Epstein-Barr Virus DNA level in nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) DNA has been recognized as a promising tumor marker for nasopharyngeal carcinoma (NPC). This study aims to demonstrate the prevalence of plasma EBV DNA and its temporal correlation with treatment outcomes in the modern era. A total of 204 patients with Stage I-IVB NPC treated with intensity-modulated radiotherapy (IMRT) were enrolled. Quantitative plasma EBV DNA measurement was performed before treatment (pre-IMRT), on the fifth week of radiation (mid-IMRT), at 3 months after radiation (post-IMRT), then every 6 months until disease relapse. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Plasma EBV DNA was detected in 110 patients (53.9%), with a median pre-IMRT EBV DNA level of 8005 copies/ml. Significant correlation was noted between pre-IMRT EBV DNA level and disease stage, but not between pre-IMRT EBV DNA level and World Health Organization classification. With a median follow-up time of 35.1 months, the 3-year PFS and OS rates were higher in the group with undetectable pre-IMRT EBV DNA level compared with in the group in which it was detectable. When classified according to disease stage and pre-IMRT EBV DNA, patients with early disease and detectable pre-IMRT EBV DNA experienced poorer survival than those with locally advanced disease and undetectable pre-IMRT EBV DNA. According to the dynamic changes in EBV DNA level between pre-IMRT and mid/post IMRT, survival was significantly higher in patients who achieved an undetectable level following treatment. On multivariate analysis, post-IMRT EBV DNA level was the strongest predictor of all treatment outcomes (P < 0.001). Our study demonstrated the clinical significance of the plasma EBV DNA level at specific time points, as well as of the dynamic changes in the EBV DNA level. Disappearance of plasma EBV DNA after treatment was associated with better survival.