Trehalose versus carboxymethylcellulose oral spray for relieving radiation-induced xerostomia in head and neck cancer patients: a randomized controlled trial.

BACKGROUND: The aim of this study was to investigate the effect of trehalose oral spray to relieve radiation-induced xerostomia on a randomized controlled trial (RCT). METHODS: Prior to RCT, the effect of trehalose (5-20%) on the epithelial growth of fetal mouse salivary gland (SG) explants was evaluated to confirm if 10% trehalose exerted the best epithelial outcomes. Participants who completed radiotherapy for head and neck cancer (HNC) treatment were enrolled in a double-blind RCT, according to inclusion and exclusion criteria as per the CONSORT statement. The experimental group (n = 35) received 10% trehalose spray, while the control group (n = 35) received carboxymethylcellulose (CMC) spray to apply intra-orally 4 times/day for 14 days. Salivary pH and unstimulated salivary flow rate were recorded pre- and post-interventions. The Xerostomia-related Quality of Life scale (XeQoLs) was filled, and scores assessed post-interventions. RESULTS: In the SG explant model, pro-acinar epithelial growth and mitosis was supported by 10% topical trehalose. As for RCT outcomes, salivary pH and unstimulated salivary flow rate were significantly improved after use of 10% trehalose spray when compared to CMC (p < 0.05). Participants reported an improvement of XeQoLs dimension scores after using trehalose or CMC oral sprays in terms of physical, pain/discomfort, and psychological dimensions (p < 0.05), but not social (p > 0.05). When comparing between CMC and trehalose sprays, XeQoLs total scores were not statistically different (p > 0.05). CONCLUSIONS: The 10% trehalose spray improved salivary pH, unstimulated salivary flow rate, and the quality-of-life dimensions linked with physical, pain/discomfort, and psychological signs. The clinical efficacy of 10% trehalose spray was equivalent with CMC-based saliva substitutes for relieving radiation-induced xerostomia; therefore, trehalose may be suggested in alternative to CMC-based oral spray.(Thai Clinical Trials Registry; https://www.thaiclinicaltrials.org/ TCTR20190817004).

Long-term patient-rated cosmetic and satisfactory outcomes of early breast cancer treated with conventional versus hypofractionated breast irradiation with simultaneous integrated boost technique.

To compare patient-rated cosmetic and satisfactory outcomes between conventional fractionation with simultaneously integrated boost (C-SIB) vs hypofractionation with SIB (H-SIB) in early breast cancer. Patients with stage I and II breast cancer who received breast-conserving surgery followed by radiation with SIB to tumor bed and completed questionnaire were included in this study. Radiotherapy was as follows: C-SIB arm = 50 Gy and 65 Gy in 25 fractions and H-SIB arm = 43.2 Gy and 52.8 Gy in 16 fractions to the whole breast and tumor bed, respectively. Single cross-sectional assessment of the breast cosmesis was done by patients and radiation oncologist at a follow-up visit. Breast cosmetic and satisfaction scores were collected using a four-point Harvard/NSABP/RTOG cosmesis criteria scale and a four-point Likert-type scale, respectively. Of a total of 114 patients (C-SIB = 57) and (H-SIB = 57) arms, a median time from radiotherapy completion to questionnaire response was 7.2 years. Patient-rated cosmetic outcome in C-SIB vs H-SIB was "excellent" in 40.3% vs 45.6%, "good" in 33.3% vs 42.1%, "fair" in 21.1% vs 10.5%, and "poor" in 5.3% vs 1.8% (P = .288). Corresponding satisfaction was "very satisfied" in 52.6% vs 57.9%, "satisfied" in 40.4% vs 35.1%, "neutral" in 7.0% vs 5.2%, and "unsatisfied" in 0% vs 1.8% (P = .683). Stage I and older age at radiotherapy were predictors for favorable (good or excellent) cosmesis and satisfaction, respectively. In early-stage breast cancer, H-SIB provided a trend for better cosmesis than C-SIB while maintaining satisfaction. The reduction in treatment duration and cost as well as favorable cosmesis outcomes encourages the use of H-SIB.

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.

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.

Effects of NaF versus SDF treatment on microhardness of artificial radiation caries at cervical and root areas.

This study aimed to compare the effect of silver diamine fluoride (SDF) and fluoride varnish (NaF) on the Vickers microhardness (VHN) of enamel and dentin after radiotherapy and pH-cycling. Human premolars were cut longitudinally, embedded and serially polished. The VHN of enamel/dentin and irradiated enamel/dentin were evaluated. The irradiated specimens were treated with either NaF or SDF, subjected to pH-cycling then VHN test for 4 days. Consequently, they were subjected to energy-dispersive X-ray (EDX) analysis. Radiation adversely affect enamel VHN (p<0.05), whereas dentin VHN was not affected (p>0.05). After pH-cycling, a significant decrease in dentin VHN was observed on day 2 for all groups, whereas enamel VHN was significantly decreased in the control group on day 4. SDF-treated enamel demonstrated higher VHN than that of NaF on day 3. Caries prevention effect of SDF and NaF were observed on enamel, where SDF was proved to be superior to NaF.

Development and validation of a practical score to predict 3-year distant metastatic free survival in nasopharyngeal carcinoma incorporating the number of lymph node regions.

INTRODUCTION: The improvement in diagnosis and treatment for nasopharyngeal carcinoma (NPC) has shifted the pattern of failure toward distant metastasis. This study aimed to develop a simplified prognostic scoring model to predict distant metastatic free survival (DMFS) for NPC patients. MATERIALS AND METHODS: Patients with non-metastatic NPC were identified from a retrospective cohort diagnosed between 2010 and 2018. Flexible parametric survival analysis was used to identify potential predictors for DMFS and establish a scoring model. The prognostic accuracy between the 8th AJCC system and the scoring model was compared using Harrell's C-index. RESULTS: Of the total 393 patients, the median follow-up time was 85 months. The 3-year DMFS rate was 83.3%. Gender, T-stage, pre-EBV (cut-off 2300 copies/ml), and the number of metastatic lymph node regions were identified as independent risk factors for distant metastasis and were included in the final scoring model. Our established model achieved a high C-index in predicting DMFS (0.79) and was well-calibrated. The score divided patients into two categories: low-risk (score 0-4) and high-risk (score 5-7), corresponding with the predicted 3-year DMFS of 96% and 64.5%, respectively. CONCLUSIONS: A feasible and applicative prognostic score was established and validated to discriminate NPC patients into low- and high-risk groups.

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.

The Prognostic Predictors of Airway Stenting in Malignant Airway Involvement From Esophageal Carcinoma.

BACKGROUND: In locoregional esophageal carcinoma (EC), airway involvement is the most common route of extraesophageal metastasis. The prognosis remains poor even with a multimodality approach. Although airway stenting is well known for restoration of the airway, the survival benefit is still lacking. METHODS: A total of 37 of patients with airway involvement from EC who underwent airway stenting at a single institution from 2015 to 2020 were retrospectively reviewed. Survival curves after stent placement among different groups were analyzed using Kaplan-Meier method. RESULTS: Of 37 patients, 34 were male, and the mean age was 58.9 years (42 to 80). EC was commonly located at midesophagus (51.4%). The site of airway involvement was left main bronchus (48.6%), trachea (32.4%), multiple sites (16.2%), and right main bronchus (2.7%). The nature of airway involvement was tumor invasion (91.9%), compression (62.2%), and fistula (37.8%). Twenty-three patients (62.2%) had airway involvement at the time of esophageal cancer diagnosis. Only 4 patients underwent esophageal stenting. The median survival time after stent placement was 97 days (5 to 539). Chemotherapy and/or radiotherapy were given before stent placement in 18 patients (48.6%). Treatment-naive before airway stenting and diagnosis of airway involvement at the same time of EC diagnosis were independent predictors for the increased survival after stent placement ( P <0.05). Poststent treatment was associated with improved survival ( P =0.002). CONCLUSION: In patients with malignant airway involvement from EC who underwent airway stenting, the prognostic predictors for improved survival were treatment-naive status, receiving treatment after airway stenting, and early-onset of airway involvement.

Digital fabrication of customized intraoral appliances for head and neck radiotherapy.

Introduction: The radiotherapy received by head and neck cancer patients commonly has adverse effects on oral tissue and the muscles of mastication. This short communication describes the digital fabrication of intraoral appliances for radiotherapy and muscle exercises. Methods: Three patients diagnosed with tongue squamous carcinoma were treatment-planned for radiotherapy using different radiation techniques. The patients were referred for oral scanning and digital bite records, and the appliance was collaboratively designed by a radiation oncologist, dentist, and laboratory technician. The appliance covered the occlusal surface of the remaining teeth with a 1-mm engagement. The lingual plate was 2-mm below the occlusal plane, and extended 4-mm distally, and the jaws were opened by 20-mm. The appliances were printed overnight using a rigid and biocompatible 3D printing material. Results: Requiring minimal chair-time, the appliance was easily inserted and adjusted to comfortably fit in the mouth. The patients were trained to insert it themselves. The tongue was at a pre-determined position during daily radiotherapy, and the healthy tissues were separated from the radiation field. The patients had mild adverse effects on their oral mucosa. Additionally, the appliances were used for muscle exercises after the radiation courses to prevent trismus. Conclusions: The interprofessional collaboration to fabricate customized intraoral appliances using digital workflow to maximize patients' benefits is feasible. Clinical significance: The use of intraoral appliances is potentially increased when the fabrication process is facilitated. Using an intraoral appliance precisely targets the tumor are for better treatment outcomes, and the healthy adjacent tissues will be preserved to maintain the patient's quality of life.

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.

Safety and Immunogenicity of Homologous and Heterologous Adenoviral-Vectored and mRNA COVID-19 Vaccine Regimens in Radiotherapy Patients.

Diminished immune response after vaccination occurs in cancer patients. This observational study evaluated the immune response and safety profile after COVID-19 vaccination in radiotherapy patients. The study comprised 53 cancer patients undergoing radiotherapy and voluntarily received the COVID-19 vaccine. The two regimens were homologous ChAdOx1-S recombinant (AstraZeneca, AZ), "AZ-AZ" and heterologous "AZ-mRNA". The seroconversion rate and anti-RBD immunoglobulin geometric mean titers (GMT) were assessed and compared with healthy controls. Adverse effects were assessed using a questionnaire. The seroconversion rate was 52.4% 1 month after the first dose with GMT 4.3 U/mL (95%CI 1.4-13). Following the second dose, the AZ-AZ group achieved 95% seroconversion rate with GMT = 188.4 U/mL (95%CI 67.1-529), which was significantly lower than the healthy cohort, GMT = 945 U/mL (95%CI 708-1261). Cancer patients in AZ-mRNA group achieved a 100% seroconversion rate with a high GMT = 1400.8 U/mL (95%CI 429.5-4566), which was significantly lower than the healthy cohort, GMT = 5169.9 U/mL (95%CI 3582.2-7461.5). Most adverse effects were mild. Our findings suggest that radiotherapy patients had fair immunogenicity after the first dose, but achieved a high seroconversion rate after the second dose with manageable adverse effects. However, their immunologic response was lower than in healthy individuals, indicating that other preventive strategies are needed.

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.

Safety and efficacy of salvage conventional re-irradiation following stereotactic radiosurgery for spine metastases.

PURPOSE: There has been limited work assessing the use of re-irradiation (re-RT) for local failure following stereotactic spinal radiosurgery (SSRS). We reviewed our institutional experience of conventionally-fractionated external beam radiation (cEBRT) for salvage therapy following SSRS local failure. MATERIALS AND METHODS: We performed a retrospective review of 54 patients that underwent salvage conventional re-RT at previously SSRS-treated sites. Local control following re-RT was defined as the absence of progression at the treated site as determined by magnetic resonance imaging. RESULTS: Competing risk analysis for local failure was performed using a Fine-Gray model. The median follow-up time was 25 months and median overall survival (OS) was 16 months (95% confidence interval [CI], 10.8-24.9 months) following cEBRT re-RT. Multivariable Cox proportional-hazards analysis revealed Karnofsky performance score prior to re-RT (hazard ratio [HR] = 0.95; 95% CI, 0.93-0.98; p = 0.003) and time to local failure (HR = 0.97; 95% CI, 0.94-1.00; p = 0.04) were associated with longer OS, while male sex (HR = 3.92; 95% CI, 1.64-9.33; p = 0.002) was associated with shorter OS. Local control at 12 months was 81% (95% CI, 69.3-94.0). Competing risk multivariable regression revealed radioresistant tumors (subhazard ratio [subHR] = 0.36; 95% CI, 0.15-0.90; p = 0.028) and epidural disease (subHR = 0.31; 95% CI, 0.12-0.78; p =0.013) were associated with increased risk of local failure. At 12 months, 91% of patients maintained ambulatory function. CONCLUSION: Our data suggest that cEBRT following SSRS local failure can be used safely and effectively. Further investigation is needed into optimal patient selection for cEBRT in the retreatment setting.

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.

Machine learning-based normal tissue complication probability model for predicting albumin-bilirubin (ALBI) grade increase in hepatocellular carcinoma patients.

PURPOSE: The aim of this study was to develop a normal tissue complication probability model using a machine learning approach (ML-based NTCP) to predict the risk of radiation-induced liver disease in hepatocellular carcinoma (HCC) patients. MATERIALS AND METHODS: The study population included 201 HCC patients treated with radiotherapy. The patients' medical records were retrospectively reviewed to obtain the clinical and radiotherapy data. Toxicity was defined by albumin-bilirubin (ALBI) grade increase. The normal liver dose-volume histogram was reduced to mean liver dose (MLD) based on the fraction size-adjusted equivalent uniform dose (2 Gy/fraction and α/ß = 2). Three types of ML-based classification models were used, a penalized logistic regression (PLR), random forest (RF), and gradient-boosted tree (GBT) model. Model performance was compared using the area under the receiver operating characteristic curve (AUROC). Internal validation was performed by 5-fold cross validation and external validation was done in 44 new patients. RESULTS: Liver toxicity occurred in 87 patients (43.1%). The best individual model was the GBT model using baseline liver function, liver volume, and MLD as inputs and the best overall model was an ensemble of the PLR and GBT models. An AUROC of 0.82 with a standard deviation of 0.06 was achieved for the internal validation. An AUROC of 0.78 with a standard deviation of 0.03 was achieved for the external validation. The behaviors of the best GBT model were also in good agreement with the domain knowledge on NTCP. CONCLUSION: We propose the methodology to develop an ML-based NTCP model to estimate the risk of ALBI grade increase.

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.