Ten fraction hypofractionated stereotactic body radiotherapy for the management of ultracentral lung tumors: a retrospective analysis of dosimetry, outcomes, and toxicity.

BACKGROUND: The management of ultracentral thoracic tumors with ablative dose of radiotherapy remains challenging given proximity to critical central structures. We report patient outcomes, toxicity, and dosimetry for ultracentrally located tumors with hypofractionated stereotactic body radiotherapy (hfSBRT). METHODS: Seventy-eight individuals (50 initial radiotherapy, 28 re-irradiation) undergoing 10 fraction hfSBRT for ultracentrally located thoracic tumors treated between 2009 and 2020 at a single institution were retrospectively reviewed. Overall survival (OS), progression free survival (PFS), and local control (LC) were calculated. Incidence and grade of treatment related toxicity were evaluated. Dosimetric analysis of treatment plans and critical adjacent OARs was performed. RESULTS: At a median follow up time of 13 months, 1- and 3-year OS, PFS, and LC were 89%/63%, 37%/18%, and 84%/65%, respectively. Median dose was 65 Gy (BED10 = 107.25 Gy). Median primary bronchial tree maximum dose (Dmax) was 60 Gy (V50 = 0.96 cc). Median esophageal Dmax was 38 Gy (V40 = 0 cc). Median great vessel Dmax was 68 Gy (V50 = 3.53 cc). The most common ≥ grade 2 adverse event was pneumonitis, in 15 individuals (20%). Grade 3 or higher toxicity was observed in 9 individuals (12%): three cases of grade 3 pneumonitis (two re-irradiation, one initial radiotherapy), one grade 3 esophageal stricture following re-irradiation, two grade 3 endobronchial obstructions both following initial radiotherapy, and three grade 5 hemoptysis events (two re-irradiation, one initial radiotherapy). One hemoptysis event was categorized as "possibly" related to treatment, while the remaining two events were categorized as "unlikely" related to treatment in patients with clear evidence of disease progression. CONCLUSIONS: hfSBRT to ultracentral lung tumors delivered over 10 fractions is a safe and effective treatment option, with acceptable rates of toxicity and good rates of tumor control. TRIAL REGISTRATION: IRB registration number 12573.

Income level and treatment selection in prostate cancer: analysis of a North Carolina population-based cohort.

BACKGROUND: Disparities in treatment selection based on socioeconomic status for prostate cancer exist. However, the association between patient-level income with treatment selection priorities and treatment received has not been studied. METHODS: A population-based cohort of 1382 individuals with newly diagnosed prostate cancer was enrolled throughout North Carolina prior to treatment. Patients self-reported household income and were asked about the importance of 12 factors contributing to their treatment decision-making process. Diagnosis details and primary treatment received were abstracted from medical records and cancer registry data. RESULTS: Patients with lower income were diagnosed with more advanced disease (P < .01). Cure was deemed to be "very important" by more than 90% of patients at all income levels. However, patients with lower vs higher household income were more likely to rate factors beyond cure as "very important" such as cost (P < .01), effect on daily activities (P = .01), duration of treatment (P < .01), recovery time (P < .01), and burden on family and friends (P < .01). On multivariable analysis, high vs low income was associated with increased utilization of radical prostatectomy (odds ratio = 2.01, 95% confidence interval = 1.33 to 3.04; P < .01) and decreased use of radiotherapy (odds ratio = 0.48, 95% confidence interval = 0.31 to 0.75; P < .01). CONCLUSIONS: New insights from this study on the association between income and treatment decision-making priorities provide potential avenues for future interventions to reduce disparities in cancer care.

Bioelectrical impedance analysis as a quantitative measure of sarcopenia in head and neck cancer patients treated with radiotherapy.

BACKGROUND AND PURPOSE: Sarcopenia is associated with decreased survival in head and neck cancer patients treated with radiotherapy. This study sought to determine whether in-clinic multifrequency bioelectrical impedance analysis (BIA) can identify survival-associated sarcopenia in patients with head and neck cancer. MATERIALS AND METHODS: This prospective observational study enrolled 50 patients with head and neck cancer undergoing radiation therapy. Baseline BIA measures of skeletal muscle (SM) mass, fat-free mass (FFM), and fat mass (FM) were compared to CT-based estimates using linear regression. Sex-specific BIA-derived thresholds for sarcopenia were defined by the maximum Youden Index on receiver operator characteristic (ROC) curves. Patients were stratified by sarcopenia status and OS was compared using the Kaplan-Meier method and log-rank test. RESULTS: Among 48 evaluable patients, BIA measures of body composition were strongly correlated with CT measures: SM mass (r = 0.97; R2 = 0.94; p < 0.0001), FFM (r = 0.97; R2 = 0.94; p < 0.0001) and FM (r = 0.95; R2 = 0.90; p < 0.0001). SM mass index < 9.19 kg/m2 identified sarcopenia men with high sensitivity (91.7%) and specificity (92.9%), whereas in women SM mass index < 6.53 kg/m2 was sensitive for sarcopenia (100%), but not specific. Patients with sarcopenia, defined by either CT or BIA, exhibited decreased OS (HR = not estimable; CT p = 0.009; BIA p = 0.03). CONCLUSION: BIA provides accurate estimates of body composition in head and neck cancer patients. Implementation of BIA in clinical practice may identify patients with sarcopenia at risk for poor survival.

Radiation-Induced Hypothyroidism After Radical Intensity Modulated Radiation Therapy for Oropharyngeal Carcinoma.

PURPOSE: To evaluate 2 published normal tissue complication probability models for radiation-induced hypothyroidism (RHT) on a large cohort of oropharyngeal carcinoma (OPC) patients who were treated with intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: OPC patients treated with retrievable IMRT Digital Imaging and Communications in Medicine (DICOMs) data and available baseline and follow-up thyroid function tests were included. Mean dose (Dmean) to the thyroid gland (TG) and its volume were calculated. The study outcome was clinical HT at least 6 months after radiation therapy, which was defined as grade ≥2 HT per Common Terminology Criteria for Adverse Events grading system (symptomatic hypothyroidism that required thyroid replacement therapy). Regression analyses and Wilcoxon rank-sum test were used. Receiver operating characteristic curves and area under the curve for the fitted model were calculated. RESULTS: In the study, 360 OPC patients were included. The median age was 58 years. Most tumors (51%) originated from the base of tongue. IMRT-split field was used in 95%, and median radiation therapy dose was 69.96 Gy. In the study, 233 patients (65%) developed clinical RHT that required thyroid replacement therapy. On multivariate analysis higher Dmean and smaller TG volume maintained the statistically significant association with the risk of clinical RHT (P < .0001). Dmean was significantly higher in patients with clinical RHT versus those without (50 vs 42 Gy, P < .0001). Patients with RHT had smaller TG volume compared with those without (11.8 compared with 12.8 mL, P < .0001). AUC of 0.72 and 0.66 were identified for fitted model versus for the applied Boomsma et al and Cella et al models, respectively. CONCLUSIONS: Volume and Dmean of the TG are important predictors of clinical RHT and shall be integrated into normal tissue complication probability models for RHT. Dmean and thyroid volume should be considered during the IMRT plan optimization in OPC patients.

Machine Learning Applications in Head and Neck Radiation Oncology: Lessons From Open-Source Radiomics Challenges.

Radiomics leverages existing image datasets to provide non-visible data extraction via image post-processing, with the aim of identifying prognostic, and predictive imaging features at a sub-region of interest level. However, the application of radiomics is hampered by several challenges such as lack of image acquisition/analysis method standardization, impeding generalizability. As of yet, radiomics remains intriguing, but not clinically validated. We aimed to test the feasibility of a non-custom-constructed platform for disseminating existing large, standardized databases across institutions for promoting radiomics studies. Hence, University of Texas MD Anderson Cancer Center organized two public radiomics challenges in head and neck radiation oncology domain. This was done in conjunction with MICCAI 2016 satellite symposium using Kaggle-in-Class, a machine-learning and predictive analytics platform. We drew on clinical data matched to radiomics data derived from diagnostic contrast-enhanced computed tomography (CECT) images in a dataset of 315 patients with oropharyngeal cancer. Contestants were tasked to develop models for (i) classifying patients according to their human papillomavirus status, or (ii) predicting local tumor recurrence, following radiotherapy. Data were split into training, and test sets. Seventeen teams from various professional domains participated in one or both of the challenges. This review paper was based on the contestants' feedback; provided by 8 contestants only (47%). Six contestants (75%) incorporated extracted radiomics features into their predictive model building, either alone (n = 5; 62.5%), as was the case with the winner of the "HPV" challenge, or in conjunction with matched clinical attributes (n = 2; 25%). Only 23% of contestants, notably, including the winner of the "local recurrence" challenge, built their model relying solely on clinical data. In addition to the value of the integration of machine learning into clinical decision-making, our experience sheds light on challenges in sharing and directing existing datasets toward clinical applications of radiomics, including hyper-dimensionality of the clinical/imaging data attributes. Our experience may help guide researchers to create a framework for sharing and reuse of already published data that we believe will ultimately accelerate the pace of clinical applications of radiomics; both in challenge or clinical settings.

Epithelial-Mesenchymal Transition Markers in Breast Cancer and Pathological Responseafter Neoadjuvant Chemotherapy.

The association between pathologic complete response (pCR) following to neoadjuvant chemotherapy (NAC) and the improved survival in breast cancer has been previously reported. The aim of this study was is to explore the expression of several biomarkers described during epithelial-mesenchymal transition (EMT) and the achievement of pCR in different molecular subtypes of breast cancer. We identified archived pathology tissue from patients with breast cancer who received NAC during the year 2014. We performed immunohistochemical analysis of vimentin, nuclear factor κB (NF-κB), epidermal growth factor receptor (EGFR), E-cadherin, estrogen receptor (ER), progesterone receptor, and Her2neu and studied the association between the expression of these markers and pCR. A Fisher exact test for categorical cofactors, an unpaired t test and a nonparametric Wilcoxon test for continuous cofactors were used. The results showed a significant expression of vimentin in triple-negative breast cancer (TNBC; P = .023). An inverse correlation between vimentin and the ER expression (P = .032) was observed. No significant association was noted for vimentin, NF-κB, EGFR, and E-cadherin was associated with pCR. This study suggests that the evaluated EMT related biomarkers are not associated with pCR after NAC chemotherapy in an unselected breast cancer population. Vimentin and NF-κB expressions were associated with TNBC and could be further explored as potential therapeutic targets in this subgroup. A prevalence of vimentin and NF-κB among Hispanic patients with breast cancer warrants further investigation as a possibly contributing to the prevalence of TNBC and adverse prognosis in this population.

Incompletely treated malignancies of the major salivary gland: Toward evidence-based care.

BACKGROUND: Unexpected malignancy is common in major salivary gland tumors due to variability of workup, creating challenging treatment decisions. The purpose of this study was to define treatment-related outcomes for patients with incompletely treated major salivary gland tumors. METHODS: A retrospective cohort study was completed of patients with incompletely treated major salivary gland tumors. Tumor burden at presentation was established and treatment categorized. The Cox Proportional Hazards model was used to determine predictors of survival and failure. RESULTS: Of the 440 included patients, patients with gross residual or metastatic disease had a worse overall survival (OS; P < .001). Presentation status was an independent predictor of OS on multivariate analysis (gross residual disease adjusted hazard ratio [HRadjusted ] 2.55; 95% confidence interval [CI] 1.20-5.30; metastatic disease HRadjusted 9.53; 95% CI 3.04-27.06). CONCLUSION: Failure to achieve gross total resection during initial surgery resulted in worse OS. Adequate preoperative planning is required for initial surgical management to optimize tumor control and survival.

Three-dimensional imaging assessment of anatomic invasion and volumetric considerations for chemo/radiotherapy-based laryngeal preservation in T3 larynx cancer.

OBJECTIVES: To investigate the impact of 3-Diminsional (3D) tumor volume (TV) and extent of involvement of primary tumor on treatment outcomes in a large uniform cohort of T3 laryngeal carcinoma patients treated with nonsurgical laryngeal preservation strategies. MATERIALS AND METHODS: The pretreatment contrast-enhanced computed tomography images of 90 patients with T3 laryngeal carcinoma were reviewed. Primary gross tumor volume (GTVp) was delineated to calculate the 3D TV and define the extent of invasion. Cartilage and soft tissue involvement was coded. The extent of invasion was dichotomized into non/limited invasion versus multiple invasion extension (MIE), and was subsequently correlated with survival outcomes. RESULTS: The median TV was 6.6 cm3. Sixty-five patients had non/limited invasion, and 25 had MIE. Median follow-up for surviving patients was 52 months. The 5-year local control and overall survival rates for the whole cohort were 88% and 68%, respectively. There was no correlation between TV and survival outcomes. However, patients with non/limited invasion had better 5-year local control (LC) than those with MIE (95% vs 72%, p = .009) but did not have a significantly higher rate of overall survival (OS) (74% vs 67%, p = .327). In multivariate correlates of LC, MIE maintained statistical significance whereas baseline airway status showed a statistically significance trend with poor LC (p = .0087 and 0.06, respectively). Baseline good performance status was an independent predictor of improved OS (p = .03) in multivariate analysis. CONCLUSION: The extent of primary tumor invasion is an independent prognostic factor of LC of the disease after definitive radiotherapy in T3 larynx cancer.

Correction to: Long-term patient reported outcomes following radiation therapy for oropharyngeal cancer: cross-sectional assessment of a prospective symptom survey in patients ≥65 years old.

In the original publication [1] the name of author Jeremy M. Aymard was spelled wrong. The original article was updated to rectify this error.

Long-term patient reported outcomes following radiation therapy for oropharyngeal cancer: cross-sectional assessment of a prospective symptom survey in patients ≥65 years old.

BACKGROUND: Given the potential for older patients to experience exaggerated toxicity and symptoms, this study was performed to characterize patient reported outcomes in older patients following definitive radiation therapy (RT) for oropharyngeal cancer (OPC). METHODS: Cancer-free head and neck cancer survivors (>6 months since treatment completion) were eligible for participation in a questionnaire-based study. Participants completed the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN). Those patients ≥65 years old at treatment for OPC with definitive RT were included. Individual and overall symptom severity and clinical variables were analyzed. RESULTS: Of the 79 participants analyzed, 82% were male, 95% white, 41% T3/4 disease, 39% RT alone, 27% induction chemotherapy, 52% concurrent, and 18% both, and 96% IMRT. Median age at RT was 71 yrs. (range: 65-85); median time from RT to MDASI-HN was 46 mos. (2/3 > 24 mos.). The top 5 MDASI-HN items rated most severe in terms of mean (±SD) ratings (0-10 scale) were dry mouth (3.48 ± 2.95), taste (2.81 ± 3.29), swallowing (2.59 ± 2.96), mucus in mouth/throat (2.04 ± 2.68), and choking (1.30 ± 2.38) reported at moderate-severe levels (≥5) by 35, 29, 29, 18, and 13%, respectively. Thirty-nine % reported none (0) or no more than mild (1-4) symptoms across all 22 MDASI-HN symptoms items, and 38% had at least one item rated as severe (≥7). Hierarchical cluster analysis resulted in 3 patient groups: 1) ~65% with ranging from none to moderate symptom burden, 2) ~35% with moderate-severe ratings for a subset of classically RT-related symptoms (e.g. dry mouth, mucus, swallowing) and 3) 2 pts. with severe ratings of most items. CONCLUSIONS: The overall long-term symptom burden seen in this older OPC cohort treated with modern standard therapy was largely favorable, yet a higher symptom group (~35%) with a distinct pattern of mostly local and classically RT-related symptoms was identified.

Patterns-of-failure guided biological target volume definition for head and neck cancer patients: FDG-PET and dosimetric analysis of dose escalation candidate subregions.

BACKGROUND: To identify the radio-resistant subvolumes in pretreatment FDG-PET by mapping the spatial location of the origin of tumor recurrence after IMRT for head-and-neck squamous cell cancer to the pretreatment FDG-PET/CT. METHODS: Patients with local/regional recurrence after IMRT with available FDG-PET/CT and post-failure CT were included. For each patient, both pre-therapy PET/CT and recurrence CT were co-registered with the planning CT (pCT). A 4-mm radius was added to the centroid of mapped recurrence growth target volumes (rGTV's) to create recurrence nidus-volumes (NVs). The overlap between boost-tumor-volumes (BTV) representing different SUV thresholds/margins combinations and NVs was measured. RESULTS: Forty-seven patients were eligible. Forty-two (89.4%) had type A central high dose failure. Twenty-six (48%) of type A rGTVs were at the primary site and 28 (52%) were at the nodal site. The mean dose of type A rGTVs was 71Gy. BTV consisting of 50% of the maximum SUV plus 10mm margin was the best subvolume for dose boosting due to high coverage of primary site NVs (92.3%), low average relative volume to CTV1 (41%), and least average percent voxels outside CTV1 (19%). CONCLUSIONS: The majority of loco-regional recurrences originate in the regions of central-high-dose. When correlated with pretreatment FDG-PET, the majority of recurrences originated in an area that would be covered by additional 10mm margin on the volume of 50% of the maximum FDG uptake.

MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells.

Radiotherapy is commonly used to treat a variety of solid tumors but improvements in the therapeutic ratio are sorely needed. The aim of this study was to assess the Chk1 kinase inhibitor, MK-8776, for its ability to radiosensitize human tumor cells. Cells derived from NSCLC and HNSCC cancers were tested for radiosensitization by MK-8776. The ability of MK-8776 to abrogate the radiation-induced G2 block was determined using flow cytometry. Effects on repair of radiation-induced DNA double strand breaks (DSBs) were determined on the basis of rad51, γ-H2AX and 53BP1 foci. Clonogenic survival analyses indicated that MK-8776 radiosensitized p53-defective tumor cells but not lines with wild-type p53. Abrogation of the G2 block was evident in both p53-defective cells and p53 wild-type lines indicating no correlation with radiosensitization. However, only p53-defective cells entered mitosis harboring unrepaired DSBs. MK-8776 appeared to inhibit repair of radiation-induced DSBs at early times after irradiation. A comparison of MK-8776 to the wee1 inhibitor, MK-1775, suggested both similarities and differences in their activities. In conclusion, MK-8776 radiosensitizes tumor cells by mechanisms that include abrogation of the G2 block and inhibition of DSB repair. Our findings support the clinical evaluation of MK-8776 in combination with radiation.