6007 Background: We previously reported that surgery to the primary site with hypoxia-directed de-escalated radiation to the neck for human papillomavirus associated oropharyngeal carcinoma (HPV+ OPC) can lead to excellent oncologic outcomes. We now report the results of a successor multi-center phase II trial of hypoxia-directed de-escalated chemoradiotherapy without surgery for HPV+OPC. Methods: HPV+ OPC (T0-2/N1-N2c/AJCC 7th) patients were eligible for enrollment. Tumors without evidence of hypoxia on 18F-FMISO (fluoromisonidazole) PET received de-escalated chemoradiation to 30Gy while those with hypoxia received chemoradiation to 70Gy. The primary objective was achieving a 2-year locoregional control (LRC) of 95% (failure was locoregional recurrence where surgical salvage was unfeasible) with a 7% non-inferiority margin. We enrolled a total of 158 subjects upfront to account for a 5% loss due to death (of reasons other than cancer) or follow-up. Secondary objectives were local failure (LF), regional failure (RF), distant metastasis (DM), overall survival (OS), toxicities, and patient-reported MD Anderson Dysphagia Inventory (MDADI) scores. LF, RF, and DM were estimated using the Cumulative Incidence Function, and OS was estimated using the Kaplan-Meier method. Results were reported up to 1/31/2024. Results: From 4/28/20-4/17/23, 158 HPV+ OPC patients were enrolled where150 patients were eligible for analyses. Patient characteristics: Tonsil (43%); Base of Tongue (47%); unknown primary (10%); >/=10 pack years (22%); T0 (9%), T1 (44%), T2 (47%); N1 (14%), N2a (11%), N2b (59%), N2c (16%). 111 (74%) received 30Gy; 95% cisplatin. With 24 months (8-43) of median follow-up, the 2-year LF, RF, DM rates were 4.2%, 6.9%, 2.0%, respectively. The 2-year overall survival probability was 99%. Only 2 patients could not undergo salvage surgery [one 30Gy (second recurrence); one 70Gy (M1)], both received systemic therapy with durable response. Acute grade 3-4 toxicities were 32% (67% neutropenia). Mean MDADI scores: 92.93 (baseline); 68.24 (3 weeks), 91.45 (4 months) after chemoradiation. Conclusions: These early data indicate that major de-escalation to 30Gy based on hypoxia status achieved significant toxicity reduction without compromise in survival for HPV+ OPC treated with chemoradiation without surgery. Clinical trial information: NCT03323463 .

Objectives:Auto-segmentation promises greater speed and lower inter-reader variability than manual segmentations in radiation oncology clinical practice. This study aims to implement and evaluate the accuracy of the auto-segmentation algorithm, "Masked Image modeling using the vision Transformers (SMIT)," for neck nodal metastases on longitudinal T2-weighted (T2w) MR images in oropharyngeal squamous cell carcinoma (OPSCC) patients.Methods:This prospective clinical trial study included 123 human papillomaviruses (HPV-positive [+]) related OSPCC patients who received concurrent chemoradiotherapy. T2w MR images were acquired on 3 T at pre-treatment (Tx), week 0, and intra-Tx weeks (1-3). Manual delineations of metastatic neck nodes from 123 OPSCC patients were used for the SMIT auto-segmentation, and total tumor volumes were calculated. Standard statistical analyses compared contour volumes from SMIT vs manual segmentation (Wilcoxon signed-rank test [WSRT]), and Spearman's rank correlation coefficients (ρ) were computed. Segmentation accuracy was evaluated on the test data set using the dice similarity coefficient (DSC) metric value. P-values <0.05 were considered significant.Results:No significant difference in manual and SMIT delineated tumor volume at pre-Tx (8.68 ± 7.15 vs 8.38 ± 7.01 cm3, P = 0.26 [WSRT]), and the Bland-Altman method established the limits of agreement as -1.71 to 2.31 cm3, with a mean difference of 0.30 cm3. SMIT model and manually delineated tumor volume estimates were highly correlated (ρ = 0.84-0.96, P < 0.001). The mean DSC metric values were 0.86, 0.85, 0.77, and 0.79 at the pre-Tx and intra-Tx weeks (1-3), respectively.Conclusions:The SMIT algorithm provides sufficient segmentation accuracy for oncological applications in HPV+ OPSCC.Advances in knowledge:First evaluation of auto-segmentation with SMIT using longitudinal T2w MRI in HPV+ OPSCC.

Background and purpose Volume regression during radiotherapy can indicate patient-specific treatment response. We aimed to identify pre-treatment multimodality imaging (MMI) metrics from positron emission tomography (PET), magnetic resonance imaging (MRI), and computed tomography (CT) that predict rapid tumor regression during radiotherapy in human papilloma virus (HPV) associated oropharyngeal carcinoma. Materials and methods Pre-treatment FDG PET-CT, diffusion-weighted MRI (DW-MRI), and intra-treatment (at 1, 2, and 3 weeks) MRI were acquired in 72 patients undergoing chemoradiation therapy for HPV+ oropharyngeal carcinoma. Nodal gross tumor volumes were delineated on longitudinal images to measure intra-treatment volume changes. Pre-treatment PET standardized uptake value (SUV), CT Hounsfield Unit (HU), and non-gaussian intravoxel incoherent motion DW-MRI metrics were computed and correlated with volume changes. Intercorrelations between MMI metrics were also assessed using network analysis. Validation was carried out on a separate cohort (N = 64) for FDG PET-CT. Results Significant correlations with volume loss were observed for baseline FDG SUVmean (Spearman ρ = 0.46, p < 0.001), CT HUmean (ρ = 0.38, p = 0.001), and DW-MRI diffusion coefficient, Dmean (ρ = -0.39, p < 0.001). Network analysis revealed 41 intercorrelations between MMI and volume loss metrics, but SUVmean remained a statistically significant predictor of volume loss in multivariate linear regression (p = 0.01). Significant correlations were also observed for SUVmean in the validation cohort in both primary (ρ = 0.30, p = 0.02) and nodal (ρ = 0.31, p = 0.02) tumors. Conclusions Multiple pre-treatment imaging metrics were correlated with rapid nodal gross tumor volume loss during radiotherapy. FDG-PET SUV in particular exhibited significant correlations with volume regression across the two cohorts and in multivariate analysis.

BACKGROUND:We report the outcomes of cisplatin-ineligible HNSCC patients treated with definitive chemoradiation and concurrent carboplatin and paclitaxel.MATERIALS AND METHODS:We included consecutive HNSCC patients treated from 2013 to 2021 that received definitive chemoradiation with carboplatin and paclitaxel. Locoregional recurrences (LRR) and distant metastases (DM) were estimated using cumulative incidence functions. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods.RESULTS:Sixty-five patients were identified with median age of 71 years (range 44-85). Median radiation dose was 70 Gy and the median doses of carboplatin and paclitaxel were AUC 1 and 40 mg/m2 , respectively. At a median follow-up of 29 (range 5-91) months, the 2-year rates of LRR, DM, PFS, and OS were 8.8%, 9.4%, 72.2%, and 88.7%, respectively. In total, there were 5 LRR, 7 DM, and 12 deaths.CONCLUSIONS:Chemoradiation with carboplatin and paclitaxel is an excellent option for cisplatin-ineligible HNSCC patients.

Supplementary Table S1. MSK Memorial Hospital IMPACT genomic sequencing data for the JMN human mesothelioma cell line. Supplementary Table S2. Sh RNA used. Supplementary Table S3. List of antibodies used. Supplementary Table S4. Top 5 negative regulatory and top 5 positive regulatory kinase genes that were hits from the screen for regulating surface HLA-A expression. Supplementary Figure S1. Knockdown of HLA-A causes resistance to antibody dependent cellular cytotoxicity by the ESK-M mAb. Supplementary Figure S2. Coordinated regulation of total surface HLA-A, B, and C with knockdown of either MAP2K1 of EGFR. Supplementary Figure S3. Validation of MAP2K1, EGFR, and RET as negative kinase regulators in mesothelioma cell lines. Supplementary Figure S4. DDR2 and MINK1 acts as positive regulators of surface HLA-A. Supplementary Figure S5. Treatment with IFN gamma and/or kinase inhibitors, afatinib or trametinib, on cells with mutant EFGR (H1975) or mutant BRAF (SK-Mel5 and UACC257). Supplementary Figure S6. Viability of JMN after treatment with MEKi trametinib and EGFRi Afatinib. Supplementary Figure S7. Titration of trametinib to determine optimal inhibition of MEK using pERK as a marker of inhibition. Supplementary Figure S8. JMN was treated with 50 nM trametinib and lysate was analyzed as in Figure 4C at different time points.

Purpose: Reports of proton beam therapy (PBT) utilization for cutaneous melanoma of the head and neck (HN) region is virtually non-existent. This study reports on the efficacy and acute toxicities of PBT for primary HN cutaneous melanoma. Materials and Methods: We queried the prospectively collected, multi- institutional Proton Collaborative Group registry for all consecutive patients with HN cutaneous melanoma receiving PBT from May 2010 to December 2019. Kaplan-Meier methods were used to estimate overall survival (OS), progression free survival (PFS), and local regional recurrence free survival (LRFS). Toxicity was reported per CTCAE version 4.0. Results: A total of 8 patients were identified with a median age of 69 (range, 37-88). All patients (100%) underwent surgery followed with postoperative PBT. There were 3 patients (37.5%) with T3 or T4 disease and 4 (50%) with N2 or N3 disease. The median radiation dose was 46 GyRBE (range, 27-70) and median dose per fraction was 2.4 GyRBE ( range, 2.0-6.0) with the most common dose fractionation being 44 or 48 GyRBE in 20 fractions (n = 4). At a median follow- up of 40.1 months (range, 1.6-62.4) the 1 and 3 year OS rates were 85.7% and 35.7%, respectively. The median PFS was 25.40 months (95% CI, 2.53-58.70) while PFS at 1 year and 3 years was 85.7% and 35.7%, respectively. LRFS was 100% at 1 year and 85.7% at 3 years. Five of the 8 patients developed distant metastases, of which 3 received immunotherapy. Acute G2thornand G3thorntoxicities occurred in 5 of 8 patients and 2 of 8 patients, respectively. G3 toxicities included radiation dermatitis ( n = 1) and immunotherapy-related rash (n = 1). No G4+ toxicities were reported. Conclusion: Single modality PBT for HN melanomas in the definitive setting provides effective and durable local control rates with tolerable acute toxicity. Distant failure remains the primary pattern of failure.

Ann Palliat Med 2020 | http://dx.doi.org/10.21037/apm-20-990 Patients with metastatic epidural spinal cord compression (MESCC) often present with loss of neurologic function, pain, and reduction in quality of life, all of which can be improved with palliative radiation therapy (1). A more prolonged treatment course for MESCC, typically delivered as 30 Gy in 10 fractions, has the advantage of delivering a higher biologically equivalent dose (BED), which could allow for more durable local control in a disease state where local control directly impacts spinal cord compromise and paralysis (2). However, many patients with MESCC have limited prognoses, and even one week of treatment may impose significant burdens for patients and their caregivers. As a result, shorter courses of palliative radiation therapy in this population can be desirable. Severa l prev ious t r i a l s spec i f i c to s imple , or uncomplicated bone metastases have demonstrated similar efficacy between single-fraction radiotherapy (SFRT) and multi-fraction radiotherapy (MFRT) for symptom relief (3-5). Radiation therapy can provide rapid responses for patients with uncomplicated bone metastases (6), and metaanalyses inclusive of over two dozen randomized trials from McMaster University, the Cochrane review, University of Toronto, and other international investigators have all concluded there is no significant difference in treatment response between SFRT and MFRT (7-11). Despite increasing data from phase III randomized clinical trials suggesting non-inferiority of SFRT with similar efficacy in terms of pain control and prevention of future fractures or spinal cord compression, as well as ASTRO publishing guidelines (12) advocating for the utilization of SFRT, the usage rates of SFRT remain low. This indicates a general hesitancy for clinicians to adopt SFRT. In fact, an international survey of radiation oncologists published in 2015 inquiring about the use of fractionation regimens for metastatic spinal cord compression found that SFRT was rarely employed at a rate of 8% to 18% (13). While existing data to date demonstrate no difference in survival or motor outcomes with five fraction versus ten or more fraction schedules, 73% of respondents in the United States treat to 30 Gy in 10 fractions in these patients. In Canada and Australia/New Zealand, 20 Gy in 5 fractions is the most commonly used fractionation regimen. Given this current landscape of treatment patterns for simple bone metastases, the utilization of SFRT for MESCC will certainly remain limited unless more robust data from well conducted phase III clinical trials provide further evidence and reassurance. The previously mentioned bone metastases trials that compared palliative radiotherapy fractionation schedules specifically omitted patients with complex bone metastases and spinal cord compression. The standard of care for patients with MESCC involves Editorial Commentary

Introduction: To date, no studies examining the effect of treatment interruptions (TI) with proton beam therapy (PBT) have been published. The goal of our study was to determine the predictors of TI amongst patients with prostate cancer (PCa) treated with PBT and to determine whether TI are associated with biochemical failure (BF). We hypothesized that any correlation between TI and biochemical control would be more pronounced in high risk groups. Methods: Data for 4278 patients with PCa was obtained from the prospectively collected Proton Collaborative Group (PCG) data registry. Univariate and multivariate logistic regression analysis (MVA) was used to model possible predictors of BF. A subset analysis was performed for high risk patients treated with ADT and PBT. Finally, propensity score (PS) analysis was performed to account for any indication bias caused by lack of randomization. Results: Total treatment duration (OR, 1.05 [1.04–1.06]; p < 0.001) increased the likelihood of TI on MVA. TI did not have a statistically significant correlation with BF (OR, 1.44 [0.86–2.39]; p = 0.162) amongst PS matched patients. However, on subset analyses of high risk group patients with PS matching, there was a trend towards worse BF in patients with TI (OR 3.85; 95%CI (0.96–15.44); p = 0.057). Conclusion: In the first analysis of its kind, the results suggest that TI in high risk PCa patients treated with PBT and ADT have worse BF rates. Interventions such as increased patient education, proper maintenance of proton facilities, and decreasing total treatment duration with alternative fractionation schedules may help avoid the unintended negative effects on tumor control due to TI. However, future analyses on a larger patient population is needed.

Abstract Purpose/Objectives Data are conflicting on the effects of time interval from neoadjuvant chemoradiation (NCRT) to surgery for locally advanced non‐small‐cell lung cancer (LA‐NSCLC). This study investigated the impact of surgical timing after NCRT and radiation dose on postoperative mortality and overall survival (OS). Materials and Methods Using the National Cancer Database, we identified 3489 LA‐NSCLC patients treated with NCRT and surgery. Multivariate Cox proportional hazards analysis (MVA) was used to examine the effects of surgery >7 weeks from NCRT completion on OS. Propensity score (PS)‐matched survival analysis for surgery ≤7 and >7 weeks was performed. Postoperative mortality was assessed. Results Median OS for surgery ≤7 weeks and >7 weeks after NCRT were 56.9 versus 45.6 months (hazard ratio, HR 1.18 [1.07–1.30]; p < 0.001). Surgery >7 weeks correlated with decreased OS on MVA (HR 1.15 [1.04–1.27]; p = 0.009) and PS matching (HR 1.16 [1.049–1.29]; p = 0.004). Time as a continuous variable correlated with OS on MVA (HR 1.003 [1.001–1.006]; p = 0.0056) and PS matching (HR 1.004 [1.001–1.006]; p = 0.004). Among 2902 lobectomy patients, the mortality rate for surgery ≤66 days was 5.2% versus 8.1% for >66 days (MVA HR 1.59 [1.02–2.49]; p = 0.04). Higher neoadjuvant radiotherapy dose correlated with surgery >7 weeks and lobectomy >66 days on MVA. Conclusions Increased interval >7 weeks from NCRT to surgery for LA‐NSCLC is correlated with worse OS and lobectomy ≤66 days correlated with improved OS. Surgery ≤7weeks may improve tumor control, whereas higher mortality for surgery >66 days may relate to late NCRT manifestations. Neoadjuvant doses of 44–50.4 Gy may minimize risks of radiation‐induced lung injury and surgical complications and facilitate surgery within the optimal 7‐week interval.

Background Neoadjuvant chemotherapy (NAC) trials in endemic regions of nasopharyngeal carcinoma (NPC) found improved survival, but studies are lacking in nonendemic regions. We assessed whether adding NAC to concurrent chemoradiation (CRT) improves overall survival (OS), especially in high-risk nonendemic patients. Methods Definitively treated NPC patients (n = 5424) from the National Cancer Database were analyzed for predictors of NAC and NAC effects on OS with multivariate Cox proportional hazards analysis (multivariate analysis [MVA]). Propensity score matched (1:2) survival analysis of NAC (n = 968) and CRT alone (n = 1914) was also performed. Effects on OS were stratified by risk group. Results On MVA, NAC-improved OS among the total cohort (hazard ratio [HR] 0.89, P = .049), particularly among stratified keratinizing histology (HR 0.82, P = .015) and N3 disease (HR 0.73, P = .046). Among propensity matched patients, NAC improved OS in patients with N3 disease (n = 336; HR 0.71, P = .046). Conclusions NAC may improve OS among nonendemic NPC patients at higher risk of distant micrometastases, particularly N3 disease and those with unfavorable histology.

Chemotherapy followed by prophylactic cranial irradiation (PCI) is associated with increased survival in patients with small cell lung cancer but is associated with fatigue and cognitive impairment. This retrospective study evaluated regional differences in 18F-FDG uptake by the brain before and after PCI. The null hypothesis was that direct toxic effects on the brain from PCI and chemotherapy are symmetric; thus, asymmetric deviations may reflect functional changes due to therapy. Methods: Electronic medical records from 2013 to 2016 were reviewed for patients with small cell lung cancer, MRI of brain negative for metastasis, and 18F-FDG PET/CT scans before and after PCI. As the standard of care, patients received first-line chemotherapy or chemoradiation to the thorax followed by PCI. The 18F-FDG PET/CT scans nearest the PCI were selected. Sixteen patients met these initial criteria. Commercially available PET software was used to register and subtract the PET scans before and after PCI to obtain difference maps. Occipital and cerebellar regions were excluded from the final statistical analysis given the known high variability and misregistration. The χ2 test was used to analyze the data. Results: Two patients had 18F-FDG uptake differences only in the occipital and cerebellar regions. The software registration failed on 1 patient’s scans. Therefore, 13 patients were included in the final analysis. Nine of 13 patients demonstrated significant unilateral changes in only 1 region of the brain, and 3 of 13 showed significant changes unilaterally in 2 regions. The χ2 test revealed a significant unilateral regional difference on a patient level (χ2 = 6.24, P = 0.025). The most commonly affected brain region was the frontal lobe. Conclusion: Significantly more patients had unilateral than bilateral regional differences (both increases and decreases) in 18F-FDG uptake in the brain before and after PCI. This finding suggests that differences in unilateral distribution are related to functional changes, since direct toxicity alone from PCI and chemotherapy would be symmetric. The frontal region was the most commonly affected, suggesting a potential contributing etiology for cognitive impairment and decreased executive function after therapy.

Abstract The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8+ T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference–based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output–dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. Cancer Immunol Res; 4(11); 936–47. ©2016 AACR.

BACKGROUND:We report treatment outcomes for a large non-endemic cohort of patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) and chemotherapy. METHODS:We identified 177 consecutive patients with newly diagnosed, non-metastatic nasopharyngeal cancer treated with definitive IMRT between 1998 and 2011. Endpoints included local, regional, distant control, and overall survival. RESULTS:Median follow-up was 52months. The 3-/5-year actuarial rates of local control, regional control, distant control, and overall survival were 92%/83%, 93%/91%, 86%/83%, and 87%/74%, respectively. The median time to local recurrence was 30months; the annual hazard of local recurrence did not diminish until the 6th year of follow-up. CONCLUSIONS:Overall, we observed excellent rates of disease control and survival consistent with initially reported results from our institution. Attaining locoregional control in patients with extensive primary tumors remains a significant clinical challenge. With mature follow-up we observed that more than half of observed local relapses occurred after 2years, a pattern distinct from that of carcinomas arising from other head and neck sites. These findings raise the possibility that patients with NPC may benefit from close follow-up during post-treatment years 3-5.

Better known as Taxol® (Bristol-Myers Squibb), paclitaxel is the first member of the taxane family to be used in cancer chemotherapy. The taxanes exert their cytotoxic effect by arresting mitosis through microtubule stabilization, resulting in cellular apoptosis. The use of paclitaxel as a chemotherapeutic agent has become a broadly accepted option in the treatment of patients with ovarian, breast and non-small cell lung cancers, malignant brain tumors, and a variety of other solid tumors. However, significant toxicities, such as myelosuppression and peripheral neuropathy, limit the effectiveness of paclitaxel-based treatment regimens. This review addresses the toxicities associated with paclitaxel treatment and describes existing and future strategies of paclitaxel administration directed at limiting these toxicities.