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Purpose:Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti–PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC.Patients and Methods:This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling.Results:Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%–84%) and 75% (51%–88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells.Conclusions:Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.

T cell gating

PFS and OS by AJCC 8

B cell gating

PurposeThe Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) system was the first published radiation therapy (RT)-compatible system to reduce the need for pediatric anesthesia through video-based distraction. We evaluated the feasibility of AVATAR implementation and effects on anesthesia use, quality of life, and anxiety in a multicenter pediatric trial.Methods and materialsPediatric patients 3 to 10 years of age preparing to undergo RT at 10 institutions were prospectively enrolled. Children able to undergo at least 1 fraction of RT using AVATAR without anesthesia were considered successful (S). Patients requiring anesthesia for their entire treatment course were nonsuccessful (NS). The PedsQL3.0 Cancer Module (PedsQL) survey assessed quality of life and was administered to the patient and guardian at RT simulation, midway through RT, and at final treatment. The modified Yale Preoperative Anxiety Scale (mYPAS) assessed anxiety and was performed at the same 3 time points. Success was evaluated using the χ2 test. PedsQL and mYPAS scores were assessed using mixed effects models with time points evaluated as fixed effects and a random intercept on the subject.ResultsEighty-one children were included; median age was 7 years. AVATAR was successful at all 10 institutions and with photon and proton RT. There were 63 (78%) S patients; anesthesia was avoided for a median of 20 fractions per patient. Success differed by age (P=.04) and private versus public insurance (P < .001). Both patient (P=.008) and parent (P=.006) PedsQL scores significantly improved over the course of RT for patients aged 5 to 7. Anxiety in the treatment room decreased for both S and NS patients over RT course (P < .001), by age (P < .001), and by S versus NS patients (P < .001).ConclusionsIn this 10-center prospective trial, anesthesia avoidance with AVATAR was 78% in children aged 3 to 10 years, higher than among age-matched historical controls (49%; P < .001). AVATAR implementation is feasible across multiple institutions and should be further studied and made available to patients who may benefit from video-based distraction.

Background Adavosertib (AZD1775) is an inhibitor of the Wee1 kinase. The authors conducted a phase 1b trial to evaluate the safety of adavosertib in combination with definitive chemoradiotherapy for patients with newly diagnosed, intermediate-risk/high-risk, locally advanced head and neck squamous cell carcinoma (HNSCC). Methods Twelve patients with intermediate-risk/high-risk HNSCC were enrolled, including those with p16-negative tumors of the oropharynx, p16-positive tumors of the oropharynx with ≥10 tobacco pack-years, and tumors of the larynx/hypopharynx regardless of p16 status. All patients were treated with an 8-week course of concurrent intensity-modulated radiotherapy at 70 grays (Gy) (2 Gy daily in weeks 1-7), cisplatin 30 mg/m2 weekly (in weeks 1-7), and adavosertib (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8). The primary objective was to determine the maximum tolerated dose and the recommended phase 2 dose of adavosertib given concurrently with radiation and cisplatin. Secondary objectives were to determine the 12-week objective response rate and progression-free and overall survival. Results Three patients (25%) experienced a dose-limiting toxicity, including febrile neutropenia (n = 2) and grade 4 thromboembolism (n = 1). Two dose-limiting toxicities occurred with adavosertib at 150 mg. The median follow-up was 14.7 months. The 12-week posttreatment objective response rate determined by positron emission tomography/computed tomography was 100%. The 1-year progression-free and overall survival rates were both 90%. The maximum tolerated dose of adavosertib was 100 mg. Conclusions Adavosertib 100 mg (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8), in combination with 70 Gy of intensity-modulated radiotherapy and cisplatin 30 mg/m2 , is the recommended phase 2 dose for patients with HNSCC.

Background Only high‐risk tumors with extranodal extension (ENE) and/or positive surgical margins (PSM) benefit from adjuvant therapy (AT) with concurrent chemoradiation (CRT) compared to radiation therapy (RT) in locally advanced head and neck squamous cell carcinoma (HNSCC). Optimal treatment for intermediate‐risk tumors remains controversial. We categorized patients based on their surgical pathologic risk factors and described AT treatment patterns and associated survival outcomes. Methods Patients were identified from CHANCE, a population‐based study, and risk was classified based on surgical pathology review. High‐risk patients (n = 204) required ENE and/or PSM. Intermediate‐risk (n = 186) patients had pathological T3/T4 disease, perineural invasion (PNI), lymphovascular invasion (LVI), or positive lymph nodes without ENE. Low‐risk patients (n = 226) had none of these features. Results We identified 616 HPV‐negative HNSCC patients who received primary surgical resection with neck dissection. High‐risk patients receiving AT had favorable OS (HR 0.50, p = 0.013) which was significantly improved with the addition of chemotherapy compared to RT alone (HR 0.47, p = 0.021). When stratified by node status, the survival benefit of AT in high‐risk patients persisted only among those who were node‐positive (HR: 0.17, p, The addition of chemotherapy to adjuvant radiotherapy could improve survival. This is observed only among high‐risk patients. When stratified by nodal status, the benefit exists only in node‐positive patients. In intermediate‐risk patients chemotherapy addition decreases survival. Risk categorization is important for treatment selection and survival outcomes.

Background Whole brain radiation (WBRT) may lead to acute xerostomia and dry eye from incidental parotid and lacrimal exposure, respectively. We performed a prospective observational study to assess the incidence/severity of this toxicity. We herein perform a secondary analysis relating parotid and lacrimal dosimetric parameters to normal tissue complication probability (NTCP) rates and associated models. Methods Patients received WBRT to 25–40 Gy in 10–20 fractions using 3D-conformal radiation therapy without prospective delineation of the parotids or lacrimals. Patients completed questionnaires at baseline and 1 month post-WBRT. Xerostomia was assessed using the University of Michigan xerostomia score (scored 0–100, toxicity defined as ≥ 20 pt increase) and xerostomia bother score (scored from 0 to 3, toxicity defined as ≥ 2 pt increase). Dry eye was assessed using the Subjective Evaluation of Symptom of Dryness (SESoD, scored from 0 to 4, toxicity defined as ≥ 2 pt increase). The clinical data were fitted by the Lyman–Kutcher–Burman (LKB) and Relative Seriality (RS) NTCP models. Results Of 55 evaluable patients, 19 (35%) had ≥ 20 point increase in xerostomia score, 11 (20%) had ≥ 2 point increase in xerostomia bother score, and 13 (24%) had ≥ 2 point increase in SESoD score. For xerostomia, parotid V10Gy–V20Gy correlated best with toxicity, with AUC 0.68 for xerostomia score and 0.69–0.71 for bother score. The values for the D50, m and n parameters of the LKB model were 22.3 Gy, 0.84 and 1.0 for xerostomia score and 28.4 Gy, 0.55 and 1.0 for bother score, respectively. The corresponding values for the D50, γ and s parameters of the RS model were 23.5 Gy, 0.28 and 0.0001 for xerostomia score and 32.0 Gy, 0.45 and 0.0001 for bother score, respectively. For dry eye, lacrimal V10Gy–V15Gy were found to correlate best with toxicity, with AUC values from 0.67 to 0.68. The parameter values of the LKB model were 53.5 Gy, 0.74 and 1.0, whereas of the RS model were 54.0 Gy, 0.37 and 0.0001, respectively. Conclusions Xerostomia was most associated with parotid V10Gy–V20Gy, and dry eye with lacrimal V10Gy–V15Gy. NTCP models were successfully created for both toxicities and may help clinicians refine dosimetric goals and assess levels of risk in patients receiving palliative WBRT.

We analyzed 25 patients receiving whole brain radiation (WBRT) for secondary CNS lymphoma (SCNSL), grouped by consolidative intent (after complete/partial response, n = 13) vs. palliative intent (i...

Purpose: Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti–PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC. Patients and Methods: This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling. Results: Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%–84%) and 75% (51%–88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells. Conclusions: Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.

PURPOSE Plasma circulating tumor human papillomavirus DNA (ctHPVDNA) is a sensitive and specific biomarker of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). We investigated whether longitudinal monitoring of ctHPVDNA during post-treatment surveillance could accurately detect clinical disease recurrence. METHODS AND MATERIALS A prospective biomarker clinical trial was conducted among patients with nonmetastatic HPV-associated (p16-positive) OPSCC. All patients were treated with curative-intent chemoradiotherapy (CRT). Patients underwent a 3-month post-CRT positron emission tomography/computed tomography scan and were thereafter clinically evaluated every 2-4 months (years 1-2), then every 6 months (years 3-5). Chest imaging was performed every 6 months. Blood specimens were collected every 6-9 months for analysis of plasma ctHPVDNA using a multianalyte digital polymerase chain reaction assay. The primary endpoint was to estimate the negative predictive value (NPV) and positive predictive value (PPV) of ctHPVDNA surveillance. RESULTS One hundred fifteen patients were enrolled, and 1,006 blood samples were analyzed. After a median follow-up time of 23 months (range, 6.1-54.7 months), 15 patients (13%) developed disease recurrence. Eighty-seven patients had undetectable ctHPVDNA at all post-treatment time points, and none developed recurrence (NPV, 100%; 95% CI, 96% to 100%). Twenty-eight patients developed a positive ctHPVDNA during post-treatment surveillance, 15 of whom were diagnosed with biopsy-proven recurrence. Sixteen patients had 2 consecutively positive ctHPVDNA blood tests, 15 of whom developed biopsy-proven recurrence. Two consecutively positive ctHPVDNA blood tests had a PPV of 94% (95% CI, 70% to 99%). Median lead time between ctHPVDNA positivity and biopsy-proven recurrence was 3.9 months (range, 0.37-12.9 months). CONCLUSION Detection of ctHPVDNA in two consecutive plasma samples during post-treatment surveillance has high PPV and NPV for identifying disease recurrence in patients with HPV-associated oropharyngeal cancer and may facilitate earlier initiation of salvage therapy.

Auger radiopharmaceutical therapy is a promising strategy for micrometastatic disease given high linear energy transfer and short range in tissues, potentially limiting normal tissue toxicities. We previously demonstrated anti-tumor efficacy of a small-molecule Auger electron emitter targeting the prostate-specific membrane antigen (PSMA), 2-[3-[1-carboxy-5-(4-[125I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid), or 125I-DCIBzL, in a mouse xenograft model. Here, we investigated the therapeutic efficacy, long-term toxicity, and biodistribution of 125I-DCIBzL in a micrometastatic model of prostate cancer (PC). Methods: To test the therapeutic efficacy of 125I-DCIBzL in micrometastatic PC, we used a murine model of human metastatic PC in which PSMA+ PC3-ML cells expressing firefly luciferase were injected intravenously in NSG mice to form micrometastatic deposits. One week later, 0, 0.37, 1.85, 3.7, 18.5, 37, or 111 MBq of 125I-DCIBzL was administered (intravenously). Metastatic tumor burden was assessed using bioluminescence imaging (BLI). Long-term toxicity was evaluated via serial weights and urinalysis of non-tumor-bearing mice over a 12-month period, as well as final necropsy. Results: In the micrometastatic PC model, activities of 18.5 MBq 125I-DCIBzL and above significantly delayed development of detectable metastatic disease by BLI and prolonged survival in mice. Gross metastases were detectable in control mice and those treated with 0.37-3.7 MBq 125I-DCIBzL at a median of 2 weeks post-treatment, versus 4 weeks for those treated with 18.5-111 MBq 125I-DCIBzL (P

Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosurgery (SRS). We have previously risk stratified patients into high, intermediate, and low-risk BMV groups, which correlates with overall survival (OS). We sought to externally validate BMV in a multi-institutional setting.Patients from nine academic centers were treated with upfront SRS; the validation cohort consisted of data from eight institutions not previously used to define BMV. Patients were classified by BMV into low (4 BMV), intermediate (4-13 BMV), and high-risk groups (13 BMV). Time-to-event outcomes were estimated using the Kaplan-Meier method. Cox proportional hazards methods were used to estimate the effect of BMV and salvage modality on OS.Of 2829 patients, 2092 patients were included in the validation dataset. Of these, 921 (44.0%) experienced distant brain failure (DBF). Median OS from initial SRS was 11.2 mo. Median OS for BMV 4, BMV 4-13, and BMV 13 were 12.5 mo, 7.0 mo, and 4.6 mo (p 0.0001). After multivariate regression modeling, melanoma histology (β: 10.10, SE: 1.89, p 0.0001) and number of initial brain metastases (β: 1.52, SE: 0.34, p 0.0001) remained predictive of BMV (adjusted RThis multi-institutional dataset validates BMV as a predictor of OS following initial SRS. BMV is being utilized in upcoming multi-institutional randomized controlled trials as a stratification variable for salvage whole brain radiation versus salvage SRS after DBF.

OBJECTIVE For patients with HER2-positive breast cancer metastatic to brain, HER2-directed systemic therapies are increasingly used with stereotactic radiosurgery (SRS). These include monoclonal antibodies such as trastuzumab (H) and pertuzumab (P), antibody-drug conjugates such as ado-trastuzumab emtansine (T-DM1), and tyrosine kinase inhibitors such as lapatinib. Limited data exist regarding appropriate timing with SRS and outcomes of this treatment regimen. METHODS A single-institution retrospective review collected clinical data on patients with breast cancer metastatic to brain who were treated with SRS from 2009-2020. Statistical analyses were performed using the Kaplan-Meier method and chi-square statistic. RESULTS Of 82 patients with breast cancer metastatic to brain treated with SRS, 33 (40%) were HER2-positive, 18 of whom were hormone receptor-positive. At brain metastasis diagnosis, 15 patients (45%) had >1 intracranial metastasis (range 2-7), and the median brain metastasis maximal dimension was 2.0 cm. Fifteen patients had uncontrolled extracranial disease. After brain metastasis diagnosis, 9 patients (27%) were treated with systemic therapy first (T-DM1+/-HP, lapatinib+HP, chemotherapy+/-HP) followed by SRS at a median of 18.6 months after starting systemic therapy. Seven patients (21%) were treated with SRS first, followed by systemic therapy in 6 of these patients (multi-agent regimens, 4 including T-DM1 or lapatinib). Seventeen (52%) received concurrent systemic therapy and SRS (T-DM1+/-chemotherapy, lapatinib, HP, hormone therapy, chemotherapy). Median follow-up time was 21.1 months. Median overall survival was 24.8 months and not statistically different between treatment groups. Four patients (12%) developed symptomatic radionecrosis; 3 were on T-DM1 concurrent with SRS. CONCLUSION In this small patient sample, we noted favorable survival outcomes for patients with HER2-positive breast cancer metastatic to brain when treated with HER2-targeted therapies together with SRS. The sequence of systemic therapy and SRS does not appear to impact survival outcomes. Concurrent treatment with T-DM1 and SRS may be associated with higher rates of radionecrosis.

Human papillomavirus (HPV) causes the majority of oropharyngeal, cervical, and anal cancers, among others. These HPV-associated cancers cause substantial morbidity and mortality despite ongoing vaccination efforts. Aside from the earliest stage tumors, chemoradiation is used to treat most HPV-associated cancers across disease sites. Response rates are variable, and opportunities to improve oncologic control and reduce toxicity remain. HPV malignancies share multiple commonalities in oncogenesis and tumor biology that may inform personalized methods of screening, diagnosis, treatment and surveillance. In this review we discuss the current literature and identify promising molecular targets, prognostic and predictive clinical factors and biomarkers in HPV-associated oropharyngeal, cervical and anal cancer.

Background NUT carcinoma is an aggressive malignancy characterized by translocations in the NUTM1 gene. There are currently no consensus treatment recommendations for NUT carcinomas. Methods Here, we describe the case of a previously healthy male diagnosed with NUT carcinoma after presenting with sinus pressure, found to have a sinonasal mass and distant metastatic disease in the lungs. While pathologic evaluation and immunohistochemistry were consistent with NUT carcinoma, initial genomic profiling did not demonstrate a NUTM1 translocation. Results Whole transcriptomic RNA sequencing of the tumor revealed a YAP1‐NUTM1 fusion. Based on an in vitro drug sensitivity screen, the patient was treated with gemcitabine and nab‐paclitaxel, achieving a partial response that persisted for 9 months. Conclusions Unbiased transcriptomic sequencing may identify previously uncharacterized NUTM1 fusion partners. Gemcitabine and nab‐paclitaxel is a well‐tolerated combination chemotherapy regimen and could offer a novel treatment approach for NUT carcinoma., Unbiased transcriptome sequencing may identify previously uncharacterized NUTM1 fusion partners. Gemcitabine and nab‐paclitaxel is a well‐tolerated combination chemotherapy regimen and could offer a novel treatment approach for NUT carcinoma.

Dry eye is not typically considered a toxicity of whole brain radiation therapy (WBRT). We analyzed dry eye syndrome as part of a prospective study of patient-reported outcomes after WBRT.Patients receiving WBRT to 25 to 40 Gy were enrolled on a study with dry mouth as the primary endpoint and dry eye syndrome as a secondary endpoint. Patients received 3-dimensional WBRT using opposed lateral fields. Per standard practice, lacrimal glands were not prospectively delineated. Patients completed the Subjective Evaluation of Symptom of Dryness (SESoD, scored 0-4, with higher scores representing worse dry eye symptoms) at baseline, immediately after WBRT (EndRT), and at 1 month (1M), 3 months, and 6 months. Patients with baseline SESoD ≥3 (moderate dry eye) were excluded. The endpoints analyzed were ≥1-point and ≥2-point increase in SESoD score at 1M. Lacrimal glands were retrospectively delineated with fused magnetic resonance imaging scans.One hundred patients were enrolled, 70 were eligible for analysis, and 54 were evaluable at 1M. Median bilateral lacrimal V20Gy was 79%. At 1M, 17 patients (32%) had a ≥1-point increase in SESoD score, and 13 (24%) a ≥2-point increase. Lacrimal doses appeared to be associated with an increase in SESoD score of both ≥1 point (V10Gy: P = .042, odds ratio [OR] 1.09/%; V20Gy: P = .071, OR 1.03/%) and ≥2 points (V10Gy: P = .038, OR 1.15/%; V20Gy: P = .063, OR 1.04/%). The proportion with increase in dry eye symptoms at 1M for lacrimal V20Gy ≥79% versus79% was 46% versus 15%, respectively, for ≥1 point SESoD increase (P = .02) and 36% versus 12%, respectively, for ≥2 point SESoD increase (P = .056).Dry eye appears to be a relatively common, dose/volume-dependent acute toxicity of WBRT. Minimization of lacrimal gland dose may reduce this toxicity, and patients should be counseled regarding the existence of this potential side effect and treatments for dry eye.

The clinical outcomes for infants with malignant tumors are often worse than older children due to a combination of more biologically aggressive disease in some cases, and increased toxicity-or deintensification of therapies due to concern for toxicity-in others. Especially in infants and very young children, finding the appropriate balance between maximizing treatment efficacy while minimizing toxicity-in particular late side effects-is crucial. We review here the management of malignant tumors in infants and very young children, focusing on central nervous system (CNS) malignancies and rhabdomyosarcoma.

Purpose/Objective(s) Immune checkpoint inhibitors (ICIs) have led to improved treatment outcomes in a variety of cancers; however, the majority of patients exhibit resistance to ICIs. Overcoming this resistance is a major challenge in immune-oncology. Radiation therapy (RT) has emerged as a promising combination with ICIs since it may act synergistically with ICIs by producing an immunomodulatory effect. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases RT energy deposit inside tumor cells and subsequent tumor cell death, without adding toxicity to healthy tissues. Preclinical data demonstrate NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders or convert ICI non-responders to responders. Materials/Methods This multicenter, open-label, phase I trial [NCT03589339] is evaluating NBTXR3/RT/anti-PD-1 in 3 cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to HN re-irradiation and (2) lung or (3) liver metastases from any primary cancer eligible for anti-PD-1. Stereotactic body RT (SBRT) is delivered at tumor-site selective doses per standard practice. The primary objective is to determine the NBTXR3/RT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety, and feasibility of NBTXR3 injection. Results Nine patients have been treated: 3 HNSCC, 4 lung, 2 liver. Overall tumor regression was observed in 8/9 patients of which 7 were anti-PD-1 non-responders. A complete response lasting over 1 year was observed in the injected lymph node in 1 anti-PD-1 naive patient. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naive HNSCC patient and considered DLTs. This patient also experienced 2 other G4 SAEs related to anti-PD-1 (diabetic ketoacidosis, acute kidney injury). SBRT-related safety profile was as expected. Updated safety and efficacy results with additional patients and longer follow-up will be presented. Conclusion Safety data from this first-in-human phase I trial evaluating NBTXR3/RT/anti-PD-1 in patients with advanced cancers, show NBTXR3 intratumoral injection is feasible and well-tolerated in HNSCC, lung, and liver. NBTXR3/RT/anti-PD-1 demonstrated promising signs of efficacy and led to tumor regression in patients having progressed on prior anti-PD-1. These data support further development of NBTXR3 in combination with anti-PD-1 as well as other ICIs.

PURPOSE/OBJECTIVE(S): To test for associations in virtual visit use among radiation oncology patients. MATERIALS/METHODS: Using the electronic medical record, we extracted encounter data and corresponding patient information the 6 months prior to and 6 months of COVID-enabled virtual visits (10/1/2019-3/22/2020 versus 3/23/2020-9/1/2020) at a large tertiary cancer center. Encounters during COVID were categorized as in-person or virtual visits. Descriptive and univariate analysis was conducted on the characteristics of patient populations during the pre-COVID period to establish baseline demographics and compare to the during COVID period. Examined demographic variables included race, ethnicity, age, sex, marital status, preferred language, insurance status and tumor characteristics including disease site. Univariate and multivariable (MVA) logistic regression examined patient demographic and disease characteristics associated with virtual visit use. RESULTS: We analyzed 4,974 total encounters, (2,287 pre-COVID and 2,687 during COVID), among 3,960 total patients. All (100%) pre-COVID encounters were in-person whereas during COVID, 21% of encounters were via virtual visits. Overall, there were no differences identified in pre- versus during COVID patient characteristics. However, we found significant differences in patient characteristics for in-person versus virtual encounters during COVID. On MVA, virtual visit use was less common among patients of minority race (white n = 321 versus black n = 100 and other n = 35, OR 0.73, 95% CI 0.57-0.94, P = 0.014) and not married (OR 0.78, 95% CI 0.61-1.00, P = 0.048). Patients diagnosed with head and neck (OR 0.64, 95% CI 0.42-0.96, P = 0.030), breast (OR 0.35, 95% CI 0.20-0.60, P = < 0.001), GI/abdominal (OR 0.31, 95% CI 0.16-0.62, P = 0.001) or hematologic malignancy (OR 0.18, 95% CI 0.04-0.84, P = 0.029), were less likely to use virtual visits relative to patients with genitourinary malignancy. CONCLUSION: While the patient populations were similar prior to and during COVID, when controlling for available variables, we found significant differences in virtual visit use by patient characteristics, including race and marital status as well as disease characteristics. Further study is needed to elucidate additional factors that underlie these differences in virtual visit utilization; health equity should be considered when implementing virtual visits. Our findings raise the hypothesis that vulnerable patient groups may benefit from additional interventions and outreach to enable equitable access.

PURPOSE/OBJECTIVE(S) IMRT planning is challenging, at least in part, due to the essentially-infinite number of possibilities, and since the planner is never sure that they have gotten "the best", or at least "nearly the best" achievable plan. We prospectively assessed the impact of providing IMRT planners with a priori knowledge of the maximum achievable dose sparing for organs at risk (OARs) for patients on both dosimetric and clinical endpoints. We hypothesized that a priori knowledge of maximum achievable sparing would improve dosimetric and clinical (i.e., patient reported outcome) measures. MATERIALS/METHODS We examined patients receiving IMRT for oropharynx cancer on prospective clinical trials from 2012-2019 at our institution. A tool that generates estimates of maximum achievable dose sparing for organs at risk was used starting July 2016. Patients treated pre-implementation (i.e., baseline) and post-implementation (i.e., experimental) were compared for the endpoints: (1) Doses received by various OARs MINUS doses achievable (per the tool), termed the 'excess of feasible dose'; (2) Plan quality metrics (e.g., target homogeneity and conformity), and (3) Patient reported outcomes (PRO) per questionnaires completed at 3-, 6- and 12-months post-treatment. RESULTS 139 patients were analyzed (60-baseline cohort, 79-experimental). (1) The excess of feasible dose was lower in the experimental (vs baseline) cohort, for the contralateral parotid (9.6 vs 5.5 Gy; P < 0.001), the ipsilateral parotid (17.6 vs 6.8 Gy; P < 0.001), larynx (12.5 vs 8.2 Gy; P = < 0.001), oral cavity by (15.8 vs 14.3 Gy; P = 0.002), and contralateral submandibular gland (17.4 vs 17 Gy; P = 0.40). Lesser variation of excess of feasible dose (i.e., more consistent sparing) was seen in the experimental (vs. baseline) cohort for the parotid and contralateral submandibular glands (P < 0.05). (2) Some small differences in target homogeneity and conformity were observed but not felt to be clinically significant. (3) The average post-RT PROs were significantly better in the experimental cohort vs baseline at 6 months post-RT. Dry mouth severity, sticky saliva, meal enjoyment, severity of pain, and EAT10 composite (swallowing) were all significantly improved; P < 0.05). CONCLUSION Clinical plans aided by an a priori estimate of maximum achievable dose sparing for OARs was associated with improved (and more consistent) OAR sparing and better clinical outcomes (i.e., better post-RT PROs). Clinical implementation of this tool can yield quantifiable dosimetric and patient benefits.

Purpose/objective(s) Immune checkpoint inhibitors (ICI) can improve outcomes in patients who respond to treatment, however most patients exhibit resistance. Overcoming this resistance is the main challenge in immune-oncology and recent studies suggest radiotherapy (RT) may improve ICI response rates. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases RT energy deposit inside tumor cells and subsequent tumor cell death, without adding toxicity to healthy tissues. Here we present evidence that NBTXR3 activated by RT primes the immune system, producing an anti-tumor immune response, including activation of the cGAS-STING pathway, that overcomes anti-PD-1 resistance both in murine models and patients. Materials/methods Abscopal assays were conducted in immunocompetent mice. Anti-PD-1 sensitive or resistant lung tumor cell lines were injected in both flanks. Intratumoral injection of NBTXR3 (or vehicle) followed by RT was performed in right flank (primary) tumors only. Some mice also received anti-PD-1 injections. Tumor growth was monitored, and tumor immune cell infiltrates analyzed by immunohistochemistry (IHC). Separately, in the phase II/III randomized Act.in.Sarc [NCT02379845] trial patients with locally advanced soft tissue sarcoma (STS) received either NBTXR3+RT or RT alone followed by tumor resection. Pre- and post-treatment tumor samples from patients in both groups were analyzed by IHC and Digital Pathology for immune biomarkers. The safety and efficacy of NBTXR3 plus stereotactic body radiotherapy (SBRT) in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers in the Phase I 1100 [NCT03589339] trial. Results Pre-clinical studies demonstrated that NBTXR3+RT induces an immune response not observed with RT alone and enhances systemic control. IHC showed significant increase of CD8+ T-cell infiltrates in both NBTXR3+RT treated and untreated tumors compared to RT alone. Increased CD8+ T-cell and decreased FOXP3+ Treg density (pre- vs post-treatment) was also observed in tumors from STS patients treated with NBTXR3+RT. Furthermore, NBTXR3+RT in combination with anti-PD-1 improved local and systemic control in mice bearing anti-PD-1 resistant lung tumors, produced long-term memory, and reduced spontaneous lung metastases. Preliminary efficacy data from the 1100 trial showed tumor regression in 8/9 patients. Of note, tumor regression was observed in 6/7 patients who had progressed on prior anti-PD-1. Conclusion The clinical efficacy of NBTXR3+RT has been demonstrated as a single agent in STS. Here we demonstrate that it overcomes resistance to anti-PD-1 treatment mechanisms in mice and led to tumor regression in patients having progressed on anti-PD-1 therapy. These results highlight the potential of NBTXR3+RT to positively impact the immuno-oncology field.

Objective The objective of this study was to evaluate the clinical outcomes in a cohort of patients with early-stage oral tongue squamous cell carcinoma (OTSCC). Materials and methods We conducted a retrospective analysis of patients with pT1-T2N0 (American Joint Committee on Cancer [AJCC] seventh edition) OTSCC treated from 2000 to 2018. Two-year actuarial rates of local regional control, cancer-specific survival, and overall survival were calculated for the entire cohort and patients with/without adjuvant radiation. Results Ninety-six patients met the criteria with a median follow-up of 4 years; 14 had adjuvant radiation, while 82 had surgery alone. Two-year local regional control was 82.7% (75.4% to 90.8%) for the entire cohort, 84.9% (77.8% to 93.2%) for surgery only, and 70.7% (50.2% to 99.6%) for patients with adjuvant radiation. Two-year progression-free survival was 82.7% (75.3% to 90.8%). Of the 20 patients with recurrence, 11 (55%) were successfully salvaged. Conclusion Local regional recurrence remains modest in early-stage OTSCC, but salvage is possible with high survival rates. Level of evidence Level III-retrospective cohort study.

Adenoid cystic carcinoma (ACC) is a rare salivary gland tumor, displaying aggressive behavior with frequent recurrence and metastasis. Little information exists regarding the impact of clinicopathological parameters and adjuvant radiotherapy (aRT) on ACC disease specific (DSS) and overall survival (OS). We extracted demographic, treatment, and survival information of 1439 patients with major or minor intraoral salivary gland ACC from the Surveillance, Epidemiology, and End Results (SEER) database. The associations between tumor characteristics and aRT with OS and DSS were estimated using hazard ratios (HR) and 95% confidence intervals (CI). Submandibular gland ACCs had the worst prognosis (adjusted DSS HR = 1.48, 95% CI = 0.99–2.20, compared to parotid), and this difference was more pronounced among patients with advanced-stage tumors (adjusted DSS HR = 1.93, 95% CI = 1.13–3.30). aRT was associated with increased overall survival only among stage III submandibular ACC patients (HR = 0.64, 95% CI = 0.42–0.98) and had no benefit in any other group. In conclusion, submandibular gland ACC carries a worse prognosis than other gland subsites and may benefit from aRT. The different outcomes between submandibular gland and other major or minor gland ACCs warrant further mechanistic investigation.

Background Cancer immunotherapies have shown promising clinical outcomes; however, the majority of patients are non-responders or will develop resistance during the course of treatment. One of the current challenges is to increase the response rate to immune checkpoint inhibitors (ICIs). Combining immunotherapy with radiation therapy (RT) is emerging as a valuable strategy to prime the immune response. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. First-in-class radioenhancer NBTXR3, administered by one-time direct intratumoral injection, is designed at the nanoscale to increase RT dose deposit with subsequent increase in tumor cell killing, without increasing toxicity to normal tissue. Preclinical and early clinical data suggest NBTXR3/RT can prime the immune system and act as an in situ vaccine leading to an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize NBTXR3/RT in combination with anti-PD-1 (NBTXR3/RT/PD-1), will act synergistically to increase the proportion of ICI responders or convert ICI non-responders to responders. Methods A multicenter, open-label, phase I trial [NCT03589339] evaluating safety and tolerability of NBTXR3/RT/PD-1 in three cohorts: (1; HN lung) lung or (3; liver) liver metastases from any primary cancer eligible for approved anti-PD-1 treatment. NBTXR3 injected volume is based on a percentage of baseline tumor volume. Stereotactic body RT (SBRT) is delivered as per standard practice. The primary objective is to determine NBTXR3/RT/PD-1 recommended phase II dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Results To date 6 patients have been treated: 3 in H&N (2 anti-PD-1 naive) and 3 in lung (all anti-PD-1 non-responders. No DLT or SAE has been observed. Grade 2 nausea related to NBTXR3 or injection procedure was observed in H&N. 2 H&N patients and 3 lung patients have completed RT and initiated anti-PD-1 treatment. RT-related safety profile was as expected. Tumor shrinkage was observed in 1 anti-PD-1 naive and 2 anti-PD-1 non-responders and additional preliminary efficacy and updated safety results will be presented. Conclusions To date, NBTXR3 administration activated by SBRT in combination with anti-PD-1 treatment has been safe and well tolerated in patients with advanced cancers. Promising early signs of efficacy in anti-PD-1 naive, as well as in patients having progressed on previous anti-PD-1 therapy will be presented. Trial Registration NCT03589339 Ethics Approval This study was approved by local institution’s review board

Background Despite recent advances, resistance to immune checkpoint inhibitors (ICI), observed in over 80% of treated patients, is currently the main challenge immuno-oncology is facing. Intense efforts are being made to identify combination therapies that could improve ICI response rates. Administered intratumorally, NBTXR3 enhances the energy dose deposited by ionizing radiation within tumor cells, increasing the anti-tumor efficacy of radiation therapy (XRT) without adding toxicity to surrounding tissues. Here we present evidence that NBTXR3 activated by XRT primes the immune system, producing an anti-tumor response, including activation of the cGAS-STING pathway, that overcomes anti-PD-1 resistance both in mice models and patients. Methods Abscopal assays were conducted in immunocompetent mice. Tumor cell lines, sensitive or resistant to anti-PD-1, were injected in both flanks of mice. Intratumoral injection of NBTXR3 (or vehicle) followed by XRT was performed in right flank (primary) tumors only. Some mice also received anti-PD-1 injections. Tumor growth was monitored, and tumor immune cell infiltrates were analyzed by immunohistochemistry (IHC). Separately, in the phase II/III randomized trial Act.in.Sarc [NCT02379845] patients with locally advanced soft tissue sarcoma (STS) received either NBTXR3+XRT or XRT alone followed by wide tumor resection. Pre- and post-treatment tumor samples from patients in both groups were analyzed by IHC and Digital Pathology for immune biomarkers. The safety and efficacy (RECIST 1.1/iRECIST) of NBTXR3 plus stereotactic ablative radiotherapy (SABR) in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers [NCT03589339]. Results Pre-clinical studies demonstrated that NBTXR3+XRT induces an immune response a not observed with XRT alone and enhances systemic control. IHC showed significant increase of CD8+ T-cell infiltrates in both NBTXR3+XRT treated and untreated tumors compared to XRT alone. Similarly, increased CD8+ T-cell density (pre- vs post-treatment) was observed in tumor tissues from STS patients treated with NBTXR3+XRT. Tumor samples from the NBTXR3+XRT group also displayed increased PD-1+ cell density. Furthermore, in combination with anti-PD-1, NBTXR3+XRT improved local and systemic control in mice bearing anti-PD-1 resistant lung tumors, as well as resulted in reduced number of spontaneous lung metastases.Preliminary efficacy data from the first in human trial of NBTXR3+XRT in combination with anti-PD-1 showed tumor response in patients who progressed on prior anti-PD-1. Conclusions The clinical efficacy of NBTXR3+XRT has been demonstrated as a single agent. We now demonstrate that it potentiates anti-PD-1 treatment to overcome resistance mechanisms. These results highlight the potential of NBTXR3+XRT to positively impact the immuno-oncology field. Ethics Approval This study was approved by local institution’s review board

The treatment of patients with HPV-associated oropharyngeal cancer (HPV-OPC) is rapidly evolving and challenging the standard of care of definitive radiotherapy with concurrent cisplatin. There are numerous promising de-escalation strategies under investigation, including deintensified definitive chemoradiotherapy, transoral surgery followed by de-escalated adjuvant therapy, and induction chemotherapy followed by de-escalated locoregional therapy. Definitive radiotherapy alone or with cetuximab is not recommended for curative-intent treatment of patients with locally advanced HPV-OPC. The results of ongoing phase III studies are awaited to help answer key questions and address ongoing controversies to transform the treatment of patients with HPV-OPC. Strategies for de-escalation under investigation include the incorporation of immunotherapy and the use of novel biomarkers for patient selection for de-escalation.

Purpose In the treatment of resected metastatic brain disease, a recent phase 3 trial by the North Central Cancer Treatment Group (N107C/CEC.3) surprisingly found that the local control rate for whole-brain radiation therapy was better than that of stereotactic radiation surgery (SRS). To optimize target delineation, we performed a quantitative analysis of local failure patterns after postoperative SRS. Methods and materials Patients with brain metastases who were treated with surgery and SRS to the cavity were evaluated. Local failure was defined by pathologic confirmation or magnetic resonance imaging evidence of progression leading to further overlapping radiation therapy. T1 postgadolinium magnetic resonance imaging scans that were taken preoperatively and at recurrence were co-registered to the simulation computed tomography. Three volumes were compared: (1) Preoperative tumors, (2) resection cavities that were originally contoured as clinical target volumes for SRS, and (3) recurrent tumors. Overlap volume histograms quantified the proximity of the three volumes to the meninges. Results In the cohort of 173 patients, 18 patients experienced local failure in 19 resection cavities. The original SRS target volume overlapped with a median of 69.6% of the recurrent tumor. When the entire preoperative tumor was included, the overlap with the recurrent tumor increased to a median of 76.8%. Recurrent tumors were closer to the meninges than corresponding preoperative tumors (P = .03) but a median 8.2 mm expansion of the target volume from the meninges was needed to increase overlap with the recurrent tumor to 90%. Increases in overlap with the recurrent tumor were achieved most efficiently by uniformly expanding the contoured cavity and a median 2.8 mm expansion covered 90% of the recurrent tumor. Conclusions Our quantitative analysis of recurrence patterns suggests that a larger 3 mm uniform expansion of the SRS target volume substantially increases coverage of the volume that is later occupied by the recurrent tumor and may provide improved local control. The extent of the preoperative tumor in the target volume or expanding the target volume from the meninges provides little benefit.

Purpose: Reirradiation for recurrent glioma remains controversial without knowledge of optimal patient selection, dose, fractionation, and normal tissue tolerances. We retrospectively evaluated outcomes and toxicity after conventionally fractionated reirradiation for recurrent high-grade glioma, along with the impact of concurrent chemotherapy. Methods and materials: We conducted a retrospective review of patients reirradiated for high-grade glioma recurrence between 2007 and 2016 (including patients with initial low-grade glioma). Outcome metrics included overall survival (OS), prognostic factors for survival, and treatment-related toxicity. Results: Patients (n = 118; median age 47 years; median Karnofsky performance status score: 80) were re-treated at a median of 28 months (range, 5-214 months) after initial radiation therapy. The median reirradiation dose was 41.4 Gy (range, 12.6-54.0 Gy) to a median lesion volume of 202 cm3 (range, 20-901 cm3). The median cumulative (initial radiation and reirradiation combined) potential maximum brainstem dose was 76.9 Gy (range, 5.0-108.3 Gy) and optic apparatus dose was 56.0 Gy (range, 4.5-90.9 Gy). Of the patients, 56% received concurrent temozolomide, 14%, bevacizumab, and 11%, temozolomide plus bevacizumab; 19% had no chemotherapy. The planned reirradiation was completed by 90% of patients. Median OS from the completion of reirradiation was 9.6 months (95% confidence interval [CI], 7.5-11.7 months) for all patients and 14.0, 11.5, and 6.7 months for patients with initial grade 2, 3, and 4 glioma, respectively. On multivariate analysis, better OS was observed with a >24-month interval between radiation treatments (hazard ratio [HR]: 0.3; 95% CI, 0.2-0.5; P < .001), reirradiation dose >41.4 Gy (HR: 0.6; 95% CI, 0.4-0.9; P = .03), and gross total resection before reirradiation (HR: 0.6, 95% CI, 0.3-0.9; P = .02). Radiation necrosis and grade ≥3 late neurotoxicity were both minimal (41.4 Gy in conventional fractionation, along with chemotherapy, was safe and well tolerated with meaningful survival duration. These data provide information that may be useful in implementing safe reirradiation treatments for appropriately selected patients and guiding future studies to define optimal reirradiation doses, maximal safe doses to critical structures, and the role of systemic therapy.

Many eligible women with invasive breast cancer do not receive recommended adjuvant radiation (RT), despite its role in local control and overall survival. We examined trends in RT use over 10 years, and the impact of sociodemographic factors on the receipt of standard-of-care RT, using the National Cancer Database (NCDB). Women under age 70 with invasive breast cancer who underwent BCS from 2004 to 2014 were analyzed. Receipt of RT was evaluated in the whole cohort and by time period to identify temporal trends. Multiple logistic regression models were used to assess associations between factors such as race, insurance status, ethnicity, and receipt of RT. A total of 501,733 patients met eligibility criteria. The percentage of patients undergoing adjuvant RT increased from 86.7% in 2004 to 92.4% in 2012, and then decreased in 2013 and 2014 to 88.9%. On univariate analysis, patients of white race were significantly more likely to receive RT compared with patients of black race (90.4% vs 86.9%, p

This abstract was withdrawn by the authors.

PURPOSE/OBJECTIVE(S) Stereotactic radiosurgery (SRS), compared to whole brain radiotherapy is limited in its ability to prevent development of brain metastases in untreated areas. The purpose of this study is to assess whether low-dose volumes delivered to uninvolved regions of the brain during SRS can reduce the risk of developing brain metastases in those regions. MATERIALS AND METHODS Data were collected for 69 patients with brain metastases who were treated with SRS at least two occasions. The regions of uninvolved brain receiving a high, intermediate, and low dose of incidental radiotherapy were defined as the volume receiving at least 10, 5, and 2.5 Gy if the prescribed dose was < 25 Gy (1-3 fraction plans) or the volume receiving at least 15, 7.5, and 5 Gy if the prescribed dose was ≥ 25 Gy (5 fraction plans). A second round metastasis was considered to occur within a given dose level if 20% or more of the tumor was found within that dose level. Probabilities were calculated based on the volume of each dose level as a percentage of total brain volume and were used to estimate the expected number of cases with at least one metastasis occurring in each dose level. RESULTS The average number of metastases treated in both rounds of SRS was two. The expected and observed number of cases with at least one second round metastasis were 0 and 2 for the high dose level (p=0.151), 7 and 3 for the intermediate dose level (p=0.018), and 17 and 11 for the low dose level (p=0.094). CONCLUSION We observed fewer than expected new metastases within prior SRS low dose levels based on volumetric probabilities, though this difference was only significant for the intermediate dose level. This suggests that low dose volumes from SRS may provide benefit in preventing future regional metastases.

BACKGROUND For patients with operable intracranial neoplasms, there are opportunities to augment local control beyond traditional methods, such as external beam radiation therapy. Brachytherapy, the implantation of radioactive sources into the resection cavity, can be useful in this setting by providing immediate initiation of radiation and limiting the exposure of surrounding normal tissue to radiation. Traditional intracranial brachytherapy has been limited by uneven dose distributions, complicated workflows, extended procedural times, cost of dedicated equipment, and frequent adverse events. To address these issues, a permanently implanted device with Cs-131 radiation seeds embedded in a bioresorbable collagen carrier tile (GammaTile, GT Medical Technologies, Tempe, AZ USA) was developed. Described as surgically targeted radiation therapy (STaRT), it is FDA-cleared for use in newly-diagnosed malignant intracranial neoplasms and recurrent intracranial tumors, and has demonstrated excellent safety and efficacy in early commercial use. The primary objectives of this multicenter, prospective, observational (phase IV) registry study are to evaluate “real-world” clinical outcomes and patient-reported outcomes that measure the safety and efficacy of STaRT using the GammaTile. METHODS Patients undergoing resection (R) of brain tumors with intra-operative GammaTile placement are eligible for enrollment. Planned sample size is 600 at up to 50 enrolling sites. First subject was enrolled 10/14/2020. Tumor pathology, overall survival, radiation- and surgery-related adverse events, patient- and provider-reported quality of life, serial MRIs, and timing of surgical bed and/or distant recurrence are collected. Powered primary endpoints for recurrent brain metastases, recurrent glioblastoma, and recurrent meningioma (surgical bed-progression free survival (PFS), overall survival, and PFS, respectively), compare STaRT to standard-of-care benchmarks. Results will be used to improve awareness and access to this treatment, benchmark clinical outcomes in the real-world setting, allow for comparisons to existing treatments, facilitate the design of future clinical trials, and contribute to the optimal sequencing of treatments for intracranial neoplasms.

Purpose/Objective(s) For patients with HER2-positive breast cancer metastatic to brain, HER2-directed systemic therapies are increasingly used with stereotactic radiosurgery (SRS), with a goal to avoid or delay whole brain radiotherapy. These include monoclonal antibodies such as trastuzumab (Herceptin, H) and pertuzumab (Perjeta, P), antibody-drug conjugates such as ado-trastuzumab emtansine (T-DM1), and tyrosine kinase inhibitors such as lapatinib. Limited data exist regarding appropriate timing with SRS and outcomes of this treatment regimen for HER2-positive breast cancer metastatic to the brain. Materials/Methods A single-institution retrospective review was performed to identify and collect clinical data on patients with biopsy-proven breast cancer metastatic to the brain who were treated with SRS. Outcomes analyses were performed using the Kaplan-Meier method, and the chi-square statistic was used to compare different treatment groups. Results Of 82 patients with breast cancer metastatic to the brain treated with SRS from 2009-2020, 33 (40%) had positive HER2 status, 18 of whom had hormone receptor positivity. At brain metastasis diagnosis, 15 patients (45%) had > 1 intracranial metastasis (range 2-7), and the median maximal brain metastasis dimension was 2.0 cm. Fifteen patients had uncontrolled extracranial disease. After brain metastasis diagnosis, 9 patients (27%) were treated with systemic therapy first (3 with T-DM1, 1 with T-DM1+HP, 1 with lapatinib+HP, 3 with chemotherapy+HP, 1 with chemotherapy) with a median of 18.6 months between the start of systemic therapy and SRS. Seven patients (21%) were treated with SRS first, followed by systemic therapy in 6 of these patients (these were multi-agent regimens with 4 including T-DM1 or lapatinib). Seventeen (52%) received concurrent systemic therapy and SRS upfront (3 with T-DM1, 2 with T-DM1+chemotherapy, 2 with lapatinib, 4 with HP, 5 with hormone therapy, 1 with chemotherapy). Median follow-up time was 21.1 months. Median overall survival was 24.8 months and not statistically different between treatment groups (table). Four patients (12%) developed symptomatic radionecrosis; 3 were on T-DM1 concurrent with SRS (of a total of 10 patients treated with this combination whether upfront or following initial systemic therapy). Conclusion In this small patient sample, we noted favorable survival outcomes for patients with HER2-positive breast cancer metastatic to the brain when treated with HER2-targeted therapies together with SRS. The sequence of systemic therapy and SRS does not appear to impact survival outcomes. Concurrent treatment with T-DM1 and SRS may be associated with higher rates of radionecrosis.

PURPOSE/OBJECTIVE(S) The treatment planning of intensity-modulated radiotherapy (IMRT) is often time-consuming and needs multiple rounds of trials and errors. The unknown optimal dosimetry of anatomy mainly causes the difficulty. This study aims to develop a deep learning model to predict the dose distribution of a new patient, which has a similar diametric quality to previous clinical plans. MATERIALS/METHODS The dataset comes from the international competition for the dosimetry prediction of head and neck patients (2020 OpenKBP) with three target prescriptions (56 Gy, 63 Gy, and 70 Gy). The evaluation criterion is pixel-by-pixel dose discrepancy and point-by-point DVH difference. The organizer provides 200 training cases. Each has one planning CT image, one dose distribution, and one segmentation mask of seven organs-at-risks (OARs, brainstem, spinal cord, right parotid, left parotid, larynx, esophagus, and mandible). 40 cases are provided as a validation set with CT and segmentation mask only. The organizer reported the prediction quality for these 40 validation patients to help the model refining, but did not disclose the ground truth dosimetry. Finally, 100 testing cases were used to evaluate the model performance. We proposed a triple-stage cascaded U-Net to predict the dose distribution in a coarse-to-fine manner using the auto-context mechanism. Specifically, the first U-Net takes the CT image and structure contours as input and outputs a coarse dose distribution. This distribution is then fed into the second U-Net together with the CT image and contours, to predict a refined dose distribution. Finally, the third U-Net takes both dose distribution predicted by the first and second U-Net together with the CT image and contours to generate the final dose distribution, which is a refinement of the previous two predictions. The network is fully implemented in 3D manners (which means it takes the 3D CT volume as input, not 2D CT slices). It takes about 17 hours to train the model for 400 epochs, using a batch size of 6 and Adam optimizer with a base learning rate of 0.0005 on a GPU server equipped with six NVIDIA TITAN Xp graphic cards with 12 GBytes of memory each. The prediction is almost instantaneous, about 0.2 seconds per case. RESULTS We found the proposed method's performance is better with 200 training cases than with 160 cases, which demonstrated the data reliance of the deep learning-based methods. The dose similarity score and DVH similarity score from 100 testing cases are 2.753 and 1.559, respectively. Our model has one of the best performances among the participants. The predicted dosimetry is similar to the realistic one, with no clinically meaningful difference. CONCLUSION We developed a novel cascaded auto-context deep learning model to predict optimal dosimetry of a head and neck patient. The model achieved satisfactory performance for clinical use.

Purpose/objective(s) Literature suggests that salivary gland stem cells, capable of regenerating salivary tissue, may preferentially reside in the large ducts of salivary glands. We conducted a prospective trial in patients receiving definitive chemoradiotherapy (CRT) for oropharyngeal cancer where we preferentially spared the major parotid ducts (localized via MRI sialography) during treatment planning. We hypothesized that (1) this technique would yield improvements in patient reported xerostomia (PRX) at 6- and 12-months post-CRT compared to a prospectively accrued cohort of similar patients, and (2) that parotid duct doses would be predictive for PRX. Materials/methods A total of 38 Patients were prospectively enrolled and underwent MRI sialography guided ductal sparing. 28/38 patients received de-escalated CRT (60Gy). PRX was classified as none/mild versus moderate to very severe. (1) PRX in the 28 de-escalated patients were compared using a fisher exact test to a cohort of 232 patients on the same clinical trials but who did not undergo ductal sparing. (2) Competing nested multivariate logistic models (+/- parotid duct doses) were assessed using dosimetric data from all 38 patients for their ability to predict PRX. Models included contralateral submandibular mean dose, mean parotid gland dose (both) +/- parotid duct mean dose (both). The two nested models were compared using a likelihood ratio test to determine if incorporating mean parotid duct doses significantly improved model fit. Results (1) Patients reporting moderate to very severe xerostomia was lower in patients with vs without parotid-ductal sparing at 6 months post-CRT (46% vs 67%, P = 0.03), and trended lower at 12 months post-CRT (32% vs 49%, P = 0.11). At 6 months post CRT, the mean parotid duct dose was the only covariate significantly associated with PRX (P = 0.047). At 12 months post CRT, no covariate was significantly associated with PRX but both mean contralateral submandibular dose and mean parotid duct dose approached significance (P = 0.06 and 0.07, respectively). (2) The models +/- parotid duct doses were compared and the addition of parotid ductal mean dose significantly improved model fit at 6- and 12-months post CRT (P = 0.030 and 0.047, respectively). Conclusion The absolute rates of moderate to very severe patient reported xerostomia were approximately 20% lower for those undergoing MRI sialography guided parotid ductal sparing versus those without ductal sparing at 6- and 12-months post CRT. The significant improvement of model fit upon adding mean parotid ductal dose to the mean major salivary gland doses at 6 and 12 months suggests that the dose received by the parotid ducts relates to patient reported xerostomia severity even when considering traditional metrics such as mean parotid and contralateral submandibular dose.

We evaluated the toxicity associated with stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) in elderly and very elderly patients with brain metastases, as the role of SRS in geriatric patients who would traditionally receive WBRT is unclear.We conducted a retrospective review of elderly patients (aged 70-79 years) and very elderly patients (aged ≥80 years) with brain metastases who underwent RT from 2010 to 2015 at Johns Hopkins Hospital. Patients received either upfront WBRT or SRS for metastatic solid malignancies, excluding small cell lung cancer. Acute central nervous system toxicity within 3 months of RT was graded using the Radiation Therapy Oncology Group acute radiation central nervous system morbidity scale. The toxicity data between age groups and treatment modalities were analyzed using Fisher's exact test and multivariate logistic regression analysis. Kaplan-Meier curves were used to estimate the median overall survival, and the Cox proportion hazard model was used for multivariate analysis.A total of 811 brain metastases received RT in 119 geriatric patients. The median overall survival from the diagnosis of brain metastases was 4.3 months for the patients undergoing WBRT and 14.4 months for the patients undergoing SRS. On multivariate analysis, WBRT was associated with worse overall survival in this cohort of geriatric patients (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9-7.0, P.0001) and age ≥80 years was not. WBRT was associated with significantly greater rates of any grade 1 to 4 toxicity (OR 7.5, 95% CI 1.6-33.3, P=.009) and grade 2 to 4 toxicity (OR 2.8, 95% CI 1.0-8.1, P=.047) on multivariate analysis. Elderly and very elderly patients did not have significantly different statistically acute toxicity rates when stratified by age.WBRT was associated with increased toxicity compared with SRS in elderly and very elderly patients with brain metastases. SRS, rather than WBRT, should be prospectively evaluated in geriatric patients with the goal of minimizing treatment-related toxicity.

BACKGROUND Proton radiotherapy remains a limited resource despite its clear potential for reducing radiation doses to normal tissues and late effects in children in comparison with photon therapy. This study examined the impact of race and socioeconomic factors on the use of proton therapy in children with solid malignancies. METHODS This study evaluated 12,101 children (age ≤ 21 years) in the National Cancer Data Base who had been diagnosed with a solid malignancy between 2004 and 2013 and had received photon- or proton-based radiotherapy. Logistic regression analysis was used to evaluate patient, tumor, and socioeconomic variables affecting treatment with proton radiotherapy versus photon radiotherapy. RESULTS Eight percent of the patients in the entire cohort received proton radiotherapy, and this proportion increased between 2004 (1.7%) and 2013 (17.5%). Proton therapy was more frequently used in younger patients (age ≤ 10 years; odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6-2.2) and in patients with bone/joint primaries and ependymoma, medulloblastoma, and rhabdomyosarcoma histologies (P < .05). Patients with metastatic disease were less likely to receive proton therapy (OR, 0.4; 95% CI, 0.3-0.6). Patients with private/managed care were more likely than patients with Medicaid or no insurance to receive proton therapy (P < .0001). A higher median household income and educational attainment were also associated with increased proton use (P < .001). Patients treated with proton therapy versus photon therapy were more likely to travel more than 200 miles (13% vs 5%; P < .0001). CONCLUSIONS Socioeconomic factors affect the use of proton radiotherapy in children. Whether this disparity is related to differences in the referral patterns, the knowledge of treatment modalities, or the ability to travel for therapy needs to be further clarified. Improving access to proton therapy in underserved pediatric populations is essential. Cancer 2017;123:4048-56. © 2017 American Cancer Society.