Preoperative stereotactic radiosurgery for cerebral metastases: safe, effective, and decreases steroid dependency.

OBJECTIVE: Preoperative stereotactic radiosurgery (SRS) is emerging as a viable alternative to standard postoperative SRS. Studies have suggested that preoperative SRS provides comparable tumor control and overall survival (OS) and may reduce the incidence of leptomeningeal disease (LMD) and adverse radiation effects (AREs). It is unknown, however, if preoperative SRS remains effective in cohorts including large brain metastases (> 14 cm3) or if preoperative SRS affects steroid taper/immunotherapy. Here, the authors report the results of a phase 2 single-arm trial assessing a prospectively acquired series of 26 patients who underwent preoperative SRS, without a volumetric cutoff, compared with a propensity score-matched concurrent cohort of 30 patients who underwent postoperative SRS to address these salient questions. METHODS: Demographics, oncological history, surgical details, and outcomes were collected from the medical records. Coprimary endpoints were local tumor control (LTC) and a composite outcome of LTC, ARE, and LMD. Additional outcomes were OS, steroid taper details, and immunotherapy resumption. For survival analyses, cohorts were propensity score matched. RESULTS: Preoperative and postoperative SRS patients were comparable in terms of age, sex, Karnofsky Performance Status score, oncological history, and operative details. Gross tumor volume (GTV) was significantly higher in the preoperative group (median 12.2 vs 5.3 cm3, p < 0.001). One-year LTC (preoperative SRS: 77.2% vs postoperative SRS: 82.5%, p = 0.61) and composite outcome (68.3% vs 72.7%, p = 0.38) were not significantly different between the groups. In multivariable analysis, preoperative SRS did not have a significant effect on LTC (HR 1.57 [95% CI 0.38-6.49], p = 0.536) or the composite outcome (HR 1.18 [95% CI 0.38-3.72], p = 0.771), although the confidence intervals were large. The median OS (preoperative SRS: 17.0 vs postoperative SRS: 14.0 months, p = 0.61) was not significantly different. Rates of LMD were nonsignificantly lower in the preoperative SRS group (3.8% vs 16.7%, p = 0.200). Greater GTV volume was associated with prolonged (> 10 days) steroid taper (OR 1.24 [95% CI 1.04-1.55], p = 0.032). However, in multivariable analysis, preoperative SRS markedly reduced the steroid taper length (OR 0.13 [95% CI 0.02-0.61], p = 0.016). Time to immunotherapy was shorter in the preoperative SRS group (36 [IQR 26, 76] vs OR 228 [IQR 129, 436] days, p = 0.02). CONCLUSIONS: Compared with postoperative SRS, preoperative SRS is a safe and effective strategy in the management of cerebral metastases of all sizes and provides comparable tumor control without increased adverse effects. Notably, preoperative SRS enabled rapid steroid taper, even in larger tumors. Future studies should specifically examine the interaction of preoperative SRS with steroid usage and resumption of systemic therapies and the subsequent effects on systemic progression and OS.

Human papillomavirus circulating tumor DNA: a diagnostic tool in squamous cell carcinoma of unknown primary-a pilot study.

Introduction: Neck mass is the most common presentation of human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinoma (OPSCC). Recently, circulating tumor HPV-DNA (ctHPVDNA) assays have been developed to detect active OPSCC. This pilot study investigates the diagnostic accuracy of ctHPVDNA in establishing HPV status for known vs. unknown OPSCC presenting as a neck mass. Methods: A single-institution pilot study was conducted on all patients with OPSCC presenting as a neck mass between 2021 and 2022. The diagnostic accuracy of ctHPVDNA was compared to that of standard diagnostic procedures used to obtain HPV status according to the American Society of Clinical Oncology (ASCO) guideline for squamous cell carcinoma of unknown primary (SCCUP). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ctHPVDNA were calculated. Results: A total of 27 patients were included; 70.4% were current or former smokers, 48.1% (N = 13) had identifiable primaries, and 51.9% (N = 14) had SCCUP. Four patients with known primaries required operative direct laryngoscopy with biopsy (DLB) to establish HPV status. Two patients with SCCUP underwent diagnostic transoral robotic surgery (TORS) to establish HPV status and localize the primary. Twelve patients underwent therapeutic TORS and neck dissection. The gold standard for HPV status was based on final histopathologic p16 or HPV in situ hybridization (ISH) staining during workup/treatment. ctHPVDNA had 95.8% sensitivity, 100% specificity, 100% PPV, and 75% NPV in predicting HPV-positive OPSCC in the whole sample. Binary logistic regression model using ctHPVDNA results to predict HPV-positive OPSCC was significant (-2 log likelihood = 5.55, χ2 = 8.70, p <.01, Nagelkerke's R squared = .67). Among patients with identifiable primaries, all patients had HPV-positive tumors on final pathology, and ctHPVDNA was positive in 100%. In the unknown primary patients, ctHPVDNA had 90.9% sensitivity, 100% specificity, 100% PPV, and 75% NPV. Discussion: ctHPVDNA demonstrated good diagnostic accuracy for both known and unknown primaries. Incorporation of ctHPVDNA into the diagnostic algorithm for SCCUP may reduce the need for multiple procedures to establish HPV status.

A novel approach to infectious disease control and radiotherapy risk management.

BACKGROUND: Infectious disease outbreaks have always presented challenges to the operation of healthcare systems. In particular, the treatment of cancer patients within Radiation Oncology often cannot be delayed or compromised due to infection control measures. Therefore, there is a need for a strategic approach to simultaneously managing infection control and radiotherapy risks. PURPOSE: To develop a systematic risk management method that uses mathematical models to design mitigation efforts for control of an infectious disease outbreak, while ensuring safe delivery of radiotherapy. METHODS: A two-stage failure mode and effect analysis (FMEA) approach is proposed to modify radiotherapy workflow during an infectious disease outbreak. In stage 1, an Infection Control FMEA (IC-FMEA) is conducted, where risks are evaluated based on environmental parameters, clinical interactions, and modeling of infection risk. occupancy risk index (ORI) is defined as a metric for infection transmission risk level in each room, based on the degree of occupancy. ORI, in combination with ventilation rate per person (Rp ), is used to provide a broad infection risk assessment of workspaces. For detailed IC-FMEA of clinical processes, infection control failure mode (ICFM) is defined to be any instance of disease transmission within the clinic. Infection risk priority number (IRPN) has been formulated as a function of time, distance, and degree of protective measures. Infection control measures are then systematically integrated into the workflow. Since the workflow is perturbed by infection control measures, there is a possibility of introducing new radiotherapy failure modes or increased likelihood of existing failure modes. Therefore, in stage 2, a conventional radiotherapy FMEA (RT-FMEA) should be performed on the adjusted workflow. RESULTS: The COVID-19 pandemic was used to illustrate stage 1 IC-FMEA. ORI and Rp values were calculated for various workspaces within a clinic. A deep inspiration breath hold (DIBH) CT simulation was used as an example to demonstrate detailed IC-FMEA with ICFM identification and IRPN evaluation. A total of 90 ICFMs were identified in the DIBH simulation process. The calculated IRPN values were found to be progressively decreasing for workflows with minimal, moderate, and enhanced levels of protective measures. CONCLUSION: The framework developed in this work provides tools for radiotherapy clinics to systematically assess risk and adjust workflows during the evolving circumstances of any infectious disease outbreak.

The schedule of ATR inhibitor AZD6738 can potentiate or abolish antitumor immune responses to radiotherapy.

Inhibitors of the DNA damage signaling kinase ATR increase tumor cell killing by chemotherapies that target DNA replication forks but also kill rapidly proliferating immune cells including activated T cells. Nevertheless, ATR inhibitor (ATRi) and radiotherapy (RT) can be combined to generate CD8+ T cell-dependent antitumor responses in mouse models. To determine the optimal schedule of ATRi and RT, we determined the impact of short-course versus prolonged daily treatment with AZD6738 (ATRi) on responses to RT (days 1-2). Short-course ATRi (days 1-3) plus RT caused expansion of tumor antigen-specific, effector CD8+ T cells in the tumor-draining lymph node (DLN) at 1 week after RT. This was preceded by acute decreases in proliferating tumor-infiltrating and peripheral T cells and a rapid proliferative rebound after ATRi cessation, increased inflammatory signaling (IFN-ß, chemokines, particularly CXCL10) in tumors, and an accumulation of inflammatory cells in the DLN. In contrast, prolonged ATRi (days 1-9) prevented the expansion of tumor antigen-specific, effector CD8+ T cells in the DLN, and entirely abolished the therapeutic benefit of short-course ATRi with RT and anti-PD-L1. Our data argue that ATRi cessation is essential to allow CD8+ T cell responses to both RT and immune checkpoint inhibitors.

Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRG/RTOG 0912): a randomised, double-blind, placebo-controlled, multicentre, phase 2 trial.

BACKGROUND: Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population. METHODS: Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mg/m2) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m2), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete. FINDINGS: The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group). INTERPRETATION: To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated. FUNDING: National Cancer Institute and Novartis.

Quality of Life in Patients With Recurrent and Second Primary Head and Neck Cancer.

OBJECTIVE: In the setting of similar outcomes, quality of life (QOL) measures can be utilized to compare treatment modalities in head and neck squamous cell carcinoma (HNSCC). We evaluate QOL and symptoms in patients treated for primary, second primary, and recurrent HNSCC. STUDY DESIGN: Retrospective cohort study. SETTING: Head and neck cancer survivorship clinic. METHODS: We identified patients seen between 2016 and 2019. QOL and symptoms were assessed with the University of Washington Quality of Life (UW-QOL) questionnaire, 10-item Eating Assessment Tool, 8-item Patient Health Questionnaire, 7-item Generalized Anxiety Disorder, and Neck Disability Index. Regression analysis was utilized to explore associations and compare QOL outcomes. RESULTS: Our cohort comprised 662 patients: 546 with primary HNSCC, 34 with second primary HNSCC, and 82 with recurrent HNSCC. Multimodality therapy was associated with lower UW-QOL Physical Subscale (UW-QOL-PS) vs single modality: chemoradiation therapy (-12.17 [95% CI, -16.57 to -7.78]) and surgery + postadjuvant treatment (-12.11 [-16.06 to -8.16]). Multimodality therapy was also associated with lower UW-QOL Social-Emotional Subscale (UW-QOL-SS): chemoradiation therapy (-6.70 [-11.41 to -1.99]) and surgery + postadjuvant treatment (-7.41 [-11.63 to -3.19]). Recurrence (-14.42 [-18.80 to -10.04]) and second primary (-11.15 [-17.71 to -4.59]) demonstrated lower UW-QOL-PS vs primary. Radiation for recurrence or second primary had worse UW-QOL-PS (-10.43 [-19.27 to -1.59]) and UW-QOL-SS (-10.58 [-18.76 to -1.54]) and higher Eating Assessment Tool (6.08 [1.39-10.77]) than surgery alone. Surgery + postadjuvant treatment showed worse UW-QOL-PS (-12.65 [-23.76 to -1.54]) and UW-QOL-SS (-12.20 [-22.38 to -2.03]). CONCLUSION: Multimodality therapy, particularly with recurrent and second primary HNSCC, is more likely to contribute to diminished QOL and symptoms. This important consideration should play a role in framing informed discussions with patients regarding treatment.

Factors associated with ductal carcinoma in situ (DCIS) treatment patterns and patient-reported outcomes across a large integrated health network.

PURPOSE: To examine associations between ductal carcinoma in situ (DCIS) patients' characteristics, treating locations and DCIS treatments received and to pilot assessing quality-of-life (QoL) values among DCIS patients with diverse backgrounds. METHODS: We performed a retrospective tumor registry review of all patients diagnosed and treated with DCIS from 2018 to 2019 in the UPMC-integrated network throughout central and western Pennsylvania. Demographics, clinical information, and administered treatments were compiled from tumor registry records. We categorized contextual factors such as different hospital setting (academic vs. community), socioeconomic status based on the neighborhood deprivation index (NDI) as well as age and race. QoL survey was administered to DCIS patients with diverse backgrounds via QoL questionnaire breast cancer module 23 and qualitative assessment questions. RESULTS: A total of 912 patients were reviewed. There were no treatment differences noted for age, race, or NDI. Mastectomy rate was higher in academic sites than community sites (29 vs. 20.4%; p = 0.0045), while hormone therapy (HT) utilization rate was higher in community sites (74 vs. 62%; p = 0.0012). QoL survey response rate was 32%. Only HT side effects negatively affected in QoL scores and there was no significant difference in QoL domains and decision-making process between races, age, NDI, treatment groups, and treatment locations. CONCLUSION: Our integrated health network did not show chronically noted disparities arising from social determinates of health for DCIS treatments by implementing clinical pathways and system-wide peer review. Also, we demonstrated feasibility in collecting QoL for DCIS women with diverse backgrounds and different socioeconomic statuses.

Safety of Nivolumab Added to Chemoradiation Therapy Platforms for Intermediate and High-Risk Locoregionally Advanced Head and Neck Squamous Cell Carcinoma: RTOG Foundation 3504.

PURPOSE: Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown. METHODS AND MATERIALS: We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤2 of the first 8 evaluable patients experienced a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to 1 year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms. RESULTS: Of 39 patients (10 in arms 1, 3, 4 and 9 in arm 2), 72% had T3-4 tumors, 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in 1 and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol. CONCLUSIONS: Concomitant nivolumab with the 4 tested regimens was safe for patients with intermediate- and high-risk HNSCC, and subsequent adjuvant nivolumab was feasible as defined (NCT02764593).

A phase â ¡ prospective trial of photobiomodulation therapy in limiting oral mucositis in the treatment of locally advanced head and neck cancer patients.

Objective: This study aimed to compare the historical incidence rate of severe oral mucositis (OM) in head and neck cancer patients undergoing definitive concurrent chemoradiation therapy (CRT) versus a prospective cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with prophylactic photobiomodulation therapy (PBMT). Methods: This US-based, institutional, single-arm, phase Ⅱ prospective clinical trial was initiated in 50 patients (age ≥ 18 years, Karnofsky Performance Scale Index > 60, with locally advanced HNSCC (excluding oral cavity) receiving definitive or adjuvant radiation therapy (RT) with concurrent platinum-based chemotherapy (CT). PBMT was delivered three times per week throughout RT utilizing both an intraoral as well extraoral delivery system. Primary outcome measure was incidence of severe OM utilizing both the National Cancer Institute Common Toxicity Criteria, version 4.0 (NCI-CTCAE) Grade ≥3 and the World Health Organization Mucositis Grading Scale (WHO) Grade ≥3 versus historical controls; secondary outcome measures included time to onset of severe OM following therapy initiation. Results: At baseline, all patients included in final analysis (N = 47) had OM Grade 0. Average RT and CT dose was (66.3 ± 5.1) Gy and (486.1 ± 106.8) mg/m2, respectively. Severe OM was observed in 11 of 47 patients (23%, confidence interval: 12, 38). OM toxicity grade trended upward during treatment, reaching a maximum at 7 weeks (WHO: 1.8 vs. NCI-CTCAE: 1.7). Subsequently, OM grade returned to baseline 3 months following completion of RT. The mean time to onset of severe OM was (35 ± 12) days. The mean time to resolution of severe OM was (37 ± 37) days. Conclusions: Compared to historical outcomes, PBMT aides in decreasing severe OM in patients with locally advanced HNSCC. PBMT represents a minimally invasive, prophylactic intervention to decrease OM as a major treatment-related side effect.

Definitive local therapy to head and neck squamous cell carcinoma with distant metastasis.

Objectives: Data on the efficacy of including definitive local therapy to the primary site for head and neck squamous cell carcinoma (HNSCC) patients with synchronous distant metastasis are lacking. In multiple different solid tumor types, there has been benefit when using systemic therapy followed by local consolidative therapy (stereotactic ablative radiotherapy or surgery) directed at metastases. We proposed to retrospectively evaluate patients at our institution that received definitive treatment to the primary. Methods: Single institution retrospective study evaluating 40 patients with metastatic HNSCC treated with definitive surgery (55%) or chemoradiation (45%) to the primary site from 2000 to 2020. The major endpoints were overall survival (OS) and progression-free survival (PFS) for the total population and multiple sub-groups. Some variables were evaluated with multiple covariates Cox model. Results: The median PFS was 8.6 months (95% CI, 6.4-11.6), and OS was 14.2 months (95% CI, 10.9-27.5). In 28% of patients that received induction therapy, there was a twofold increase in median overall survival to 27.5 months. In the 33% of patients that received anti-PD-1 mAb as part of their treatment course, the median OS was significantly increased to 41.7 months (95% CI, 8.7-NR) versus 12.1 months (95% CI, 8.4-14.4) with a 5-year OS of 39%. Multivariate analysis for OS showed significance for age at diagnosis, use of IO, and number of metastatic sites. Conclusion: We observed impressive survival outcomes in metastatic HNSCC patients treated with definitive local therapy to the primary site in addition to induction and/or immunotherapy. Further study is warranted.Level of Evidence: 3.

Dose-dependent bioavailability, absorption-rate limited elimination, and tissue distribution of the ATR inhibitor BAY-1895344 (elimusertib) in mice.

PURPOSE: Ataxia Telangiectasia and Rad3-related (ATR) is a pivotal component of the DNA damage response and repair pathways that is activated in responses to cytotoxic cancer treatments. Several ATR inhibitors (ATRi) are in development that block the ATR mediated DNA repair and enhance the damage associated with cytotoxic therapy. BAY-1895344 (elimusertib) is an orally available ATRi with preclinical efficacy that is in clinical development. Little is known about the pharmacokinetics (PK) which is of interest, because tissue exposure and ATR inhibition may relate to toxicities or responses. METHODS: To evaluate BAY-1895344 PK, a sensitive LC-MS/MS method was utilized for quantitation in mouse plasma and tissues. PK studies in mice were first conducted to determine dose linearity. In vivo metabolites were identified and analyzed semi-quantitatively. A compartmental PK model was developed to describe PK behavior. An extensive PK study was then conducted in tumor-bearing mice to quantitate tissue distribution for relevant tissues. RESULTS: Dose linearity was observed from 1 to 10 mg/kg PO, while at 40 mg/kg PO bioavailability increased approximately fourfold due to saturation of first-pass metabolism, as suggested by metabolite analyses and a developed compartmental model. Longer half-lives in PO treated mice compared to IV treated mice indicated absorption-rate limited elimination. Tissue distribution varied but showed extensive distribution to bone marrow, brain, and spinal cord. CONCLUSIONS: Complex PK behavior was limited to absorption processes which may not be recapitulated clinically. Tissue partition coefficients may be used to contrast ATR inhibitors with respect to their efficacy and toxicity.

Dose-dependent bioavailability and tissue distribution of the ATR inhibitor AZD6738 (ceralasertib) in mice.

PURPOSE: Ataxia telangiectasia and Rad3-related (ATR) initiates and regulates cellular responses to DNA damage, such as those caused by cancer treatments. Several ATR inhibitors (ATRi) are in clinical development including AZD6738. Therapeutic indices among ATRi may differ as a result of varying potencies and concentrations at both tumor and off-target sites. Additionally, AZD6738 contributes to anti-tumor immune responses necessitating evaluation of exposure at immunological sites. METHODS: Using mouse models and a highly sensitive LC-MS/MS assay, the pharmacokinetics of AZD6738 were studied, including dose linearity, bioavailability, metabolism, and tissue distribution in tumor-bearing mice. RESULTS: Initial studies identified dose-dependent bioavailability, with greater than proportional increases in exposure as dose increased resulting in a ~ twofold increase in bioavailability between the lowest and highest investigated doses. These behaviors were successfully captured with a compartmental PK model. Analysis of metabolite PK revealed decreasing metabolic ratios with increasing dose, indicative of saturable first-pass metabolism. Further analysis revealed that intestinal and gut metabolism contribute to metabolism and these saturable mechanisms. Studies of tumor and tissue distribution found rapid and extensive drug distribution to most tissues except brain and spinal cord. CONCLUSION: The complex non-linear behavior of AZD6738 PK in mice was due to pre-systemic saturation and which appears to be recapitulated clinically at low doses. PK reported here will allow future correlation of tissue related toxicities with drug exposure as well as exposure with immunological responses. These results can also be compared with those from similar studies of other ATRi to contrast drug exposure with responses.

Phase I Trial of Cetuximab, Radiotherapy, and Ipilimumab in Locally Advanced Head and Neck Cancer.

PURPOSE: Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4-positive (CTLA-4+) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti-CTLA-4 mAb, to cetuximab-radiotherapy. PATIENTS AND METHODS: A (3 + 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus-negative (HPV-)] or intermediate-risk HPV-positive (HPV+)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives. RESULTS: From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation of ipilimumab to 1 mg/kg. Dose level -1 was expanded to N = 12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival were 72% [90% confidence interval (CI), 57-92] and 72% (90% CI, 56-92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83-37.8; P = 0.08). CONCLUSIONS: The RP2D for ipilimumab plus standard cetuximab-radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.

Quality of life after radiation and transoral robotic surgery in advanced oropharyngeal cancer.

OBJECTIVES: Oropharyngeal squamous cell carcinoma (OPSCC) treatment results in impaired swallowing and quality of life (QOL). We analyzed a cross-section of advanced stage OPSCC patients treated with multimodal therapies at our Survivorship Clinic to investigate treatment factors associated with QOL. METHODS: Retrospective analysis of patient-reported outcomes (PROMs) after primary OPSCC treatment using AJCC seventh edition staging. RESULTS: A total of 73 patients were included (90.1% human papillomavirus positive [HPV+]). There were no QOL differences between robotic surgery with radiation ± chemotherapy patients (n = 29) and those treated by radiation ± chemotherapy (n = 44). Radiation field analysis demonstrated significant correlations between increasing doses to larynx and contralateral parotid and submandibular gland and worse swallowing as measured by the Eating Assessment Tool-10 (P = .02; P = .01; P = .01). CONCLUSIONS: In advanced, mostly HPV+, OPSCC, we did not find clinically significant differences between QOL PROMs between surgical and radiation ± chemotherapy treatment groups. This highlights the need for continued therapy de-escalation along with improved interventions for treatment related toxicities. LEVEL OF EVIDENCE: 4.

NRG-HN003: Phase I and Expansion Cohort Study of Adjuvant Pembrolizumab, Cisplatin and Radiation Therapy in Pathologically High-Risk Head and Neck Cancer.

The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin-radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III-IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted.

The Use of Crowdfunding to Support Radiation Therapy Cancer Treatments.

BACKGROUND/AIM: The purpose of this study was to assess patients' use of a crowdfunding platform to raise funds for radiation treatment and to better understand the direct and indirect costs associated with treatments. MATERIALS AND METHODS: The GoFundMe crowdfunding database was queried for four unique categories related to radiation treatment campaigns. Covariates identified included clinical and demographic variables, and associations between amount raised and these predictors were analyzed using a generalized linear model. RESULTS: While 56% percent of campaigns cited direct costs associated with treatment, 73.4% of campaigns cited indirect costs related to treatment. Indirect expenses related to travel (31.7%) as well as living expenses (29.2%) were cited most often across all four treatment categories. CONCLUSION: This study enhances understanding regarding patients use of crowdfunding for radiation treatment. Increased focus should be placed on discussing the indirect costs of care with patients and their families.

Initial Data Pooling for Radiation Dose-Volume Tolerance for Carotid Artery Blowout and Other Bleeding Events in Hypofractionated Head and Neck Retreatments.

PURPOSE: Dose-volume data for injury to carotid artery and other major vessels in stereotactic body radiation therapy (SBRT)/SABR head and neck reirradiation were reviewed, modeled, and summarized. METHODS AND MATERIALS: A PubMed search of the English-language literature (stereotactic and carotid and radiation) in April 2018 found 238 major vessel maximum point doses in 6 articles that were pooled for logistic modeling. Two subsequent studies with dose-volume major vessel data were modeled separately for comparison. Attempts were made to separate carotid blowout syndrome from other bleeding events (BE) in the analysis, but we acknowledge that all except 1 data set has some element of BE interspersed. RESULTS: Prior radiation therapy (RT) dose was not uniformly reported per patient in the studies included, but a course on the order of conventionally fractionated 70 Gy was considered for the purposes of the analysis (with an approximately ≥6-month estimated interval between prior and subsequent treatment in most cases). Factors likely associated with reduced risk of BE include nonconsecutive daily treatment, lower extent of circumferential tumor involvement around the vessel, and no surgical manipulation before or after SBRT. CONCLUSIONS: Initial data pooling for reirradiation involving the carotid artery resulted in 3 preliminary models compared in this Hypofractionated Treatment Effects in the Clinic (HyTEC) report. More recent experiences with alternating fractionation schedules and additional risk-reduction strategies are also presented. Complications data for the most critical structures such as spinal cord and carotid artery are so limited that they cannot be viewed as strong conclusions of probability of risk, but rather, as a general guideline for consideration. There is a great need for better reporting standards as noted in the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic introductory paper.

Long term outcomes with linear accelerator stereotactic radiosurgery for treatment of jugulotympanic paragangliomas.

BACKGROUND: Data supporting linear accelerator (linac) stereotactic radiosurgery (SRS) for jugulotympanic paragangliomas (JTPs) come from small series with minimal follow-up. Herein, we report a large series of JTPs with extended follow-up after frameless linac-based SRS. METHODS: JTPs treated with linac-based SRS from 2002 to 2019 with 1+ follow-up image were reviewed for treatment failure (radiographic or clinical progression, or persistent symptoms after SRS requiring intervention) and late toxicities (CTCAE v5.0). RESULTS: Forty JTPs were identified; 30 were treated with a multifraction regimen. Median clinical and radiographic follow-up was 79.7 (interquartile range [IQR] 31.7-156.9) and 54.4 months (IQR 17.9-105.1), respectively, with a median 4.5 follow-up scans (IQR 2-9). Seven-year progression-free survival (PFS) was 97.0% (95% confidence interval 91.1%-100.0%). PFS was similar between single- and multifraction regimens (log rank P = .99). Toxicity was seen in 7.7% (no grade III). CONCLUSIONS: With extended clinical and radiographic follow-up, frameless linac-based SRS provides excellent local control with mild toxicity <8%.

Head and Neck Tumor Control Probability: Radiation Dose-Volume Effects in Stereotactic Body Radiation Therapy for Locally Recurrent Previously-Irradiated Head and Neck Cancer: Report of the AAPM Working Group.

PURPOSE: Stereotactic body radiation therapy (SBRT) has emerged as a viable reirradiation strategy for locally recurrent previously-irradiated head and neck cancer. Doses in the literature have varied, which challenges clinical application of SBRT as well as clinical trial design. MATERIAL & METHODS: A working group was formed through the American Association of Physicists in Medicine to study tumor control probabilities for SBRT in head and neck cancer. We herein present a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally recurrent previously-irradiated head and neck cancer. Dose-response models are generated that present tumor control probability as a function of dose. RESULTS: Data from more than 300 cases in 8 publications suggest that there is a dose-response relationship, with superior local control and possibly improved overall survival for doses of 35 to 45 Gy (in 5 fractions) compared with <30 Gy. CONCLUSION: Stereotactic body radiation therapy doses equivalent to 5-fraction doses of 40 to 50 Gy are suggested for retreatment.

Targeting DNA damage response in head and neck cancers through abrogation of cell cycle checkpoints.

PURPOSE: Head and neck cancers (HNSCC) are routinely treated with radiotherapy; however, normal tissue toxicity remains a concern. Therefore, it is important to validate treatment modalities combining molecularly targeted agents with radiotherapy to improve the therapeutic ratio. The aim of this study was to assess the ability of the PARP inhibitor niraparib (MK-4827) alone, or in combination with cell cycle checkpoint abrogating drugs targeting Chk1 (MK-8776) or Wee1 (MK-1775), to radiosensitize HNSCCs in the context of HPV status. MATERIALS AND METHODS: PARP1, PARP2, Chk1 or Wee1 shRNA constructs were analyzed from an in vivo shRNA screen of HNSCC xenografts comparing radiosensitization differences between HPV(+) and HPV(-) tumors. Radiosensitization by niraparib alone or in combination with MK-8776 or MK-1775 was assessed by clonogenic survival in HPV(-) and HPV(+) cells; and the role of p16 in determining response was explored. Relative expressions of DNA repair genes were compared by PCR array in HPV(+) and HPV(-) cells, and following siRNA-mediated knockdown of TRIP12 in HPV(-) cells. RESULTS: In vivo shRNA screening showed a modest preferential radiosensitization by Wee1 and PARP2 in HPV(-) and Chk1 in HPV(+) tumor models. Niraparib alone enhanced the radiosensitivity of all HNSCC cell lines tested. However, HPV(-) cells were sensitized to a greater degree, as suggested by the shRNA screen. When combined with MK-8776 or MK-1775, radiosensitization was further enhanced in an HPV dependent manner with HPV(+) cells enhanced by MK-8776 and HPV(-) cells enhanced by MK-1775. A PCR array for DNA repair genes showed PARP and HR proteins BRCA1 and RAD51 were much lower in HPV(+) cells than in HPV(-). Similarly, directly knocking down p16-dependent TRIP12 decreased expression of these same genes. Overexpressing p16 decreased TRIP12 expression and increased radiosensitivity in HPV(-) HN5. However, while PARP inhibition led to significant radiosensitization in the control, it led to no further significant radiosensitization in p16 overexpressing cells. Forced p16 expression in HPV(-) HN5 increased accumulation in G1 and subG1 and limited progression to S phase, thus reducing effectiveness of PARP inhibition. CONCLUSIONS: Niraparib effectively radiosensitizes HNSCCs with a greater benefit seen in HPV(-). HPV status also plays a role in response to MK-8776 or MK-1775 when combined with niraparib due to differences in DNA repair mechanisms. This study suggests that using cell cycle abrogators in combination with PARP inhibitors may be a beneficial treatment option in HNSCC, but also emphasizes the importance of HPV status when considering effective treatment strategies.