Proton Therapy for Unresectable and Medically Inoperable Locally Advanced Pancreatic Cancer: Results From a Multi-Institutional Prospective Registry.

Purpose: Compared with photon-based techniques, proton beam radiation therapy (PBT) may improve the therapeutic ratio of radiation therapy (RT) for locally advanced pancreatic cancer (LAPC), but available data have been limited to single-institutional experiences. This study examined the toxicity, survival, and disease control rates among patients enrolled in a multi-institutional prospective registry study and treated with PBT for LAPC. Methods and Materials: Between March 2013 and November 2019, 19 patients with inoperable disease across 7 institutions underwent PBT with definitive intent for LAPC. Patients received a median radiation dose/fractionation of 54 Gy/30 fractions (range, 50.4-60.0 Gy/19-33 fractions). Most received prior (68.4%) or concurrent (78.9%) chemotherapy. Patients were assessed prospectively for toxicities using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Kaplan-Meier analysis was used to analyze overall survival, locoregional recurrence-free survival, time to locoregional recurrence, distant metastasis-free survival, and time to new progression or metastasis for the adenocarcinoma cohort (17 patients). Results: No patients experienced grade ≥3 acute or chronic treatment-related adverse events. Grade 1 and 2 adverse events occurred in 78.7% and 21.3% of patients, respectively. Median overall survival, locoregional recurrence-free survival, distant metastasis-free survival, and time to new progression or metastasis were 14.6, 11.0, 11.0, and 13.9 months, respectively. Freedom from locoregional recurrence at 2 years was 81.7%. All patients completed treatment with one requiring a RT break for stent placement. Conclusions: Proton beam RT for LAPC offered excellent tolerability while still maintaining disease control and survival rates comparable with dose-escalated photon-based RT. These findings are consistent with the known physical and dosimetric advantages offered by proton therapy, but the conclusions are limited owing to the patient sample size. Further clinical studies incorporating dose-escalated PBT are warranted to evaluate whether these dosimetric advantages translate into clinically meaningful benefits.

Efficacy of ketamine mouthwash in the management of oral and pharyngeal toxicity associated with head and neck chemoradiotherapy: protocol for a phase II, Simon's two-stage trial.

INTRODUCTION: Curative intent treatment of head and neck cancer (HNC) is frequently radiation therapy over 7 weeks with concurrent chemotherapy. This regimen is effective but carries a burden of toxicity leading to severe pain and treatment breaks portending inferior outcomes. Conventional palliation methods include opioids, anticonvulsants and local anaesthetics. Breakthrough toxicities are nevertheless ubiquitous and present an urgent unmet need. Ketamine is an inexpensive drug with mechanisms of analgesia outside the opioid pathway including N-methyl-D-aspartate (NMDA) receptor antagonism and a pharmacologically unique property of opioid desensitisation. Systemic ketamine is validated in randomised controlled trials for efficacy in reducing pain and/or opioid burden in the oncologic setting. Literature supports peripherally administered ketamine for pain control without systemic toxicity. These data support our rationale of using ketamine mouthwash to decrease acute toxicity of curative treatment of HNC, the efficacy of which is our aim to elucidate. METHODS AND ANALYSIS: This is a phase II, Simon's two-stage trial. Patients have pathologically confirmed HNC and an intended regimen of 70 Gy of radiation with concurrent cisplatin. The protocol is initiated on diagnosis of grade 3 mucositis and consists of 2 weeks of 4 times daily (QID) ketamine mouthwash use. The primary endpoint is pain response defined as a combination of pain score and opioid use. 23 subjects will be enrolled in stage 1. If statistical criteria are met, 33 subjects will be enrolled in stage 2. Secondary endpoints include daily pain, daily opioid use, dysphagia at baseline and completion, nightly sleep quality, feeding tube placement and any unscheduled treatment breaks. ETHICS AND DISSEMINATION: All trial data will be stored in an Institutional Review Board (IRB) approved database. The protocol is registered under Northwell IRB registration number #22-0292 and U.S. Food and Drug Administration (FDA) Investigational New Drug (IND) approval has been granted under IND number 161609. Results are intended to be published in an open-source journal and further data, statistics and source documents are available on request. TRIAL REGISTRATION NUMBER: NCT05331131.

Effect of Immunotherapy and Stereotactic Body Radiation Therapy Sequencing on Local Control and Survival in Patients With Spine Metastases.

Purpose: Stereotactic body radiation therapy (SBRT) is commonly used to treat spinal metastases in combination with immunotherapy (IT). The optimal sequencing of these modalities is unclear. This study aimed to investigate whether sequencing of IT and SBRT was associated with differences in local control (LC), overall survival (OS), and toxicity when treating spine metastases. Methods and Materials: All patients at our institution who received spine SBRT from 2010 to 2019 with systemic therapy data available were reviewed retrospectively. The primary endpoint was LC. Secondary endpoints were toxicity (fracture and radiation myelitis) and OS. Kaplan-Meier analysis was used to determine whether IT sequencing (before versus after SBRT) and use of IT were associated with LC or OS. Results: A total of 191 lesions in 128 patients met inclusion criteria with 50 (26%) lesions in 33 (26%) patients who received IT. Fourteen (11%) patients with 24 (13%) lesions received the first IT dose before SBRT, whereas 19 (15%) patients with 26 (14%) lesions received the first dose after SBRT. LC did not differ between lesions treated with IT before SBRT versus after SBRT (1 year 73% versus 81%, log rank = 0.275, P = .600). Fracture risk was not associated with IT timing (χ2 = 0.137, P = .934) or receipt of IT (χ2 = 0.508, P = .476), and no radiation myelitis events occurred. Median OS was 31.8 versus 6.6 months for the IT after SBRT versus IT before SBRT cohorts, respectively (log rank = 13.193, P < .001). On Cox univariate analysis and multivariate analysis, receipt of IT before SBRT and Karnofsky performance status <80 were associated with worse OS. IT treatment versus none was not associated with any difference in LC (log rank = 1.063, P = .303) or OS (log rank = 1.736, P = .188). Conclusions: Sequencing of IT and SBRT was not associated with any difference in LC or toxicity, but delivering IT after SBRT versus before SBRT was associated with improved OS.

Burnout in Radiation Oncology Physician Workforce: The Effect of Mindfulness and Fulfillment.

Purpose: Mindfulness, defined as awareness of the moment while acknowledging and accepting one's feelings, thoughts, and sensations, is the aim of mindfulness meditation. Our objective was to investigate the relationship between burnout, mindfulness, fulfillment, and other personal characteristics in radiation oncology (RO) residents/attendings compared with other specialties. Methods and Materials: From December 2019 to February 2020, residents and attendings in multiple specialties at a single tertiary care academic institution were sent surveys, including the mindfulness attention awareness scale, Stanford professional fulfillment index, and a personal questionnaire. A Pearson correlation was conducted on the relationship between mindfulness, fulfillment, disengagement, and exhaustion. To determine risk factors for burnout (overall burnout ≥ 1.33), a univariate analysis was conducted to yield odds ratios (ORs) on debt, specialty, income, sleep, exercise, marital status, number of children, work hours, mindfulness (mindfulness attention awareness scale ≥ 4), fulfillment (professional fulfillment ≥ 3), and time with family/friends. Significant factors on univariate analysis were entered into multivariate analysis. Results: There were 180 surveys completed by 60 residents and attendings across 17 specialties. Eighteen (30%) respondents were in RO. Mindfulness positively correlated with fulfillment (P < .001, r = 0.534), negatively correlated with exhaustion (P < .001, r = -0.578), and negatively correlated with disengagement (P < .001, r = -0.483). Univariate analysis for factors associated with burnout was significant for mindfulness (OR = 0.065, P < .001), RO versus other specialty (OR = 0.024, P = .044), working >60 h/wk (OR = 5.091, P = .018), spending >10 h/wk with family or friends (OR = 0.120, P = .001), and fulfillment (OR = 0.103, P < .001). Multivariate analysis showed mindfulness and fulfillment to significantly decrease odds of burnout. Conclusions: RO physicians experienced less burnout than physicians in other specialties at our institution. Mindfulness, professional fulfillment, moderate work hours, and spending time with loved ones protected against burnout. Further study of interventions to promote mindfulness and fulfillment may help us understand how best to improve the mental and emotional health of RO physicians.

Implementation of External Beam Five-Fraction Adjuvant Breast Irradiation in a US Center.

Five-fraction adjuvant whole breast radiation has been shown to be a safe and effective alternative to longer fractionation regimens. Given the lack of international consensus on patient selection for the protocol, we developed a consensus protocol to guide patient selection and facilitate safe and efficient five-fraction radiation in our radiation medicine department. In developing the directive, we surveyed departmental physicians about their choice of adjuvant breast regimen for various clinical scenarios. Patient travel burden was the factor most strongly impacting radiation oncologists' decision-making when considering prescribing a five-fraction course of adjuvant breast radiation; the length of clinical trial follow-up data and acute and late normal tissue effects also impacted it, along with personal clinical experience and experience of dosimetry and physics personnel. Relative value unit (RVU) reimbursement and financial toxicity to the patient were reported to be less important in decision-making. Physicians were most comfortable using five-fraction radiation in women >50 years of age with low-risk cancer and for patients unable to attend for longer treatment courses. Eight months after implementation, the protocol accounts for 4.7% of breast irradiation delivered in our department.

Thyroid-optimized and thyroid-sparing radiotherapy in oral cavity and oropharyngeal carcinoma: A dosimetric study.

BACKGROUND: Radiation-induced hypothyroidism is a common toxicity of head and neck radiation. Our re-planning study aimed to reduce thyroid dose while maintaining target coverage with IMRT. METHODS: We retrospectively identified patients with oral-cavity (n = 5) and oropharyngeal cancer (n = 5). Treatment plans were re-optimized with 45 Gy thyroid mean dose constraint, then we cropped the thyroid out of PTVs and further reduced thyroid dose. Target coverage was delivering 100% dose to ≥ 93% of PTV and 95% of dose to > 99% of PTV. RESULTS: Originally, average mean dose to thyroid was 5580 cGy. In model I, this dropped to 4325 cGy (p < 0.0001). In model II, average mean dose was reduced to 3154 cGy (p < 0.0001). For PTV low and PTV int, all had acceptable target coverage. CONCLUSION: In patients with oral-cavity and oropharyngeal cancers, mean dose could be significantly reduced using a thyroid-optimized or thyroid-sparing IMRT technique with adequate coverage.

Guidelines for Palliative Treatment of Spinal Metastases: Choosing Between Stereotactic Body Radiation Therapy and Conventional Fractionation.

Symptomatic spinal metastasis is a frequent complication of cancer that had been treated, until relatively recently, with primitive techniques to modest radiation dose levels, with a baseline assumption of limited survival and poor patient performance in that setting. In the era of targeted and personalized therapies, many patients are living longer and more functionally and are able to manage their disease on the model of chronic illness. Given these developments, an attractive option is the use of stereotactic body radiation therapy (SBRT) to deliver high biologically effective doses of radiation conformally to maximize the palliative gains of treatment. However, randomized data to guide practice are scarce. We review the extant literature and present an algorithmic approach to selecting patients with metastatic disease for palliative spinal SBRT favoring the results of available randomized studies and remaining within the safety constraints supported by evidence from randomized trials.

A series of typical and atypical cases of Bazex syndrome: Identifying the red herring to avoid delaying cancer treatment.

Bazex syndrome is a rare paraneoplastic dermatosis that precedes diagnosis of cancer. Awareness of this syndrome is important, as it allows early detection of underlying malignancy and may prevent misdiagnosis and delays in cancer treatment.

Primary vs nodal site PET/CT response as a prognostic marker in oropharyngeal squamous cell carcinoma treated with intensity-modulated radiation therapy.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) in staging of advanced oropharyngeal squamous cell carcinoma (OPSCC) and at 3 months posttreatment (PETpost) is often utilized to assess response. The significance of lymph node vs primary site treatment response is incompletely understood. METHODS: We reviewed 230 patients treated with radiation therapy. PETpost response was graded at primary and nodal sites and correlated with survival. RESULTS: Median age was 58, and 83% were p16-positive. Median follow-up was 24.3 months. Nodal response at PETpost predicted improved 2-year local recurrence-free survival (LRFS) (93% vs 72%, P =.004), 2-year disease-free survival (DFS) (80% vs 61.3%, P =.021), and 2-year overall survival (OS) (89% vs 83%, P =.051), while primary response only predicted improved 2-year LRFS (91% vs 76% P = .035). CONCLUSION: In OPSCC patients, both nodal and primary response at 3 months on PET/CT predicted for improved LRFS, but only nodal response predicted DFS and OS.

Evaluation of the use of abdominal compression of the lung in stereotactic radiation therapy.

The goal of this retrospective study was to determine the benefit in using abdominal compression to reduce tumor motion for patients treated with lung stereotactic body radiotherapy. Forty-four lung lesions (n = 44) from 37 patients (N = 37) treated at the University of Toledo's Dana Cancer Center were assessed by determining the overall tumor displacement along with possible surrogates such as change in tidal volume and diaphragm displacement, with and without abdominal compression. Measurements of lung capacity were acquired from the 4DCT at maximum and minimum respiration in order to determine the tidal volume, with and without abdominal compression. Tumor centroid and diaphragm apex motion was then assessed in 3 dimensions from phase 0 to phase 50. This was measured in centimeters using the ruler method on MIM software, both with and without the compression belt. Change in overall tumor movement was 0.61 cm ± 0.09 cm with compression, and 0.60 cm ± 0.09 cm without the compression belt. Delta tumor motion was reduced in 5 cases, increased (made worse) in 6 cases, and did not clinically impact the remaining 33 cases. Average tidal volume with abdominal compression was 379.7 mL or 12.0% ± 0.724% of total lung volume while average tidal volume without abdominal compression was 337.7 mL or 10.5% ± 0.649% of total lung volume. Change in diaphragm position throughout the breathing cycle was 1.21 cm ± 0.10 cm with compression, and 1.28 ± 0.13 cm without the compression belt. These findings indicate that abdominal compression may not be an effective method in the reduction of respiratory motion, and can even negatively impact tumor motion by increasing its displacement. Compression decreased tumor motion in 5 out of the 44 cases studied. The 5 cases that benefitted tended to be lesions close to the diaphragm but these 5 corresponded to less than half of the inferior lesions, suggesting that even inferior lung lesions may not be prime candidates for abdominal compression.

BBB-Permeable, Neuroprotective, and Neurotrophic Polysaccharide, Midi-GAGR.

An enormous amount of efforts have been poured to find an effective therapeutic agent for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). Among those, neurotrophic peptides that regenerate neuronal structures and increase neuron survival show a promise in slowing neurodegeneration. However, the short plasma half-life and poor blood-brain-barrier (BBB)-permeability of neurotrophic peptides limit their in vivo efficacy. Thus, an alternative neurotrophic agent that has longer plasma half-life and better BBB-permeability has been sought for. Based on the recent findings of neuroprotective polysaccharides, we searched for a BBB-permeable neuroprotective polysaccharide among natural polysaccharides that are approved for human use. Then, we discovered midi-GAGR, a BBB-permeable, long plasma half-life, strong neuroprotective and neurotrophic polysaccharide. Midi-GAGR is a 4.7kD cleavage product of low acyl gellan gum that is approved by FDA for human use. Midi-GAGR protected rodent cortical neurons not only from the pathological concentrations of co-/post-treated free reactive radicals and Aß42 peptide but also from activated microglial cells. Moreover, midi-GAGR showed a good neurotrophic effect; it enhanced neurite outgrowth and increased phosphorylated cAMP-responsive element binding protein (pCREB) in the nuclei of primary cortical neurons. Furthermore, intra-nasally administered midi-GAGR penetrated the BBB and exerted its neurotrophic effect inside the brain for 24 h after one-time administration. Midi-GAGR appears to activate fibroblast growth factor receptor 1 (FGFR1) and its downstream neurotrophic signaling pathway for neuroprotection and CREB activation. Additionally, 14-day intranasal administration of midi-GAGR not only increased neuronal activity markers but also decreased hyperphosphorylated tau, a precursor of neurofibrillary tangle, in the brains of the AD mouse model, 3xTg-AD. Taken together, midi-GAGR with good BBB-permeability, long plasma half-life, and strong neuroprotective and neurotrophic effects has a great therapeutic potential for the treatment of neurodegenerative diseases, especially AD.