Common Prescription Research Articles

RADT-24. A PROSPECTIVE TRIAL EVALUATING THE EFFICACY OF REIRRADIATION TO BONY METASTASES WITH STEREOTACTIC BODY RADIATION THERAPY

Abstract INTRODUCTION Bone metastasis is common in advanced-stage cancer patients. While reirradiation of metastatic tumors offers significant symptom control, major limits exist on the possible dose delivered to previously irradiated disease sites. Stereotactic body radiation therapy (SBRT) offers the potential to avoid delivering toxic radiation doses to the spinal cord and other organs at risk by delivering large doses with steep dose gradients. METHODS We developed a prospective study including 44 patients with recurrent bone metastasis that were treated to assess the effectiveness of SBRT on local control at or before 6 months as a primary endpoint and local progression-free survival (LPFS), Progression-free survival (PFS), and overall survival (OS) as a secondary objective. RESULTS Patients median age was 62.5 years (22.7% female and 77.3% male). The majority of patients received reirradiation to a spinal lesion (29/44, 65.9%) of various primary disease sites predominantly prostate (13/44, 29.5%), lung (8/44, 18.2%), and renal cell (5/44, 11.4%). The most common dose prescriptions were 30 Gy in 5 fractions (24/44, 54.5%). Of the participants, 41 (93.2%) experienced local control at or before 6 months, with 3.6 median months to local progression for those who progressed. 48% and 36.5% of the cohort maintained LPFS at 2 years, and 3 years respectively with a local progression-free rate of 89.5% at 2 and 3 years. OS was maintained in 50.9% and 38.8% of patients at 2 years and 3 years respectively. CONCLUSION SBRT offers an effective and less toxic approach for the reirradiation of recurrent metastatic tumors as it can prevent associated toxicities to the surrounding normal tissues and maintain a local progression-free rate in a large percentage of patients. We believe that more clinicians should offer SBRT as an effective option for recurrent metastatic bone tumors especially involving the spinal vertebrae.

Detroit Interventional Pain Assessment Scale: A Pain Score and Method for Measuring and Evaluating Post-Operative Pain Management-A Prospective Study.

Background and Objectives: Orthopedic surgeons commonly prescribe opioids, surpassing all medical specialties. Our objective was to develop a pain management scale that captures medication use, patient-reported pain scores, and helps orthopedic surgeons evaluate their post-operative prescribing practice. Materials and Methods: An IRB-approved prospective study followed 502 post-operative orthopedic surgery patients over a six-month period. All patients were surveyed in an orthopedic clinic at a Level 1 US Trauma Center, during a routine follow-up. Patient pain satisfaction was assessed using the validated Interventional Pain Assessment (IPA) scale, which uses three categories: 0 (no pain), 1 (tolerable pain), and 2 (intolerable pain). Daily narcotic use was translated to morphine milligram equivalents (MMEs) using the Michigan Automated Prescription System (MAPS) narcotics registry. When patient pain satisfaction and narcotic usage were combined, this scale was called the Detroit Interventional Pain Assessment (DIPA) scale. Results: The five classes based on common prescription and usage of narcotics in this cohort include the following: A (no pain medication), B (over-the-counter medication), C (occasional use of short-acting narcotics 1-30 MMEs), D (consistent/regular use of short-acting narcotics 31-79 MMEs), and E (long-duration or stronger short-acting narcotics 80+ MMEs). Patients were most satisfied with their pain management at six weeks (80.5%) and three months (75.65%), and least satisfied at two weeks (62.5%) and six months (60.9%). Additional information displayed on the DIPA graph revealed there was a significant decrease in the percentage of patients on narcotics at two weeks (65.2%) to six months (32.6%) at p < 0.001. Conclusions: The DIPA pain scale shows the relationship between patient pain perception and opioid prescription/usage, while also tracking prescriber tendencies. Providers were able to visualize their post-operative pain management progression at each designated clinic visit with corresponding alphabetical daily MME categories. In this study, results suggest that surgeons were not effective at managing the pain of patients at two weeks post-operative, which is attributed to an inadequate number of pain pills prescribed upon discharge. Overall, the DIPA graph signaled that better pain management interventions are necessitated in periods with lower efficiency scores.

Palliative whole brain radiation therapy: an international state of practice.

Improvements in radiation delivery and systemic therapies have resulted in few remaining indications for palliative whole brain radiation therapy (WBRT). Most centers preferentially use stereotactic radiotherapy (SRT) and reserve WBRT for those with >15 lesions, leptomeningeal presentation, rapidly progressive disease, or limited estimated survival. Despite regional differences among preferred dose, fractionation, and treatment technique, we predict survival post-WBRT will remain poor-indicating appropriate application of WBRT in this era of SRT and improved systemic therapies. A multi-center, international retrospective analysis of patients receiving WBRT in 2022 was performed. Primary end point was survival after WBRT. De-identified data were analyzed centrally. Patients receiving WBRT as part of a curative regimen, prophylactically, or as bridging therapy were excluded. The collected data consisted of patient parameters including prescription dose and fractionation, use of neurocognitive sparing techniques and survival after WBRT. Survival was calculated via the Kaplan-Meier method. Of 29,943 international RT prescriptions written at ten participating centers in 2022, 462 (1.5%) were for palliative WBRT. Participating centers were in the United States (n=138), the United Kingdom (n=111), Hong Kong (n=72), Italy (n=49), Belgium (n=45), Germany (n=27), Ghana (n=15), and Cyprus (n=5). Twenty-six different dose regimens were used. The most common prescriptions were for 3,000 cGy over 10 fractions (45.0%) and 2,000 cGy over 5 fractions (43.5%) with significant regional preferences (P<0.001). Prior SRT was delivered in 32 patients (6.7%), hippocampal avoidance (HA) was used in 44 patients (9.5%), and memantine was prescribed in 93 patients (20.1%). Survival ranged from 0 days to still surviving at 402 days post-treatment. The global median overall survival (OS) was 84 days after WBRT [95% confidence interval (CI): 68.0-104.0]. Actuarial survival at 7 days, 1 month, 3 months, and 6 months were 95%, 78%, 48%, and 32%, respectively. Twenty-seven patients (5.8%) were unable to complete their prescribed WBRT. This moment-in-time analysis confirms that patients with poor expected survival are being appropriately selected for WBRT-illustrating the dwindling indications for WBRT-and demonstrates the variance in global practice. Since poor survival precludes patients from deriving benefit, memantine and HA are best suited in carefully selected cases.

Endogenous and Exogenous Thyrotoxicosis and Risk of Incident Cognitive Disorders in Older Adults

Thyroid hormone is among the most common prescriptions in the US and up to 20% may be overtreated. Endogenous hyperthyroidism may be a risk factor for dementia, but data are limited for iatrogenic thyrotoxicosis. To determine whether thyrotoxicosis, both endogenous and exogenous, is associated with increased risk of cognitive disorders. This cohort study performed a longitudinal time-varying analysis of electronic health records for patients receiving primary care in the Johns Hopkins Community Physicians Network between January 1, 2014, and May 6, 2023. Patients 65 years and older with at least 2 visits 30 days apart to their primary care physicians were eligible. None of the 65 931 included patients had a history of low thyrotropin (TSH) level or cognitive disorder diagnoses within 6 months of their first visit. Data analysis was performed from January 1 through August 5, 2023. The exposure variable was a low TSH level, characterized based on the clinical context as due to endogenous thyrotoxicosis, exogenous thyrotoxicosis, or unknown cause, excluding those attributable to acute illness or other medical factors such as medications. The outcome measure was cognitive disorders, including mild cognitive impairment and all-cause dementia, to improve sensitivity and account for the underdiagnosis of dementia in primary care. A total of 65 931 patients were included in the analysis (median [IQR] age at first visit, 68.0 [65.0-74.0] years; 37 208 [56%] were female; 46 106 [69.9%] were White). Patients exposed to thyrotoxicosis had cognitive disorder incidence of 11.0% (95% CI, 8.4%-14.2%) by age 75 years vs 6.4% (95% CI, 6.0%-6.8%) for those not exposed. After adjustment, all-cause thyrotoxicosis was significantly associated with risk of cognitive disorder diagnosis (adjusted hazard ratio, 1.39; 95% CI, 1.18-1.64; P < .001) across age groups. When stratified by cause and severity, exogenous thyrotoxicosis remained a significant risk factor (adjusted hazard ratio, 1.34; 95% CI, 1.10-1.63; P = .003) with point estimates suggestive of a dose response. In this cohort study among patients 65 years and older, a low TSH level from either endogenous or exogenous thyrotoxicosis was associated with higher risk of incident cognitive disorder. Iatrogenic thyrotoxicosis is a common result of thyroid hormone therapy. With thyroid hormone among the most common prescriptions in the US, understanding the negative effects of overtreatment is critical to help guide prescribing practice.

Long-Term Safety and Efficacy of SAbR for Metastatic RCC.

Metastasis-directed stereotactic ablative radiation (SAbR) in metastatic renal cell carcinoma (mRCC) has been shown to prolong time to systemic therapy start/change. However, there is a paucity of data on the durability of local control by SAbR and long-term side effects, limiting its investigation in prospective trials. Here we report the long-term local control rates of SAbR for mRCC, focusing on factors that lead to local failure where dose escalation may be beneficial. We retrospectively reviewed 354 metastatic RCC patients who received SAbR to 902 lesions between 2005 and September 2021. Acute and late adverse events and their Common Terminal Criteria for Adverse Events (CTCAE) v. 5.0 grades were collected. RECIST v. 1.1 was used to evaluate treatment response. LC was estimated using the cumulative incidence function, with death as a competing risk. Local control (LC) was calculated using the Kaplan-Meier method. Lesions were followed for a median of 16 months; 136 lesions had >36 months of follow-up. The most common radiation prescription was 36 Gy in 3 fractions, and the median biological effective dose was 72 Gy10. 3-year local control was 80% (95% CI 75, 83). 3-year LC differed according to lesion location, ranging from 65% (95% CI 52, 75) in the spine to 93% (95% CI 80, 98) in the lungs. Radiation-induced adverse events were experienced by 101 patients: 79 had an acute (≤90 days of SAbR) grade 1-2 toxicity; 20 had an acute grade 3-4 toxicity; 59 had a late grade 1-2 toxicity; 15 had a late grade 3-4 toxicity. The most common acute grade 1-2 toxicity was pain (n = 32), followed by nausea (n = 22) and fatigue (n = 16). There were 7 occurrences of acute grade 3-4 pain, 4 of nausea, and 2 fractures. The most common late grade 1-2 toxicity was fracture (n = 16), followed by pain (n = 15) and pneumonitis (n = 12). Hyperglycemia was the only late grade 3-4 toxicity that occurred more than once (n = 2). SAbR offers durable LC of mRCC lesions with an acceptable toxicity profile. LC was affected by treated lesion location, with bone (including long bones and ribs) and spine locations experiencing less durable LC, corresponding to locations that received lower-BED treatments.

A Review of Recent Chinese Clinical Studies on Herbal Medicine Treatments for Chronic Pancreatitis

Objectives: This study summarizes current trends and results in clinical studies on herbal medicine treatments for chronic pancreatitis.Methods: Studies published from 2014 to 2023 were searched for on the China National Knowledge Infrastructure (CNKI), PubMed, and KMbase using the keywords “chronic pancreatitis”, “herbal medicine”, “herb”, “만성 췌장염”, and “한약”. The studies were analyzed according to year, study design, characteristics of the patients, and traditional Chinese medicine (TCM) intervention.Results: In total, 23 studies were selected. There were 21 randomized controlled trials and 2 case-control studies. The most common herbal prescriptions were Qingyi-tang (淸胰湯), &lt;i&gt;Radix Bupleuri&lt;/i&gt; (柴胡), &lt;i&gt;Radix Paeoniae Alba&lt;/i&gt; (白芍藥), &lt;i&gt;Radix Glycyrrhizae&lt;/i&gt; (甘草), &lt;i&gt;Radix Scutellariae&lt;/i&gt; (黃芩), and &lt;i&gt;Rhei Rhizoma&lt;/i&gt; (大黃). In all the studies, herbal medicine treatments were effective in the treatment of chronic pancreatitis, and efficacy was assessed using clinical symptoms, physicochemical examination, radiological examination, and relapse.Conclusions: Herbal medicine treatment can be an effective treatment for chronic pancreatitis and has potential in clinical practice.

Safety and Efficacy of Stereotactic Body Radiotherapy for Ultra-Central Thoracic Tumors

Stereotactic body radiotherapy (SBRT) is increasingly utilized in the management of ultra-central thoracic tumors, although concerns regarding significant toxicity remain. We sought to evaluate the toxicity and efficacy of SBRT to these tumors at our institution. Patients with ultra-central lung tumors or nodes treated at our institution with SBRT between 2009 and 2019 were retrospectively reviewed. Ultra-central was defined as having the planning target volume (PTV) overlapping or abutting the central bronchial tree and/or esophagus. All SBRT plans were generated with homogenous dose distributions using target coverage objectives of ITV V100% >99%, PTV V95% >99%, and an ideal PTV Dmax <105% (strict <120%). All plans were reviewed in quality assurance rounds by a team of dosimetrists, physicists, and radiation oncologists. The primary endpoint was incidence of severe toxicity (ST), defined as SBRT-related grade ≥3 toxicities, graded using the Common Terminology Criteria for Adverse Events V5.0. Secondary endpoints included local failure (LF), progression-free survival (PFS) and overall survival (OS). Competing risk analysis was used to estimate incidence and predictors of ST and LF, with death as a competing risk. Kaplan-Meier method was used to estimate PFS and OS. A total of 154 patients who received 162 ultra-central courses of SBRT were included, with a median follow-up of 21.5 months. Treatment intent was most commonly for oligoprogression (46%), oligometastasis (30%), followed by curative (20%). The most frequent tumor histologies were NSCLC (41%) and RCC (26%). SBRT prescription doses ranged from 30-55 Gy in 5 fractions (BED10 range 48-115 Gy). The most common prescription was 50 Gy in 5 fractions (42%). The cumulative incidence of ST was 8.9% at 3-years. The most common ST was pneumonitis (n = 4). Notable toxicities included bronchopleural fistula (n = 2, grade 3 and 4), bronchial stricture (n = 1, grade 3), and esophagitis leading to bleeding (n = 1, grade 4). There were no esophageal strictures or perforations, and no bronchial bleeds. There was 1 possible treatment related death from pneumonitis/pneumonia. Predictors of any ST included increased lung V5 Gy, decreased PTV V95%, and not having prior radiation therapy to the chest. The cumulative incidence of LF was 4.8%, 11% and 14% at 1-, 2-, and 3-years respectively. Predictors of LF included younger age, and greater volume of overlap between the PTV and esophagus. Median PFS was 8.4 months, while median OS was 3.7 years. In one of the largest case series of ultra-central thoracic SBRT reported to date, homogenously prescribed SBRT plans were associated with relatively low rates of ST and LF across a variety of treatment indications. Predictors of ST should be interpreted recognizing the heterogeneity in toxicities observed. Identified predictors of both ST and LF can contribute to future work to optimize the therapeutic ratio in treatment of ultra-central thoracic tumors.

Definitive Radiotherapy for Oligometastatic and Oligoprogressive Thyroid Cancer

Local consolidative radiotherapy (LCT) for oligometastatic disease is a promising paradigm improving outcomes for various malignancies but has been underexplored for metastatic thyroid cancer. We hypothesize that LCT to distant sites with definitive RT doses can yield favorable outcomes and defer systemic therapy escalation for these patients. We reviewed 96 thyroid cancer patients who received 175 LCT courses from 2010-2022 to 228 metastatic sites, including: thorax (45%), bone (40%), brain (6%), head/neck (5%), and abdomen (3%). Common prescriptions were 50-55Gy/4-5fxs or 56-70Gy/8-10fxs for lung; 52.5-60Gy/15fxs for mediastinum; and 18-24Gy/1fx or 27-30Gy/3fxs for bone. RECIST v1.1 and CTCAE v5.0 were used to define progression and toxicities, respectively. Outcomes were evaluated via Kaplan-Meier and associations examined via Cox proportional hazards modeling. Median age was 63 years (range: 26-92), with 62 oligometastatic cases (total 1-5 sites) and 34 oligoprogressive (with 1-5 growing sites). Primary disease was controlled in all patients, with 39% receiving post-op RT and 66% prior RAI. Histologies included papillary (40%), anaplastic (25%), follicular (12%), medullary (9%), Hurthle (7%), and poorly-differentiated (7%). Median time from initial diagnosis to LCT was 3 yrs (IQR 1-8), and median follow-up from 1st LCT was 21 mos (IQR 9-51). Patients received an average 2 LCT courses (range 1-8) treating 1-4 sites. Median survival (OS) from 1st LCT was 9 yrs (95% CI = 5-14). On multivariable analysis (MVA), worse OS was associated with anaplastic histology (HR 4.6, p<.01), but longer OS was associated with prior RAI (HR 0.33, p = .02) and oligometastatic disease (HR 0.3, p = .01). For anaplastic histology, median OS was 1.2 years vs. 9.3 years for non-anaplastic; 3-yr OS was 36% vs. 88% (log-rank, p<.01). Five-year OS for oligometastatic cases was 75% vs 53% for oligoprogressive (log-rank, p = .04). Median progression free survival (PFS) from 1st LCT was 15.5 mos (95% C I = 11-20). On MVA for all LCT courses, time to any progression (TTP) was negatively associated with anaplastic histology (HR 1.7, p = .02) and 2nd or higher LCT course (HR 1.45, p = .05), but favorably associated with thoracic site (HR 0.49, p<.01). Following later LCT courses, median TTP was 11 mos vs 17 mos for initial LCT course (log-rank, p = .03). After LCT to lung/chest, TTP was 18.6 mos vs 9.5 mos for non-thoracic sites (log-rank, p<.01). Only 6% of failures occurred at previously treated lesions. Most LCT courses (67%) were without ongoing chemotherapy, while 25% entailed continuing the same regimen and 9% had planned treatment post-RT. There were 2 Grade 3 toxicities (pneumonitis and esophagitis) and no Grade 4-5 events. With high local control rates and minimal toxicity, LCT can be a feasible strategy to defer systemic therapy escalation for oligometastatic and oligoprogressive thyroid cancer.

Frameless Fractionated Stereotactic Radiosurgery for Brain Metastases: An Institutional Series of 145 Cases

Cobalt-60 stereotactic radiosurgery (SRS) typically involves single fraction treatment with frame immobilization. However, large tumor size, proximity to critical structures, and prior radiation treatment sometimes necessitate fractionated SRS with mask immobilization. We present a large institutional experience with fractionated mask-based SRS for brain metastases. In this single-institution, IRB-approved study, all patients treated with mask-based fractionated SRS for brain metastases from March 2017 to January 2023 were identified. The primary outcomes were 1- and 2-year local control (LC) by Kaplan-Meier method. A total of 118 patients with a total of 145 metastases were treated. The median follow-up time was seven months. The median age at treatment was 64.1 years (range: 26-95 years). 55.9% of patients were female. The most common primary tumors were breast (25.5%), non-small cell lung (23.4%), small-cell lung (8.3%), and melanoma (8.3%). For most cases (59.3%), the indication for fractionation was retreatment. Large size (28.3%), critical location (9.7%), and medical comorbidity (2.1%) were other indications. For all cases, the mean maximal linear size was 34.9 mm and mean target volume was 15.6 cc. For cases fractionated due to size, the mean size was 43.9 mm and mean target volume was 23.8 cc. Median total dose was 2,700 cGy (range: 1,620-3,000), and median dose per fraction (fx) was 600 cGy (range: 405-900). The most common prescriptions were 3,000 cGy/5 fx (40.0% of patients) and 2500 cGy in 500 cGy per fraction (37.2% of patients). Mean maximum dose was 4,833 cGy (range: 2,920-7,500). For 75.2% of treatments, the prescription isodose line was 50 to 59% (mean, 56.9%). Target coverage was 100% in all but one case (99%). For lesions near the brainstem, mean brainstem maximum point dose (MPD) was 9.3 Gy ± 9.8 Gy and brainstem mean dose was 3.3 Gy ± 3.3 Gy. For lesions near the optic pathway, mean optic nerve MPD was 14.4 Gy ± 9.2, optic nerve mean dose was 6.4 Gy ± 5.4 Gy, mean optic chiasm MPD was 11.7 Gy ± 7.9 Gy, and optic chiasm mean dose was 5.4 Gy ± 4.7 Gy. 1-year LC was 88.2% and 2-year LC was 80.4%. When retreatments were excluded, 1-year LC was 98.0% and 2-year LC was 98.0%. 18% of patients had acute grade 1-2 toxicities (fatigue, headache, nausea, and/or alopecia), and one patient had acute grade 3 fatigue. There was no other grade 3+ acute toxicities. 14% of patients had grade 1-2 radiation necrosis (RN); there were no cases of grade 3+ RN. Cobalt-60 frameless fractionated SRS for brain metastases offers excellent local control, rigorous sparing of critical structures, and minimal toxicity. Frameless fractionated SRS should be considered for large, retreated, or critically located metastases.

Feasibility and Safety of Single-Isocenter/Multi-Lesion (SIML) HyperArc Brain SRT: Clinical Implementation and Early Outcomes

Patients with multiple brain metastases may not tolerate relatively longer treatment times for traditional stereotactic radiation therapy (SRT) with individual isocenter plans for each lesion due to discomfort or co-morbidities. SRT using a single-isocenter/multi-lesion (SIML) HyperArc volumetric modulated arc therapy (VMAT) plan with flattening filter free (FFF) beam could significantly shorten overall treatment time, and improve patient comfort, compliance, and clinic efficiency. We report early clinical results of treating multiple brain metastases with SIML HyperArc SRT. Twenty-three patients with multiple brain metastatic tumors (range, 2-9 lesions; total treated lesions, n = 96) were simulated using Encompass support and Q-fix mask, and treated with a highly-conformal SIML VMAT SRT plans via non-coplanar HyperArc geometry. Mean tumor distance to isocenter was 5.3 cm, maximum up to 7 cm. Common prescriptions were 25-30 Gy/5 fractions, 24-27 Gy/3 fractions, and 20 Gy/1 fraction prescribed to each planning target volume (PTV) using 2 mm margin around standard gross tumor volume (GTV) delineated on contrasted enhanced MP-RAGE MRI fusion. Acuros dose calculation for 6MV-FFF beam was used for tissue heterogeneity corrections. Alliance A071801 criteria was used for dose constraints to organs at risk (OAR) and target conformality. Treatment was delivered every other day with CBCT-guidance, adjustments made with 6DOF couch corrections on a medical linear accelerator, and treatment delivery time within 15 minutes. Local control rates were reported, and toxicity profile rated based on CTCAE v5.0 for brain radionecrosis, optic neuropathy, and brainstem dysfunction. All plans met Alliance A071801 requirements for each tumor coverage, dose to OAR including optic apparatus, brainstem, and spinal cord. Mean GTV and PTV volume were 9.4 cc (range, 0.3-54.8 cc) and 16.13 cc (range, 1.0-80.2 cc). Patient-specific quality assurance results were 98.3% for gamma passing criteria of 2%/2mm. Independent in-house Monte Carlo physics second check agreed with HyperArc plans by ±3.0%. Mean follow up was 6 months (range, 0.0-18.6 months). Of the 23 patients treated, 17 (74%) had post-treatment MRI imaging to assess local control and toxicity. Local control was achieved in 69/73 (95%) of treated and followed lesions. CTCAE grade 2 radionecrosis occurred in 2 patients and were managed with dexamethasone. No CTCAE grade 3+ events of radionecrosis, optic pathway dysfunction, or brainstem toxicity were observed. SIML HyperArc Brain SRT for multiple brain metastases has excellent local control and low toxicity profile in our patients. It can significantly reduce treatment delivery time as compared to traditional multiple-isocenter brain SRT or chronologically separate treatment courses and thus, help to improve patient comfort, compliance, ease of care, and clinic workflow. Longer median follow up of SIML brain SRT on larger patient cohort is warranted.

Clinical Outcomes of Synchronous Lung Stereotactic Body Radiation Therapy Lesions via Single-Isocenter/Multi-Lesion Treatments

Lung cancer patients with synchronous primary or oligometastatic (< 5 lesions) with associated co-morbidities may not retain their treatment position for the extended stereotactic body radiotherapy (SBRT) treatment times with individual isocenter plans for each lesion due to discomfort or shortness of breath. SBRT using a single-isocenter/multi-lesion (SIML) volumetric arc therapy (VMAT) plan with flattening filter free (FFF) beam could significantly shorten overall treatment time, improve patient comfort and compliance and clinic efficiency. We report clinical results of treating multiple lung metastases or synchronous primary lung cancers with SIML lung SBRT. Eighty patients with synchronous primary lung cancers or oligometastatic lung tumors (two, n = 61; three, n = 10; four, n = 4; five n = 5; total treated lesions, n = 193) were simulated with abdominal compression and/or 4D-CT MIP images and treated with a highly-conformal SIML VMAT lung SBRT plans via 3-4 non-coplanar arcs. Common prescriptions were 50-55 Gy/5 fractions and 54 Gy/3 fractions prescribed 70-80% isodose line to the each PTV. Acuros dose calculation for 6MV-FFF beam was used for tissue heterogeneity corrections. RTOG-0618/0813 criteria were used to dose constraints to organs at risk (OAR) and target conformality. Treatment was delivered every other day or twice weekly with CBCT-guidance, adjustments made with 6DOF couch corrections on a medical linear accelerator, and treatment delivery time within 15 minutes. Local control rates and toxicity profile was evaluated using CTCAE v. 5.0 grading for pneumonitis, rib fracture and chest wall pain. All plans met RTOG-0618/0813 requirements for each tumor coverage, dose to OAR including normal lung and ribs. Mean follow up after last fraction of treatment was 16.9 months (range, 1.0-54.2 months). PTV volume ranged from 2.17 to 167.8 cc with mean volume of 16.1 cc. Of the 80 patients treated, 71 had adequate post-treatment thoracic CT imaging to assess local control. Local control was achieved in 167/175 (95.4%) of treated and followed lesions. CTCAE grade 1 asymptomatic pneumonitis was noted on thoracic CT scans in 42/71 (59.2%) of patients and occurred, on average 4.8 months after SBRT. Symptomatic pneumonitis and rib fracture did not occur in any patient. CTCAE grade 2 chest wall pain occurred in 4/80 (5.0%) treated patients and was managed conservatively with over-the-counter NSAIDS or acetaminophen. SIML lung SBRT for synchronous primary lung cancers or multiple lung metastases can be used as a variant to traditional multiple isocenter SBRT or chronologically separate treatment courses, and has excellent local control rates and low toxicity profile in our patient population. It can help improve comfort and compliance of the patients who have difficulty lying still for an extended treatment course, and significantly reduces treatment time via isocenter shifts/repeated CBCTs for image guidance, thus improving clinic efficiency.

Palliative Whole Brain Radiotherapy: International State of Practice 2022

Increasing technology of radiation treatment planning and delivery, better systemic therapies, and randomized trials in the population of patients (pts) with brain metastases have provided robust targeted options. This has resulted in palliative whole brain radiation therapy (WBRT) being used far less frequently than previously. Most centers preferentially use stereotactic radiation surgery (SRS) for pts with several lesions and may reserve WBRT for those with poor performance, with rapidly progressive disease, or with leptomeningeal presentation. We hypothesize that different trends in current WBRT regimens exist across different continents with varying rates of use of hippocampal avoidance (HA) and memantine. Despite differences in dose, fractionation, and treatment technique, we predict that survival post-WBRT will remain poor-indicating appropriate application of whole brain treatment in this era of SRS and improved systemic therapies. A multi-center international analysis of pts receiving WBRT in 2022 was performed. Primary end point was survival after WBRT. Participating centers were located in Belgium, the United Kingdom, Hong Kong, Cyprus, Italy, Germany, Ghana, and the United States. De-identified data were collected and analyzed centrally. Pts receiving WBRT as part of a curative regimen (e.g., medulloblastoma, primary CNS lymphomas), prophylactically in small cell lung cancer, or as bridging prior to CAR-T were excluded. The collected data consisted of pt parameters including prior stereotactic radiosurgery (SRS), prescription dose and fractionation, use of HA technique with or without memantine, and survival after WBRT. Survival was calculated via the Kaplan-Meier method. Of 23,332 RT prescriptions written at these centers in 2022, 399 (1.7%) were for palliative WBRT. Most frequent primary cancers were lung (42%) and breast (28%). Twenty-seven different dose regimens were used. The most common prescriptions were for 3 Gy daily fractions for 10 fractions (45%) and 4 Gy daily for 5 fractions (37%). Prior CNS SRS was delivered in 32 pts (7%). HA technique was used in 44 pts (10%); this technique was almost exclusively used in the United States. Memantine was prescribed in 93 pts (20%). Survival ranged from zero days to still surviving. The global median overall survival was 84 days after completion of treatment (95% CI: 68.0-104.0). Cumulative 3-month and 6-month actuarial survivals were 48% and 32%. This "moment in time" analysis confirms that pts with poor expected survival are being appropriately selected for WBRT and demonstrates the variance in global practice. Since poor survival precludes these pts from deriving much benefit, memantine and HA may be best suited only for carefully selected cases; use of these is not Standard of Care in the participating European, Asian, and African centers.

A Prospective Study Assessing the Efficacy and Toxicity of Stereotactic Body Radiation Therapy for Oligometastatic Bone Metastases

Stereotactic body radiation therapy (SBRT) is a promising treatment for oligometastatic disease in bone due to its delivery of high dose to target tissue and minimal dose to surrounding tissue. The purpose of this study is to assess efficacy and toxicity of this treatment in patients with previously unirradiated oligometastatic bony disease. In this prospective phase II trial, patients with oligometastatic bone disease, defined as ≤3 active sites of disease, were treated with SBRT at one of two academic institutions between December 2016 and May 2019. Local progression-free survival (LPFS), progression-free survival (PFS), prostatic specific antigen (PSA) progression, and overall survival (OS) were reported. Treatment-related toxicity was also reported. A total of 98 patients and 131 lesions arising from various tumor histologies were included in this study. The median age of patients enrolled in the study was 72.8 years (80.6% male, 19.4% female). Median follow-up was 26.7 months. The most common histology was prostate cancer (68.4%, 67/98). The most common dose prescriptions were 27/30 Gy in 3 fractions (26.0%, 34/131), 30 Gy in 5 fractions (19.1%, 25/131), or 30/35 Gy in 5 fractions (16.0%, 21/131). Multiple doses per treatment regimen reflect dose painting employing the lower dose to the clinical target volume (CTV) and higher dose to the gross tumor volume (GTV). Four patients (4.1%, 4/98) experienced local progression at one site for each patient (3.1%, 4/131). Among patients who progressed locally, the median time to local recurrence was 25.8 months (31.0 months among prostate cancer patients, N = 2, and 14.5 months among non-prostate cancer patients, N = 2). Among the entire cohort, 2-year LPFS (including death without local progression) was 85.0%, 2-year PFS (including deaths as well as local, distant, and PSA-based progression) was 47.0%, and 2-year OS was 87.5%. Twenty-seven patients (27.6%, 27/98) developed treatment-related toxicities, and most were Grade 1 (19.4%, 19/98) and 2 (4.1%, 4/98). Four patients (4.1%, 4/98) developed Grade 3 toxicities; there were no Grade 4 toxicities. The most common toxicity was fatigue (10.2%, 10/98). Of 68 treated spine metastases, there were four (5.9%, 4/68) vertebral fractures. Among these four patients, median time to fracture was 23.5 months (range 14.2-39.2 months). Our study supports existing literature in showing that SBRT is effective and tolerable in patients with oligometastatic bone disease. Larger phase III trials are necessary and reasonable to determine long-term efficacy and toxicities.

An Update of Stereotactic Body Radiotherapy (SBRT) for the Palliation of Unirradiated Mucosal Head and Neck Squamous Cell Carcinoma (SCC)

We report the treatment outcomes of palliative Stereotactic Body Radiation Therapy (SBRT) in patients with primary mucosal head and neck cancer (HNC) who were not eligible to receive conventional radiation therapy (RT). This is a retrospective study that reviewed the medical records of patients with primary SCC mucosal HNC who were treated with SBRT between 2011 and 2022. Patients with other histologies, skin cancer, parotid tumors, or recurrent previously irradiated tumors were excluded from the study. A total of 74 patients and 77 tumors were treated with SBRT in this cohort. The median age in the study was 81 (52-97) years and the median follow-up was 7.2 months. The most common site of HNC was the oral cavity (62%), followed by the oropharynx (18%), hypopharynx (8%), larynx (5%), nasal cavity/sinonasal cancer (3%), and unknown primary (1%). T3-4 lesions were found in most patients (76%). SBRT doses ranged from 35-50 Gy in 5 fractions, and the most common prescription dose was ≥45 Gy in 5 fractions (60%) for the GTV prescription. An elective nodal volume of 25 Gy in 5 fractions was infrequently (17%) used. Most patients (81%) who were treated twice a week completed in ≤14 days. The predominant symptoms at presentation were: pain (41%), mass effect (39%), dysphagia/odynophagia (14%), headache/nasal obstruction (1.4%), bleeding (1.4%), stridor (1.4%), asymptomatic (1.4%), and unknown (1.4%). 84% of patients had symptomatic response to treatment with 24% of them having complete symptom response. Cumulative incidence of local failure (LF) was 6.7% and at 6 months and 17.9% at 12 months, respectively. Cumulative incidence of distant metastasis was 7.3% and 10.5% at 6 and 12 months. Cancer was the most common cause of death in 29 patients (51%). The median overall survival (OS) was 8 months with 6 and 12-month OS rates of 67% and 36%, respectively. 39% of patients developed acute G3 toxicity, including 30% with G3 mucositis, 5% with G3 dysphagia, and 4% with G3 dermatitis. A crude rate of late G ≥3 toxicity was observed in 11% of patients including (5%, n = 4) with osteoradionecrosis, and a single case of dysphagia, soft tissue necrosis, supraglottic ulceration, and mucosal necrosis. This study highlights the feasibility of SBRT as a treatment option for primary mucosal head and neck cancer patients who are not eligible for conventional radiation therapy. The results indicate that SBRT was effective in achieving local control and symptom relief, but larger prospective studies are needed to confirm the findings. The Canadian Cancer Trials Group has endorsed HN-13, a randomized control trial comparing HN SBRT to palliative RT.

P03.06.A FRAMELESS FRACTIONATED STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: AN INSTITUTIONAL SERIES OF 145 CASES

Abstract BACKGROUND Cobalt-60 stereotactic radiosurgery (SRS) typically involves single fraction treatment with frame immobilization. However, large tumor size, proximity to critical structures, and prior radiation treatment sometimes necessitate fractionated SRS with mask immobilization. We present a large institutional experience with fractionated mask-based SRS for brain metastases. MATERIAL AND METHODS In this single-institution, IRB-approved study, all patients treated with mask-based fractionated SRS for brain metastases from March 2017 to January 2023 were identified. The primary outcomes were 1- and 2-year local control (LC) by Kaplan-Meier method. RESULTS 118 patients with a total of 145 metastases were treated. The median follow-up time was seven months. The median age at treatment was 64.1 years (range: 26-95 years). 55.9% of patients were female. The most common primary tumors were breast (25.5%), non-small cell lung (23.4%), small-cell lung (8.3%), and melanoma (8.3%). For most cases (59.3%), the indication for fractionation was retreatment. Large size (28.3%), critical location (9.7%), and medical comorbidity (2.1%) were other indications. For all cases, the mean maximal linear size was 34.9 mm and mean target volume was 15.6 cc. For cases fractionated due to size, the mean size was 43.9 mm and mean target volume was 23.8 cc. Median total dose was 2,700 cGy (range: 1,620-3,000), and median dose per fraction (fx) was 600 cGy (range: 405-900). The most common prescriptions were 3,000 cGy/5 fx (40.0% of patients) and 2500 cGy in 500 cGy per fraction (37.2% of patients). Mean maximum dose was 4,833 cGy (range: 2,920-7,500). For 75.2% of treatments, the prescription isodose line was 50 to 59% (mean, 56.9%). Target coverage was 100% in all but one case (99%). For lesions near the brainstem, mean brainstem maximum point dose (MPD) was 9.3 Gy ± 9.8 Gy and brainstem mean dose was 3.3 Gy ± 3.3 Gy. For lesions near the optic pathway, mean optic nerve MPD was 14.4 Gy ± 9.2, optic nerve mean dose was 6.4 Gy ± 5.4 Gy, mean optic chiasm MPD was 11.7 Gy ± 7.9 Gy, and optic chiasm mean dose was 5.4 Gy ± 4.7 Gy. 1-year LC was 88.2% and 2-year LC was 80.4%. When retreatments were excluded, 1-year LC was 98.0% and 2-year LC was 98.0%. 18% of patients had acute grade 1-2 toxicities (fatigue, headache, nausea, and/or alopecia), and one patient had acute grade 3 fatigue. There were no other grade 3+ acute toxicities. 14% of patients had grade 1-2 radiation necrosis (RN); there were no cases of grade 3+ RN. CONCLUSION Cobalt-60 frameless fractionated SRS for brain metastases offers excellent local control, rigorous sparing of critical structures, and minimal toxicity. Frameless fractionated SRS should be considered for large, retreated, or critically located metastases.

Zhisou powder displays therapeutic effect on chronic bronchitis through inhibiting PI3K/Akt/HIF-1α/VEGFA signaling pathway and reprograming metabolic pathway of arachidonic acid

Ethnopharmacological relevanceZhisou Powder (ZP), one of the most common prescriptions in traditional Chinese medicine, has been widely used in the treatment of acute or chronic bronchitis and chronic cough. The ZP was composed of Ziwan (Aster tataricus L. f.), Jiegeng (Platycodon grandiflorus (Jacq.) A. DC.), Jingjie (Nepeta cataria L.), Baibu (Stemona sessilifolia (Miq.) Miq.), Baiqian (Vincetoxicum glaucescens (Decne.) C. Y. Wu & D. Z. Li), Chenpi (Citrus × aurantium f. deliciosa (Ten.) M. Hiroe) and Gancao (Glycyrrhiza uralensis Fisch. ex DC.), with plant names among it checked with MPNS (http://mpns.kew.org). But until now, the key active components and targets of ZP, and related mechanism of ZP in the treatment of chronic bronchitis (CB) remain unclear. Aim of the studyThis study combined UPLC-Q-Exactive-Orbitrap-MS, network pharmacology, metabonomics with experiment verification to explore potential mechanism of ZP in the treatment of CB. Materials and methodsUPLC-Q-Exactive-Orbitrap-MS was performed to analyze the chemical components of ZP. The potentially effective components, attractive targets and critical signaling pathways of Zhisou Powder in the treatment of CB were screened by UPLC-Q-Exactive-Orbitrap-MS combined with network pharmacology. Additionally, the CB model rats induced by SO2 were used to evaluate the anti-chronic bronchitis activity of ZP in vivo. The pulmonary pathology was determined by hematoxylin-eosin staining. Meanwhile, PI3K/Akt/HIF-1α/VEGFA signaling pathway predicted from network pharmacology was verified by Western blot and RT-PCR. Lastly, the metabolic changes of arachidonic acid (AA) in ZP-treated rats were quantitatively analyzed by LC-MS targeted metabonomics, and the proteins expression involved in AA metabolic pathway were detected by immunohistochemistry, immunofluorescence and Western blot. ResultsThe main active components of ZP in the treatment of CB selected by network pharmacology and UPLC-Q-Exactive-Orbitrap-MS technology were quercetin, kaempferol, luteolin, galangin, isorhamnetin, naringenin, nobiletin, formononetin and so on. The core targets of these components were predicted to be TP53, TNF, IL-6, VEGFA, CASP3, IL-1β, JUN, PTGS2. Enrichment of KEGG pathway analysis found that PI3K/Akt/HIF-1α/VEGFA signaling pathway might play a key role in the treatment of CB with ZP. The in vivo study showed that ZP significantly improved the pathological changes of SO2-treated lung tissue and inhibited the activation of PI3K/Akt/HIF-1α/VEGFA signaling pathway. The changes of AA and its metabolites in vivo were studied by targeted metabonomics, and it showed that ZP could reprogram the disorder of AA metabolism which contributed to the treatment of CB with ZP. ConclusionZP displayed good therapeutic effect on CB model rats through inhibiting PI3K/Akt/HIF-1α/VEGFA signaling pathway to exhibit anti-inflammatory effect and reprogramming disordered metabolic pathway of arachidonic acid.

Palliative radiotherapy in pancreatic cancer: a retrospective study of 100 cases and regional patterns of practice.

Pancreatic cancer is often incurable and can be associated with significant pain and abdominal symptoms. This study aims to characterize the symptomatic burden of patients with pancreatic cancer receiving palliative radiotherapy and the corresponding symptomatic and radiographic responses. Patients with pancreatic adenocarcinoma referred to BC Cancer for palliative radiation from 2006 to 2013 were retrospectively reviewed. Logistic regression and Cox proportional hazards model were used to evaluate variables predictive of symptomatic response and survival respectively. One hundred patients were identified. The majority had good performance status (Eastern Cooperative Oncology Group score 0-1, 82%), received only one line of chemotherapy (91%), and presented with pain (84%). The most common radiotherapy prescription was 30 Gy in 10 fractions (22%). Pain improved in 69%, early satiety and bloating improved in 59%, and hemostasis was achieved in 73% of cases. Treatment toxicity occurred in 47% of cases and were predominantly grade 1-2 with 1 case of grade 3 toxicity. Median survival was 5.1 months. Tumor size, radiotherapy dose, and concurrent chemotherapy were not predictive of symptomatic response nor prolonged survival. In the largest cohort to date evaluating palliative radiotherapy in pancreatic adenocarcinoma, radiation was efficacious in improving pain and gastrointestinal bleeding and was generally well-tolerated. Additional studies on the efficacy and optimal prescriptions for palliative radiotherapy are necessary in this population.

Evaluation of common prescription analgesics and adjuvant analgesics as markers of suicide risk: a longitudinal population-based study in England.

Analgesics prescriptions may provide a marker for identifying individuals at higher risk of suicide. In particular, awareness of which analgesics are implicated may help clinicians assess and modify risk. A case-control study in England using the Clinical Practice Research Datalink (for primary care records) linked with hospital and national mortality electronic registries. We included patients aged ≥15 who died by suicide between 2001 and 2019 (N=14,515), to whom we individually matched 580,159 controls by suicide date and general practice (N=594,674). Odds ratios (ORs) for suicide, controlled for age and sex, were assessed using conditional logistic regression. Suicide risks were highest in those prescribed adjuvant analgesics (pregabalin, gabapentin and carbamazepine) (adjusted OR 4.07; 95% confidence intervals CI: 3.62-4.57), followed by those prescribed opioids (adjusted OR 2.01; 95% CI: 1.88-2.15) and those prescribed non-opioid analgesics (adjusted OR 1.48; 95% CI: 1.39-1.58) compared to those not prescribed these medications. By individual analgesic, the highest suicide risks were seen in patients prescribed oxycodone (adjusted OR 6.70; 95% CI: 4.49-9.37); pregabalin (adjusted OR 6.50; 95% CI: 5.41-7.81); morphine (adjusted OR 4.54; 95% CI: 3.73-5.52); and gabapentin (adjusted OR 3.12; 95% CI: 2.59-3.75). Suicide risk increased linearly with the number of analgesic prescriptions in the final year (p<0.01 based on the likelihood ratio test), and the more different analgesics categories were prescribed in the final year (p<0.01 based on the likelihood ratio test). Analgesic prescribing was associated with higher suicide risk. This is a particular issue with regard to adjuvant non-opiate analgesics. There was no funding for this study.

Study on the neuroprotective effect of Zhimu-Huangbo extract on mitochondrial dysfunction in HT22 cells induced by D-galactose by promoting mitochondrial autophagy

Ethnopharmacological relevanceZhimu-Huangbo (ZB) herb pair is a common prescription drug used by physicians of all dynasties, and has significant neuroprotective effect, such as the ZB can significantly promote neuronal cell regeneration, repair neuronal damage, and improve cognitive disorders. However, its ingredients are urgently needed to be identified and mechanisms is remained unclear. Aim of the studyUsing ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS), the study of neuroprotective mechanism of Zhimu-Huangbo extract (ZBE) is investigated, and the network pharmacology technology and experimental validation is also performed. Material and methodsFirstly, UPLC-Q-TOF-MS technology was used to characterize the chemical components contained in the ZBE. After that, the TCMSP database and the Swiss Target Prediction method were used to search for potential target genes for ZBE compounds. At the same time, the OMIM and GeneCards disease databases were used to search for Alzheimer's disease (AD) targets and expanded with the GEO database. Then, GO and KEGG enrichment analysis was performed using OECloud tools. Subsequently, the potential mechanism of ZBE therapeutic AD predicted by network pharmacological analysis was experimentally studied and verified in vitro. ResultsIn the UPLC-Q-TOF-MS analysis of the ZBE, a total of 39 compounds were characterized including Neomangiferin, Oxyberberine, Timosaponin D, Berberine, Timosaponin A-III, Anemarsaponin E, Timosaponin A-I, Smilagenin and so on. A total of 831 potential targets and 13995 AD-related target genes were screened. A further analysis revealed the number of common targets between ZBE and AD is 698. Through GO and KEGG enrichment analysis, we found that ZBE's anti-AD targets were significantly enriched in autophagy and mitochondrial autophagy related pathways. The results of cell experiments also confirmed that ZBE can promote mitochondrial autophagy induced by D-galactose (D-gal) HT22 cells through the PTEN-induced kinase 1/Parkin (PINK1/Parkin) pathway. ConclusionZBE can promote autophagy of mitochondria and play a protective role on damaged neurons.

The use of telephone and video consultations in upper limb musculoskeletal rehabilitation: A scoping review.

In 2020, the COVID-19 pandemic caused a rapid uptake of virtual consultations (VCs) to minimise disease transmission and for this reason, research into telerehabilitation has been expanding. This review aimed to map and synthesize evidence on the use of VCs in upper limb musculoskeletal rehabilitation, describe key characteristics, and identify gaps in the research. This scoping review investigated synchronous rehabilitation consultations performed over VC. All asynchronous, wearable or pre-recorded technology was excluded. CINAHL Complete, Medline, PEDro, Google Scholar and grey literature sources were searched. Screening and data extraction were done by a single researcher. Frequency counts were used to analyse the data. Nineteen studies were identified, with patients with shoulder injury/pain most frequently studied. Most sources (n = 9) used bespoke video programmes. Range of motion (ROM) was the most common assessment (n = 10) and exercise prescription (n = 7) was the most common treatment. Benefits included time and cost savings, maintaining therapeutic relationships and increasing patient independence. Most diagnostic assessments, except joint and nerve tension tests, were found to be reliable and valid. Studies noted increased function in activities, decreased pain and increased ROM after VCs. Limitations included restricted 'hands-on' treatment, resource and training concerns and limiting patient factors. This review mapped available evidence and identified several gaps in the literature. Further robust research into VCs for hand/wrist disorders, ROM assessment and cost-effectiveness is needed.