Evaluating scholastic achievement in pediatric brain tumor survivors compared to healthy controls.

BACKGROUND: Radiotherapy (RT) causes cognitive deficits in pediatric brain tumor survivors (PBTS). Traditionally, this is measured using neuropsychological testing, which lack pre-diagnosis baseline and do not necessarily trigger action. This pilot project investigated a novel patient-centered outcome of scholastic performance using state-collected educational data. METHODS: We retrospectively analyzed scholastic achievements in children residing in Florida. Eligibility in the treatment group received brain-directed RT between 2007 - 2020 at our institution. Controls were matched at a 3:1 ratio by age, grade, district, and free or reduced lunch (FRL) eligibility. The Florida Department of Education provided educational records for both groups. Generalized linear mixed-effects models were used to predict scholastic outcomes with covariates age, time (binary value of pre- or post-RT), treatment group, and the primary independent variable as the interaction term between time and treatment. Scholastic data was matched with institutional clinical data. RESULTS: Fifty PBTS and 150 matched controls were included for analysis. Median age of PBTS was 12, 12% identified as Black, and 18% as Hispanic. Fifty-two percent were FRL eligible. Forty percent received craniospinal irradiation, and 56% received chemotherapy. Post-RT PBTS had 21 times the odds of receiving accommodations (p=0.006), twice the odds of being retained (p=0.010), and 42% lower odds than controls receiving a passing mathematics score (p=0.068). CONCLUSIONS: To our knowledge, this is the first American experience to successfully link individual scholastic and clinical data. Scholastic performance serves as a meaningful patient-centered outcome complementing the existing suite of neuropsychological testing.

Long-term outcomes following proton therapy for pediatric spinal low-grade glioma.

BACKGROUND: Due to its rarity, no standard treatment guidelines exist for pediatric spinal low-grade glioma (LGG-S). Proton therapy (PT) offers an attractive modality to minimize toxicity. Herein, we present the first published series of pediatric patients who received PT for progressive LGG-S. PROCEDURES: We identified eight consecutive patients with nonmetastatic LGG-S treated with PT. Cumulative incidence method was used to estimate local control (LC), freedom from distant metastases (FFDM), and freedom from progression (FFP). The Kaplan-Meier product limit method assessed overall survival (OS). Toxicity was assessed according to the Common Terminology Criteria for Adverse Events Version 5.0. RESULTS: Median age at diagnosis was 4 years. All patients underwent attempted resection and developed recurrence/progression prior to referral for PT, with median duration between initial surgery and PT of 4.4 years. Median age at the start of PT was 8 years. Most patients (n = 5) received PT as ≥third line treatment. Seven patients were treated with PT to the primary tumor. Most patients (n = 7) received between 45-50.4 CGE. Median follow up was 7.8 years. The 10-year estimates for LC, FFDM, FFP, and OS were 85, 88, 73, and 55%, respectively. One patient experienced malignant transformation and two developed pseudoprogression following PT. No pulmonary, gastrointestinal, or musculoskeletal toxicities were observed during or after PT. CONCLUSIONS: Despite negative selection bias our experience suggests PT for pediatric LGG-S offers long-term disease control with limited toxicity. The favorable therapeutic ratio of PT suggests it should be considered among first-line therapy in children with nonmetastatic, unresectable LGG-S.

Nanoscale synchrotron x-ray analysis of intranuclear iron in melanised neurons of Parkinson's substantia nigra.

Neuromelanin-pigmented neurons of the substantia nigra are selectively lost during the progression of Parkinson's disease. These neurons accumulate iron in the disease state, and iron-mediated neuron damage is implicated in cell death. Animal models of Parkinson's have evidenced iron loading inside the nucleoli of nigral neurons, however the nature of intranuclear iron deposition in the melanised neurons of the human substantia nigra is not understood. Here, scanning transmission x-ray microscopy (STXM) is used to probe iron foci in relation to the surrounding ultrastructure in melanised neurons of human substantia nigra from a confirmed Parkinson's case. In addition to the expected neuromelanin-bound iron, iron deposits are also associated with the edge of the cell nucleolus. Speciation analysis confirms these deposits to be ferric (Fe3+) iron. The function of intranuclear iron in these cells remains unresolved, although both damaging and protective mechanisms are considered. This finding shows that STXM is a powerful label-free tool for the in situ, nanoscale chemical characterisation of both organic and inorganic intracellular components. Future applications are likely to shed new light on incompletely understood biochemical mechanisms, such as metal dysregulation and morphological changes to cell nucleoli, that are important in understanding the pathogenesis of Parkinson's.

Experiences of families post treatment for childhood brain tumours during medical clinic consultations regarding health-related quality of life, unmet needs and communication barriers: A qualitative exploration.

BACKGROUND: Many studies highlight poor health-related quality of life (HRQoL) in children treated for brain tumours and their parents. However, little is known about the extent to which their informational, healthcare and communication needs regarding HRQoL are met during medical outpatient consultations. AIM: To explore the experiences of families regarding communication with physicians about HRQoL issues during consultations after treatment for childhood brain tumours. METHODS: Interviews were conducted with 18 families of children and adolescents aged 8-17 years after completion of brain tumour treatment. Participants had completed treatment within the last 5 years and were receiving regular outpatient follow-up care. Thematic analysis was undertaken using the Framework Method. RESULTS: Five main themes were identified: (i) unmet emotional and mental health needs; (ii) double protection; (iii) unmet information needs; (iv) communication barriers within consultations; and (v) finding a new normal. CONCLUSION: There was a need to improve communication between clinicians and these families, improve information provision, and overcome barriers to conversing with children within these outpatient consultations. Children and their parents should be supported to voice their current needs and concerns regarding their HRQoL. These findings will inform further development of the UK version of the 'KLIK' patient- and parent-reported outcome (PROM) portal.

Long-term outcomes following proton therapy for non-metastatic central nervous system germinoma in children and adolescents.

BACKGROUND/PURPOSE: Radiation is a key component in the treatment of central nervous system pure germinoma (PG) in children and adolescents. Proton therapy (PT) improves normal tissue sparing and potentially reduces adverse effects (AE). The aim of this study was to present the largest single institution experience utilizing PT for the management of PG. MATERIALS METHODS: We enrolled 35 non-metastatic patients with PG that were treated with PT at our institution between July 2007 - September 2021. Most received induction chemotherapy (n = 31, 89 %) and whole ventricular irradiation with an involved field boost (n = 29, 83 %). The most common total dose was 30 CGE (n = 18, 51.4 %). We utilized the cumulative incidence method to estimate local control (LC), freedom from distant metastases (FFDM), freedom from progression (FFP), and overall survival (OS). Treatment related toxicity was assessed per CTCAE version 5. RESULTS: Median follow-up was 6.2 years (range, 0.9---15.2). The 10-year Kaplan-Meier estimates for LC, FFDM, FFP, and OS were 100 %, 100 %, 100 %, and 94 % respectively. The most common AE were hearing impairment requiring hearing aids (n = 3), transient hypersomnia requiring medication (n = 3), and new onset endocrinopathy (n = 1). Of the 23 evaluable patients ≥ 18 years old at last follow-up, 8 were high school graduates/in college, 8 college graduates, and 7 others gainfully employed. CONCLUSIONS: When utilized in modern multimodality treatment of non-metastatic PG, the precise dosimetry of PT does not compromise disease control. Although serious radiation side effects are rare, the 100% cure rate supports further investigation into selective radiation dose and volume de-escalation.

Long-Term Outcomes Following Definitive or Adjuvant Proton Radiotherapy for Adenoid Cystic Carcinoma.

Purpose: Adenoid cystic carcinoma (ACC) is a rare malignancy accounting for 1% of all head and neck cancers. Treatment for ACC has its challenges and risks, yet few outcomes studies exist. We present long-term outcomes of patients with ACC of the head and neck treated with proton therapy (PT). Materials and Methods: Under an institutional review board-approved, single-institutional prospective outcomes registry, we reviewed the records of 56 patients with de novo, nonmetastatic ACC of the head and neck treated with PT with definitive (n = 9) or adjuvant PT (n = 47) from June 2007 to December 2021. The median dose to the primary site was 72.6 gray relative biological equivalent (range, 64-74.4) delivered as either once (n = 19) or twice (n = 37) daily treatments. Thirty patients received concurrent chemotherapy. Thirty-one patients received nodal radiation, 30 electively and 1 for nodal involvement. Results: With a median follow-up of 6.2 years (range, 0.9-14.7), the 5-year local-regional control (LRC), disease-free survival, cause-specific survival, and overall survival rates were 88%, 85%, 89%, and 89%, respectively. Intracranial extension (P = .003) and gross residual tumor (P = .0388) were factors associated with LRC rates. While the LRC rate for those with a gross total resection was 96%, those with subtotal resection or biopsy alone were 81% and 76%, respectively. The 5-year cumulative incidence of clinically significant grade ≥3 toxicity was 15%, and the crude incidence at the most recent follow-up was 23% (n = 13). Conclusion: This is the largest sample size with the longest median follow-up to date of patients with ACC treated with PT. PT can provide excellent disease control for ACC of the head and neck with acceptable toxicity. T4 disease, intracranial involvement, and gross residual disease at the time of PT following either biopsy or subtotal resection were significant prognostic features for worse outcomes.

Axillary Surgery for Chemoresidual (ypN-Positive) Nodal Disease.

This cohort study using pooled data from 2 randomized clinical trials examines whether removing more lymph nodes with axillary lymph node dissection improved outcomes over sentinel lymph node biopsy when most patients received adjuvant radiation therapy or regional nodal irradiation.

Association between psoas major muscle mass and CPET performance and long-term survival following major colorectal surgery: A retrospective cohort study.

OBJECTIVES: To evaluate whether computed tomography (CT)-derived psoas major muscle measurements could predict preoperative cardiopulmonary exercise testing (CPET) performance and long-term mortality in patients undergoing major colorectal surgery and to compare predictive performance of psoas muscle measurements using 2D approach and 3D approach. METHODS: A retrospective cohort study compliant with STROCSS standards was conducted. Consecutive patients undergoing major colorectal surgery between January 2011 and January 2017 following CPET as part of their preoperative assessment were included. Regression analyses were modelled to investigate association between the CT-derived psoas major muscle mass variables [total psoas muscle area (TPMA), total psoas muscle volume (TPMV) and psoas muscle index (PMI)] and CPET performance and mortality (1-year and 5-year). Discriminative performances of the variables were evaluated using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: A total of 457 eligible patients were included. The median TPMA and TPMV were 21 â€‹cm2 (IQR: 15-27) and 274 â€‹cm3 (IQR: 201-362), respectively. The median PMI measured via 2D and 3D approaches were 7 â€‹cm2/m2 (IQR: 6-9) and 99 â€‹cm3/m2 (IQR: 76-120), respectively. The risks of 1-year and 5-year mortality were 7.4% and 27.1%, respectively. Regression analyses showed TPMA, TPMV, and PMI can predict preoperative CPET performance and long-term mortality. However, ROC curve analyses showed no significant difference in predictive performance amongst TPMA, TPMV, and PMI. CONCLUSION: Radiologically-measured psoas muscle mass variables may predict preoperative CPET performance and may be helpful with informing more objective selection of patients for preoperative CPET and prehabilitation.

Stereotactic Radiosurgery for Vestibular Schwannoma With Radiographic Brainstem Compression.

OBJECTIVE: The safety of single-treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression but without motor deficit is controversial. Data on linear accelerator (linac)-based SRS in this setting are scarce. We address this with an outcomes report from an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS. METHODS: We included 139 patients with unilateral VS (any size) with radiographic brainstem compression (all without serious brainstem neurological deficits). The SRS prescription dose was 12.5 Gy (single fraction) using 6MV linac-produced photon beams, delivered with a multiple arc technique. Inclusion criteria required at least 1 year of radiographic follow-up with magnetic resonance imaging. The primary endpoint was freedom from serious brainstem toxicity (≥grade 3 Common Terminology Criteria for Adverse Events v5); the secondary was freedom from enlargement (tumor progression or any requiring intervention). We assessed serious cranial nerve complications, excluding hearing loss, defined as Common Terminology Criteria for Adverse Events v5 grade 3 toxicity. RESULTS: Median magnetic resonance imaging follow-up time was 5 years, and median tumor size was 2.5 cm in greatest axial dimension and 5 ml in volume. The median brainstem D0.03 ml=12.6 Gy and median brainstem V10 Gy=0.4 ml. At 5 years, the actuarial freedom from serious brainstem toxicity was 100%, and freedom from tumor enlargement (requiring surgery and/or due to progression) was 90%. Severe facial nerve damage in patients without tumor enlargement was 0.9%. CONCLUSION: Linac-based SRS, as delivered in our series for VS with radiographic brainstem compression, is safe and effective.

Outcomes following proton therapy for pediatric esthesioneuroblastoma.

BACKGROUND: Pediatric esthesioneuroblastoma (EN) can infiltrate skull base anatomy, presenting challenges due to high radiation doses and pediatric tissue sensitivity. This study reports outcomes of pediatric EN treated with proton radiotherapy (PT). PROCEDURE: Using an IRB-approved prospective outcomes registry, we evaluated patient, tumor, and treatment-related variables impacting disease control and toxicity in pediatric nonmetastatic EN treated with modern multimodality therapy, including PT. RESULTS: Fifteen consecutive patients (median age 16) comprising Kadish stage B (n = 2), C (n = 9), and D (n = 4) tumors were assessed, including six with intracranial involvement, four with cranial nerve deficits, and four with cervical lymphadenopathy. Before radiation, two had subtotal and 13 had gross total resections (endoscopic or craniofacial). Two underwent neck dissection. Eleven received chemotherapy before radiation (n = 5), concurrent with radiation (n = 4), or both (n = 2). Median total radiation dose (primary site) was 66 Gy/CGE for gross disease and 54 Gy/CGE (cobalt Gray equivalent) for microscopic disease. Median follow-up was 4.8 years. No patients were lost to follow-up. Five-year disease-free and overall survival rates were 86% (no local or regional recurrences). Two patients developed vertebral metastases and died. Two required a temporary feeding tube for oral mucositis/dysphagia. Late toxicities included symptomatic retinopathy, major reconstructive surgery, cataracts, chronic otitis media, chronic keratoconjunctivitis, hypothyroidism, and in-field basal cell skin cancer. CONCLUSIONS: A multimodality approach for pediatric EN results in excellent local control. Despite the moderate-dose PT, serious radiation toxicity was observed; further dose and target volume reductions may benefit select patients. Longer follow-up and comparative data from modern photon series are necessary to fully characterize any relative PT advantage.

Impact of Maximum Point Dose Within the Planning Target Volume on Local Control of Nonsmall Cell Lung Cancer Treated With Stereotactic Body Radiotherapy.

BACKGROUND: No consensus exists on the maximum dose delivered to the planning target volume (PTV) in the delivery of stereotactic body radiotherapy (SBRT) for primary lung cancer. We investigated whether higher biologically effective doses (BED) within the PTV were associated with improved tumor control. METHODS: We reviewed patients with early-stage, node-negative nonsmall cell lung cancer who received curative-intent SBRT between 2005 and 2018. We calculated the maximum BED (maxBED) within the PTV for all patients, analyzing outcomes using the cumulative incidence method and Fine-Gray test statistics to assess prognostic impact. RESULTS: We analyzed 171 patients (median age, 70.2; range, 43 to 90 y) with 181 lung nodules. Median follow-up was 2.7 years (range, 0.1 to 12 y) for all patients and 4.2 years (range, 0.2 to 8.4 y) for living patients. Median maximum tumor diameter was 1.9 cm (range, 0.7 to 5.6 cm). Patients received a prescription of 48 or 50 Gy in 4 or 5 fractions, respectively, except for one who received 60 Gy in 5 fractions. Median maxBED was 120 Gy (range, 101 to 171 Gy). There was no difference in the 3-year local control (LC) rate among patients treated with a maxBED<120 Gy versus ≥120 Gy ( P =0.83). CONCLUSIONS: No significant differences in LC were observed between patients with early-stage nonsmall cell lung cancer treated with SBRT in 4 or 5 fractions with a maxBED≥120 Gy. However, a higher maxBED trended toward improved LC rates, suggesting a maxBED threshold greater than 120 Gy may be needed to improve LC rates.

Impact of mandated drug monitoring on opioid use during highly conformal radiotherapy for oropharynx cancer.

BACKGROUND: Prescription drug monitoring programs (PDMPs) have proliferated due to increasing opioid-related deaths. We evaluated acute opioid use changes for 64 patients treated with highly conformal radiotherapy (RT) following a state-mandated PDMP. METHODS: Patients receiving proton therapy (PT) (n=40), intensity-modulated RT (IMRT) (n=14), or both (n=10) were divided into preintervention (n=26) and postintervention cohorts (n=38); records were reviewed retrospectively under an institutional review board (IRB)-approved tracking protocol. Dosages prescribed during acute therapy (during RT-3 months post-RT) and patient-reported pain (Defense and Veterans Pain Rating Scale) were endpoints. Dosages were treated as responses in Chi-square tests (three-level ordinal response). RESULTS: Overall, 72% (n=46) received opioids; of which 22% (n=10) of all patients and 10% (n=2) of opioid-naive patients continued analgesic management 3 months post-RT. Median total doses were 975 and 1,025 morphine milligram equivalents (MME) in pre- and postintervention groups, with no significant differences in MME prescribed (P=0.8) or uncontrolled pain (P=0.3). Statistically significant factors were tonsil primaries (P<0.01) and alcohol use (P=0.02). Uncontrolled pain episodes during and post-RT did not vary per cohort (P=0.19). CONCLUSIONS: PDMP use was not associated with management changes in patient-reported acute pain during RT (IMRT or PT). Following highly conformal RT, few patients remained on narcotics 3 months post-RT.

Allied health professionals' views on important outcomes of children's elective lower limb orthopaedic surgery: a qualitative interview study to inform a core outcome set.

PURPOSE: A common methodological limitation of research that guides surgical procedure selection for children's elective lower limb orthopaedic surgeries is inconsistent outcome selection. Improving outcome consistency can be achieved through the development of a core outcome set (COS). The aim of this study is to identify which outcomes are considered important for children's elective lower limb orthopaedic surgeries by allied health professionals (AHPs) and explore why they select these outcomes, to inform a COS development project. METHODS: Online semi-structured interviews were conducted with relevant AHPs. Participants were selected using maximum variation purposive sampling; selection was based on profession and inpatient/outpatient role. The data set was analysed using an inductive and deductive approach to thematic analysis. RESULTS: Four physiotherapists, three orthotists, three prosthetists, and two occupational therapists were interviewed. Most identified outcomes of importance related to "activities and participation". From the data, we conceptualised that AHPs with effective multidisciplinary communication focused on child-centred outcomes, while clinicians with limited multidisciplinary teamwork focused on role-based outcomes. CONCLUSIONS: There is concurrence between outcomes identified as important in this study, and other qualitative studies in similar populations. These important outcomes were seldom measured in previous studies or in routine clinical practice.Implications for rehabilitationAllied health professionals (AHPs) prioritise activity and participation outcomes after children's elective lower limb orthopaedic surgery.It is important to the rehabilitation of children after elective lower limb orthopaedic surgery that all involved AHPs collaborate with the wider multidisciplinary team.Multidisciplinary team communication encourages collaborative outcome identification, and discourages role defined outcome focus.

Analysis of the Pediatric Radiotherapy Landscape in Mexico and a Subsequent Educational e-Contouring Intervention.

PURPOSE: Mexico and Central America have the highest childhood cancer incidence in the West. Pediatric-specific oncology knowledge contributes to the disparity. We sought to (1) determine the self-identified treatment patterns and needs of Mexican pediatric radiation oncologists and (2) pilot a workshop to improve contouring accuracy. MATERIALS AND METHODS: Partnering with local experts and the Sociedad Mexicana de Radioterapeutas (SOMERA), a 35-question survey was designed to ascertain pediatric radiotherapy capacity and distributed through the SOMERA listserv. The most challenging malignancies were selected for workshop. Participants received precontouring and postcontouring homework to assess improvement per the Dice metric. The Wilcoxon sign-rank test was used for comparative statistics. RESULTS: Ninety-four radiation oncologists attempted and 79 completed the survey. Forty-four (76%) felt comfortable treating a pediatric patient, and 36 (62%) were familiar with national protocols for pediatric treatment. Most had access to nutrition, rehabilitation, endocrinology, and anesthesia; 14% had access to fertility services and 27% to neurocognitive support; 11% noted no support, and only one respondent had child-life support. The postsurvey contouring workshop was conducted for high-grade glioma, medulloblastoma, and Hodgkin lymphoma. Significant improvements were seen in all target volumes. CONCLUSION: We present the first national survey of Mexico's pediatric radiotherapy capacity and Latin American e-contouring educational intervention with preworkshop and postworkshop Dice metrics, noting statistically significant improvement in all target volumes. Participation improved compared with prior experience through SOMERA partnership and Continuing Medical Education incentivization.

Incidence of Rib Fracture following Treatment with Proton Therapy for Breast Cancer.

Purpose: To determine the rib fracture rate in a cohort of patients with breast cancer treated with proton therapy. Patient and Methods: From a prospective database, we identified 225 patients treated with proton therapy between 2012 and 2020 (223 women; 2 men). Clinical and dosimetric data were extracted, the cumulative incidence method assessed rib fracture rate, and Fine-Gray tests assessed prognostic significance of select variables. In-field rib fracture was defined as a fracture that occurred in a rib located within the 10% isodose line. Out-of-field rib fracture was defined as a fracture occurring in a rib location outside of the 10% isodose line. Results: Of the patients, 74% had left-sided breast cancer; 5%, bilateral; and 21%, right-sided. Dual-energy x-ray absorptiometry scans showed normality in 20%, osteopenia in 34%, and osteoporosis in 6% (test not performed in 40%). Additionally, 57% received an aromatase inhibitor. Target volumes were breast ± internal mammary nodes (IMNs) (16%), breast and comprehensive regional lymphatics (32%), chest wall ± IMNs (1%), and chest wall/comprehensive regional lymphatics (51%). Passive-scattered proton therapy was used for 41% of patients, 58% underwent pencil-beam scanning (PBS), and 1% underwent a combination (passive scattering/PBS), with 85% of patients receiving a boost. Median follow-up was 3.1 years, with 97% having >12-month follow-up. The 3-year cumulative in-field rib fracture incidence was 3.7%. Eight patients developed in-field rib fractures (1 symptomatic, 7 imaging identified) for a 0.4% symptomatic rib fracture rate. Median time from radiation completion to rib fracture identification was 1.8 years (fractures were identified within 2.2 years for 7 of 8 patients). No variables were associated with rib fracture on univariate analysis. Three fractures developed outside the radiation field (0.9% cumulative incidence of out-of-field rib fracture). Conclusion: In this series of patients with breast cancer treated with proton therapy, the 3-year rib fracture rates remain low (in-field 3.7%; symptomatic 0.4%). As in photon therapy, the asymptomatic rate may be underestimated owing to a lack of routine surveillance imaging. However, patients experiencing symptomatic rib fractures after proton therapy for breast cancer are rare.

PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis.

Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by "switching" interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak double-knockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.

Multi-institutional study of clinical outcomes of patients with head and neck cancer presenting with cN3 disease.

BACKGROUND: To evaluate disease control, toxicities, and variables associated with clinical outcomes for patients with head and neck squamous cell carcinoma and clinical N3 disease (HNSCC N3) treated with definitive chemoradiation therapy. METHODS: We performed a retrospective review of patients with HNSCC N3 treated at two high-volume academic centers between 1996 and 2019. RESULTS: We identified 85 patients with a median follow-up of 2.8 years. Five-year overall survival, regional control, and freedom from distant metastases rates were 38%, 80%, and 80%, respectively. Severe complications were identified in 19% of patients. CONCLUSIONS: Favorable regional control is achievable with definitive chemoradiation therapy for patients with HNSCC N3 disease. Distant metastases are a common pattern of failure and should be a focus of prospective study.

Radiation Treatment for Cancer of the Anal Margin.

OBJECTIVE: To identify best treatment practices by examining outcomes of anal margin cancer patients treated with radiotherapy. METHODS: Relevant literature was compared with 38 patients at our institution treated 1979 to 2019 with curative radiotherapy. Median age was 51. Four patients had T1, 22 had T2, and 12 had T3 disease based on the American Joint Committee on Cancer (AJCC) staging at time of diagnosis. Nodal staging distribution was: N0=33; N1=2; N2=2; N3=1. Median radiation dose was 56 Gy/30 fractions. Five received nodal radiation for node positivity, 29 received elective nodal radiation, and 29 had perineal boost. Twenty-seven received concurrent chemotherapy. RESULTS: Three patients experienced isolated local recurrence, 2 had isolated inguinal node recurrences, and 2 developed distant metastases, 1 of whom also had local and regional recurrence. Ten-year disease-free survival (DFS), cause-specific survival, and overall survival were 87%, 92%, and 68%, respectively. One patient did not complete radiation, and 4 had unexpected treatment breaks. Two received salvage abdominoperineal resections. At last follow-up, 17 were alive with no evidence of disease, 2 were alive with anal margin cancer present, 3 had died with anal margin cancer present at 11, 18, and 21 months from radiation therapy, and 16 had died from intercurrent disease. Median follow-up was 6.6 years (range 0.9 to 29.0 y). Age ≥51 was associated with worse locoregional control ( P =0.018) and DFS ( P =0.0233), males had worse DFS ( P =0.0311), and HIV-positive patients had worse overall survival ( P =0.006). CONCLUSIONS: Radiation provides high locoregional control of anal margin cancer with good long-term outcomes.

A Contemporary Report of Low-Dose-Rate Brachytherapy for Prostate Cancer Using MRI for Risk Stratification: Disease Outcomes and Patient-Reported Quality of Life.

PURPOSE: We examined a prospective consecutive cohort of low dose rate (LDR) brachytherapy for prostate cancer to evaluate the efficacy of monotherapy for unfavorable-intermediate risk (UIR) disease, and explore factors associated with toxicity and quality of life (QOL). METHODS: 149 men with prostate cancer, including 114 staged with MRI, received Iodine-125 brachytherapy alone (144-145 Gy) or following external beam radiation therapy (110 Gy; EBRT). Patient-reported QOL was assessed by the Expanded Prostate Index Composite (EPIC) survey, and genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively recorded (CTC v4.0). Global QOL scores were assessed for decline greater than the minimum clinically important difference (MCID). Univariate analysis (UVA) was performed, with 30-day post-implant dosimetry covariates stratified into quartiles. Median follow-up was 63 mo. RESULTS: Men with NCCN low (n = 42) or favorable-intermediate risk (n = 37) disease were treated with brachytherapy alone, while most with high-risk disease had combined EBRT (n = 17 of 18). Men with UIR disease (n = 52) were selected for monotherapy (n = 42) based on clinical factors and MRI findings. Freedom from biochemical failure-7 yr was 98%. Of 37 men with MRI treated with monotherapy for UIR disease, all 36 men without extraprostatic extension were controlled. Late Grade 2+/3+ toxicity occurred in 55/3% for GU and 8/2% for GI, respectively. Fifty men were sexually active at baseline and had 2 yr sexual data; 37 (74%) remained active at 2 yr. Global scores for urinary incontinence (UC), urinary irritation/obstruction (UIO), bowel function, and sexual function (SF) showed decreases greater than the MCID (p < 0.05) in UC at 2 mo, UIO at 2 and 6 mo, and SF at 2-24 mo, and >5 yr. Analysis did not reveal any significant associations with any examined rectal or urethral dosimetry for late toxicity or QOL. CONCLUSION: Disease outcomes and patient-reported QOL support LDR brachytherapy, including monotherapy for UIR disease.

Proton Therapy With Concurrent Chemotherapy for Thoracic Esophageal Cancer: Toxicity, Disease Control, and Survival Outcomes.

Purpose: When treating esophageal cancer with radiation therapy, it is critical to limit the dose to surrounding structures, such as the lung and/or heart, as much as possible. Proton radiation therapy allows a reduced radiation dose to both the heart and lungs, potentially reducing the risk of cardiopulmonary toxicity. Here, we report disease control, survival, and toxicity outcomes among patients with esophageal cancer treated with proton radiation therapy and concurrent chemotherapy (chemoradiation therapy; CRT) with or without surgery. Materials and Methods: We enrolled 17 patients with thoracic esophageal carcinoma on a prospective registry between 2010 and 2021. Patients received proton therapy to a median dose of 50.4-GyRBE (range, 50.4-64.8) in 1.8-Gy fractions.Acute and late toxicities were graded per the Common Terminology Criteria for Adverse Events, version 4.0 (US National Cancer Institute, Bethesda, Maryland). In addition, disease control, patterns of failure, and survival outcomes were collected. Results: Nine patients received preoperative CRT, and 8 received definitive CRT. Overall, 88% of patients had adenocarcinoma, and 12% had squamous cell carcinoma. With a median follow-up of 2.1 years (range, 0.5-9.4), the 3-year local progression-free, disease-free, and overall survival rates were 85%, 66%, and 55%, respectively. Two patients (1 with adenocarcinoma and 1 with squamous cell carcinoma) recurred at the primary site after refusing surgery after a complete clinical response to CRT. The most common acute nonhematologic and hematologic toxicities, respectively, were grades 1 to 3 esophagitis and grades 1 to 4 leukopenia, both affecting 82% of patients. No acute cardiopulmonary toxicities were observed in the absence of surgical resection. Reagarding surgical complications, 3 postoperative cardiopulmonary complications occurred as follows: 1 grade 1 pleural effusion, 1 grade 3 pleural effusion, and 1 grade 2 anastomotic leak. Two severe late CRT toxicities occurred: 1 grade 5 tracheoesophageal fistula and 1 grade 3 esophageal stenosis requiring a feeding tube. Conclusion: Proton radiation therapy is a safe, effective treatment for esophageal cancer with increasing evidence supporting its role in reducing cardiopulmonary toxicity.