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BACKGROUND: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. METHODS: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). RESULTS: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1-391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5-142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00-0.69) and the right lacrimal gland (median 0.59, range 0.42-0.78). CONCLUSIONS: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. TRIAL REGISTRATION: NCT05871021.

PURPOSE OF REVIEW: The aim of this review is to highlight key published oral immunotherapy (OIT) protocols and post-desensitization strategies for the major food allergens and to cover important concepts to consider when evaluating OIT for food-allergic patients. Shared decision-making should help identify patient and family values which will help influence the type of evidence-based protocol and maintenance strategy to use. RECENT FINDINGS: With food OIT emerging as a treatment option, there is a pressing need for patients, physicians, and other providers to have a nuanced understanding of the management choices available to them. There are now randomized controlled trials (RCT) of OIT for peanut, egg, milk, and wheat, and reports of cohorts of patients who have undergone OIT for tree nuts and sesame clinically. The current published protocols contain significant diversity in terms of starting dose, build-up schedule, maintenance dose, and even the product used for desensitization. Emerging data can help direct the long-term maintenance strategy for patients on OIT. Based on patient and family values elicited through the shared decision-making process, an OIT protocol may be selected that balances the level of desensitization, potential side effects, frequency of clinic visits, and potential to induce sustained unresponsiveness, among other factors. Once maintenance dosing is reached, most patients will need to maintain regular exposure to the food allergen to remain desensitized. The option to transition to commercial food products with equivalent amounts of food protein as the OIT maintenance dose would simplify the dosing process and perhaps improve palatability as well. Less frequent or decreased OIT dosing can provide practical benefits but may affect the level of desensitization and safety for some patients.

Background: A novel anti-human epidermal growth factor receptor 2 (HER2) antibody–drug conjugate (ADC) GQ1001 was assessed in patients with previously treated HER2 positive advanced solid tumors in a global multi-center phase Ia dose escalation trial. Methods: In this phase Ia trial, a modified 3 + 3 study design was adopted during dose escalation phase. Eligible patients were enrolled, and GQ1001 monotherapy was administered intravenously every 3 weeks. The starting dose was 1.2 mg/kg, followed by 2.4, 3.6, 4.8, 6.0, 7.2 and 8.4 mg/kg. Extra patients were enrolled into 6.0, 7.2, and 8.4 mg/kg cohorts as dose expansion phase. The primary endpoints were safety and to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLTs). Pharmacokinetics and anti-tumor efficacy of GQ1001 were assessed. The plasma concentration of free DM1, the payload of GQ1001, was quantitated. Results: A total of 32 patients were enrolled, predominantly in breast (9), gastric or gastro-esophageal junction (9) and salivary gland cancer (4). Median number of prior-line of therapies was 3 (0–11) and 37.5% patients received ≥ 2 lines of anti-HER2 therapies. No DLT was observed during dose escalation. MTD was not reached and dose recommended for dose expansion (DRDE) was determined as 8.4 mg/kg. Grade ≥ 3 treatment-related adverse events rate was 28.1% (9/32) and platelet count decreased (4/32, 12.5%) was the most common one. No drug-related death was observed. Objective response rate and disease control rate of 15 evaluable patients in 7.2 mg/kg and 8.4 mg/kg cohorts were 40.0% (6/15) and 60.0% (9/15). Pharmacokinetics analysis showed low exposure and accumulation of free DM1 in circulation. Conclusion: GQ1001 is well tolerated and shows promising efficacy in previously treated HER2-positive advanced solid tumors. DRDE was determined as 8.4 mg/kg for following trials. Trial registration NCT, NCT04450732, Registered 23 June 2020, https://clinicaltrials.gov/study/NCT04450732 [ABSTRACT FROM AUTHOR]

The R1 addendum to ICH E9 (E9-R1) provides guidance on the definition of estimands in clinical drug development. While the E9-R1 has seen uptake in randomized late-stage clinical trials, its implementation in early clinical development remains sporadic potentially jeopardizing clarity, consistency, and coherency in early phase. In this article, we call for a more systematic use of the estimand thinking in phase 1 dose escalation oncology trials. In these adaptive trials, the primary clinical objective is usually to characterize the dose-toxicity relationship and to ascertain the maximum tolerated dose (MTD). One estimand of interest is the probability of dose-limiting toxicity (DLT). Intercurrent events (ICE) interfering with the existence or interpretation of DLT outcomes are common in these studies. Three types of ICEs are reviewed in detail: treatment discontinuation for reasons not related to toxicity (e.g., disease progression), treatment discontinuation due to adverse events which would not qualify as DLT, and dose modifications or omissions. The concept of replacement of non-DLT evaluable participants, often used so far, is not an acceptable general solution to ICEs in dose escalation studies. To address clinically relevant questions, adequate ICE handling strategies and estimators aligned to these settings should be used. [ABSTRACT FROM AUTHOR]

Background: Treprostinil, which is administered via continuous subcutaneous or intravenous infusion, is a medication applied in the treatment of pulmonary arterial hypertension (PAH). The dose of treprostinil is adjusted on an individual basis for each patient. A number of factors determine how well patients respond to treatment. Objectives: The aim of this study was to identify factors that may influence the clinical response to the dose of treprostinil at 3 months after the start of therapy. Methods: The factors influencing treatment response were analyzed in consecutive PAH patients who started receiving treprostinil treatment. The treatment efficacy was assessed as improvement in 6 min walk distance (6MWD) and WHO functional class (WHO FC), a reduction in N-terminal prohormone of brain natriuretic peptide (NTproBNP), and the percentage of patients achieving low-risk status after 12 months of treatment. Results: A total of 83 patients were included in this analysis. Classification of patients according to the tertiles of treprostinil dose achieved at 3 months after drug inclusion shows that after 12 months of follow-up, the median WHO FC in the highest dose group was lower than that in the intermediate dose group (WHO FC II vs. WHO FC III, p = 0.005), the median NTproBNP was lower (922 pg/mL, vs. 1686 pg/mL, p = 0.036) and 6MWD was longer (300 m vs. 510 m, p = 0.015). The French Noninvasive Criteria (NIFC) scale score was higher (2 vs. 0, p = 0.008), and the Reveal scale score was lower (5.0 vs. 8.5, p = 0.034). In the group of patients who exceeded a dose of 19.8 ng/kg/min within 3 months, an improvement in 6MWD was observed significantly more often after one year of therapy, and they were more likely to show an increase in NIFC scale scores after one year of therapy than the group of patients who received the lower dose (65% vs. 30%, p = 0.02). In the group of patients younger than 50 years of age, a statistically significant correlation was observed between the dose of treprostinil achieved after three months of treatment and the parameters assessed after 12 months of treatment, including WHO FC, 6MWD, and NIFC prognostic scale scores (all p < 0.05). Conclusions: The clinical effect of treatment is critically dependent on the rapid escalation of the treprostinil dose during the first three months of treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT Dose‐finding studies in oncology often include an up‐and‐down dose transition rule that assigns a dose to each cohort of patients based on accumulating data on dose‐limiting toxicity (DLT) events. In making a dose transition decision, a key scientific question is whether the true DLT rate of the current dose exceeds the target DLT rate, and the statistical question is how to evaluate the statistical evidence in the available DLT data with respect to that scientific question. This article introduces generalized likelihood ratios (GLRs) that can be used to measure statistical evidence and support dose transition decisions. Applying this approach to a single‐dose likelihood leads to a GLR‐based interval design with three parameters: the target DLT rate and two GLR cut‐points representing the levels of evidence required for dose escalation and de‐escalation. This design gives a likelihood interpretation to each existing interval design and provides a unified framework for comparing different interval designs in terms of how much evidence is required for escalation and de‐escalation. A GLR‐based comparison of commonly used interval designs reveals important differences and motivates alternative designs that reduce over‐treatment while maintaining MTD estimation accuracy. The GLR‐based approach can also be applied to a joint likelihood based on a nonparametric (e.g., isotonic regression) model or a parametric model. Simulation results indicate that the isotonic GLR performs similarly to the single‐dose GLR but the GLR based on a parsimonious model can improve MTD estimation when the underlying model is correct. [ABSTRACT FROM AUTHOR]

Objectives: To analyze the results of interstitial (IRT) high-dose-rate (HDR) brachytherapy (BT) in the primary treatment of patients with unresectable superior sulcus tumors (SST) combined with external beam radiotherapy (EBRT). Methods: Between 2013 and 2023, seven patients with unresectable SST were treated with combined BT and EBRT with or without concomitant chemotherapy. The patients' median age was 64 years (range, 49–79 years) and median tumor volume was 146.8 cm3 (range, 29.3–242.3 cm3). A median BT dose of 8 Gray (Gy) (range, 5–10 Gy) was prescribed and delivered in a single fraction. A median EBRT dose of 54 Gy (range, 30–59 Gy) was prescribed and administered normofractionated (single dose: 1.8 Gy). Results: We report the results of seven patients with SST treated with combined BT and EBRT and followed for a median of 38 months. The overall clinical response rate was 83.33% with five out of six patients achieving local control, while one out of six (16.66%) showed local and general progression. No deaths were attributed to the treatment itself; rather, one patient died during the course of therapy as a result of systemic progression. The most common radiation-related adverse events were grade I–II fatigue and mild paresthesia. No severe toxicity (CTCAE ≥ III°) was observed with interstitial high-dose-rate (HDR) BT combined with EBRT. Conclusions: For patients with unresectable superior sulcus tumors, interstitial HDR BT in combination with EBRT is a feasible treatment option that offers the potential for local control and long-term survival. The findings of this study should be validated in a larger patient cohort. [ABSTRACT FROM AUTHOR]

Up to 40% of newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) discontinue treatment by 5 years, primarily due to resistance or intolerance. Rates of resistance to second-line (2L) treatment are also high. Some patients with resistance respond with dose escalation of tyrosine kinase inhibitors (TKIs). Asciminib demonstrated safety and efficacy across a broad dosage range. ASC2ESCALATE is an ongoing, Phase II, multicenter, single-arm, dose-escalation study of asciminib in 2L and first-line treatment of CML-CP. The primary end point is major molecular response at 12 months in 2L. Secondary end points include molecular responses at and by scheduled time points, survival, and safety. ASC2ESCALATE is the first study investigating asciminib in CML-CP following failure of one prior TKI. [ABSTRACT FROM AUTHOR]

BACKGROUND: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DLCO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment. RESULTS: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DLCO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DLCO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event. CONCLUSION: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691.

Abstract Background We investigated the clinical outcomes of involved‐field high‐dose (≥66 Gy) chemoradiotherapy (CRT) combined with respiratory motion management for esophageal squamous cell carcinoma (ESCC). Methods Patients who underwent definitive CRT for histologically confirmed ESCC in our department between 2012 and 2018 were retrospectively analyzed. Respiratory motion management strategies included breath‐holding (63%) and mask immobilization (29%) based on individual measurements of respiratory tumor motion using radiographic fluoroscopy with endoscopically placed clip markers as landmarks. We evaluated patient characteristics, treatment efficacy, failure patterns, and toxicities. Results We enrolled 35 patients with a prescribed dose of 66–70 Gy in 33–35 fractions. The overall response rate within 6 months post‐CRT was 94.3%; the median follow‐up period for survivors was 43 months. The 2‐year overall survival (OS), progression‐free survival, and locoregional failure‐free survival rates were 51.4%, 42.9%, and 42.9%, respectively. A significant difference in OS was observed between patients with and without esophageal fistulas after CRT (p = 0.002, log‐rank test). Disease failure occurred in 16 patients (45.7%), including one (2.9%) with out‐of‐field regional nodal failure. Major grade 3 or higher toxicities included decreased white blood cell count (48.6%), neutrophil count (34.3%), and esophageal stenosis (31.4%). No grade 3 or higher cardiopulmonary toxicities were observed. Bronchial/tracheal tumor compression and a higher radiotherapy dose (70 Gy) were significantly correlated with esophageal fistulas. Conclusion Involved‐field high‐dose CRT with respiratory motion management may be a feasible treatment option for ESCC. However, a comprehensive assessment of esophageal fistula risk is required to identify suitable candidates.

Abstract Introduction Anaplastic meningiomas, categorized as WHO grade 3 tumors, are rare and highly aggressive, accounting for 1-2% of all meningioma cases. Despite aggressive treatment, including surgery and Radiation, they exhibit a high recurrence rate and poor survival outcomes. The aggressive histopathological features emphasize the urgent need for effective management strategies. Methods A retrospective multi-institutional analysis was conducted on patients with recurrent anaplastic meningioma who underwent re-irradiation between 2017 and 2023. Clinical, dosimetric, and outcome data were collected and analyzed, focusing on local control, progression free survival and treatment-related adverse events. Results Thirty-four cases were analyzed, with a median follow-up 11 months after re-irradiation. Progression-free survival at 12 months was 61.9%, with higher doses correlating with better outcomes. Concomitant Bevacizumab improves progression-free survival and reduces the risk of radiation necrosis. CDKN2A homozygote deletion correlated with a higher risk of local failure. Symptomatic radiation necrosis occurred in 20.5% of cases, but its incidence was lower with concomitant Bevacizumab treatment. Conclusion Re-irradiation presents a viable option for recurrent anaplastic meningioma despite the associated risk of radiation necrosis. Higher doses with concomitant Bevacizumab improve clinical outcomes and reduce toxicity. Individualized treatment approaches are necessary, emphasizing the importance of further research to refine management strategies for this challenging disease.

Abstract Introduction Cetuximab, used to treat head and neck squamous cell carcinoma and metastatic colorectal cancer, can cause severe infusion reactions. Case presentation We report an 87-year-old East Asian woman with stage IV ileocecal signet ring cell carcinoma who experienced severe allergic reactions to cetuximab despite pre-treatment. A dose escalation method, involving weekly incremental doses with comprehensive pre-treatment and close monitoring, was employed, successfully reducing allergic reactions and allowing safe administration. Conclusion This approach demonstrates a viable alternative for patients with hypersensitivity to cetuximab, warranting further research for personalized treatment optimization.

Background: We investigated the clinical outcomes of involved‐field high‐dose (≥66 Gy) chemoradiotherapy (CRT) combined with respiratory motion management for esophageal squamous cell carcinoma (ESCC). Methods: Patients who underwent definitive CRT for histologically confirmed ESCC in our department between 2012 and 2018 were retrospectively analyzed. Respiratory motion management strategies included breath‐holding (63%) and mask immobilization (29%) based on individual measurements of respiratory tumor motion using radiographic fluoroscopy with endoscopically placed clip markers as landmarks. We evaluated patient characteristics, treatment efficacy, failure patterns, and toxicities. Results: We enrolled 35 patients with a prescribed dose of 66–70 Gy in 33–35 fractions. The overall response rate within 6 months post‐CRT was 94.3%; the median follow‐up period for survivors was 43 months. The 2‐year overall survival (OS), progression‐free survival, and locoregional failure‐free survival rates were 51.4%, 42.9%, and 42.9%, respectively. A significant difference in OS was observed between patients with and without esophageal fistulas after CRT (p = 0.002, log‐rank test). Disease failure occurred in 16 patients (45.7%), including one (2.9%) with out‐of‐field regional nodal failure. Major grade 3 or higher toxicities included decreased white blood cell count (48.6%), neutrophil count (34.3%), and esophageal stenosis (31.4%). No grade 3 or higher cardiopulmonary toxicities were observed. Bronchial/tracheal tumor compression and a higher radiotherapy dose (70 Gy) were significantly correlated with esophageal fistulas. Conclusion: Involved‐field high‐dose CRT with respiratory motion management may be a feasible treatment option for ESCC. However, a comprehensive assessment of esophageal fistula risk is required to identify suitable candidates. [ABSTRACT FROM AUTHOR]

Introduction: Cetuximab, used to treat head and neck squamous cell carcinoma and metastatic colorectal cancer, can cause severe infusion reactions. Case presentation: We report an 87-year-old East Asian woman with stage IV ileocecal signet ring cell carcinoma who experienced severe allergic reactions to cetuximab despite pre-treatment. A dose escalation method, involving weekly incremental doses with comprehensive pre-treatment and close monitoring, was employed, successfully reducing allergic reactions and allowing safe administration. Conclusion: This approach demonstrates a viable alternative for patients with hypersensitivity to cetuximab, warranting further research for personalized treatment optimization. [ABSTRACT FROM AUTHOR]

Introduction: Anaplastic meningiomas, categorized as WHO grade 3 tumors, are rare and highly aggressive, accounting for 1-2% of all meningioma cases. Despite aggressive treatment, including surgery and Radiation, they exhibit a high recurrence rate and poor survival outcomes. The aggressive histopathological features emphasize the urgent need for effective management strategies. Methods: A retrospective multi-institutional analysis was conducted on patients with recurrent anaplastic meningioma who underwent re-irradiation between 2017 and 2023. Clinical, dosimetric, and outcome data were collected and analyzed, focusing on local control, progression free survival and treatment-related adverse events. Results: Thirty-four cases were analyzed, with a median follow-up 11 months after re-irradiation. Progression-free survival at 12 months was 61.9%, with higher doses correlating with better outcomes. Concomitant Bevacizumab improves progression-free survival and reduces the risk of radiation necrosis. CDKN2A homozygote deletion correlated with a higher risk of local failure. Symptomatic radiation necrosis occurred in 20.5% of cases, but its incidence was lower with concomitant Bevacizumab treatment. Conclusion: Re-irradiation presents a viable option for recurrent anaplastic meningioma despite the associated risk of radiation necrosis. Higher doses with concomitant Bevacizumab improve clinical outcomes and reduce toxicity. Individualized treatment approaches are necessary, emphasizing the importance of further research to refine management strategies for this challenging disease. [ABSTRACT FROM AUTHOR]

Background: Treatment options for patients with differentiated thyroid cancer (DTC) who experience disease progression on lenvatinib treatment are limited. Although dose escalation of treatment with tyrosine kinase inhibitors at disease progression has been reported across cancer types, clinical significance in patients with DTC has not been investigated. Methods: We retrospectively reviewed patients with DTC who experienced disease progression on lenvatinib treatment from September 2011 to June 2022. We compared subjects who received dose-escalation treatment with standard treatment of termination at the time of initial disease progression. The escalated dose was decided by referencing to the previous effective and tolerated dose. Results: Thirty-three patients were identified, 15 with dose escalation and 18 with lenvatinib termination. In both groups, the starting dose of lenvatinib was 24 mg/day, and the median dose at initial disease progression was 10 mg/day. In the former, the median dose escalation was 6 mg/day (range: 4–12). Objective response rate, clinical benefit rate by escalation, and median treatment duration of the dose-escalation phase were 13.3%, 73.3%, and 9.9 months (95% confidence interval [CI] 5.71–27.6), respectively. Median overall survival from initial disease progression was significantly longer in the dose-escalation group (median OS: 20.4 months [95% CI 7.0–NA] vs. 3.9 months [95% CI 1.7–7.9], log-rank p-value; 0.0004, hazard ratio; 0.22 [95% CI 0.09–0.55]). There were no grade 5 adverse events, and one patient discontinued due to a grade 3 lung abscess. Conclusion: The dose-escalation strategy appears to be a safe and effective treatment option after disease progression in patients treated with lenvatinib for DTC. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate the radiotherapy planning feasibility of dose escalation with intensity‐modulated proton therapy (IMPT) to hypoxic tumor regions identified on 18F‐Fluoromisonidazole (FMISO) positron emission tomography and computed tomography (PET‐CT) in NPC. Materials and methods: Nine patients with stages T3‐4N0‐3M0 NPC underwent 18F‐FMISO PET‐CT before and during week 3 of radiotherapy. The hypoxic volume (GTVhypo) is automatically generated by applying a subthresholding algorithm within the gross tumor volume (GTV) with a tumor to muscle standardized uptake value (SUV) ratio of 1.3 on the 18F‐FMISO PET‐CT scan. Two proton plans were generated for each patient, a standard plan to 70 Gy and dose escalation plan with upfront boost followed by standard 70GyE plan. The stereotactic boost was planned with single‐field uniform dose optimization using two fields to deliver 10 GyE in two fractions to GTVhypo. The standard plan was generated with IMPT with robust optimization to deliver 70GyE, 60GyE in 33 fractions using simultaneous integrated boost technique. A plan sum was generated for assessment. Results: Eight of nine patients showed tumor hypoxia on the baseline 18F‐FMISO PET‐CT scan. The mean hypoxic tumor volume was 3.9 cm3 (range.9–11.9cm3). The average SUVmax of the hypoxic volume was 2.2 (range 1.44–2.98). All the dose‐volume parameters met the planning objectives for target coverage. Dose escalation was not feasible in three of eight patients as the D0.03cc of temporal lobe was greater than 75GyE. Conclusions: The utility of boost to the hypoxic volume before standard course of radiotherapy with IMPT is dosimetrically feasible in selected patients. Clinical trials are warranted to determine the clinical outcomes of this approach. [ABSTRACT FROM AUTHOR]

Local failure remains the major concern in grade 4 glioma or glioblastoma (GBM). Pilot studies have shown a radiotherapy (RT) dose–response relationship in GBM. Here we present our preliminary data of RT dose escalation using 68Ga-Pentixafor PET scan. High 68Ga-pentixafor uptake in glioma cells helps in sharp demarcation between tumour and normal brain. This phase II prospective study was conducted from 2018 to 2020. Thirty, biopsy-proven cases of grade 4 glioma were included. All patients underwent post-operative MRI of the brain and 68Ga-Pentixafor PET scan. RT was planned in 2-phases. Phase-1 GTV (GTV1) comprised of T2/flair abnormality, PET-avid disease and post-op cavity. A margin of 2cm was given to GTV-1 to create phase-1 CTV (CTV1), which was further expanded to 0.5cm to generate phase-1 PTV (PTV1). A radiation dose of 46Gy/23fr was prescribed to PTV-1. Phase-2 GTV (GTV2) consisted of CT/MRI contrast-enhancing lesion, PET avid disease and post-op cavity. A margin of 0.5 cm was given to GTV2 to create phase-2 CTV (CTV2) which was expanded to 0.5 cm to create phase-2 PTV (PTV2). RT dose of 14 Gy/7 fr was prescribed to PTV2. PET avid disease was delineated as GTV PET and a margin of 3mm was given to generate PTV-PET which received escalated RT dose of 21 Gy/7fr by simultaneous integrated boost (SIB) in phase 2 (Total dose to PTV PET = 67 Gy/30 fr). All patients received concurrent and adjuvant temozolomide. The data was prospectively maintained in Microsoft Excel sheet. SPSS v 23 was used for statistical analysis. The primary endpoints were estimation of the overall survival (OS) and progression-free survival (PFS), and secondary endpoint was to measure the incidence of radiation necrosis. Categorical variables were reported as frequency and percentage and quantitative variables were reported as median and range. Data from thirty patients were analysed. A median OS of 23 months was observed with estimated 1, 2 and 3 years OS of 90%, 40% and 17.8% respectively. A significant association of OS was seen with the extent of surgery (p = 0.04) and kernofsky performance status (p = 0.007). No patient developed significant radiation necrosis. The index study did not show any survival benefit from dose escalation RT. However, all of the patients tolerated the treatment well and none of them developed radiation necrosis. Considering the small sample size as a limitation of the index study, the role of 68Ga-pentixafor PET scan for radiation dose escalation should be further explored. CTRI/2019/05/019146. • Radiotherapy dose escalation in grade 4 glioma using 68Ga-Pentixafor PET scan. • Increased RT dose (67Gy/30#/6 weeks) was used for PET avid lesion. • None of the patients developed radiation necrosis. • No survival benefit from RT dose escalation. • Limitation – Small sample size. [ABSTRACT FROM AUTHOR]

Background: High‐dose‐rate (HDR) brachytherapy (BT) has been acknowledged as a widely utilized treatment for patients with intermediate‐ and high‐risk prostate cancer, despite its side effects such as edema, incontinence, and impotence. Nevertheless, the treatment is consistently limited by the potential danger of excessive irradiation to organs‐at‐risk (OARs) like the urethra, bladder, and rectum. Purpose: This study aims to introduce curvilinear catheter implantation in the prostate gland for HDR treatment. The objective is to improve the radiation dose distribution by offering access channels conformal to the prostate anatomy. This approach seeks to minimize toxicity to nearby OARs while utilizing a reduced number of needles, potentially leading to improved clinical outcomes. Methods: Curvilinear catheters were first pre‐planned for an anonymized patient using Oncentra treatment planning system (TPS) and hybrid inverse planning optimization (HIPO) algorithm. The trajectories of the catheters were then analyzed using MATLAB to extract their radius of curvature. Tendon‐driven active needles were then used to implant curvilinear catheters inside an anthropomorphic phantom. Results: Proposed curvilinear catheter implantation resulted in significant improvement in terms of dosimetric constraints to the OARs and coverage to the prostate. Tendon‐driven active needles were shown to be capable of realizing the required pre‐planned curvatures inside prostate. It was shown that the active needle can realize a desired radius of curvature and a desired trajectory with an average accuracy of 9.1 ± 8.6 and 1.27 ± 0.50 mm in air and inside a tissue‐mimicking phantom, respectively. Conclusion: This work demonstrates the feasibility of using tendon‐driven active curvilinear catheter implantation in prostate to improve the outcomes of HDR‐BT via improved radiation dose distribution to the prostate and reduced toxicity to the OARs. [ABSTRACT FROM AUTHOR]

First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the "3 + 3" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope. [ABSTRACT FROM AUTHOR]

Introduction: Anti-inflammatory and anti-fibrotic properties maximize the therapeutic potential of bone marrow aspiration concentrate (BMAC) in osteoarthritis (OA) knee. There is a lack of studies to standardize the treatment procedure to make the studies done across various centers comparable to understand the lacunae better and develop further the deficiency in our understanding of BMAC for OA knee. We aimed to assess the degree of pain relief, functional outcome, and cartilage thickness with different doses of BMAC in primary OA knee. Materials and Methods: A single-centered prospective observational study was conducted with 80 patients of OA knee who were divided into 4 groups where group A (n = 20), group B (n = 20), group C (n = 20), and group D (n = 20) received intra-articular 1, 2, 5 million BMAC cells per kg body weight, and intra-articular saline, respectively. All patients were followed up with Visual Analog Scale (VAS), knee Injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) scores both pre and post-procedurally at 1, 3, 6, and 12 months follow-up. Results: The study found no significant differences in demographics or co-morbidities across four participant groups (A, B, C, D). However, clinical outcomes varied markedly: Groups B and C showed significant improvements in pain perception (VAS scores), knee function, and quality of life (KOOS and WOMAC scores), while Group A showed marginal or non-significant changes, and Group D exhibited no significant improvements. These findings suggest that treatments in Groups B and C reached the Minimal Clinically Important Difference, significantly enhancing patient-reported outcomes. Conclusion: A dose of 2 million BMAC cells per kg body weight for knee OA serves as the better regenerative modality of choice in cartilage regeneration. With our dose-escalation study, we would be able to standardize the treatment procedure and enable global comparison of the treatment method across various regions of the world. [ABSTRACT FROM AUTHOR]

The use of bevacizumab has been hampered by safety concerns despite demonstrable progression-free survival (PFS) benefit in subjects with platinum-resistant ovarian cancer, highlighting the need for novel effective and safe antiangiogenic agents. This study aimed to characterize the tolerability, safety, and antitumor activities of escalating doses of anti-VEGF antibody suvemcitug plus chemotherapy in platinum-resistant ovarian cancer patients. This open-label, dose-escalation trial enrolled adult patients (≥18 years) with platinum-resistant histologically or cytologically-confirmed epithelial ovarian, fallopian tube and primary peritoneal cancer. Eligible patients received paclitaxel or topotecan plus escalating doses of suvemcitug 0.5, 1, 1.5, or 2 mg/kg once every two weeks. The primary endpoints were safety and tolerability, and antitumor activities of suvemcitug. Twenty-nine subjects received paclitaxel (n = 11) or topotecan (n = 18). No dose-limiting toxicities occurred. The most common adverse events of special interest were proteinuria (41.4%), hypertension (20.7%) and epistaxis (10.3%). No gastrointestinal perforations occurred. Nine subjects (31.0%, 95% CI 15.3–50.8) demonstrated investigators-confirmed objective response, including complete response in 1 and partial response in 8. The median PFS was 5.4 months (95% CI 2.2–7.4). Suvemcitug demonstrated an acceptable safety profile and promising antitumor activities in platinum-resistant ovarian cancer patients, supporting its further clinical development. • In this trial, 29 platinum-resistant ovarian cancer patients received escalating doses of suvemcitug plus chemotherapy. • No dose-limiting toxicities occurred and no gastrointestinal perforations were reported. • Nine patients showed investigators-confirmed objective response, with a median progression-free survival of 5.4 months. • The recommended dose for phase 2 study is suvemcitug 1.5 mg/kg every two weeks. • The safety and antitumor activities of suvemcitug support its clinical development for platinum-resistant ovarian cancer. [ABSTRACT FROM AUTHOR]

Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted. [ABSTRACT FROM AUTHOR]

Ustekinumab is a monoclonal antibody approved for the treatment of IBD. This drug has a well-established efficacy; however, patients may not respond or lose response. The availability of other biological therapies prompts the need for comparative data between different agents to suggest first- or second-line strategies. Aim of this review is to compare the effectiveness of ustekinumab to other biologics in Crohn's disease and ulcerative colitis, as well as report the available data on dose escalation and reinduction. A systematic electronic search of the English literature was performed up to November 2023, using Medline (PubMed), Web of Science, Scopus and the Cochrane Library. Conference proceedings were also screened. Out of 659 citations, 80 relevant articles were selected and included in the present narrative review. Head-to-head comparisons of different biological drugs are relatively scarce, mostly deriving from indirect comparison or retrospective studies. Overall available data indicate similar effectiveness in the treatment of IBD patients. Dose escalation and reinduction strategies are well documented, but the optimal treatment schedule is still to be defined. Response and remission rates vary in different studies, and a proportion of patients fail to achieve clinical and endoscopic outcomes. However, both approaches are effective and safe in nonresponders and secondary loss of response. IBD patients may benefit from dose escalation or reinduction. Both strategies prove effective in regaining response in a proportion of patients, avoiding unnecessary early switch. Head-to-head trials are still needed to determine the exact placement of this drug compared to other biologics. [ABSTRACT FROM AUTHOR]

Introduction: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated‐dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. Methods: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas‐directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional‐dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. Results: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas‐directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80–0.91; p < 0.001) with longer OS versus CDR. Discussion and Conclusions: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real‐world results additionally provide an estimate of effect size of EDR for future prospective trials. [ABSTRACT FROM AUTHOR]

For high-risk neuroblastoma, planning target volume coverage is often compromised to respect adjacent kidney tolerance. This trial investigated whether intensity-modulated arc radiotherapy techniques (IMAT) could facilitate dose escalation better than conventional techniques. Children with high-risk abdominal neuroblastoma referred for radiotherapy to the primary tumour site and involved regional lymph nodes were randomised to receive either standard dose (21 Gy in 14 fractions) or escalated dose (36 Gy in 24 fractions) radiotherapy. Dual planning with both a conventional anterior-posterior parallel opposed pair radiotherapy technique and an IMAT technique was performed. The quality of target volume and organ-at-risk delineation, and dosimetric plans, were externally reviewed. Dosimetric parameters were used to judge the superior technique for treatment. This feasibility trial was not powered to detect improvement in outcome with dose escalation. Between 2017 and 2020, 50 patients were randomised and dual-planned. The IMAT technique was judged more favourable in 48 patients. In all patients randomised to receive 36 Gy, IMAT would have permitted delivery of the full dose (median D50% 36.0 Gy, inter-quartile range 36.0–36.1 Gy) to the target volume, whereas dose compromise would have been required with conventional planning (median D50% 35.6 Gy, inter-quartile range 28.7–35.9 Gy). IMAT facilitates safe dose escalation to 36 Gy in patients receiving radiotherapy for neuroblastoma. The value of dose escalation is now being evaluated in a current prospective phase III randomised trial. • The standard tumour bed radiotherapy dose used for neuroblastoma is 21 Gy. • The optimal dose is uncertain, and a higher dose may lead to better local control. • Organ-at-risk tolerance may limit the desired dose to the target volume. • Intensity-modulated arc therapy facilitates better delivery of higher doses. [ABSTRACT FROM AUTHOR]

Background Glioblastoma (GBM) poses therapeutic challenges due to its aggressive nature, particularly for patients with poor functional status and/or advanced disease. Hypofractionated radiotherapy (RT) regimens have demonstrated comparable disease outcomes for this population while allowing treatment to be completed more quickly. Here, we report our institutional outcomes of patients treated with 2 hypofractionated RT regimens: 40 Gy/15fx (3w-RT) and 50 Gy/20fx (4w-RT). Methods A single-institution retrospective analysis was conducted of 127 GBM patients who underwent 3w-RT or 4w-RT. Patient characteristics, treatment regimens, and outcomes were analyzed. Univariate and multivariable Cox regression models were used to estimate progression-free survival (PFS) and overall survival (OS). The impact of chemotherapy and RT schedule was explored through subgroup analyses. Results Median OS for the entire cohort was 7.7 months. There were no significant differences in PFS or OS between 3w-RT and 4w-RT groups overall. Receipt and timing of temozolomide (TMZ) emerged as the variable most strongly associated with survival, with patients receiving adjuvant-only or concurrent and adjuvant TMZ having significantly improved PFS and OS (P <.001). In a subgroup analysis of patients that did not receive TMZ, patients in the 4w-RT group demonstrated a trend toward improved OS as compared to the 3w-RT group (P =.12). Conclusions This study demonstrates comparable survival outcomes between 3w-RT and 4w-RT regimens in GBM patients. Receipt and timing of TMZ were strongly associated with survival outcomes. The potential benefit of dose-escalated hypofractionation for patients not receiving chemotherapy warrants further investigation and emphasizes the importance of personalized treatment approaches. [ABSTRACT FROM AUTHOR]

Focal boost to intra-prostatic lesions (IPLs) in radiotherapy could enhance treatment efficacy. Brachytherapy (BT), delivering highly conformal dose with sharp dose gradients emerges as a potentially optimal approach for precise dose escalation to IPLs. This study aims to consolidate clinical and planning studies that implemented whole gland prostate BT and focal dose escalation to IPLs, with the view to synthesize evidence on the strategy’s effectiveness and variability. In this review, we identified nine clinical studies and ten planning/simulation studies focusing on whole gland prostate BT with IPL dose escalation. From the clinical studies, the use of whole gland prostate BT with focal dose escalation in combination with external beam radiotherapy (EBRT) appears to be a safe and effective 21 form of treatment for men with T1b – T2c prostate cancer with average five-year biochemical failure22 free survival (BFFS) of 94 % (range 81.1 %−100 %) and minimal grade three toxicities reported. Both clinical and planning studies exemplified the high level of focal dose escalation achievable using BT with a mean IPL D90 % of 132 % and 146 %, respectively (expressed as a % of the whole gland prescription dose). There was considerable variation in the reporting of clinical and technical data in the identified studies. To facilitate a more widespread and uniform adoption of the technique, recommendations on essential and desirable items to be included in future studies incorporating whole gland prostate BT with focal boost to IPLs are provided.

Introduction: Tildrakizumab, a humanized monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), has shown promise in the management of moderate-to-severe plaque psoriasis, offering potential improvements in clinical outcomes and quality of life. Objectives: The study aimed to identify patient characteristics that indicate the initiation of a 200-mg dosage of tildrakizumab in a real-world setting, focusing on factors that enhance treatment efficacy and safety. Methods: This prospective study included 54 adult patients with moderate-to-severe plaque psoriasis treated with tildrakizumab 200 mg from March 2023 to March 2024 across 13 Italian Dermatology Units. Data collected included demographics, disease duration, comorbidities, and previous treatments. PASI, BSA, and DLQI scores were recorded at baseline, week 4, 16, and 28. Safety was assessed through adverse event reporting. Univariate analysis was performed to identify baseline characteristics significantly associated with achieving PASI ≤ 5 at week 16. Results: Significant reductions in PASI scores were observed at week 4 (9 ± 6.9, p 30) had higher odds (OR = 4.333, p < 0.05) of achieving PASI ≤ 5. Longer disease duration and starting with a 100 mg dose also correlated with better outcomes. The safety profile was favorable, with minimal adverse events reported. Conclusions: Tildrakizumab 200 mg is effective and safe for moderate-to-severe psoriasis, particularly in obese patients. These findings support its use as a long-term treatment option.

BackgroundNeratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies.MethodsPatients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L.Results563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed.ConclusionsThese complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective.ClinicaltrialsGov registration numberNCT02400476.

Background: Treprostinil, which is administered via continuous subcutaneous or intravenous infusion, is a medication applied in the treatment of pulmonary arterial hypertension (PAH). The dose of treprostinil is adjusted on an individual basis for each patient. A number of factors determine how well patients respond to treatment. Objectives: The aim of this study was to identify factors that may influence the clinical response to the dose of treprostinil at 3 months after the start of therapy. Methods: The factors influencing treatment response were analyzed in consecutive PAH patients who started receiving treprostinil treatment. The treatment efficacy was assessed as improvement in 6 min walk distance (6MWD) and WHO functional class (WHO FC), a reduction in N-terminal prohormone of brain natriuretic peptide (NTproBNP), and the percentage of patients achieving low-risk status after 12 months of treatment. Results: A total of 83 patients were included in this analysis. Classification of patients according to the tertiles of treprostinil dose achieved at 3 months after drug inclusion shows that after 12 months of follow-up, the median WHO FC in the highest dose group was lower than that in the intermediate dose group (WHO FC II vs. WHO FC III, p = 0.005), the median NTproBNP was lower (922 pg/mL, vs. 1686 pg/mL, p = 0.036) and 6MWD was longer (300 m vs. 510 m, p = 0.015). The French Noninvasive Criteria (NIFC) scale score was higher (2 vs. 0, p = 0.008), and the Reveal scale score was lower (5.0 vs. 8.5, p = 0.034). In the group of patients who exceeded a dose of 19.8 ng/kg/min within 3 months, an improvement in 6MWD was observed significantly more often after one year of therapy, and they were more likely to show an increase in NIFC scale scores after one year of therapy than the group of patients who received the lower dose (65% vs. 30%, p = 0.02). In the group of patients younger than 50 years of age, a statistically significant correlation was observed between the dose of treprostinil achieved after three months of treatment and the parameters assessed after 12 months of treatment, including WHO FC, 6MWD, and NIFC prognostic scale scores (all p < 0.05). Conclusions: The clinical effect of treatment is critically dependent on the rapid escalation of the treprostinil dose during the first three months of treatment.

Patients receiving interleukin (IL)‐inhibiting biologics for moderate‐to‐severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL‐inhibiting biologic treatment and ≥1 post‐induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non‐persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL‐inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable‐adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS. [ABSTRACT FROM AUTHOR]

Background: Simultaneous involvement of multiple distinct brain regions occurs in 2-5% of all high-grade gliomas (HGG) and is associated with poor prognosis. Whereas radiotherapy (RT) is an important and well-established treatment for high-grade glioma, the role of dose-escalated radiotherapy has yet to be established. In this case series, we report upon the dosimetry, adverse effects, and response in patients with multiple un-methylated high-grade gliomas receiving dose-escalated radiation. Materials and methods: We reviewed charts of patients with multifocal high grade glioma treated at our institution since January 2022. All patients had stereotactic biopsies after an magnetic resonance imaging (MRI) contrast-enhanced with T1, T2, FLAIR sequences and were discussed in a multidisciplinary oncology team. MGMT-positive patients received either TMZ alone or RT with TMZ and were excluded from this analysis. Un-methylated patients received dose-escalated RT without temezolamide (TMZ). Following computed tomography (CT) and MR simulation, the gros tumor volume (GTV) was delineated and prescribed 52.5 Gy in 15 fractions within the standard 40.05 Gy planning treatment volume (PTV). Treatment planning was volumetric modulated arc therapy. Results: A total of 20 patients with multiple un-methylated MGMT glioblastoma multiforme were treated with dose-escalated radiation therapy between January 2022 and June 2023. All patients completed dose escalated radiotherapy without acute adverse effects. Progression-free survival at six months was 85%, as defined by the RANO criteria. Conclusion: In this case series, we showed that un-methylated multiple high-grade glioma could be safely treated with dose escalation. Results of progression-free survival should be validated in a larger prospective clinical trial. [ABSTRACT FROM AUTHOR]

Background/Aim: To investigate the institutional experience of dose-escalated salvage whole-pelvic radiotherapy (WPRT) with the simultaneous integrated boost (SIB) technique in patients with biochemical recurrence (BCR) after radical prostatectomy for high-risk prostate cancer. Patients and Methods: This retrospective study included 21 patients with BCR who received radical prostatectomy for high-risk prostate cancer and underwent salvage RT. Clinical target volume (CTV) of the whole pelvis (CTV56) included the prostate bed, common iliac, external iliac, internal iliac, and obturator lymph node regions. The boost CTV (CTV66) included the prostate bed. Planning target volumes (PTV) were generated by adding a margin of 6-8 mm to CTV (PTV56 and PTV66). Doses of 56.1 and 66 Gy in 33 fractions were delivered to PTV56 and PTV66, respectively. Results: The 5-year biochemical progressionfree survival, overall survival, and cause-specific survival rates were 72%, 94%, and 94%, respectively. A grade 3 late genitourinary toxicity event of gross hematuria was observed in one patient (4%). Acute and late toxicities of grade ≥3, other than gross hematuria, were not observed in any patient. Conclusion: Dose-escalated salvage WPRT using the SIB technique provides appropriate tumor control without increasing the incident of significant toxicities. [ABSTRACT FROM AUTHOR]

Simple Summary: While stereotactic body radiation therapy (SBRT) has become increasingly used for the treatment of non-metastatic prostate cancer since its insurance coverage in Japan in 2016, optimal dose fractionation remains undetermined. This study was a phase 1 dose escalation trial of SBRT, aiming to assess the maximum tolerated dose (MTD) of SBRT using five fractions. Patients were planned to receive SBRT at doses of 42.5, 45, or 47.5 Gy, with toxicity as the primary endpoint. No dose-limiting toxicities were observed at 42.5 Gy, and one patient experienced a grade 4 rectal perforation at 45 Gy, leading to the determination of 42.5 Gy as the MTD. There were no deaths or biochemical recurrences during the follow-up period. This study underscores the need for further trials to ascertain the optimal SBRT dose fractionation, balancing efficacy and safety for non-metastatic prostate cancer treatment. The purpose of this study was to determine the maximum tolerated dose (MTD) for stereotactic body radiation therapy (SBRT) in the treatment of non-metastatic prostate cancer. This study was a phase 1 dose escalation trial conducted in Japan. Patients with histologically proven prostate cancer without lymph nodes or distant metastases were enrolled. The prescribed doses were 42.5, 45, or 47.5 Gy in five fractions. Dose-limiting toxicity (DLT) was defined as grade (G) 3+ gastrointestinal or genitourinary toxicity within 180 days after SBRT completion, and a 6 plus 6 design was used as the method of dose escalation. A total of 16 patients were enrolled, with 6 in the 42.5 Gy group and 10 in the 45 Gy group. No DLT was observed in the 42.5 Gy group. In the 45 Gy group, one patient experienced G3 rectal hemorrhage, and another had G4 rectal perforation, leading to the determination of 42.5 Gy as the MTD. None of the patients experienced biochemical recurrence or death during the follow-up period. We concluded that SBRT for non-metastatic prostate cancer at 42.5 Gy in five fractions could be safely performed, but a total dose of 45 Gy increased severe toxicity. [ABSTRACT FROM AUTHOR]

Bayesian logistic regression model (BLRM) is widely used to guide dose escalation decisions in phase 1 oncology trials. An important feature of BLRM design is the appealing safety performance due to its escalation with overdose control (EWOC). However, some recent literature indicates that BLRM with EWOC may have a relatively low probability to find the maximum tolerated dose (MTD) compared to some other dose escalation designs. This work discusses this design problem and proposes a practical solution to improve the performance of BLRM design. Specifically, we suggest increasing the EWOC cutoff from routine value 0.25 to a value between 0.3 and 0.4, which will increase the chance of finding the correct MTD with minimal compromise to overdosing risk. Our comparative simulation studies indicate that BLRM with an increased EWOC cutoff has comparable operating characteristics on the correct MTD selection and over-toxicity control as other dose escalation designs (BOIN, mTPI, keyboard, etc.). Moreover, we compare the methodology and operating characteristics of BLRM designs with various decision rules that allow more flexible overdosing control. A case study of dose escalation in a recent phase 1 oncology trial is provided to show how BLRM with optimal EWOC cutoff operates well in practice. [ABSTRACT FROM AUTHOR]

Purpose of Review: The aim of this review is to highlight key published oral immunotherapy (OIT) protocols and post-desensitization strategies for the major food allergens and to cover important concepts to consider when evaluating OIT for food-allergic patients. Shared decision-making should help identify patient and family values which will help influence the type of evidence-based protocol and maintenance strategy to use. Recent Findings: With food OIT emerging as a treatment option, there is a pressing need for patients, physicians, and other providers to have a nuanced understanding of the management choices available to them. There are now randomized controlled trials (RCT) of OIT for peanut, egg, milk, and wheat, and reports of cohorts of patients who have undergone OIT for tree nuts and sesame clinically. The current published protocols contain significant diversity in terms of starting dose, build-up schedule, maintenance dose, and even the product used for desensitization. Emerging data can help direct the long-term maintenance strategy for patients on OIT. Summary: Based on patient and family values elicited through the shared decision-making process, an OIT protocol may be selected that balances the level of desensitization, potential side effects, frequency of clinic visits, and potential to induce sustained unresponsiveness, among other factors. Once maintenance dosing is reached, most patients will need to maintain regular exposure to the food allergen to remain desensitized. The option to transition to commercial food products with equivalent amounts of food protein as the OIT maintenance dose would simplify the dosing process and perhaps improve palatability as well. Less frequent or decreased OIT dosing can provide practical benefits but may affect the level of desensitization and safety for some patients. [ABSTRACT FROM AUTHOR]

This study aims to compare dose escalation between two groups of reirradiated cancer patients, one with the previous contour and radiotherapy plan available on the treatment planning system and the other without. First group is identified as DICOM-group, while the other one is called non-DICOM group. The current study included 89 patients, 57 in the DICOM, and 32 in the non-DICOM group, who received reirradiation for recurrent or second primary tumours between 2019 and 2021. For the DICOM group, doses to 0.2cc volume for spine, brainstem, and optic apparatus from first radiation were converted into structures and transferred to reirradiation CT using deformable registration. First, one radiotherapy plan was created using the doctor prescribed dose (baseline prescription RxD_B); further an escalated dose (RxD_E) plan, taking into account all the dose volume parameters from previous radiation, was created only for DICOM group. In non-DICOM group patients were planned only for RxD_B. The maximum accepted dose escalation was 21 Gy. Radiotherapy prescription dose during earlier (first) treatment in DICOM and non-DICOM groups were 61 ± 5.6 Gy and 30–66 Gy, respectively. DICOM and non-DICOM groups had nearly identical baseline doses: 52.5 ± 10.7 Gy and 50.6 ± 6.9 Gy (difference 1.9 ± 12.7 Gy). Dose escalation was possible for 51 out of 57 patients in the DICOM-group. Average escalated dose in DICOM-group was 59.2 ± 6.2 Gy, with an incremental dose of 6.7 ± 12.4 Gy from the baseline prescription. No dose escalation was opted for in the non-DICOM group due to the unavailability of dose volume information from previous radiation. Reirradiation for head and neck cases allowed for a moderate to high dose escalation, facilitated by the presence of pertinent DICOM information from the initial radiotherapy. [ABSTRACT FROM AUTHOR]

In non-small-cell lung cancer (NSCLC), improving local control through radiotherapy dose escalation might improve survival. However, a photon-based RCT showed increased organ at risk dose exposure and worse overall survival in the dose escalation arm. In this study, intensity-modulated proton therapy plans with dose escalation to the primary tumour were created for 20 NSCLC patients. The mediastinal envelope was delineated to spare structures around the heart. It was possible to increase primary tumour dose up to 74.0 Gy without a significant increase in organ at risk doses and predicted toxicity.

Abstract Background Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DLCO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment. Results Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DLCO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DLCO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event. Conclusion Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691

Abstract Background Approximately 40% of patients with hormone receptor (HR)‐positive and human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer (ABC) exhibit PIK3CA mutations. Aims This study aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of HS‐10352, a selective PI3Kα inhibitor, in this patient population. Materials and Methods Conducted as a phase 1 dose‐escalation trial, HS‐10352 was administered orally once‐daily (QD) at dose levels of 2, 4, 6, and 8 mg. The primary endpoints were dose‐limiting toxicity (DLT) and the maximum tolerated dose (MTD). This study is registered at ClinicalTrials.gov (NCT04631835). Results Between August 2020 and March 2022, a total of 18 female patients were enrolled. DLT, manifested as hyperglycemia, occurred in two patients in the 8 mg QD group, establishing an MTD of 6 mg QD. The most common treatment‐related adverse events were hyperglycemia (88.9%) and weight loss (61.3%). In the 6 mg QD group, four patients (66.7%) had a partial response (PR), and one (16.7%) had stable disease (SD). Among the four patients with PIK3CA mutated tumors in this dosage group, three (75.0%) had PR and one (25.0%) had SD. The median progression‐free survival was not reached (95% confidence interval, 11.1‐NA). Discussion and Conclusion HS‐10352 at 6 mg QD was well‐tolerated in patients with HR‐positive, HER2‐negative ABC, and showed preliminary antitumor activity in patients with PIK3CA mutated tumors. These findings support the further clinical development of HS‐10352.

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Abstract Background The THUNDER-2 phase II single institutional trial investigates the benefits of MRI-guided radiotherapy (MRIgRT) in treating locally advanced rectal cancer (LARC). This study focuses on evaluating the impact of escalating radiation therapy dose in non-responder patients using the Early Tumour Regression Index (ERI) for predicting complete response (CR). The trial’s primary endpoint is to increase the CR rate in non-responders by 10% and assess the feasibility of the delta radiomics-based MRIgRT predictive model. This interim analysis assesses the feasibility and safety of the proposed MRIgRT dose escalation strategy in terms of acute toxicity (gastrointestinal, genitourinary and haematological) and treatment adherence. Methods Stage cT2-3, N0-2, or cT4 patients with anal sphincter involvement, N0-2a, M0, but without high-risk features were enrolled. MRIgRT treatment consisted of a standard dose of 55 Gy to the Gross Tumor Volume (GTV) and mesorectum, and 45 Gy to the mesorectum and drainage nodes in 25 fractions with concomitant chemotherapy. 0.35 T MRI was used for simulation imaging and daily alignment. ERI was calculated at the 10th fraction. Non-responders with an ERI above 13.1 received intensified dose escalation from the 11th fraction, resulting in a total dose of 60.1 Gy. Acute toxicity was assessed using the CTCAE v.5 scale. Results From March 2021 to November 2022, 33 out of the total number of 63 patients to be enrolled (52.4%) were included, with one withdrawal unrelated to treatment. Sixteen patients (50%) underwent dose escalation. Treatment was well tolerated, with only one patient (3.1%) in the standard treatment group experiencing acute Grade 3 diarrhea, proctitis, and cystitis. No significant differences in toxicity were observed between the two groups (p = 0.5463). Conclusions MRIgRT treatment with dose escalation up to 60.1 Gy is well tolerated in LARC patients predicted as non-responders by ERI, confirming the feasibility and safety of this approach. The THUNDER-2 trial’s primary and secondary endpoints will be fully analyzed when all planned patients will be enrolled.

Simple Summary: The standard treatment of choice for inoperable esophageal cancer is concurrent chemoradiation therapy. However, the treatment effect varies among patients. Currently, the optimal dose for esophageal cancer for different histologies is still under debate, and the guidelines still recommend using the same dose to treat both squamous cell carcinoma and adenocarcinoma despite their differences in radiation sensitivity. In this review article, we analyzed previous studies treating esophageal cancers with definitive radiotherapy, with or without concurrent chemotherapy. We found that squamous cell carcinoma shows an overall survival benefit with the use of radiation dose escalation, while no advantage was found for adenocarcinoma. Based on these findings, we suggest that further dose escalation can be performed for esophageal squamous cell carcinoma. Esophageal cancer, ranked as the eighth most prevalent cancer globally, is characterized by a low survival rate and poor prognosis. Concurrent chemoradiation therapy (CCRT) is the standard therapy in the non-surgical treatment of localized carcinoma of the esophagus. Nevertheless, the radiation doses employed in CCRT remain notably lower compared to the curative definite chemoradiation therapy utilized in the management of other carcinomas. In order to increase the local control rates and enhance the treatment outcomes, several clinical trials have used high-dose radiation to analyze the effect of dose escalation. Despite the integration of technically advanced RT schemes such as intensity-modulated radiation therapy (IMRT), the results of these trials have failed to demonstrate a significant improvement in overall survival or local progression-free survival. In this review, we investigated previous clinical trials to determine the ineffectiveness of radiation dose escalation in the context of CCRT for esophageal cancer. We aim to clarify the factors contributing to the limited efficacy of escalated radiation doses in improving patient outcomes. Furthermore, we delve into recent research endeavors, exploring prospective radiation dose modifications being altered based on the histological characteristics of the carcinoma. The exploration of these recent studies not only sheds light on potential refinements to the existing treatment protocols but also seeks to identify novel approaches that may pave the way for more efficacious and personalized therapeutic strategies for esophageal cancer management. [ABSTRACT FROM AUTHOR]