Standard Radiation Research Articles

A phase I/II trial of neoadjuvant pegylated arginine deiminase (ADI-PEG 20) with ifosfamide and radiotherapy in soft tissue sarcomas (STS) of the trunk or extremity.

TPS11591 Background: Outcomes for the treatment of metastatic STS remain poor. Better therapies are needed for local and distant control. Arginine is essential to neoplastic growth, yet up to 88% of STS do not express argininosuccinate synthetase (ASS1), an enzyme necessary to produce arginine. ADI-PEG 20 is a microbial enzyme that degrades arginine causing auxotrophy in cancer cells that are ASS1 negative. Pre-clinical data demonstrates that arginine deprivation shunts glutamine towards oxidation via the TCA cycle, thus depleting glutathione stores and increasing oxidative stress to the cell. We hypothesize that the combination of ADI-PEG 20, ifosfamide, and radiation therapy can potentiate cellular death. The encouraging safety and clinical data from the ADI-PEG 20 + radiation + temozolomide trial (NCT04587830) further support this combination. We are conducting a phase I/II trial examining the safety and tolerability to determine the recommended phase II dose (R2PD) and evaluate the efficacy of ADI-PEG 20 in combination with ifosfamide and radiation in patients with high-grade STS. Methods: Eligible patients include untreated intermediate or high-grade extremity or truncal STS planned for definitive resection with performance status 0-1 and adequate organ function. Metastatic disease is exclusionary as well as receiving prior treatment for the study cancer. The total number of patients to be enrolled is approximately 35. Up to 15 patients will be enrolled in the phase I portion with a 3 + 3 dose escalation design with ADI-PEG 20 in combination with escalating doses of ifosfamide and radiation. The primary objectives include determining safety and tolerability as well as the recommended phase II dose (RP2D). Patients will be treated neoadjuvantly with ADI-PEG 20 dosed once weekly starting on Cycle 1 Day -7 with ifosfamide for up to three cycles in combination with standard radiotherapy given over approximately 5 weeks. Ifosfamide will be administered on Days 1 - 5 of all 3 cycles. The phase II participants will receive the combination with ifosfamide at the RP2D determined during phase I. The primary objective of the phase II portion is to determine the percent necrosis and pathologic complete response (pCR) at the time of resection. These endpoints will be summarized by proportions along with the associated 2-sided exact 95% CIs. Assuming the true pCR rate is 25%, enrolling 20 patients will result in a 90% CI for estimating the pCR (10%, 45%). The trial has begun accrual and is soon to open at multiple sites. Clinical trial information: NCT05813327 .

RMS13: A phase II trial using risk adapted focal proton beam radiation and/or surgery with the addition of maintenance chemotherapy in intermediate risk rhabdomyosarcoma.

10008 Background: European trials have demonstrated improved outcomes in SIOP high-risk/COG intermediate risk (IR) rhabdomyosarcoma (RMS) when 6 months of maintenance therapy (MTC) was added to ifosfamide, vincristine (VCR), dactinomycin (DAC) +/-doxorubicin chemotherapy. The effectiveness of MTC integrated with VCR, DAC and cyclophosphamide (CYC), standard North American chemotherapy, remains unclear. Methods: RMS13 is a phase II multicenter trial evaluating the safety and efficacy of risk adapted proton radiation therapy (RT) and the addition of MTC in patients with IR RMS (embryonal stage 1, Group III non-orbit, and stage 3 Group I, II were not eligible for MTC). Patients received 12 cycles of VCR (1.5mg/m2 weekly), DAC (0.045mg/kg q3weeks), and CYC (1200mg/m2 q3weeks) (VAC) followed by MTC with 4 cycles of oral CYC (50mg/m2 daily), bevacizumab (15mg/kg) q3wks, and sorafenib (90mg/m2 bid) (CBvSor). RT was prescribed based on local tumor status at the time of RT (Table 1). Five-year disease-free survival (DFS) using the Kaplan-Meier method and the cumulative incidence (CI) of primary site local failure (LF) was described. Results: 46 patients were enrolled (Table 1). One patient refused further therapy and was removed from the analysis. 5-year DFS for the entire cohort was 67.5% with a median follow up of 54 mo. The trial was halted since < 75% of enrolled patients received all prescribed CBvSor MTC. Of the 35 who were eligible for MTC, 24 initiated MTC and 18 completed protocol-directed MTC. Three pts received vinorelbine/CYC MTC after enrollment was stopped. Reasons for not completing CBvSor MTC included: progression prior (6), toxicity (5), refusal (3). The 5-year DFS for the 24 patients that started cycle 3 was 70.3%. When limited to patients classified as high-risk in RMS2005 trial, the 5-year DFS was 81.4%. No patients experienced LF after margin negative surgery. The CI of LF was: 0% following 36GyRBE RT for microscopic residual disease, 8% for patients with unresected tumors < 5cm receiving standard dose RT (50.4GyRBE), and 10% for patients with unresected tumors > = 5cm receiving dose escalated RT (59.4GyRBE). 5/6 patients with alveolar N1 disease recurred. Conclusions: Local control with risk adapted dose-escalated RT was excellent in IR patients. Those with nodal involvement fared poorly. While 4-cycles of MTC with CBvSor was not feasible, those who underwent at least 3 cycles experienced enhanced DFS outcomes, aligning with the positive results seen in other trials incorporating MTC. Clinical trial information: NCT01871766 . [Table: see text]

A phase II study of plerixafor combined with whole brain radiation therapy (WBRT) for patients with newly diagnosed glioblastoma.

2075 Background: Plerixafor inhibits the binding of stromal cell-derived factor 1 (SDF-1a / CXCL12) to its receptor on CD11b+ monocytes, inhibiting vasculogenesis and tumor recurrence in preclinical models. An early phase trial demonstrated that Plerixafor administration decreased cerebral blood volume (CBV) within the irradiated field of glioblastoma patients, and that the majority of recurrences occurred outside of the irradiated field (Thomas R. et al, Clin Cancer Res). This follow up study investigates the efficacy of Plerixafor in combination with WBRT, with the hypothesis that widening the radiation therapy (RT) field with WBRT may reduce out-of-field tumor recurrence and improve survival. Methods: This was a Phase II, open-label, non-randomized, single-arm trial.Adults between 18-75 years old with newly diagnosed high grade glioma as defined by WHO 2016 criteria and KPS ≥ 60 were eligible for enrollment. Patients underwent maximal safe resection followed by 6 weeks of concurrent radiation therapy and temozolomide (TMZ). Of note, modifications to the conventional treatment paradigm included completing 30 Gy of standard intensity-modulated RT followed by 30 Gy of WBRT, as well as completing a 4-week continuous infusion of Plerixafor dosed at 400 µg/kg/day. Patients then started adjuvant TMZ after completing Plerixafor. Primary endpoint was 6-month progression free survival (PFS6) after chemoradiation. Secondary endpoints included median overall survival (mOS), adverse events (AEs), MRI-based patterns of recurrence, and neurocognitive outcomes measured by the Trail Making Test, Controlled Oral Word Association Test, and the Hopkins Verbal Learning Test. Additionally, maximum arterial spin labeling-cerebral blood flow (ASL-CBF) values of primary lesions were compared over various time points during the study. Results: 14 of 17 enrolled patients completed the Plerixafor infusion, and all 17 patients completed WBRT. Median age was 57 years. 15 patients (88.2%) were IDH wildtype and 13 patients (76.5%) were pMGMT unmethylated. 13 patients (76.5%) underwent gross total resection, 2 (11.8%) underwent subtotal resection, and 2 (11.8%) underwent biopsy only. The PFS6 was 91.7%. The mOS was 15.11 months. 3 patients discontinued Plerixafor early due to rash (n=1), rising creatinine (n=1), or worsening confusion and agitation (n=1). Common Gr2 treatment-related AEs included alopecia (n=4), nausea (n=4), and vomiting (n=2). 1 patient had Gr3 alopecia. There were no Grade 4/5 AEs. 80% of patients scored worse on their neurocognitive assessments at 6 months compared to screening. ASL-CBF values of primary lesions appeared relatively stable throughout the study. Conclusions: The combination of Plerixafor and WBRT did not improve mOS compared to the original study using focused RT only. There was an overall decline in neurocognitive performance over the course of the study. Clinical trial information: NCT03746080 .

Conditional Risk and Predictive Factors Associated With Late Toxicity in Patients With Prostate Cancer Treated With External Beam Radiation Therapy Alone in the Randomized Trial RTOG 0126

The objective of this study was to characterize the conditional risk of developing grade 2+ urinary or gastrointestinal (GI) toxicity for patients treated with external beam radiation therapy in Radiation Therapy Oncology Group 0126. A secondary objective was to analyze baseline patient and treatment characteristics and determine their relevance in predicting toxicity both at the time of trial enrollment and at later points of follow-up. One thousand five hundred thirty-two patients with localized prostate cancer were enrolled between March 2002 and August 2008, of whom 1499 were eligible and included in data analysis with a median follow-up of 8.4 years (range, 0.02-13 years). Patients were treated with either 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy according to institutional practice without the addition of androgen deprivation and randomized to receive either standard-dose radiation therapy of 70.2 Gy or dose-escalated radiation therapy of 79.2 Gy of radiation therapy to the prostate only with standard fractionation. Univariate and multivariate analyses were performed to determine whether initial factors were predictive of late toxicity at the time of treatment and at later time points. As patients proceed further from completion of radiation therapy without the development of toxicity, the subsequent risk of both grade 2+ genitourinary (GU) and GI toxicity decreases with time. At the time of enrollment, the risk of developing grade 2+ toxicity over the next 5 years was 9.57% and 17.89%, respectively. After 5 years of toxicity-free survival, the risk of developing grade 2+ GU or GI toxicity in the subsequent 5 years was 3.02% and 1.54%, respectively. Baseline treatment and patient-related factors predicted late toxicity both at trial enrollment and after 2 years of toxicity-free survivorship. Baseline urinary dysfunction and dose-escalated radiation therapy were associated with increased late GU toxicity. Acute GI toxicity and dose-escalated radiation therapy were associated with increased risk of late GI toxicity. Treatment with intensity-modulated radiation therapy was associated with reduced risk of either toxicity. The conditional risk of grade 2+ toxicities decreases as patients proceed further from treatment, with most toxicities occurring in the first few years after treatment completion. Baseline patient and treatment characteristics remain relevant at both enrollment and later time points.

Outcome analysis of the traditional therapeutic approach in patients with bronchopulmonary cancer and advanced anesthetic-surgical risk

Background. Lung cancer exhibits high global incidence and mortality rates. Surgical resection remains crucial to diagnosis, staging, and treatment of non-small cell lung cancer (NSCLC). However, advanced stages often require multimodal approaches. Prehabilitation, innovative perioperative techniques, and the exploration of immunotherapy hold promise for improving outcomes. Materials and methods. This two-phase observational cohort study included a retrospective arm (100 patients, traditional treatment) and a prospective arm (100 patients, innovative perioperative management, and risk stratification). Descriptive and inferential statistics were used to evaluate data, identify risk factors, and compare the 2-year survival between treatment groups. Results. Despite advances, lung cancer prognosis remains poor, with limited cure rates. Mean survival in the traditional approach was 1.3 years with a 5-year survival of only 1%. While prehabilitation and innovative techniques showed potential, no statistically significant differences in survival times were observed between the treatment groups. Patients with stage III (Charlson score 0-4) and stage I-II (Charlson score 5-12) demonstrated comparable outcomes, highlighting the importance of comorbidity burden. Conclusions. Targeted screening protocols are of paramount importance for early detection and intervention. Populationwide smoking cessation programs, environmental protection measures, and the promotion of healthy lifestyles are vital for prevention and reducing incidence. Standard chemotherapy and radiotherapy offer limited therapeutic benefits in advanced lung cancer. This highlights a pressing need for breakthroughs in basic research to develop novel treatment paradigms that significantly improve outcomes. While this study did not reveal statistically significant survival differences between traditional and innovative perioperative approaches, prehabilitation and optimization techniques hold promise and deserve further research. The development of anti-tumor immunotherapy offers a significant potential in non-surgical lung cancer treatment, especially given the limitations in advanced-stage disease management. Harnessing the immune system to fight cancer represents a promising new frontier.

A phase III randomized trial of radiotherapy optimization for low-risk HER2-positive breast cancer (HERO): NRG-BR008.

TPS613 Background: Breast radiotherapy (RT) is the standard of care for patients with early-stage breast cancer (BC) who undergo breast-conserving surgery (BCS). However, the magnitude of benefit of RT is less clear in BCS patients with low-risk disease who receive effective systemic therapy. Among patients with early-stage HER2-positive (HER2+) BC, 10-year locoregional recurrence has been reported as low as 1.5% following BCS, adjuvant chemotherapy and HER2-targeted therapy, and RT. Given these exceedingly favorable outcomes, with the addition of HER2-directed therapy, we seek to evaluate the feasibility of omitting RT among patients with early-stage HER2+ BC following BCS and appropriate systemic therapy. Methods: This is a phase III randomized trial for patients ≥40 years with early-stage, node-negative, HER2+ (IHC/FISH) BC treated with BCS with negative margins and sentinel lymph node biopsy or axillary dissection. Patients undergoing primary surgery must have pathologic T1 (≤2 cm) N0 disease, while patients receiving neoadjuvant therapy must have clinical T1-2 (with radiographically T≤3.0 cm) N0 disease and exhibit a pathologic complete response (ypT0N0) at surgery. All patients must receive cytotoxic chemotherapy and HER2-targeted therapy, either in the adjuvant or neoadjuvant setting. Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1 cm), estrogen-receptor status (positive; negative), and systemic therapy sequencing (adjuvant vneoadjuvant). Patients will be randomized to standard breast RT in addition to continuation of trastuzumab to complete one year of treatment (Arm 1), or trastuzumab alone (Arm 2). Endocrine therapy will be recommended for patients with hormone-receptor positive tumors. The primary endpoint is the recurrence-free interval (RFI). Secondary endpoints include time to ipsilateral breast recurrence, locoregional recurrence, disease-free survival, and overall survival, in addition to the 7-year ipsilateral breast recurrence rate among those not receiving RT. A health-related quality of life sub-study will assess differences in patient-reported breast pain and worry. We estimate a 7-year RFI of 97.5% with RT and allow for a clinically acceptable decrement of 3.63% without RT (7-year RFI of 93.87%; HR 2.5) to establish omission of RT as non-inferior. NRG-BR008 aims to enroll 1,300 patients over 4.5 years, yielding 80% power to detect the non-inferiority of RT omission with a one-sided α=0.05. We expect to observe the required 38 RFI events within 6 years of additional follow-up. The NRG-BR008/HERO trial opened to accrual in March 2023. Accrual is 13/1,300 as of 02-05-2024. Clinical trial information: NCT05705401 .

Pyrotinib in HER2-altered advanced salivary gland carcinomas: Analysis of two cohorts from an exploratory study.

6108 Background: The HER2 altered in a subset of salivary gland cancers (SGCs). Pyrotinib is an oral irreversible pan-HER receptor tyrosine kinase inhibitor targeting HER1, HER2, and HER4. In this study, we assessed the efficacy and safety of pyrotinib in patients with HER2-amplified/overexpressed/mutated advanced SGCs, including recurrent/metastatic(R/M) and locally advanced (LA) patients with high-risk of recurrence. Methods: R/M and high-risk LA SGCs with HER2-alteration were enrolled. Pyrotinib (400 mg) was given orally once daily. In LA cohort, pyrotinib were given as adjuvant therapy after standard surgery and postoperative radiation. Results: Between August 2019 and August 2023, 18 patients were enrolled (10 in R/M cohort and 8 in LA cohort). In R/M cohort, the median age was 58.5 years, and all patients were grade III. The ORR was 90%, including 2 CRs, 7 PRs and 1PD; median DOR was 5.7 months (range: 3.1-13.7) and median PFS was 7.6 months (range: 2.7-16.8). In LA cohort, the median age was 59.0 years, and all patients but one were grade III. All patients but one had T4 disease; 5 patients had N3 and 2 had N2b disease; 5 patients had ENE and 5 patients had positive margin. With a median follow up 21.3 months, only 3 patients experienced recurrence, and one patient died due to non-tumor reasons. The estimated 2-years PFS and 2-years OS were 75% and 100%. The most common adverse event was diarrhea, which occurred in 11/18 (61.1%) patients and 3/18 (16.7%) were grade III. Conclusions: Pyrotinib showed promising antitumor activity in recurrent/metastatic HER2-altered SGCs, and had a potential to prolong survival outcome as adjuvant treatment in LA patients setting, which needs further randomized studies. Clinical trial information: NCT05087706 .

Transcriptomic and epigenetic characterization of mucinous adenocarcinoma of the cervix.

e17518 Background: Mucinous adenocarcinoma of the cervix (MAC) is a rare and aggressive histologic subtype of cervical cancer with poorer prognosis than its more common counterparts, usual type endocervical adenocarcinoma (UEA) and squamous cell carcinoma (SCC). MAC is also known to be less responsive to standard chemotherapy and radiation approaches used to treat cervical cancer. In this study, we sought to identify transcriptomic and epigenetic features of MAC that distinguish MAC from UEA and SCC, and to identify features that may contribute to poorer prognosis in MAC compared to UEA and SCC. Methods: Clinical data, gene expression, miRNA expression, and methylation data for 17 MAC, 27 UEA, and 247 SCC from The Cancer Genome Atlas Cervical Cancer Project were obtained and analyzed. Clinical data were compared for the histologic groups using Fisher’s Exact, ANOVA, and Kruskal-Wallis statistics where appropriate. Kaplan-Meier curves were used for survival analyses. Gene expression data was analyzed using DESeq2 for differential expression of mRNA. Pathway enrichment analysis of gene expression data was completed using Qiagen IPA Core Analysis software. Comparative marker selection was used to determine differential expression of miRNA, and differential methylation across histologic subtypes. Analyses were completed both by histology and by disease-progression status. Data across all three platforms were integrated to evaluate for potential explanatory relationships of interest. Results: RNAseq analysis revealed a number of genes differentially expressed in MAC as compared to UEA and SCC. Several of these genes were also found to be differentially expressed in samples from patients with disease progression compared to those without known disease progression including increased expression of PPARGC1A, SLC2A1, and ZNF703 and decreased expression of NR4A3. Analysis also revealed hypomethylation at CpG probe sites mapping to SLC2A1 and decreased expression of miRNAs known to target SLC2A1 and PPARGC1A in MAC tumors . Pathways involving translation regulation, EIF2 signaling, and oxidative phosphorylation were downregulated in MAC whereas pathways involving mitochondrial dysfunction, glucose metabolism, and estrogen receptor signaling were upregulated in MAC. Downregulation of immune and inflammatory response pathways and upregulation of tumor-supporting macrophage activation was seen in MAC tumors with disease progression. Conclusions: We identified novel transcriptomic and epigenetic features and altered pathways in MAC, as well as those features and pathways associated with poorer prognosis in this population. These findings may contribute to further confirmatory research and lead to novel therapeutic strategies for this rare cancer.

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step 40 Gy with 56 Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck: A phase III trial (JCOG1912, NEW BRIDGE).

TPS6121 Background: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. Methods: This study is a multicenter, two-arm, open-label, randomized phase III trial. The main inclusion criteria are as follows: (i) Primary lesions are located in the oropharynx, hypopharynx, or larynx. (ii) Histologically proven SCC on biopsy specimens of the primary lesion. Immunohistochemistry reveals p16 negativity in patients with oropharyngeal cancer. (iii) Clinical stage of III, IVA, or IVB (excluding N3a) based on the 8th UICC-TNM classification. Patients are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score.Patient accrual was started in May 2021 and the study is now open for accrual. A total of 186 patients have been enrolled as of January 2024. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100. Clinical trial information: jRCTs031210100 .

Monolithic all-perovskite tandem solar cells: advancing sustainable energy options

This paper discusses the results of a simulation-based study on lead-free perovskite tandem devices. Wide bandgap (1.8 eV) perovskite materials Cs2AgBi0.75Sb0.25Br6 as the top cell and narrow bandgap (1.3 eV) perovskite materials CsSnI3 as the bottom cell make up the simulated tandem cell device, respectively. The optimisation process involves individually fine-tuning both cells under standard solar radiation conditions of 100 W/m2. The tandem cells necessitate precise current matching between the two sub-cells. The current matching condition manifests at Jsc of 16 mA cm−2 when the top and bottom cells reach an optimised thickness of 700 nm and 65 nm, respectively. The optimised tandem cell achieves a 24.47% power conversion efficiency (PCE), a high Voc of 1.7278 V, and a high fill factor of 83.72%. Furthermore, tandem solar cells’ temperature dependence is examined in the 300 K to 400 K range, revealing that efficiency decreases with temperature due to a reduction in Jsc (short-circuit current). Notably, the current matching condition is primarily influenced by the top cell, which exhibits less variation than the bottom cell. This study paves the way for developing tandem solar cells made entirely of lead-free perovskites and presents a new approach for the experimental realisation of high-power conversion efficiency.

Patient-reported outcomes in N1 breast cancer: A phase III trial comparing whole-breast to whole-breast plus regional irradiation after taxane-based chemotherapy (KROG 1701).

577 Background: Recent randomized trials have highlighted the benefits of regional node irradiation (RNI) in high-risk node-positive or pN1 breast cancer, yet its impact in the context of modern taxane-based adjuvant chemotherapy remains unclear. In this multi-center phase III trial, we study to prove the hypothesis that there is no difference in terms of disease-free survival between standard whole-breast irradiation (WBI) with RNI and WBI alone in pN1 breast cancer patients receiving taxane-based adjuvant chemotherapy. Comprehensive patient-reported outcomes (PROs) collected at multiple time points are now reported. Methods: The KROG 17-01 trial (NCT03269981), a prospective, multicenter, non-inferiority study, randomized patients with pN1 breast cancer after breast-conserving surgery and adjuvant taxane-containing chemotherapy to WBI or WBI+RNI. Both conventional and hypofractionated radiotherapy (RT) were allowed. PROs were assessed using the EORTC QLQ-C30 and QLQ-BR23 modules. All data were collected at baseline, during RT, and at follow-up intervals of 3-6 months, 1, 2, 3, 4, and 5 years post-treatment. Linear mixed models were used to compare PROs between treatment arms. Results: From April 2017 to December 2021, 840 patients were enrolled; 777 received intervention as assigned, and 750 completed baseline PRO questionnaires (387 in WBI+RNI, 363 in WBI). Overall, PRO domains improved over time (p<0.001). During RT, the WBI+RNI group experienced more fatigue, nausea, and vomiting (p<0.05), and reported lower global health (p=0.090) and physical functioning (p=0.049) with borderline significance compared to the WBI group. At 3-6 months post-RT, WBI+RNI group also showed higher arm symptom scores (p=0.030). Apart from these specific timepoints, no significant differences were observed in other PRO domain scores, including arm and breast symptoms, between treatment arms. In addition, there was no significant differences in PRO domains according to RT techniques and fractionation, except for breast symptoms during RT, favoring hypofractionation and intensity-modulated RT. Conclusions: In patients with pN1 breast cancer treated with taxane-based adjuvant chemotherapy, adding RNI was associated with minor, transient declines in specific PRO domains. However, these differences were not clinically significant, indicating comparable overall patient experiences between the two treatment arms. Clinical trial information: NCT03269981 .

Alterations of the tumor microenvironment (TME) in recurrent glioblastoma following apatinib in combination with temozolomide.

e14018 Background: Glioblastoma (GBM) is the highly malignant primary central nervous system tumor. The standard treatment for glioblastoma is maximal surgical resection followed by concomitant radiotherapy and temozolomide chemotherapy, but patient’s survival still remains poor. At present, apatinib in combination with temozolomide (TMZ) has achieved reasonable clinical efficacy in the treatment of recurrent glioblastoma (rGBM), however, there are currently no clear biomarkers related to clinical efficacy or prognosis. Methods: This retrospective study was enrolled 22 rGBMs treated with apatinib in combination with TMZ and 6 patients who received standard radiotherapy combined with TMZ and experienced recurrence. At the same time, we collected their tissue samples for RNA transcriptome analysis by the Nanostring nCounter platform. In prognosis analysis, long survival benefit is defined as a PFS≥4.2 months, and short survival benefit is defined as a PFS<4.2 months. This PFS threshold was primarily referenced from a Phase III study of bevacizumab combined with chemotherapy for rGBM. The study was approved by the institutional ethics committee of Sanbo Brain Hospital, Capital Medical University (SBNK-YJ-2021-010-02) and informed consent was also obtained from the patients. Results: The differential gene of pre and post standard chemoradiotherapy results suggest that standard treatment has reduced the expression of genes associated with tumor proliferation and up-regulated the expression of the genes associated with the immune response in rGBM. In apatinib combined TMZ patients, compared to the non-response group, the response group had significantly up-regulated expression of genes related to endothelial cells and apoptosis. Enrichment analysis revealed that signaling pathways related to cell proliferation were down-regulated in the response group. In terms of prognosis, compared with the short-survival benefit group (< 4.2 months), four tumor progression-associated genes were down-regulated in response group (≥4.2 months). Hypoxia related-genes was significantly up-regulated in the long survival benefit group. Enrichment analysis showed that genes related to cell proliferation were also down-regulated in the long-survival benefit group, while the expression of signaling pathway genes related to cell activation, and immune response was significantly up-regulated. Conclusions: Our study suggests that the combination of apatinib and TMZ may potentially provide clinical benefits in treating rGBM by modulating genes associated with cell proliferation, promoting apoptosis, regulating hypoxia, and enhancing immune response within the tumor microenvironment. Clinical trial information: NCT04814329 .

N2M2/NOA-20: Phase I/IIa umbrella trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation.

2000 Background: Patients with glioblastoma without MGMT promoter hypermethylation are unlikely to benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Methods: This phase I/IIa umbrella trial aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to standard radiotherapy initiated within 42 days postoperatively. Molecular diagnostics and bioinformatic evaluation are performed within 28 days after surgery. Stratification for treatment takes place in five subtrials, including alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus, according to the best matching molecular alteration. Patients without matching alterations are randomized between subtrials without strong biomarkers using atezolizumab and asunercept and TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility ( H0: p=0.231). Results: From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. The alectinib and vismodegib subtrials were closed since no molecularly matching patients were accrued; the idasanutlin subtrial was closed prior to the optimal dose at nine patients at discretion of the company providing the drug. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.831) and a median overall survival (OS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and OS of 12.8 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and OS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and OS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and OS of 15.4 months. The regimen-limiting toxicity (RLT)-rate is 34.8%, which is insignificantly above the predefined unacceptable rate for RLTs of 30%. Most RLTs had severity grade 3, one RLT had severity grade 4. No RLTs resulted in death. Conclusions: N2M2 allows for elaborate molecular testing being integrated into the treatment decision and efficient determination of treatment activity for patients with newly diagnosed glioblastoma. There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients and also palbociclib in molecularly selected patients. Clinical trial information: NCT03158389 .

High versus standard radiation dose of definitive chemoradiotherapy combined with immunotherapy for inoperable esophageal squamous cell carcinoma: A multicenter propensity score matching analysis.

e16118 Background: There is no consensus of the radiation dose for esophageal squamous cell carcinoma (ESCC) in the setting of definitive chemoradiotherapy (dCRT) combined with immunotherapy. This study aimed to compare the efficacy and safety of high-dose (HD) versus standard-dose radiotherapy (SD) for locally inoperable ESCC. Methods: Patients with locally advanced unresectable ESCC or advanced ESCC with supraclavicular lymph node metastases only who received high-dose (≥ 60Gy) or standard-dose (50-50.4Gy) radiation in dCRT combined with anti-PD-1 antibody as the first-line treatment from four academic cancer centers were enrolled. Propensity score matching (PSM) was conducted to minimize the potential confounding effects. Results: Between March 2019 and July 2022, 328 patients were enrolled from four cancer centers in China, with 163 patients in the HD and 165 patients in the SD groups, respectively. The median follow-up time in the HD and SD groups were 28.9 and 25.9 months, respectively. There was no significant difference in overall survival (OS) (median OS: not reached in both, P = 0.080), progression-free survival (PFS) (median PFS: not reached vs. 30.3 months, P = 0.073), locoregional progression-free survival (LRPFS) and distant metastasis survival (DM) between the HD and SD groups. After 1:2 PSM, 156 patients in the HD and 78 patients in the SD groups were selected for further analyses. The results remained consistent and showed that the HD group had no significant benefits in OS (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.50-1.51, P = 0.624), PFS (HR = 0.79, 95%CI = 0.51-1.23, P = 0.300), LRPFS (HR = 0.75, 95%CI = 0.47-1.19, P = 0.228) and DM (HR = 1.05, 95%CI = 0.64-1.73, P = 0.849), compared with the SD group. In terms of failure patterns, the incidences of locoregional failure only (13.5% vs. 16.7%, P = 0.512), distant failure only (10.9% vs. 9.0%, P = 0.648) and synchronous locoregional and distant failure (2.6% vs. 6.4%, P = 0.164) were similar between two groups. No significant difference was found in the incidences of hematological toxicities, esophagitis, pneumonia (12.2% vs. 10.3%, P = 0.664) and fistula (7.1% vs 9.0%, P = 0.603) between the HD and SD groups. Conclusions: Compared with a radiation dose of 50-50.4Gy, the increase in radiation dose (≥60Gy) did not result in survival benefits for inoperable ESCC patients receiving dCRT combined with immunotherapy. Furthermore, similar failure patterns and toxicities were observed between the two treatment groups.

Acute and Long-Term Toxicity after Planned Intraoperative Boost and Whole Breast Irradiation in High-Risk Patients with Breast Cancer-Results from the Targeted Intraoperative Radiotherapy Boost Quality Registry (TARGIT BQR).

In the context of breast cancer treatment optimization, this study prospectively examines the feasibility and outcomes of utilizing intraoperative radiotherapy (IORT) as a boost in combination with standard external beam radiotherapy (EBRT) for high-risk patients. Different guidelines recommend such a tumor bed boost in addition to whole breast irradiation with EBRT for patients with risk factors for local breast cancer recurrence. The TARGIT BQR (NCT01440010) is a prospective, multicenter registry study aimed at ensuring the quality of clinical outcomes. It provides, for the first time, data from a large cohort with a detailed assessment of acute and long-term toxicity following an IORT boost using low-energy X-rays. Inclusion criteria encompassed tumors up to 3.5 cm in size and preoperative indications for a boost. The IORT boost, administered immediately after tumor resection, delivered a single dose of 20 Gy. EBRT and systemic therapy adhered to local tumor board recommendations. Follow-up for toxicity assessment (LENT SOMA criteria: fibrosis, teleangiectasia, retraction, pain, breast edema, lymphedema, hyperpigmentation, ulceration) took place before surgery, 6 weeks to 90 days after EBRT, 6 months after IORT, and then annually using standardized case report forms (CRFs). Between 2011 and 2020, 1133 patients from 10 centers were preoperatively enrolled. The planned IORT boost was conducted in 90%, and EBRT in 97% of cases. Median follow-up was 32 months (range 1-120, 20.4% dropped out), with a median age of 61 years (range 30-90). No acute grade 3 or 4 toxicities were observed. Acute side effects included erythema grade 1 or 2 in 4.4%, palpable seroma in 9.1%, punctured seroma in 0.3%, and wound healing disorders in 2.1%. Overall, chronic teleangiectasia of any grade occurred in 16.2%, fibrosis grade ≥ 2 in 14.3%, pain grade ≥ 2 in 3.4%, and hyperpigmentation in 1.1%. In conclusion, a tumor bed boost through IORT using low-energy X-rays is a swift and feasible method that demonstrates low rates in terms of acute or long-term toxicity profiles in combination with whole breast irradiation.

Upscaling irradiation protocols of Aedes albopictus pupae within an SIT program in Reunion Island.

The implementation of the sterile insect technique against Aedes albopictus relies on many parameters, in particular on the success of the sterilization of males to be released into the target area in overflooding numbers to mate with wild females. Achieving consistent sterility levels requires efficient and standardized irradiation protocols. Here, we assessed the effects of exposure environment, density of pupae, irradiation dose, quantity of water and location in the canister on the induced sterility of male pupae. We found that the irradiation of 2000 pupae in 130ml of water and with a dose of 40Gy was the best combination of factors to reliably sterilize male pupae with the specific irradiator used in our control program, allowing the sterilization of 14000 pupae per exposure cycle. The location in the canister had no effect on induced sterility. The results reported here allowed the standardization and optimization of irradiation protocols for a Sterile Insect Techniqueprogram to control Ae. albopictus on Reunion Island, which required the production of more than 300,000 sterile males per week.

Revolutionizing Glioblastoma Treatment: A Comprehensive Overview of Modern Therapeutic Approaches.

Glioblastoma is the most common malignant primary brain tumor in the adult population, with an average survival of 12.1 to 14.6 months. The standard treatment, combining surgery, radiotherapy, and chemotherapy, is not as efficient as we would like. However, the current possibilities are no longer limited to the standard therapies due to rapid advancements in biotechnology. New methods enable a more precise approach by targeting individual cells and antigens to overcome cancer. For the treatment of glioblastoma, these are gamma knife therapy, proton beam therapy, tumor-treating fields, EGFR and VEGF inhibitors, multiple RTKs inhibitors, and PI3K pathway inhibitors. In addition, the increasing understanding of the role of the immune system in tumorigenesis and the ability to identify tumor-specific antigens helped to develop immunotherapies targeting GBM and immune cells, including CAR-T, CAR-NK cells, dendritic cells, and immune checkpoint inhibitors. Each of the described methods has its advantages and disadvantages and faces problems, such as the inefficient crossing of the blood-brain barrier, various neurological and systemic side effects, and the escape mechanism of the tumor. This work aims to present the current modern treatments of glioblastoma.

Evaluating optimal quality assurance and quality control conditions of activation measurements at the accelerator-based boron neutron capture therapy system employing a lithium target

Evaluating neutron output is important to ensure proper dose delivery for patients in boron neutron capture therapy (BNCT). It requires efficient quality assurance (QA) and quality control (QC) while maintaining measurement accuracy. This study investigated the optimal measurement conditions for QA/QC of activation measurements using a high-purity germanium (HP-Ge) detector in an accelerator-based boron neutron capture therapy (AB-BNCT) system employing a lithium target. The QA/QC uncertainty of the activation measurement was evaluated based on counts, reproducibility, and standard radiation source uncertainties. Measurements in a polymethyl methacrylate (PMMA) cylindrical phantom using aluminum-manganese (Al–Mn) foils and aluminum-gold (Al–Au) foils and measurements in a water phantom using gold wire with and without cadmium cover were performed to determine the optimal measurement conditions. The QA/QC uncertainties of the activation measurements were 4.5% for Au and 4.6% for Mn. The optimum irradiation proton charge and measurement time were determined to be 36 C and 900 s for measurements in a PMMA cylindrical phantom, 7.0 C and 900 s for gold wire measurements in a water phantom, and 54 C and 900 s at 0–2.2 cm depth and 3,600 s at deeper depths for gold wire measurements with cadmium cover. Our results serve as a reference for determining measurement conditions when performing QA/QC of activation measurements using HP-Ge detectors at an AB-BNCT employing a lithium target.

Meta-Analysis of 5-Fraction Preoperative Radiotherapy for Soft Tissue Sarcoma.

Studies investigating preoperative 5-fraction radiation therapy (RT) for soft tissue sarcoma (STS) are limited. We performed a meta-analysis to determine the efficacy and safety of this treatment paradigm. This study-level meta-analysis was conducted using Bayesian methods. Statistical estimation for risk of outcome rates was conducted by posterior mean and 95% highest posterior density (HPD) intervals. Studies with 2-year local control (LC) and description of major wound complications (MWC) per the CAN-NCIC-SR2 study were included and served as the primary endpoints. Secondary endpoints included rates of acute and late toxicity. A total of 10 studies were identified and 7 met the inclusion criteria. Subgroup analyses were performed for ≥30 Gy vs <30 Gy. A total of 209 patients from 7 studies were included. Five studies used ≥30 Gy (n=144), and 2 studies <30 Gy (n=64). Median follow-up was 29 months (range: 21 to 57mo). Primary tumor location was lower extremity in 68% and upper extremity in 22%. Most tumors were intermediate or high grade (95%, 160/169), and 50% (79/158) were >10cm. The two-year LC for the entire cohort was 96.9%, and the rate of MWC was 30.6%. There was a trend toward improved LC with ≥ 30 Gy (95% HPD: 0.95 to 0.99 vs 0.84 to 0.99). There was no difference in MWC (95% HPD: 0.18 to 0.42 vs 0.17 to 0.55) or late toxicity between the groups. Preoperative 5-fraction RT for STS demonstrates excellent 2-year LC with MWC and toxicity similar to standard fractionation preoperative RT. Multi-institutional trials with a universal RT protocol are warranted.

A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma

This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.