Combination Of Radiotherapy Research Articles

Oesophageal cancer.

Oesophageal cancer is the seventh leading cause of cancer mortality worldwide. Two major pathological subtypes exist: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Epidemiological studies in the last decade have shown a gradual increase in the incidence of oesophageal adenocarcinoma worldwide. The prognosis of oesophageal cancer has greatly improved due to breakthroughs in screening, surgical procedures, and novel treatment modalities. The success achieved with combined modality therapies, including surgery, chemotherapy, and radiotherapy, to treat locally advanced oesophageal cancer is particularly notable. Immunotherapy has become a crucial treatment for oesophageal cancer, with immune checkpoint inhibitor-based therapies now established as the standard of care in adjuvant and metastatic first-line settings. This Seminar provides an overview of advances in the screening, diagnosis, and treatment of oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, with a particular focus on neoadjuvant therapies for locally advanced oesophageal cancer and immune checkpoint inhibitor-based therapies.

Radiotherapy in patients with brain metastases with and without concomitant immunotherapy: comparison of patient outcome and neurotoxicity.

Recently, immune checkpoint inhibitors (ICI) have been added to the treatment of brain metastases. While combining radiotherapy and ICI can enhance therapeutic effects, it might also increase the risk of severe autoimmune adverse events. This retrospective study aims to compare treatment responses and neurotoxicity in patients treated with radiotherapy alone versus those receiving a combination of radiotherapy and ICI. All patients with brain metastases who received radiotherapy at Hannover Medical School from 2017 to 2019 were included. The medical reports of all study participants were evaluated. Patients who received radiotherapy alone and those who received a combination of radiation and ICI were compared. A total of 248 patients were analyzed, with the most common tumor types being non-small cell lung cancer (NSCLC) and malignant melanoma. Half of the patients received whole-brain radiotherapy (WBRT) and the other half stereotactic radiotherapy (SRT). Of these, 29 patients received concurrent immunotherapy and radiotherapy, 30 completed immunotherapy before radiotherapy, and 29 started ICI after completing radiotherapy. Two cases lacked information on the duration of immunotherapy. Overall survival post-initial tumor diagnosis within the total cohort was 52months, with significantly worse survival for patients with multiple brain metastases (p = 0.020). No significant differences in survival or incidence of neurological adverse events were observed between patients with or without ICI. Combining radiotherapy and ICI did not significantly increase neurotoxicity or improve survival in this cohort, though the heterogeneity of the subgroups limits the generalizability of these findings.

Real-world analysis of the incidence and risk factors of pneumonitis in non-small cell lung cancer patients treated with combined thoracic radiotherapy and immunotherapy

Abstract Objectives Combining radiotherapy with immune checkpoint inhibitor (ICI) treatment has emerged as an important therapeutic regimen. However, this combined treatment may increase the risk of pneumonitis. The aim of this study is to analyze the incidence and risk factors for pneumonitis in non-small cell lung cancer (NSCLC) patients receiving combined thoracic radiotherapy and ICI (RT + ICI) treatment in the real-world clinical setting, offering a reference and guidance for clinical physicians. Methods This study identified 447 patients with pathologically confirmed NSCLC at West China Hospital of Sichuan University from 2016 to 2021. Clinical characteristics, treatment regimens, immune-related adverse events (irAEs), and hematological data were collected and analyzed. Results Patients receiving combined RT + ICI treatment had a higher risk of developing pneumonitis than those receiving ICI treatment alone (26.9 vs. 6.7 %, p<0.001). The multivariate logistic analysis identified the following independent risk factors for pneumonitis in patients undergoing combined RT + ICI treatment: history of lung disease (p=0.032), first-line ICI treatment (p=0.001), anti-PD-L1 instead of anti-PD-1 treatment (p=0.035), and the development of immunotherapy-related thyroid dysfunction (p=0.019). The independent risk factors were incorporated into a nomogram to predict the incidence of pneumonitis. The area under the receiver operating characteristic curve is 0.727, suggesting an acceptable predictive efficacy. Conclusions Compared to ICI monotherapy, NSCLC patients receiving the combination of thoracic radiotherapy and ICI treatment are at higher risk of developing pneumonitis. The nomogram holds promise for facilitating the risk assessment and early identification of pneumonitis in NSCLC patients receiving combined RT + ICI treatment.

Abstract 4138622: Cardiac Rhabdomyosarcoma: An Updated Review of the English Literature From 1980 Through 2023

Cardiac Rhabdomyosarcoma (CR) is a rare malignant neoplasm of the heart occurring in all age groups and genders. It can arise anywhere in the heart with varied clinical presentation. Available data on CR are mainly from case reports and series that are limited by small sizes. The purpose of this study was to characterize the epidemiology, presentation, management, hospital course, and outcomes of CR published in the English literature from 1980-2023. Methods: We reviewed and included all published case reports with a diagnosis of CR in adult patients (age >18 years) on PubMed and Google Scholar using the keywords “primary cardiac tumor” and “cardiac rhabdomyosarcoma”. Data was extracted onto an Excel spreadsheet for analysis and the outcomes of interest were demographics, clinical presentation, diagnostic modalities, management, complications, and outcomes. We used descriptive statistics to analyze the data. Results: Among a total of 97 patients from 19 countries included in this study, 54% were males and the median age was 49 years (range 18-80). The main symptoms were dyspnea (37.1%), palpitations (23.7%), chest pains (16.5%) and syncope (6.5%). Hypotension or heart failure and arrhythmias were present in 10.3% and 9.3%, respectively and 5.2% had pericardial effusion. In addition to those with metastatic tumors, 22.7% had chronic co-morbidities. The majority of the cases were primary tumors (85.6%), and the remainder were (14.4%). All patients had at least one imaging modality including echocardiography (89%) and CT/MRI (84%). The commonest sites of cardiac involvement were the left atrium (35%), right atrium (33%), right ventricle (20%), and left ventricle (12%). Approximately 68% involved a single cardiac site while 32% involved multiple sites. Among the patients, 96% underwent surgery while 33% and 25% had chemotherapy and 25% radiotherapy, respectively. The median length of hospital stay was 11 days (range, 2-68 days), and mortality was recorded in 79.3% (77/97) of the patients. The median survival time was reported in 42 patients, and it was 6 months (range, 0-36 months). Conclusion: Cardiac rhabdomyosarcoma is a rare and aggressive malignant neoplasm. Most cases are primary tumors with poor outcomes such as a very short median survival time and a very high mortality rate despite the combination of surgery, chemotherapy, and radiotherapy. This calls for further research into the early diagnosis and optimal management strategies to improve outcomes.

NCOG-43. THE APPLICATION OF INDUCTION CHEMOTHERAPY COMBINED WITH RADIOTHERAPY IN YOUNG ADULTS WITH CNS GERM CELL TUMORS

Abstract BACKGROUND Central nervous system (CNS) germ cell tumors are rare brain neoplasms, accounting for approximately 0.3-0.5% of all CNS tumors. A combination of radiotherapy and chemotherapy is the standard of care (SOC) in pediatric patients. However, there is no SOC for young adult or adult patients. This study evaluates a regimen of induction chemotherapy followed by radiation in treating young adults with CNS germ cell tumors. METHOD Nine young adult patients diagnosed with pure CNS germinomas were identified in our institution. They underwent a treatment regimen of induction chemotherapies that were planned for four cycles and consisted of bleomycin (three doses per cycle), cisplatin (five doses per cycle) and etoposide (five doses per cycle) followed with whole brain and/or ventricular radiotherapy. The patients’ overall survival (OS), neurological function (including cognition), and adverse events (AE) were analyzed. RESULT Among the nine patients (seven males and two females), the median age is 20 years (range: 17-33 years). They received bleomycin, cisplatin and etoposide (median: two cycles, range: 1-4), and subsequent radiotherapy with plans based on tumor location by radiation oncologists, with a median radiotherapy dose of 45 Gy (range: 36-50.4). Seven patients had a complete response after chemotherapy. The median OS is 53 months (range: 39-121). There is no identifiable cognitive impairment by neurological exam. All patients experienced at least one, reversible, grade 3 AE of myelosuppression. All patients return to their normal baseline including employment. Results of neuropsychological evaluation and all AEs will be presented at the conference. CONCLUSION Induction chemotherapy followed by radiotherapy is potentially safe and effective with manageable and reversible side effects from chemotherapy without cognitive and functional impairment in the nine young adult patients with CNS germ cell tumors. A prospective study of this approach in a clinical trial setting is warranted.

SMAD4 Limits PARP1 dependent DNA Repair to Render Pancreatic Cancer Cells Sensitive to Radiotherapy.

Dysregulation of SMAD4 (i.e. somatic mutation) is strongly associated with poor pancreatic ductal adenocarcinoma (PDAC) prognosis, yet the molecular mechanisms remain underlying this relationship obscure. Previously, we discovered that SMAD4 mutation renders pancreatic cancer resistant to radiotherapy via promotion of autophagy. In the current work, we observed a downregulation of the protein level of SMAD4 in PDAC as compared with adjacent normal tissue, and that such SMAD4low PDAC failed to benefit from chemotherapy. Furthermore, we observed that SMAD4 depletion dramatically enhanced DNA repair capacity in response to irradiation (IR) or a radiomimetic chemical. Interestingly, we found the radiomimetic chemical having induced a robust translocation of SMAD4 into the nucleus, where a direct interaction was shown to occur between the MH1 domain of SMAD4 and the DBD domain of PARP1. Functionally, the SMAD4-PARP1 interaction was found to perturb the recruitment of PARP1 to DNA damage sites. Accordingly, the combination of olaparib and radiotherapy was indicated in vivo and in vitro to specifically reduce the growth of SMAD4-deficient PDAC by attenuating PARP1 activity. Collectively, our results revealed a novel molecular mechanism for the involvement of the SMAD4-PARP1 interaction in DNA repair with a vital role in radiotherapy response in PDAC. Based on our set of findings, our findings offer a new combined therapeutic strategy for SMAD4 deficient PDAC that can significantly reduce pancreatic cancer radiotherapy resistance.

The effects of immune checkpoint inhibitors vs. chemotherapy combined with brain radiotherapy in non-small cell lung cancer patients with brain metastases

BackgroundNon-small cell lung cancer (NSCLC) is a prevalent form of cancer, often leading to brain metastases (BM) and a significant decline in patient prognosis. Whether immune checkpoint inhibitors (ICIs) combined with brain radiotherapy is superior to conventional chemotherapy combined with brain radiotherapy in those patients remains to be explored.Materials and methodsOur study enrolled 161 NSCLC patients with BM who underwent either ICIs combined with brain radiotherapy or chemotherapy combined with brain radiotherapy. End points included overall survival (OS), progression-free survival (PFS), intracranial PFS (IPFS), and extracranial PFS (EPFS). Univariate and multivariate Cox regressions were employed to identify prognostic risk variables.ResultsPatients receiving ICIs combined with brain radiotherapy exhibited significantly longer OS compared to those receiving chemotherapy combined with brain radiotherapy (34.80 months vs. 17.17 months, P = 0.005). In the Cox regression analysis, chemotherapy combined with brain radiotherapy (HR, 1.82; 95% CI, 1.09–3.05; P = 0.023), smoking (HR, 1.75; 95% CI, 1.02–2.99; P = 0.043) and squamous cell carcinoma (HR, 2.59; 95% CI, 1.31–5.13; P = 0.006) were associated with a worse prognosis. After propensity score matching (PSM), this finding remained consistent with before PSM (43.73 months vs. 17.17 months, P = 0.018). Squamous cell carcinoma (HR, 2.46; 95% CI, 1.15–5.26; P = 0.021) and CT + RT (HR, 2.11; 95% CI, 1.15–3.88; P = 0.016) were associated with a less favorable prognosis.ConclusionThe study suggests that the combination of ICIs and brain radiotherapy provides superior OS for NSCLC patients with BM, compared to the chemotherapy combined with brain radiotherapy.

Successful management of refractory Cushing's disease with severe hypercortisolemia using etomidate and temozolomide in post-surgical failure.

Corticotropinomas account for 20% of all aggressive pituitary tumors and pituitary carcinomas and are associated with high mortality. These tumors not only cause neurovascular compromise but can also be fatal due to severe hypercortisolemia itself. Although surgery is considered the primary treatment modality, it is often partially successful or unsuccessful. Moreover, these tumors frequently recur and may be resistant to conventional treatments, including surgery and radiotherapy. Therefore, early multimodal treatment and regular follow-up are necessary. We present a case of aggressive Cushing's disease managed with combined temozolomide therapy and radiotherapy following an unsuccessful transsphenoidal surgery, resulting in significant long-term radiological and biochemical remission. In addition, etomidate infusion was administered to achieve rapid cortisol reduction, highlighting its role as a bridging therapy to other modalities in treating life-threatening and severe hypercortisolemia outside an intensive care setting.

Long-Term Survey of Japanese Children with Recurrent Nephroblastoma: A Report from Japan Children’s Cancer Group

In prospective Japanese studies of pediatric renal tumors, 5-year event-free survival and overall survival (OS) for patients with nephroblastoma ranges from 75–90% and 89–97%, respectively. However, treatments strategies for recurrent nephroblastoma in Japanese patients remain unclear. This retrospective study aimed to inform the development of treatment strategies by analyzing the long-term results and side effects of salvage therapies for recurrent nephroblastoma in Japan. A questionnaire survey involving 41 institutions (74 patients) collected clinical data on recurrent cases reported to the Renal Tumor Committee of the Japan Children’s Cancer Group. Survey forms from 54 cases were evaluated. Median time to recurrence was 9.5 months among 51 patients without underlying disorders. Recurrence occurred at lung-only in 18 patients and at other sites in 33. The 5-year OS for all 51 patients was 70.6%, with recurrent disease causing death in 15 patients and one patient dying from treatment-related complications. Patients with lung-only recurrence had higher 5-year OS rates than those with other-site recurrence. Initial chemotherapy intensity also affected prognosis, with lower intensity associated with higher 5-year OS. In 17 survivors with lung-only recurrence, the most frequent treatment approach combined chemotherapy, surgery and radiotherapy. Conventional chemotherapy included platinum-containing regimens and/or Regimen I-based treatment containing cyclophosphamide and etoposide. Salvage therapies showed remarkable effectiveness for patients with lung-only recurrence or low intensity of the initial chemotherapy, highlighting the need to standardize prospective studies for post-recurrence treatment and identify risks of late complications for long-term survivors.

Primary orbital and adnexal rhabdomyosarcoma: a study of 54 Asian Indian patients

ABSTRACT Purpose To describe the clinical presentation, management, and outcomes of orbital and adnexal rhabdomyosarcoma (RMS) in an Asian-Indian cohort and analyze the factors predictive of outcomes. Methods Retrospective interventional case series of 54 patients of histopathology-proven RMS Results The mean age of presentation with RMS was 10 years (median, 7 years; range, <1–54 years). The most common tumor location was the superonasal quadrant (n = 21, 39%). Extensions beyond the orbit into the sinuses, temporal fossa, and brain were seen in 15 (28%), 3 (6%), and 8 (15%), respectively. First-line treatment modalities included a combination of surgical debulking, chemotherapy, and external beam radiotherapy in 20 (37%) patients; chemotherapy and radiation in 20 (37%); complete surgical excision and chemotherapy in 3 (6%); orbital exenteration, chemotherapy, and external beam radiotherapy in 1 (2%); chemotherapy alone in 1 (2%) patient, and 9 (17%) patients were lost to follow up. By Intergroup Rhabdomyosarcoma Study Group (IRSG) grouping, tumors belonged to groups I (n = 2,4%), II (n = 13, 29%), and III (n = 30, 67%). Kaplan-Meier survival estimates for tumor recurrence, lymph node metastasis, systemic metastasis, and death (n = 45) were 84%, 82%, 95%, and 95% at 1 year, 69%, 76%, 81%, and 77% at 5 years, 69%, 76%, 81%, and 77% at 10 years, respectively. On multivariate regression, age >18 years was found to have a significantly increased risk of locoregional LN metastasis (p = 0.005). Conclusion Despite aggressive treatment modalities, the 5–year disease-specific survival rate was 77% in Asian-Indian cohort. Age > 18 years at presentation was associated with a poorer prognosis.

Clinical characteristics and prognosis of brain metastasis in locally advanced rectal cancer

Objective: To investigate the clinical characteristics of brain metastases after radical surgery for locally advanced rectal cancer (LARC). Methods: The clinical characteristics of LARC with brain metastases treated in the Department of General Surgery, Peking Union Medical College Hospital from 2013 to 2023 were retrospectively analyzed. The inclusion criteria were rectal adenocarcinoma within 15 cm of the anal verge and having undergone radical surgery, and the exclusion criterion was primary malignant tumor of the brain. The main outcomes were overall survival (OS), disease-free survival (DFS), and disease-specific overall survival (determined as the interval between occurrence of brain metastasis to death from any causes). The Kaplan-Meier method was used for survival analysis. Results: We identified 4500 patients with LARC, 20 (0.4%) of whom had brain metastases. The mean age of patients with brain metastases was 63.8±9.3 years. They comprised five women and 15 men. The brain was the first site of metastasis in four patients (20%) whereas 18 patients had heterochronous extracranial metastases before brain metastasis. Two patients also had multi-organ metastases. The most common manifestations of brain metastases were dizziness and headache (five patients, 25%), sudden onset of limb weakness (four, 20%), sudden speech impairment (two, 10%), and polyopia (two, 10%). The metastases were diagnosed during follow-up in three patients (15%). Four of the patients were asymptomatic (20%). Treatment approaches included surgical resection (six patients, 30%), chemoradiotherapy (nine, 45%), and palliative (five, 25%). The median follow-up time was 45.5 (4-112) months until October 2023. 1y-OS, 3y-OS, and 5y-OS were 95.0%, 62.9%, and 43.3%, respectively. 1y-DFS, 3y-DFS, and 5y-DFS were 55.0%, 25.0%, and 5.0%, respectively. With brain metastasis as the starting point, the median duration of survival was 16 (10.2-21.8) months. Conclusion: The incidence of brain metastasis is relatively low in patients with LARC, who often have multiple synchronous extracranial metastases. Brain metastases lack specific manifestations and more often occur in male patients. Surgical intervention or combined radiotherapy and chemotherapy may improve disease-specific survival to a certain extent. However, the overall prognosis remains poor.

Efficacy and safety of bevacizumab combined with temozolomide in the treatment of glioma a systematic review and meta-analysis of clinical trials.

Glioma is the most common malignant brain tumor in neurosurgery. Bevacizumab (BEV) is a monoclonal antibody that inhibits tumors by inhibiting vascular endothelial growth factor and reducing tumor angiogenesis. To evaluate the efficacy and safety of BEV combined with temozolomide (TMZ) in glioma, we performed a meta-analysis. PubMed, Embase, The Cochrane Library, and Web of Science databases were searched for randomized controlled trials comparing survival outcomes between TMZ combined with BEV and TMZ alone as well as cohort studies were included in our study. The primary outcome measures analyzed were overall survival (OS) and progression-free survival (PFS). A total of six randomized controlled trials and four cohort studies with a total of 2515 patients were included in our meta-analysis. The results of meta-analysis suggested that there were no significant improvements in overall survival, but the combination of TMZ and BEV prolonged progression-free survival, improved overall response rate (ORR), and increased the incidence of some adverse reactions, compared with TMZ alone. Subgroup analysis suggested sex, recursive partitioning analysis (RPA) grade, MGMT gene status and radiotherapy combination did not affect the improvement of OS with the combination of the two drugs, and RPA grade did not affect the improvement of PFS with the combination of the two drugs. The combination of TMZ and BEV can improve PFS as well as ORR in patients and has no benefit on OS. At the same time, the adverse reactions during the combination of the two drugs were acceptable.

In-depth exploration of the focus issues of TKI combined with radiotherapy for EGFR-mutant lung adenocarcinoma patients with brain metastasis: a systematic analysis based on literature metrology, meta-analysis, and real-world observational data

BackgroundThere is a growing interest in utilizing a combination of brain radiotherapy (RT) and tyrosine kinase inhibitors (TKIs) for patients diagnosed with brain metastases (BM) in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LAC). The current status of this treatment strategy remains a subject of debate.MethodsWe initiated our study by conducting a comprehensive literature search using the SCI-expanded database of Web of Science Core Collection (WoSCC). We utilized the VOSPviewer software to analyze various aspects of the research, including the year of publication, authorship, keywords, and country.Subsequently, we performed an extensive and systematic literature search on popular online databases. Our primary outcome measures were overall survival (OS) and intracranial progression-free survival (iPFS), both quantified by hazard ratios (HRs).Additionally, for data verification, we included data from patients in non-small cell lung cancer with brain metastasis who underwent therapeutic intervention at the Cancer Prevention and Treatment Center of Sun Yat-sen University and the Radiotherapy Department of Hanzhong Central Hospital between August 2012 and November 2021.ResultsThe bibliometric analysis revealed an increasing trend in research focused on the combination of RT and TKIs for the management of lung cancer brain metastases over the previous decade. Then, nine studies consistent with the research direction were included for meta-analysis. The meta-analysis showed that the OS (HR = 0.81, 95% confidence interval: 0.69–0.94; P = 0.007) and iPFS (HR = 0.71, 95% confidence interval: 0.61–0.82; P < 0.001) of the combination therapy were significantly prolonged. Finally, 168 EGFR-mutated BM advanced LAC patients in the real world were verified, and the median iPFS of the combination therapy (n = 88 and EGFR-TKIs alone (n = 80) were 16.0 and 9.0 months, respectively, (P < 0.001). The median OS was 29.0 and 27.0 months, respectively, with no dramatic difference (P = 0.188).ConclusionsResearch on EGFR-mutant LAC brain metastasis has turned towards exploring optimal treatment strategies for this condition. Our meta-analysis and real-world data analysis consistently demonstrate that combination therapy offers a substantial improvement in patient survival compared to EGFR-TKI monotherapy. Notably, among patients undergoing salvage radiotherapy (RT), our subgroup analysis reveals that those initially treated with third-generation TKIs experience more significant benefits than those treated with first- or second-generation TKIs.

Genomic biomarkers predict response to combined ATR inhibition and radiotherapy.

For decades, chemoradiosensitization with checkpoint kinase inhibitors has been proposed but largely unexplored. A recent study reports the novel ATR kinase inhibitor, RP-3500, synergizes with radiation to control Atm-/- tumors in vivo. RP-3500 did not radiosensitize wild-type or Brca-1 deficient tumors, highlighting the need for a genotype-tailored approach.

IN VIVO APPLICATION OF LOCAL DRUG DELIVERY SYSTEMS AGAINST MEDULLOBLASTOMA GROUP 3 AND ATYPICAL/TERATOID/RHABOID TUMOURS

Abstract AIMS Local drug delivery systems (LDDSs) applied during neurosurgery offer a means of overcoming poor blood brain barrier (BBB) permeability and have been extensively investigated for the treatment of adult gliomas, but to the best of our knowledge, not for the treatment of paediatric cerebellar tumours. Here we report the applicability of an LDDS against medulloblastoma group 3 (MB3) and atypical teratoid/rhaboid tumours (AT/RT), both of which are associated with poor prognoses. METHOD We prepared and characterised an injectable and biodegradable poly(ethyleneglycol)-poly(caprolactone)- poly(ethyleneglycol) (PECE) hydrogel, which has been investigated with an array of therapeutic agents against numerous cancer types. Here, we loaded the PECE hydrogel with chemotherapeutics previously identified as being effective against primary MB3 and AT/RT in vitro, but which do not cross the BBB in vivo, namely CHIR99021, ribavirin and PG545. Biocompatibility and cytotoxicity of drug loaded hydrogels was assessed in vitro. LDDSs safety and efficacy was evaluated using patient derived MB3 and AT/RT intracranial xenograft surgical resection models. RESULTS The hydrogel was both biocompatible and effected cytotoxicity following drug release. In vivo efficacy experiments against MB3 indicated a comparable median survival in treatment arms receiving radiotherapy or CHIR99021 and PG545 loaded LDDS. However, combined radiotherapy and LDDS conferred a significant survival enhancement, including long-term survivors. Against AT/RT, the median survival of arms receiving radiotherapy was comparable to that of the CHIR99021 and ribavirin loaded LDDS, with long-term survivors observed only in the latter arm. CONCLUSION The application of LDDSs against cerebellar brain tumours offers a promising novel therapeutic alternative. For MB3, the combination of radiotherapy and a LDDS significantly enhances survival compared to radiotherapy alone. For AT/RT, the comparable survival of the LDDS and radiotherapy alone is encouraging and indicates the possibility of circumventing radiation-induced adverse effects for young children impacted by this disease.

Updated EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection - Update 1.

The standard of care for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a major part of the standard treatment, however, the predictive significance of most of the targets for treatment in systemic cancer are less well established in central nervous system (CNS) tumors . In 2023 the EANO Guideline Committee presented evidence based recommendations for rational testing of molecular targets for targeted treatments. From all targets reviewed, only testing for BRAF V600E mutations was of proven clinical benefit; despite regulatory approvals for tumor agnostic treatment of NTRK gene fusions and high Tumor Mutational Burden (TMB) for patients with adult brain tumors, the evidence of clinical benefit for patients was still limited . This guideline has a modular structure, allowing regular updating of individual sections and adding new ones. The present version (Update 1) presents a review of the rationale of testing for PTEN, H3F3A, MTAP, RET and IDH, and presents an update of the text on TMB high and mismatch repair deficiency. It also presents an overview of therapeutic yield of routine next generation sequencing for mutations and fusion detection. The supplement accompanying this version contains the in depth review of all targets, whereas in the main manuscript the final recommendations of the revised and new targets are presented. Updates will be made on a regular basis.

A combination of lymphatic drug delivery of anti-CTLA-4 antibody and local radiotherapy for solid-tumor treatment.

The combination of radiotherapy and immunotherapy is a promising approach that has been shown in clinical trials to improve significantly survival and response rates compared with monotherapy against solid tumor. Since anti-CTLA-4 antibodies block immunosuppressive signals mainly in the lymph nodes (LNs), efficient drug delivery to the lymphatic system is desirable. However, the immune checkpoint inhibitors, especially anti-CTLA-4 are currently administered intravenously (i.v.), resulting in limited efficacy in controlling solid tumor and inhibiting metastases, and the method of administration has not been optimized. Here, we show that a combination of local radiotherapy and administration of anti-CTLA-4 antibodies using a lymphatic drug delivery system (LDDS) suppresses solid tumor and metastases. We compared the efficacy of LDDS-based immunotherapy or radioimmunotherapy with i.v. administration in a solid-tumor model created by subcutaneous inoculation into LN-swollen mice with osteosarcoma cells. Tumor-bearing mice were divided into various groups (no treatment, immunotherapy [i.v. or LDDS], radiotherapy, and radioimmunotherapy [i.v. or LDDS]) and were observed for 28 days. Immunotherapy was administered with a cumulative dose of 10 mg/kg of anti-CTLA-4 monoclonal antibody, and radiotherapy was administered with a cumulative 8 Gy of fractionated X-ray irradiation. For immunotherapy alone, LDDS provided slight tumor growth inhibition but did not inhibit distant metastasis. For radioimmunotherapy, however, tumor growth was delayed and distant metastasis was suppressed compared with radiotherapy alone. In particular, the LDDS group achieved a high tumor-suppressive effect with T cell-mediated immune activity, indicating the efficacy of LDDS in radioimmunotherapy.

7826 The Identification of an Activating ESR1 Mutation in an Aggressive Prolactinoma Enabled the Use of Personalized Treatment

Abstract Disclosure: T. Paes: None. J.B. Mebarak: None. J. C. Magnotto: None. G. A. Stamatiades: None. Y. Kuang: None. C. Paweletz: None. E.R. Laws: None. R.S. Carroll: None. R. Jeselsohn: None. D. R. Mohan: None. A. Marcondes Lerario: None. W. L. Bi: None. D. A. Reardon: None. D. M. Meredith: None. U.B. Kaiser: None. A. Abreu: None. Introduction: Prolactinomas are benign tumors typically treated with dopamine agonists; few progress on medical therapy, through unclear molecular mechanisms. Although the SF3B1 mutation has been identified in one study as a driver of aggressive prolactinomas, in most cases no genetic mutations have been reported. We aimed to identify genetic alterations associated with prolactinomas using a gene panel. Method and Results: Oncopanel, a massively parallel sequencing panel, was performed to identify genomic variants and copy number variation (CNV) in a cohort of 21 patients with prolactinomas. No SF3B1 pathogenic variants were identified in this cohort. A MEN1 mutation was detected in a macroadenoma resistant to dopamine agonist. In a case of an extremely aggressive prolactinoma diagnosed in a 49-year-old woman, a somatic ESR1 [encoding estrogen receptor alpha (ERα)] mutation (ESR1Y537S) was identified in tissue from the patient’s fourth surgery. Using droplet digital PCR (ddPCR), ESR1Y537S was also detected in circulating cell-free DNA. We aimed to investigate whether ESR1Y537S may have driven initial tumor formation, or whether it was acquired as the tumor progressed. To this end, Sanger sequencing and ddPCR analyses of DNA from the first two resected tumors were performed and failed to identify ESR1Y537S. In the CNV analysis, the ESR1-mutated prolactinoma had the highest number of CNVs, compared to the rest of the cohort. Despite efforts to control tumor growth with multiple therapeutic modalities, the mutated prolactinoma had progressively enlarged post-menopausally, with invasion of surrounding structures. ESR1Y537S is a hotspot mutation in metastatic breast cancer. In breast cancer cells, ESR1Y537S activates the ERα independent of ligand binding, resulting in high cell proliferation and conferring resistance to classic hormonal treatment in ER-positive breast cancer. Elacestrant, a second-line ER degrader, increases overall free-survival in patients with resistant breast cancer and ESR1Y537S. Given the lack of response to multimodality therapy, off-label elacestrant was initiated after the third cycle of radiotherapy was completed in the patient with the aggressive prolactinoma. The combination of radiotherapy with this personalized treatment targeting ESR1 activity (elacestrant) was able to control tumor growth and significantly reduce prolactin levels. Conclusion:ESR1 regulates lactotroph differentiation and proliferation, possibly contributing to prolactinoma tumorigenesis. Our data support a role for ESR1Y537S in this prolactinoma’s unusually aggressive behavior in the postmenopausal setting. Molecular profiling revealing the mutation (ESR1Y537S) allowed the patient to receive a targeted therapy which, together with radiotherapy, resulted in a decrease in prolactin levels and a remarkable improvement in disease control. Presentation: 6/2/2024

Iron oxide nanoparticles as potential agents for combined radiotherapy

Background. Iron oxide nanoparticles (NP) represent a promising theranostic platform for combined radiotherapy: the reactivity of iron oxide enhances oxidative stress of tumor cells associated with irradiation while magnetic properties may provide additional feature as controlled delivery.Aim. To study the potency of heparinized iron oxide NP in experimental antitumor therapy.Materials and methods. The synthesis of iron oxide NP was carried out by chemical precipitation followed by magnetic separation, the resulting sol was stabilized with heparin. For each batch of newly synthesized particles, the hydrodynamic diameter was determined, IR spectrometry, X-ray diffraction analysis, and scanning electron microscopy were performed. The MX-7 tumor model of rhabdomyosarcoma chosen for the study was transplanted into female C3HA mice; NP were administered intratumorally or intravenously, once a day, according to the “5–2–5” scheme. Fractional irradiation (1–2 Gy / fraction; 1.3±0.15 Gy / min) was carried out after NP administration.Increasing life expectancy (ILE), the degree of tumor growth inhibition (TGI), a pathomorphological assessment of the lung, liver, spleen and tumor node was carried out for all experimental mice.Results. As a result of the study, it was found that when administered intratumorally, heparinized iron oxide NP are retained inside the tumor, providing a moderate additive effect, compared with isolated radiotherapy in the first week of irradiation (TGI = 40 % (day 6), TFD = 10 Gy, p &lt;0.05), however, with an increase in tumor volume by the end of the second week, the treatment regimen was not more effective than radiotherapy. with a combination of radiotherapy and intravenous administration of NP, the effect was observed within two weeks (TGI = 43 % (day 6), TGI = 29 % (day 14), TFD = 10 Gy; p &lt;0.05; ILE = 54 %, TFD = 20Gy; p &lt;0.05).Conclusion. The studied iron oxide nanopreparation enhanced capacity of radiation therapy to inhibit tumor growth when administered intravenouslyin experimental mice with rhabdomyosarcoma and irradiated subsequently.

PDOC-10 LIMITATIONS IN POST OPERATIVE- ADJUVANT CARE OF PATIENTS WITH BRAIN TUMOURS-A CASE OF SUPRATENTORIAL MEDULLOBLASTOMA IN A PAEDIATRIC PATIENT

Abstract OBJECTIVE To highlight the challenges and limitations in accessing post-operative adjuvant care of patients with brain tumours in Zimbabwe and implications on patient outcomes and to discuss potential strategies to overcome these challenges. METHODS This is a case report on a 6 year old patient with a supratentorial medulloblastoma to demonstrate the challenges encountered on accessing post-operative adjuvant care at a Central hospital in Harare. RESULTS The patient had a near total resection of the tumour done and was managed in the Intensive care unit for 1 week. HE was discharged to the general ward for another week and eventually referred to the paediatric oncologists after a histological diagnosis of a supratentorial medulloblastoma was made. Patient received cycles of chemotherapy but failed to raise money for adjuvant radiotherapy. Patient returned 5 months later with the tumour having recurred. CONCLUSION Limitations in post-operative adjuvant care may have a negative impact on the overall patient outcomes, in this case lack of access to radiotherapy. Medulloblastomas are responsive to radiotherapy and their prognosis improves significantly with a combination of surgical resection and radiotherapy. Addressing these limitations at different levels involving government and non-governmental organizations helps in mitigating inaccessibility of radiotherapy to radio-sensitive brain tumours patients after surgical resection. This case report brings out the urgent need to implement cheaper and sustainable options to address challenges in post-operative adjuvant care in order to get good patient outcomes.