Comparative evaluation of outcomes amongst different radiosurgery management paradigms for patients with large brain metastasis.

INTRODUCTION: This study compares four management paradigms for large brain metastasis (LMB): fractionated SRS (FSRS), staged SRS (SSRS), resection and postoperative-FSRS (postop-FSRS) or preoperative-SRS (preop-SRS). METHODS: Patients with LBM (≥ 2 cm) between July 2017 and January 2022 at a single tertiary institution were evaluated. Primary endpoints were local failure (LF), radiation necrosis (RN), leptomeningeal disease (LMD), a composite of these variables, and distant intracranial failure (DIF). Gray's test compared cumulative incidence, treating death as a competing risk with a random survival forests (RSF) machine-learning model also used to evaluate the data. RESULTS: 183 patients were treated to 234 LBMs: 31.6% for postop-FSRS, 28.2% for SSRS, 20.1% for FSRS, and 20.1% for preop-SRS. The overall 1-year composite endpoint rates were comparable (21 vs 20%) between nonoperative and operative strategies, but 1-year RN rate was 8 vs 4% (p = 0.012), 1-year overall survival (OS) was 48 vs. 69% (p = 0.001), and 1-year LMD rate was 5 vs 10% (p = 0.052). There were differences in the 1-year RN rates (7% FSRS, 3% postop-FSRS, 5% preop-SRS, 10% SSRS, p = 0.037). With RSF analysis, the out-of-bag error rate for the composite endpoint was 47%, with identified top-risk factors including widespread extracranial disease, > 5 total lesions, and breast cancer histology. CONCLUSION: This is the first study to conduct a head-to-head retrospective comparison of four SRS methods, addressing the lack of randomized data in LBM literature amongst treatment paradigms. Despite patient characteristic trends, no significant differences were found in LF, composite endpoint, and DIF rates between non-operative and operative approaches.

Should high-dose-rate brachytherapy boost be used in early nasopharyngeal carcinomas?

BACKGROUND: Radiation with or without chemotherapy is the main treatment of nasopharyngeal carcinomas (NPC). Local recurrence is difficult to manage. Local control is dose-dependent. AIM: To analyze the effect of an endocavitary brachytherapy boost after external beam radiation (EBRT) to decrease local recurrence. MATERIAL AND METHODS: Thirty patients with T0-T2 NPC were treated: 70% T1, 20% T2 and 10% T0; 33.3% N0, 20% N1, 43.3% N2 and 3.3% N3; 90% were undifferentiated carcinoma. All they received a 192-Ir high dose rate brachytherapy (HDR-BT) boost after 60 Gy of EBRT. The Rotterdam applicator was used in most cases, 3-4 fractions of 3.75-3 Gy in two days. RESULTS: With median follow-up (FU) of 63 months, a single parapharyngeal failure resulted in local control of 100% at 3 years and 95% at 5 years. Local control for T0-1 was 100% and for T2 67% at five years (p = 0.02). Regional-free recurrence survival was 92% at 5 years. Metastasis-free survival was 84% at 5 years. All cases of metastasis had histopathology of undifferentiated. The overall and cause-specific survival was 96% and 86% at 3 and 5 years. No late complications related to brachytherapy were described. CONCLUSION: A HDR-BT boost is useful to decrease the incidence of local recurrence of NPC to 5%. With a fractionated schedule of 3-4 fractions in two days, Rotterdam applicator and 3-D planning, no late complications are described. Therefore we recommend to use brachytherapy boost in all early NPC.

How proton therapy fits into the management of adult intracranial tumors.

Intracranial tumors include a challenging array of primary and secondary parenchymal and extra-axial tumors which cause neurologic morbidity consequential to location, disease extent, and proximity to critical neurologic structures. Radiotherapy can be used in the definitive, adjuvant, or salvage setting either with curative or palliative intent. Proton therapy (PT) is a promising advance due to dosimetric advantages compared to conventional photon radiotherapy with regards to normal tissue sparing, as well as distinct physical properties, which yield radiobiologic benefits. In this review, the principles of efficacy and safety of PT for a variety of intracranial tumors are discussed, drawing upon case series, retrospective and prospective cohort studies, and randomized clinical trials. This manuscript explores the potential advantages of PT, including reduced acute and late treatment-related side effects and improved quality of life. The objective is to provide a comprehensive review of the current evidence and clinical outcomes of PT. Given the lack of consensus and directives for its utilization in patients with intracranial tumors, we aim to provide a guide for its judicious use in clinical practice.

Clinical application of an institutional fractionated stereotactic radiosurgery (FSRS) program for brain metastases delivered with MRIdianⓇ BrainTx™.

Single-fraction stereotactic radiosurgery (SRS) or fractionated SRS (FSRS) are well established strategies for patients with limited brain metastases. A broad spectrum of modern dedicated platforms are currently available for delivering intracranial SRS/FSRS; however, SRS/FSRS delivered using traditional CT-based platforms relies on the need for diagnostic MR images to be coregistered to planning CT scans for target volume delineation. Additionally, the on-board image guidance on traditional platforms yields limited inter-fraction and intra-fraction real-time visualization of the tumor at the time of treatment delivery. MR Linacs are capable of obtaining treatment planning MR and on-table MR sequences to enable visualization of the targets and organs-at-risk and may subsequently help identify anatomical changes prior to treatment that may invoke the need for on table treatment adaptation. Recently, an MR-guided intracranial package (MRIdian A3i BrainTxTM) was released for intracranial treatment with the ability to perform high-resolution MR sequences using a dedicated brain coil and cranial immobilization system. The objective of this report is to provide, through the experience of our first patient treated, a comprehensive overview of the clinical application of our institutional program for FSRS adaptive delivery using MRIdian's A3i BrainTx system-highlights include reviewing the imaging sequence selection, workflow demonstration, and details in its delivery feasibility in clinical practice, and dosimetric outcomes.

Accelerated Hypofractionated Magnetic Resonance Guided Adaptive Radiation Therapy for Ultracentral Lung Tumors.

Radiotherapy for ultracentral lung tumors represents a treatment challenge, considering the high rates of high-grade treatment-related toxicities with stereotactic body radiation therapy (SBRT) or hypofractionated schedules. Accelerated hypofractionated magnetic resonance-guided adaptive radiation therapy (MRgART) emerged as a potential game-changer for tumors in these challenging locations, in close proximity to central organs at risk, such as the trachea, proximal bronchial tree, and esophagus. In this series, 13 consecutive patients, predominantly male (n = 9), with a median age of 71 (range (R): 46-85), underwent 195 MRgART fractions (all 60 Gy in 15 fractions) to metastatic (n = 12) or primary ultra-central lung tumors (n = 1). The median gross tumor volumes (GTVs) and planning target volumes (PTVs) were 20.72 cc (R: 0.54-121.65 cc) and 61.53 cc (R: 3.87-211.81 cc), respectively. The median beam-on time per fraction was 14 min. Adapted treatment plans were generated for all fractions, and indications included GTV/PTV undercoverage, OARs exceeding tolerance doses, or both indications in 46%, 18%, and 36% of fractions, respectively. Eight patients received concurrent systemic therapies, including immunotherapy (four), chemotherapy (two), and targeted therapy (two). The crude in-field loco-regional control rate was 92.3%. No CTCAE grade 3+ toxicities were observed. Our results offer promising insights, suggesting that MRgART has the potential to mitigate toxicities, enhance treatment precision, and improve overall patient care in the context of ultracentral lung tumors.

Somatic KMT2D loss-of-function mutations in lung squamous cell carcinoma: a single-center cohort study.

Background: The significant progress has been made in targeted therapy for lung adenocarcinoma (LUAD) in the past decade. Only few targeted therapeutics have yet been approved for the treatment of lung squamous cell carcinoma (LUSC). Several higher frequency of gene alterations are identified as potentially actionable in LUSC. Our work aimed to explore the complex interplay of multiple genetic alterations and pathways contributing to the pathogenesis of LUSC, with a very low frequency of a single driver molecular alterations to develop more effective therapeutic strategies in the future. Methods: We retrospectively analyzed the targeted next-generation sequencing (NGS) data (approximately 600 genes) of 335 patients initially diagnosed with non-small cell lung cancer (NSCLC) at our institution between January 2019 and March 2023 and explored the somatic genome alteration difference between LUSC and LUAD. Results: We analyzed that the presence of loss-of-function (LoF) mutations (nonsense, frameshift, and splice-site variants) in histone-lysine N-methyltransferase 2D (KMT2D) was much more prevalent in LUSC (11/53, 20.8%) than in LUAD (6/282, 2.1%). Moreover, our data indicated TP53 co-mutated with KMT2D LoF in 90.9% (10/11) LUSC and 33.3% (2/6) LUAD. Notably, the mutation allele fraction (MAF) of KMT2D was very similar to that of TP53 in the co-mutated cases. Genomic profiling of driver gene mutations of NSCLC showed that 81.8% (9/11) of the patients with LUSC with KMT2D LoF mutations had PIK3CA amplification and/or FGFR1 amplification. Conclusions: Our results prompted that somatic LoF mutations of KMT2D occur frequently in LUSC, but are less frequent in LUAD and therefore may potentially contribute to the pathogenesis of LUSC. Concurrent TP53 mutations, FGFR1 amplification, and PIK3CA amplification are very common in LUSC cases with KMT2D LoF mutations. It needs more deeper investigation on the interplay of the genes and pathways and uses larger cohorts in the future.

Proton Radiosurgery: Current Concepts and Limitations for CNS Radiosurgery.

Introduction: Stereotactic radiosurgery (SRS) is highly conformal, high-dose radiation therapy delivered in 1-5 fractions, and is considered the standard of care for several central nervous system (CNS) indications. Particle therapies, such as protons, have physical and dosimetric advantageous properties compared to photons. However, proton SRS (PSRS) is not widely performed given the few particle therapy facilities, high-cost, and limited outcomes research as a sole modality and in comparative studies. The data available differs from each pathology. For AVMs, especially those with deep or eloquent locations, PSRS obliteration rates outcomes appear favorable and superior. For meningiomas, PSRS has been used for grade 1 alone, and for higher grades a PSRS boost has been considered. For vestibular schwannoma, PSRS seems to have favorable control rates with modest toxicity outcomes. For pituitary tumors, data shows excellent results with PSRS for functional and non-functioning adenomas. For brain metastasis, moderate doses of PSRS achieves high local control rates with low rates of radiation necrosis. For uveal melanoma, dedicated eyeline PSRS (4-5 fractions) are associated with very high tumor control and eye retention rates. Conclusions: PSRS is effective and safe for various intracranial pathologies. Limited data, usually retrospective and single institution series exist. There are numerous advantages of protons over photons, so it is important to understand limitations with further studies. Published clinical outcomes and widespread adoption of proton therapy will be key to unlocking the potential benefits of PSRS.

Tumor treating fields: narrative review of a promising treatment modality for cancer.

BACKGROUND AND OBJECTIVE: Tumor treating fields (TTFields) therapy have emerged as a potentially effective treatment for various malignancies by delivering low-intensity, intermediate-frequency electrical fields that disrupt many processes inside cells, resulting in the interruption of cell division in cancer cells. Additionally, TTFields therapy has been found to be synergistic with existing therapeutic approaches. In this review, we provide an introduction and background to the primary mechanisms of TTFields and discuss the emerging preclinical and clinical outcomes of this novel cancer treatment technology. METHODS: We performed a literature search on PubMed, ClinicalTrials.Gov, and Google Scholar using the terms 'TTFields' and 'cancer'. We included studies, review articles, and editorials published in English from 1st January 2000 to 1st October 2023. All obtained publications were reviewed and their key references are cross-checked to ensure a balanced and high-quality review. KEY CONTENT AND FINDINGS: Clinical studies reported to date have demonstrated the survival advantage of TTFields therapy in newly diagnosed glioblastoma (GBM), non-small cell lung cancer (NSCLC), and meaningful clinical activity in recurrent GBM (rGBM) and malignant pleural mesothelioma. Moreover, TTFields therapy has exhibited promising safety profiles across a diverse range of cancers including pancreatic cancer, hepatocellular carcinoma (HCC), ovarian cancer, NSCLC, and gastric cancer, when combined with cytotoxic chemotherapy and/or immunotherapy regimens, suggesting broad applicability as an added treatment modality. CONCLUSIONS: Based on preclinical and clinical studies, TTFields therapy show promise as a potential treatment option for patients with a number of different malignancies, offering a favorable safety profile and the potential for significant clinical benefit. Further research is warranted to establish the optimal treatment parameters and identify specific patient subgroups that may derive the greatest advantage from this treatment modality.

Dosimetric Impact of Lesion Number, Size, and Volume on Mean Brain Dose with Stereotactic Radiosurgery for Multiple Brain Metastases.

We evaluated the effect of lesion number and volume for brain metastasis treated with SRS using GammaKnife® ICON™ (GK) and CyberKnife® M6™ (CK). Four sets of lesion sizes (<5 mm, 5-10 mm, >10-15 mm, and >15 mm) were contoured and prescribed a dose of 20 Gy/1 fraction. The number of lesions was increased until a threshold mean brain dose of 8 Gy was reached; then individually optimized to achieve maximum conformity. Across GK plans, mean brain dose was linearly proportional to the number of lesions and total GTV for all sizes. The numbers of lesions needed to reach this threshold for GK were 177, 57, 29, and 10 for each size group, respectively; corresponding total GTVs were 3.62 cc, 20.37 cc, 30.25 cc, and 57.96 cc, respectively. For CK, the threshold numbers of lesions were 135, 35, 18, and 8, with corresponding total GTVs of 2.32 cc, 12.09 cc, 18.24 cc, and 41.52 cc respectively. Mean brain dose increased linearly with number of lesions and total GTV while V8 Gy, V10 Gy, and V12 Gy showed quadratic correlations to the number of lesions and total GTV. Modern dedicated intracranial SRS systems allow for treatment of numerous brain metastases especially for ≤10 mm; clinical evidence to support this practice is critical to expansion in the clinic.

Accelerated hypofractionated magnetic resonance-guided adaptive radiotherapy for oligoprogressive non-small cell lung cancer.

Given the positive results from recent randomized controlled trials in patients with oligometastatic, oligoprogressive, or oligoresidual disease, the role of radiotherapy has expanded in patients with metastatic non-small cell lung cancer (NSCLC). While small metastatic lesions are commonly treated with stereotactic body radiotherapy (SBRT), treatment of the primary tumor and involved regional lymph nodes may require prolonged fractionation schedules to ensure safety especially when treating larger volumes in proximity to critical organs-at-risk (OARs). We have developed an institutional MR-guided adaptive radiotherapy (MRgRT) workflow for these patients. We present a 71-year-old patient with stage IV NSCLC with oligoprogression of the primary tumor and associated regional lymph nodes in which MR-guided, online adaptive radiotherapy was performed, prescribing 60 Gy in 15 fractions. We describe our workflow, dosimetric constraints, and daily dosimetric comparisons for the critical OARs (esophagus, trachea, and proximal bronchial tree [PBT] maximum doses [D0.03cc]), in comparison to the original treatment plan recalculated on the anatomy of the day (i.e., predicted doses). During MRgRT, few fractions met the original dosimetric objectives: 6.6% for esophagus, 6.6% for PBT, and 6.6% for trachea. Online adaptive radiotherapy reduced the cumulative doses to the structures by 11.34%, 4.2%, and 5.62% when comparing predicted plan summations to the final delivered summation. Therefore, this case study presets a workflow and treatment paradigm for accelerated hypofractionated MRgRT due to the significant variations in daily dose to the central thoracic OARs to reduce treatment-related toxicity associated with radiotherapy.

Surgically targeted radiation therapy (STaRT) for recurrent brain metastases: Initial clinical experience.

PURPOSE: This study evaluates the outcomes of recurrent brain metastasis treated with resection and brachytherapy using a novel Cesium-131 carrier, termed surgically targeted radiation therapy (STaRT), and compares them to the first course of external beam radiotherapy (EBRT). METHODS: Consecutive patients who underwent STaRT between August 2020 and June 2022 were included. All patients underwent maximal safe resection with pathologic confirmation of viable disease prior to STaRT to 60 Gy to a 5-mm depth from the surface of the resection cavity. Complications were assessed using CTCAE version 5.0. RESULTS: Ten patients with 12 recurrent brain metastases after EBRT (median 15.5 months, range: 4.9-44.7) met the inclusion criteria. The median BED10Gy90% and 95% were 132.2 Gy (113.9-265.1 Gy) and 116.0 Gy (96.8-250.6 Gy), respectively. The median maximum point dose BED10Gy for the target was 1076.0 Gy (range: 120.7-1478.3 Gy). The 6-month and 1-year local control rates were 66.7% and 33.3% for the prior EBRT course; these rates were 100% and 100% for STaRT, respectively (p < 0.001). At a median follow-up of 14.5 months, there was one instance of grade two radiation necrosis. Surgery-attributed complications were observed in two patients including pseudomeningocele and minor headache. CONCLUSIONS: STaRT with Cs-131 presents an alternative approach for operable recurrent brain metastases and was associated with superior local control than the first course of EBRT in this series. Our initial clinical experience shows that STaRT is associated with a high local control rate, modest surgical complication rate, and low radiation necrosis risk in the reirradiation setting.

Treatment of glioblastoma using MRIdian® A3i BrainTx™: Imaging and treatment workflow demonstration.

For patients with newly diagnosed glioblastoma, the current standard-of-care includes maximal safe resection, followed by concurrent chemoradiotherapy and adjuvant temozolomide, with tumor treating fields. Traditionally, diagnostic imaging is performed pre- and post-resection, without additional dedicated longitudinal imaging to evaluate tumor volumes or other treatment-related changes. However, the recent introduction of MR-guided radiotherapy using the ViewRay MRIdian A3i system includes a dedicated BrainTx package to facilitate the treatment of intracranial tumors and provides daily MR images. We present the first reported case of a glioblastoma imaged and treated using this workflow. In this case, a 67-year-old woman underwent adjuvant chemoradiotherapy after gross total resection of a left frontal glioblastoma. The radiotherapy treatment plan consisted of a traditional two-phase design (46 Gy followed by a sequential boost to a total dose of 60 Gy at 2 Gy/fraction). The treatment planning process, institutional workflow, treatment imaging, treatment timelines, and target volume changes visualized during treatment are presented. This case example using our institutional A3i system workflow successfully allows for imaging and treatment of primary brain tumors and has the potential for margin reduction, detection of early disease progression, or to detect the need for dose adaptation due to interfraction tumor volume changes.

Evaluation of factors leading to poor outcomes for pediatric acute lymphoblastic leukemia in Mexico: a multi-institutional report of 2,116 patients.

Background and aims: Pediatric acute lymphoblastic leukemia (ALL) survival rates in low- and middle-income countries are lower due to deficiencies in multilevel factors, including access to timely diagnosis, risk-stratified therapy, and comprehensive supportive care. This retrospective study aimed to analyze outcomes for pediatric ALL at 16 centers in Mexico. Methods: Patients <18 years of age with newly diagnosed B- and T-cell ALL treated between January 2011 and December 2019 were included. Clinical and biological characteristics and their association with outcomes were examined. Results: Overall, 2,116 patients with a median age of 6.3 years were included. B-cell immunophenotype was identified in 1,889 (89.3%) patients. The median white blood cells at diagnosis were 11.2.5 × 103/mm3. CNS-1 status was reported in 1,810 (85.5%), CNS-2 in 67 (3.2%), and CNS-3 in 61 (2.9%). A total of 1,488 patients (70.4%) were classified as high-risk at diagnosis. However, in 52.5% (991/1,889) of patients with B-cell ALL, the reported risk group did not match the calculated risk group allocation based on National Cancer Institute (NCI) criteria. Fluorescence in situ hybridization (FISH) and PCR tests were performed for 407 (19.2%) and 736 (34.8%) patients, respectively. Minimal residual disease (MRD) during induction was performed in 1,158 patients (54.7%). The median follow-up was 3.7 years. During induction, 191 patients died (9.1%), and 45 patients (2.1%) experienced induction failure. A total of 365 deaths (17.3%) occurred, including 174 deaths after remission. Six percent (176) of patients abandoned treatment. The 5-year event-free survival (EFS) was 58.9% ± 1.7% for B-cell ALL and 47.4% ± 5.9% for T-cell ALL, while the 5-year overall survival (OS) was 67.5% ± 1.6% for B-cell ALL and 54.3% ± 0.6% for T-cell ALL. The 5-year cumulative incidence of central nervous system (CNS) relapse was 5.5% ± 0.6%. For the whole cohort, significantly higher outcomes were seen for patients aged 1-10 years, with DNA index >0.9, with hyperdiploid ALL, and without substantial treatment modifications. In multivariable analyses, age and Day 15 MRD continued to have a significant effect on EFS. Conclusion: Outcomes in this multi-institutional cohort describe poor outcomes, influenced by incomplete and inconsistent risk stratification, early toxic death, high on-treatment mortality, and high CNS relapse rate. Adopting comprehensive risk-stratification strategies, evidence-informed de-intensification for favorable-risk patients and optimized supportive care could improve outcomes.

Is perioperative brachytherapy effective in carcinoma of the tongue?

Purpose: To analyze the results of patients treated with perioperative interstitial brachytherapy (ISBT) in tongue carcinoma (TC). Material and methods: From April 2009 to May 2015, 43 squamous cell carcinoma consecutive patients diagnosed with TC were treated with limited partial glossectomy and perioperative ISBT, using high-dose-rate (HDR). Twenty- seven patients were treated by brachytherapy (BT), and sixteen received BT as a complement to subsequent external beam radiotherapy (EBRT) after results of lymph node dissection. Median age was 66 years. Distribution by stage, included 10 patients stage I, 14 stage II, 10 stage III, and 9 stage IV. Eighteen patients had negative margins, nineteen margin involvement, and in six cases, the margin was < 5 mm. Results: With a median follow-up of 54 months, LC at 3 and 5 years was 87% and 84%, respectively. LC was 95% at five years in patients with clear margins, and 75% with involved margins. LC in N0 patients treated with BT was 83% at 5 years, and in patients N+ with posterior EBRT treatment, LC was 86%. By tumor size, we found one local relapse in 13 cases T1, in 5 of 27 patients T2 was found, and no local relapse T3 with LC of 87%, 70%, and 100% respectively at five years. Regional control (RC) was 81% at 3 and 5 years. We found a metastasis-free survival of 91% at 3- and 5-year. Twenty-three patients have died, 11 of them due to other causes, with overall survival of 56% at three years and 53% at five years. Conclusions: Combined treatment with conservative surgery and ISBT shows similar results to radical surgery or RT alone, allowing a more patient-tailored approach, with good organ function preservation and cosmetic outcomes.

Choroidal Melanoma with Ultrasound-Guided Episcleral Brachytherapy: Long-Term Results and Risk of Metastasis.

INTRODUCTION: The aim of this study was to elucidate the long-term outcomes in patients with choroidal melanoma who received episcleral brachytherapy with 125-I seeds; analyse cause-specific survival (CSS), metastasis-free survival (MFS), and local control; and establish the relationship between tumour size and metastases. METHODS: From May 2007 to February 2013, 88 patients classified according to the American Joint Committee on Cancer guidelines underwent ultrasound-guided episcleral brachytherapy with a total prescribed dose of 72.40 Gy to the apex. RESULTS: Among the included cases, 47.7 and 44.3% had a clinical tumour stage of T2 and T3, respectively. With a median follow-up of 84 (range 7-153) months, local control at 5 and 10 years was 100 and 95%, respectively. Among the 88 patients, 9 (10.2%) were enucleated after brachytherapy. Those with T1-T2 and T3-T4 disease had a 10-year CSS of 100 and 87.3%, respectively (p = 0.017). MFS at 5 and 10 years was 100% in those with T1-T2 disease and 92.1 and 83.1% in those with T3-T4, respectively (p = 0.016). Five patients had liver metastases, all of whom had T3-T4 disease. CONCLUSION: Ultrasound-guided episcleral brachytherapy with 125-I seeds yielded excellent local control for choroidal melanoma, with low complication rates and 90% eye preservation. Given the association between tumour stage and liver metastases, which remain the main cause of death, stricter control should be employed for T3-T4 tumours for the early detection and treatment of relapses.