RPA Class Research Articles

D-TERMINED, a phase 1 trial in newly diagnosed high-grade glioma with temozolomide, radiation, and minocycline followed by adjuvant minocycline/temozolomide.

Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-κB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas. Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3 + 3 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry. The MTD of minocycline was 150mg twice per day (N = 20); 1 patient (5%) experienced CTCAE grade 3 + nausea and dizziness, and 2 patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-κB activation, were correlated with the microglia marker IBA-1. Minocycline at 150mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-κB activation correlates with microglia levels in high-grade glioma.

Post-Operative Stereotactic Radiotherapy for Resected Brain Metastases: Results of the Multicenter Analysis (AURORA) of the German Working Group "Stereotactic Radiotherapy"

While the results of prospective studies support the use of postoperative stereotactic radiotherapy (RT) to the resection cavity (RC) as the standard of care after surgery, there are several issues that need to be investigated such as factors for improving local control, risk of leptomeningeal disease and radiation necrosis. Further, the optimal dose and fractionation is still under debate. The working group "Stereotactic Radiotherapy" of the German Society of Radiation Oncology (DEGRO) analyzed its multi-institutional database with 661 patients who received postoperative stereotactic RT to the RC. Treatment was performed at 13 centers between 2008 and 2021. Patient characteristics, treatment details, and follow-up data including overall survival (OS), local control (LC) were evaluated. Cox Regression and Kaplan-Meier curves with Log-rank Tests were calculated for selected variables. In this retrospective study, overall survival was 61.5% at 1 year, 47.6% at 2 years, and 35.5% at 3 years, and local control was 84.6% at 1 year, 74.8% at 2 years, and 72.8% at 3 years. 96% of patients were treated with hypofractionated stereotactic radiotherapy (HSRT), only 26 patients received single fraction radiosurgery (4%). Prognostic factors associated with overall survival were Karnofsky Performance Status, RPA and GPA class, controlled primary tumor and absence of extracranial metastases, whereas prognostic factor associated with local control was planning target volume (23 mL or less). HSRT is the most common fractionation form in the treatment of RCs in this multicenter analysis. This approach results in excellent OS and LC outcomes. OS in patients with resected brain metastases is mainly influenced by performance status. In regard to local control, RT of large cavities remain a challenge with significantly worse outcome.

P20.01.A CLINICAL APPLICATION OF RELATIONSHIP BETWEEN GENETIC ALTERATION AND INTRAOPERATIVE FLUORESCENCE ACTIVITY OF 5-AMINOLEVULINIC ACID IN BRAIN METASTASIS OF NON-SMALL CELL LUNG CANCER

Abstract BACKGROUND Distant metastasis into major organ is a major cause of death in cancer patients. Especially, metastasis to brain is known to duplicate the mortality of cancer patients because brain metastasis makes patients neurologically independent in daily activities. Despite surgical resection of brain metastasis is a core strategy for management, it is not possible for all brain metastasis due to eloquent location, multiple lesions, or clinical condition of patient. With advancement of technology in brain tumor surgery, fluorescence image, such as 5-aminolevulinic acid (5-ALA), can help detect the residual tumor during surgery. Recently, genetic alteration of cancer is additionally considered as prognostic factor with being added into traditional prognostic system, such as GPA scoring system. The primary objective of this study is to examine the fluorescence patterns of 5-ALA in brain metastasis surgery and investigate the results of genetic alteration in brain metastasis using next generation sequencing technique. MATERIAL AND METHODS Medical records of patients with brain metastasis of non-small cell lung cancer at our center from January 2017 to June 2022. Among them, the patients who were treated with surgical resection under 5-ALA fluorescence image and had NGS results were included in the analysis. RESULTS Total 72 patients were eligible for analysis. Mean follow-up duration was 12.36 months. Recurrence occurred in 28 (38.9%) patients and 46 (63.9%) patients succumbed to NSCLC. Mean recurrence-free survival (RFS) was 14.57 months and mean overall survival (OS) was 16.29 months. Strong fluorescence was obtained in 56 (77.8%) patients during surgery. In the NGS data of brain metastasis, genetic alteration of cell cycle regulation, DNA repair, tumorigenesis, proliferation, epigenetic regulation, and cancer immunology were detected in 73.6%, 44.4%, 56.9%, 66.7%, 30.6%, and 2.8%, respectively. In multivariate analysis, KPS, RPA class, extent of resection, modality of adjuvant treatment, genetic alteration of cell cycle regulation and cellular proliferation were associated with RFS. Additionally, age, KPS, status of NSCLC, RPA class, GPA score, modality of adjuvant treatment, genetic alteration of cell cycle regulation and cellular proliferation were associated with OS. CONCLUSION The presenting study suggested that microscopic complete resection with assist of fluorescence image could improve clinical outcome, and strong fluorescence image could reflect the genetic alteration of cell cycle regulation and cellular proliferation which are poor prognostic factors.

Relevance of the Updated Recursive Partitioning Analysis (U-RPA) Classification in the Contemporary Care of Patients with Brain Metastases.

Patients with brain metastases (BMETS) need information about the prognosis and potential value of treatment options to make informed therapeutic decisions, but tools to predict survival in contemporary practice are scarce. We propose an Updated Recursive Partitioning Analysis (U-RPA) instrument to predict survival and benefit from brain-directed treatment (BDT) of contemporary patients. This was a retrospective analysis of patients with BMETS treated between 2017 and 2019. With survival as the primary endpoint, we calculated the U-RPA and generated estimates using Kaplan-Meier curves and hazard ratios. Of 862 eligible patients, 752 received BDT and 110 received best supportive care (BSC). Median overall survival with BDT and BSC was 9.3 and 1.3 months, respectively. Patients in RPA class 1, 2A, 2B and 3 who underwent BDT had median survival of 28.1, 14.7, 7.6 and 3.3 months, respectively. The median survival for patients in RPA 3 who received BDT (n = 147), WBRT (n = 79) and SRS (n = 54) was 3.3, 2.9 and 4.1 months, respectively. The U-RPA defines prognosis estimates, independent of tumor type and treatment modality, which can assist to make value-based care treatment decisions. The prognosis for patients in U-RPA class 2B and 3 remains poor, with consideration for early palliative care involvement in these cases.

Surgical treatment of cerebellar metastases in elderly patients: A threshold that moves forward?

The impact of surgery for cerebellar brain metastases in elderly population has been the object of limited studies in literature. Given the increasing burden of their chronic illnesses, the decision to recommend surgery remains difficult.All patients aged ≥65 years, who underwent surgical resection of a cerebellar brain metastasis from May 2000 and May 2021 at IRCCS National Cancer Institute “Regina Elena”, were analyzed. The study cohort includes 48 patients with a mean age of 70.8 years. 7 patients belonged to the II Class according to the RPA classification, 41 to the III Class; the median GPA classification was 1.5. Median pre-operative and post-operative KPS was 60. Median Charlson Comorbidity Index (CCI) was 11; median 5-variable modified Frailty Index was 2. Overall, 14 patients (29%) presented perioperative neurologic and systemic complications. 34 patients (71%) were able to perform adjuvant therapies as RT and/or CHT after surgery. A higher CCI predicted complications occurrence (p = 0.044), while significant factors for a post-operative KPS ≥70, were i) hemispheric location of the metastasis, ii) higher pre-operative KPS, iii) RPA II classification. Median Overall Survival was 7 months. A post-operative KPS <70 (p = 0.004) and a short time interval between diagnosis of the primary tumor and cerebellar metastasis appearance, were predictive for a worse outcome (p = 0.012). Our study suggests that selected elderly patients with cerebellar metastases may benefit from microsurgery to continue their adjuvant therapies, although a high complications rate should be taken in account.

Radiosurgery and Stereotactic Brain Radiotherapy with Systemic Therapy in Recurrent High-Grade Gliomas: Is It Feasible? Therapeutic Strategies in Recurrent High-Grade Gliomas.

Purpose. For recurrent high-grade gliomas (HGG), no standard therapeutic approach has been reported; thus, surgery, chemotherapy, and re-irradiation (re-RT) may all be proposed. The aim of the study was to evaluate safety and efficacy of re-RT by radiosurgery or fractionated stereotactic radiotherapy (SRS/FSRT) in association to chemotherapy in patients with recurrent HGG. Material/Methods: All patients with histological diagnosis of HGG that suffered by recurrent disease diagnosed by magnetic resonance imaging (MRI), according to Response Assessment in Neuro-Oncology (RANO) criteria, after primary/adjuvant chemo-radiotherapy treatment and underwent to re-RT by SRS/FSRT were included in the analysis. Second-line chemotherapy was administered. Outcomes were evaluated by neurological examination and brain MRI performed 1 month after re-RT and then every 2–3 months. Results: From November 2019 to September 2021, 30 patients presenting recurrent HGG underwent re-RT. Median dose was 24 Gy (range 15–36 Gy), and median fractions was 5 (range 1–6). Twenty-one patients (70%) had RPA class ≤ IV. One patient had a histological diagnosis of anaplastic oligodendroglioma, 24 patients (80%) were affected by glioblastoma (GBM) including 3 cases of multifocal form, and 5 patients (17%) by anaplastic astrocytoma. Median time between primary/adjuvant RT and disease recurrence was 8 months. In six cases (20%) re-operation was performed, and in most cases (87%), a second line of systemic therapy was administrated. At a median follow-up time from recurrence of 13 months (range 6–56 months), 10 patients (33%) were alive: 2 patients with partial response disease, 7 patients with stable disease, and 1 patient with out-field progression disease. Of the 20 patients who died (67%), 15 (75%) died for progression disease and 5 (25%) for other causes (3 due to septic event, 1 due to thrombo-embolic event, and 1 due to car accident). Median OS and PFS after recurrence were 12.1 and 11.2 months. Six-month and one-year OS were, respectively, 81% and 51%. No acute or late neurological side effects grade ≥ 2 and no case of radio-necrosis were reported. One patient experienced, after reintervention and during Regorafenib treatment (administered 40 days after surgery), dehiscence of the surgical wound. In three cases, grade 2 distal paresthesia was reported. Grade 3–4 hematologic toxicity occurred in seven cases. Three case of grade 5 toxicities during chemotherapy were reported: three septic events and one thrombo-embolic event. Conclusion. Re-RT with SRT/FSRT in association with second-line systemic therapy is a safe and feasible treatment for patients with HGG recurrence. Validation of these results by prospective studies is needed.

CLRM-13 RELEVANCE OF RECURSIVE PARTITIONING ANALYSIS (RPA) CLASSIFICATION IN THE CURRENT CARE OF PATIENTS WITH BRAIN METASTASES (BMETS)

BACKGROUNDPatients diagnosed with BMETS want to know their prognosis and the benefit of treatment to make informed decisions. Clinician and patient biases frequently provide survival estimates that are too optimistic or pessimistic. We postulated that that RPA remains a useful tool to communicate prognosis and potential benefit from brain-directed treatment (BDT). We evaluated real-world data on RPA class and survival of patients with newly diagnosed BMETS from three academic institutions. METHODSWe retrospectively reviewed the records of patients with BMETS between 2017 and 2019 who had at least 6 months of follow up. Excluded were patients with leptomeningeal or only dural/calvarial metastases. We calculated the RPA and according to class compared Kaplan-Meier survival curves. RESULTSWe have data on 642 cases with median age of 65 years; 80% had lung, breast, melanoma, and renal as the primary cancer. Sixty (9.3%) patients received palliative care only, while 582 (90.7%) had BDT. The median survival of all patients according to RPA in months was 18.0 (I), 9.4 (II), and 2.4 (III) and for those receiving BDT (n=582), it was 19.2 (I), 11.2 (II), and 2.9 (III). There were statistically significant differences for BDT survival curves adjusted for multiple comparisons (I-II p=0.0124; II-III p<0.0001; I-III p<0.0001). For patients in RPA class III who received WBRT (n=62), the median survival was 2.9 months, and, for SRS (n=37), it was 3.5 months. We will present updated data including additional 238 cases and propose predictive/prognostic models based on our cohort that optimizes the RPA application in clinical practice. CONCLUSIONIn contemporary practice, the RPA classification remains significantly relevant in making care decisions for patients diagnosed with BMETS. Treatment recommendations for patients in RPA class III should be the result of multidisciplinary discussions with consideration for early palliative care involvement to de-escalate and avoid inefficacious BDT.

Retrospective study of hypofractionated stereotactic radiotherapy combined with whole brain radiotherapy for patients with brain metastases

Background and purposeTo evaluate the clinical outcomes of hypofractionated stereotactic radiotherapy (HFSRT) combined with whole brain radiotherapy (WBRT) in patients with brain metastases (BMs).Materials and methodsFrom May 2018 to July 2020, 50 patients (111 lesions) received HFSRT (18 Gy/3F) + WBRT (40 Gy/20F). The RECIST 1.1 and RANO-BM criteria were used to evaluate treatment efficacy. Five prognostic indexes (RPA, GPA, SIR, BS-BM, and GGS) were applied. The primary endpoint was intracranial local control (iLC). Secondary endpoints were overall survival (OS) and the safety of treatment.ResultsIntracranial objective response rates (iORR) using the RECIST 1.1 and RANO-BM criteria were 62.1% and 58.6%, respectively. The iLC rate was 93.1%, the 6- and 12-month iLC rates were 90.8% and 57.4%, respectively. The median intracranial progression-free survival (iPFS) was not reached (range 0–23 months). The 6-, 12-, and 24-month OS rates were 74.2%, 58.2%, and 22.9%, respectively. The KPS score showed statistical significance in univariate analysis of survival. The 6, 12, and 24 month OS rates for patients with KPS ≥ 70 were 83.8%, 70.5%, and 29.7%, respectively. The median survival time (MST) for all patients and for patients with KPS ≥ 70 were 13.6 and 16.5 months, respectively. Sex, KPS score, and gross tumor volume were significant factors in the multivariate analysis of survival. OS was significantly associated with RPA, SIR, BS-BM, and GGS classes. No acute toxicities of grade 3 or higher were noted.ConclusionHFSRT combined with WBRT is a safe and effective local treatment modality for BM patients.

Local control of 1-5 fraction radiotherapy regimens for spinal metastases: an analysis of the impacts of biologically effective dose and primary histology.

BackgroundThis analysis evaluates the impacts of biologically effective dose (BED) and histology on local control (LC) of spinal metastases treated with highly conformal radiotherapy to moderately-escalated doses.Materials and methodsPatients were treated at two institutions from 2010–2020. Treatments with less than 5 Gy per fraction or 8 Gy in 1 fraction were excluded. The dataset was divided into three RPA classes predictive of survival (1). The primary endpoint was LC.Results223 patients with 248 treatments met inclusion criteria. Patients had a median Karnofsky Performance Status (KPS ) of 80, and common histologies included breast (29.4%), non-small cell lung cancer (15.7%), and prostate (13.3%). A median 24 Gy was delivered in 3 fractions (BED: 38.4 Gy) to a median planning target volume (PTV) of 37.3 cc. 2-year LC was 75.7%, and 2-year OS was 42.1%. Increased BED was predictive of improved LC for primary prostate cancer (HR = 0.85, 95% CI: 0.74–0.99). Patients with favorable survival (RPA class 1) had improved LC with BED ≥ 40 Gy (p = 0.05), unlike the intermediate and poor survival groups. No grade 3–5 toxicities were reported.ConclusionsModerately-escalated treatments were efficacious and well-tolerated. BED ≥ 40 Gy may improve LC, particularly for prostate cancer and patients with favorable survival.

Linac-based stereotactic radiosurgery and fractionated stereotactic radiotherapy with a micro-multileaf collimator for brain metastasis in the primary motor cortex.

This study aimed to assess the clinical outcomes of linear accelerators (linac)-based, stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator for brain metastasis in the primary motor cortex (BMPMC). Thirty-five consecutive patients with BMPMC who were treated by linac-based SRS or fSRT between January 2012 and March 2020 were analyzed. BMPMC was defined as a tumor located in the precentral gyrus on gadolinium-enhanced magnetic resonance imaging (MRI) and T2-weghted imaging (T2WI). In total, 35 patients with 37 metastases were analyzed. The median follow-up time was 13 (range: 1–97) months. The tumor volume was 0.05–26.5 (median: 0.62) cm3. All patients were treated with SRS or fSRT using 35 Gy with 7 Gy per fraction daily. The median survival time (MST) was 16.9 months. The pretreatment KPS and RPA class significantly differed in terms of MST on the log-rank tests. Seven symptomatic patients had hemiparesis before SRS or fSRT. All symptomatic patients, except one with facial paresis and one who died within 3 months, experienced improvement at a 3 month follow-up. None of the patients presented with persistent radiation injury at the final follow-up. Two patients presented with grade 3 radiation-related central nervous system necrosis, which was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. In BMPMC, SRS and fSRT had good tumor control and did not cause serious complications. Therefore, they are suitable treatment options with an acceptable safety profile.

Re-irradiation for recurrent or second primary head and neck cancer.

PurposeTo investigate the efficacy and safety of intensity-modulated radiotherapy (IMRT)-based re-irradiation (reRT) for recurrent or second primary head and neck cancer (HNC).Materials and MethodsPatients who underwent IMRT-based reRT for recurrent or second primary HNC between 2007 and 2019 at two institutions were included. Medical records and dosimetric data were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), severe late toxicities, and clinicopathological prognostic factors were analyzed.ResultsA total of 42 patients were analyzed. With a median follow-up of 15.1 months (range, 3.7 to 85.8 months), the median OS was 28.9 months with a 2-year OS rate of 54.6%. The median PFS and 2-year PFS rates were 10.0 months and 30.9%, respectively. Multivariate analysis showed that good performance (Eastern Cooperative Oncology Group [ECOG] 0 or 1), a longer time interval (≥24 months) between radiotherapy courses, and higher reRT dose (>60 Gy) were significantly favorable factors for OS (all p < 0.05). Higher reRT dose and salvage surgery were significantly associated with improved PFS (all p < 0.05). Regarding the Multi‐Institution Reirradiation (MIRI) Collaborative RPA classification, the 2-year OS rates of each class were 87.5% in class I, 51.8% in class II, and 0% in class III (p = 0.008). Grade ≥3 late toxicity was reported in 10 (23.8%) patients. There was no significant factor associated with increased late toxicities.ConclusionIMRT-based reRT should be considered as a treatment option for patients with recurrent or second primary HNC. Further trials are needed to establish a subset of patients who may benefit from reRT without severe late toxicity.

RT-1 Treatment results of salvage gamma knife stereotactic radiosurgery and bevacizumab (AVAgamma therapy) for recurrent malignant glioma

Purpose: We report the treatment results of AVAgamma therapy combining gamma knife (GK) and bevacizumab for recurrent malignant glioma. Subjects: From August 2013 to January 2021, 71 patients (Grade 2:8 patients, Grade3:16 patients, Grade 4:47 patients) with recurrent malignant glioma treated with AVAgamma therapy as salvage therapy at the time of relapse after initial treatment. The average age is 55.7 years, with 44 men and 27 women. The tumor volume is 150 ml or less, and KPS is 40% or more as the indication of AVAgamma therapy. When the irradiation volume of the gamma knife was 15 ml or less, the marginal dose was 20 to 26 Gy, and when the irradiation volume was 15 ml or more, the marginal dose was 12 to 15 Gy in two divided doses.The mean therapeutic borderline dose was 24 Gy. Bevacizumab was administered 10 mg / kg or 15 mg / kg 1 to 10 times after GK. Methods: Median progression-free survival (mPFS) from AVAgamma treatment, median survival (mOS), and mOS from initial treatment were examined and compared with mOS in the RPA classification of recurrent glioma. Results: In relapsing glioma RPA classification, NABTT CNC class 2 mOS is 17.2 months, class 3 mOS is 3.8 months, class 5 mOS is 5.6 months, class 6 mOS is 6.4 months, but mOS from AVAgamma therapy is 18 months in class 3, 11 months in class 5, 9 months in class 6. The survival time has been extended in class3, class5, class6. Discussion: By AVAgamma therapy, it was thought that recurrent lesions were locally controlled and life prognosis was prolonged. Conclusion: AVAgamma therapy is thought to prolong the survival of recurrent malignant glioma and play an important role as salvage treatment.

Standard 6-week chemoradiation for elderly patients with newly diagnosed glioblastoma

Glioblastoma (GBM) is frequent in elderly patients, but their frailty provokes debate regarding optimal treatment in general, and the standard 6-week chemoradiation (CRT) in particular, although this is the mainstay for younger patients. All patients with newly diagnosed GBM and age ≥ 70 who were referred to our institution for 6-week CRT were reviewed from 2004 to 2018. MGMT status was not available for treatment decision at that time. The primary endpoint was overall survival (OS). Secondary outcomes were progression-free survival (PFS), early adverse neurological events without neurological progression ≤ 1 month after CRT and temozolomide hematologic toxicity assessed by CTCAE v5. 128 patients were included. The median age was 74.1 (IQR: 72–77). 15% of patients were ≥ 80 years. 62.5% and 37.5% of patients fulfilled the criteria for RPA class I–II and III–IV, respectively. 81% of patients received the entire CRT and 28% completed the maintenance temozolomide. With median follow-up of 11.7 months (IQR: 6.5–17.5), median OS was 11.7 months (CI 95%: 10–13 months). Median PFS was 9.5 months (CI 95%: 9–10.5 months). 8% of patients experienced grade ≥ 3 hematologic events. 52.5% of patients without neurological progression had early adverse neurological events. Post-operative neurological disabilities and age ≥ 80 were not associated with worsened outcomes. 6-week chemoradiation was feasible for “real-life” elderly patients diagnosed with glioblastoma, even in the case of post-operative neurological disabilities. Old does not necessarily mean worse.

Outcome Analysis and Prognostic Factors in Patients of Glioblastoma Multiforme: An Indonesian Single Institution Experience

Aims: This study was done to assess the survival of patients with glioblastoma multiform and to identify factors that can affect patient survival.&#x0D; Materials and methods: From January 2015 to December 2019, 55 patients with histopathologically confirmed glioblastoma multiform and received adjuvant radiation/chemoradiation in our department were retrospectively analyzed.&#x0D; Results: The median overall survival (OS) for entire cohort was 13 months and 1-year OS and 2-year OS rate were 52.7% and 3.6% with the mean follow-up period was 12 months. In univariate analysis, age (≤50 years vs &gt;50 years, p=0.02), performance status (≥90 vs 70-80 vs &lt;70, p&lt;0.001), RTOG RPA classification (class III vs class IV vs class V-VI, p&lt;0.001), parietal lobes tumor site (vs others, p=0.02), residual tumor volume (≤20.4cm3 vs &gt;20.4cm3, p=0.001) and time to initiate adjuvant therapy (&lt;4 weeks vs 4-6 weeks vs &gt;6 weeks, p=0.01) were significantly affect overall survival. In multivariate analysis, RTOG RPA classification and involvement of parietal lobes were independent prognostic factors for overall survival.&#x0D; Conclusions: RTOG RPA classification that consisted of age and performance status is an independent prognostic factor for the clinical outcome of GBM. Besides this well-known factor, we also identified the involvement of parietal lobe gives a strong negative influence on survival of GBM patients.

A new model outperforming RPA and DS-GPA scores for individualized survival prediction of patients following whole brain irradiation for brain metastasis

PurposeSurvival after whole brain radiation therapy (WBRT) in patients with multiple brain metastases (BM) is currently predicted by group-based scoring systems with limited usability for decision. We aimed to develop a more relevant individualized predictive model than Radiation Therapy Oncology Group – Recursive Partitioning Analysis (RTOG-RPA) and Diagnosis – Specific Graded Prognostic Assessment (DS-GPA) for patients with limited life-expectancy. MethodsBased on a Discovery cohort of patients undergoing WBRT, multivariable piecewise Cox regression models with time cut-offs at 1 and 3 months were developed to predict overall survival (OS). A final parsimonious model was defined, and an external validation cohort was used to assess its discrimination and calibration at one, six, and 12 months. ResultsIn the 173-patient Discovery cohort, the majority of patients had primary lung cancer (56%), presence of extracranial disease (ECD) (75%), Eastern Cooperative Oncolgy Group - Performance Status (ECOG-PS) score 1 (41%) and no intracranial hypertension (ICH) (74%). Most patients were classified as the RPA class II (48%). The final piecewise Cox model was based on primary site, age, ECD, ECOG-PS and ICH. An external validation of the model was carried out using a cohort of 79 patients. Individualized survival estimates obtained with this model outperformed the RPA and DS-GPA scores for overall survival prediction at 1-month, 6-months and 12- months in both Discovery and Validation cohorts. A R/Shiny web application was developed to obtain individualized predictions for new patients, providing an easy-to-use tool for clinicians and researchers. ConclusionOur model provides individualized estimates of survival for poor prognosis patients undergoing WBRT, outperforming actual scoring systems.

RT-01 Treatment results of salvage gamma knife and bevacizumab (AVAgamma therapy) for recurrent glioblastoma

Purpose: We report the treatment results of AVAgamma therapy combining gamma knife (GK) and bevacizumab for recurrent glioblastoma. Subjects: From August 2013 to April 2020, 44 patients (88 lesions) with recurrent glioblastoma treated with AVAgamma therapy as salvage therapy at the time of relapse after initial treatment. The average age is 61.5 years, with 26 men and 18 women. The tumor volume is 150 ml or less, and KPS is 40% or more as the indication of AVAgamma therapy. When the irradiation volume of GK is 15 ml or less, a single irradiation with a boundary dose of 20 to 26 Gy was performed, and when the irradiation volume was 15 ml or more, a single irradiation boundary dose was divided into two divided irradiations of 12 to 15 Gy. The mean therapeutic borderline dose was 24 Gy. Bevacizumab was administered 10 mg / kg or 15 mg / kg 1 to 10 times after GK. Methods: Median progression-free survival (mPFS), 6-month progression-free survival (PFS-6m), 6-month survival (OS-6m), median survival (mOS) from treatment with AVAgamma Considered mOS from initial treatment. Results: The mPFS from AVAgamma therapy was 5 months, PFS-6m was 37%, OS-6m was 79%, and mOS was 9 months. The mOS from initial treatment were 25 months. In relapsing glioma RPA classification, NABTT CNC class 5 mOS is 5.6 months, class 6 mOS is 6.4 months, but mOS from AVAgamma therapy is 9 months in class 5, 9 months in class 6. The survival time has been extended. Discussion: By AVAgamma therapy, it was thought that recurrent lesions were locally controlled and life prognosis was prolonged. Conclusion: AVAgamma therapy is thought to prolong the survival of recurrent glioblastoma and play an important role as salvage treatment.

INNV-03. EFFICACY AND LONG-TERM OUTCOMES IN THE MANAGEMENT OF LARGE BRAIN METASTASIS (≥ 4 CM3) USING 2-STAGED STEREOTACTIC RADIOSURGERY (2-SSRS): AN INTERNATIONAL STUDY

Abstract INTRODUCTION Stereotactic radiosurgery (SRS) for brain metastases results in time-to-local failure (TTLF) that significantly correlates with target volume and prescription dose. For large brain metastases (LBM), defined as ≥ 4 cm3, SRS monotherapy can result in &amp;lt; 40% local control (LC) rates. To overcome the TTLF limitations in the management of LBM, 2-staged SRS (2-SSRS) has demonstrated 6-month LC rates of 85–90%. This international multi-institutional study represents the largest series of patients with LBM managed with 2-SSRS. METHODS 181 patients with 218 LBM treated with 2-SSRS were retrospectively reviewed. Local failure (LF) was defined as ≥ 71.5% volumetric increase (equivalent to ≥ 20% increase in maximum diameter; RECIST criteria) from smallest volume date. Kaplan-Meier and log-rank tests were used to estimate and compare overall survival (OS) and TTLF; multivariable analysis was performed using Cox regression model. RESULTS Median age was 63 years (range: 29‒88), male sex was 50.3% with 34.8% of patients having non-small cell lung cancer. Median follow-up was 13.8 months (range:1.1‒49.4) and median OS was 14.6 months (95%CI: 12.6‒17.0). Median TTLF was 27.9 months (95%CI: 17.9‒NA) with a cumulative 6, 12 and 24-month LC of 91%, 81% and 71%, respectively. Using multivariable analysis, older age (≥ 65 years old; HR 1.58, 95%CI 1.06‒2.35, p=0.02) and larger total volume of concurrent small lesions (&amp;gt; 3 cm3; HR 2.05, 95%CI 1.25‒3.39, p=0.005) negatively impacted OS while younger age (&amp;lt; 65 years old; HR 2.60, 95%CI 1.26‒5.34, p=0.01) and RPA Class 3 (HR 3.10, 95%CI 1.26‒7.65, p=0.01) decreased TTLF. The number of concurrent LBM treated and total volume of the LBM were not significant factors. CONCLUSIONS This large multi-institutional dataset demonstrates excellent efficacy and long-term control of LBMs treated with 2-SSRS, which is independent of number or total volume of concurrent LBM.

A Single-Institution Retrospective Analysis of Proton Stereotactic Radiosurgery for Brain Metastases

In photon SRS, rates of radiation necrosis are approximately 5-10%, and grade 3 or greater toxicity can be seen in up to 40%1. The purpose of this study is to report a single institution’s experience using proton SRS. It was expected that clinical outcomes would be comparable to photon SRS. Between the years 2006 to 2017, 76 patients and 151 intact brain lesions were treated with 20-25 Gy in 1-2 fractions of radiosurgery using proton beam at one institution. A retrospective analysis was conducted of patient and treatment characteristics as well as failure patterns, toxicity and overall survival. Statistical analysis included Kaplan-Meier estimates of freedom from local failure, freedom from distant brain failure, and overall survival. The individual impact of patient and treatment factors on mortality and progression was determined using Cox proportional hazards regressions. The median follow-up from proton SRS was 6 months (interquartile range 2.9-14.4 months). Freedom from local failure, freedom from distant brain failure, and overall survival at 6 and 12 months was 88.3% (95% confidence interval [CI] 82.1%-94.9%) and 75.5% (95% CI 65.9%-86.7%), 76.7% (95% CI 66.5%-88.5%) and 67.9% (95% CI 55.5%-83.0%), and 54.8% (95% CI 44.7%-67.3%) and 33.7% (95% CI 24.4%-46.5%), respectively. Median overall survival was 6.4 months. There were no acute CTCAE grade 4 or 5 toxicities observed. Any acute toxicity occurred in 15.9% of SRS courses (grade 2 in 7.3% and grade 3 in 2.4%). There were eight cases of radiation necrosis (5.2%), three diagnosed pathologically and five based on imaging review. Factors found to predict for mortality were RPA class (p = 0.044), extent of extracranial disease (p = 0.009), and the presence of neurologic symptoms (p = 0.017). Factors found to predict for local failure were number of fractions (p = 0.0018), GTV diameter (p = 0.005), maximum dose (p = 0.0007), and conformity index (p = 0.035). Thus far one institutional series showing proton SRS to have comparable clinical outcomes to photon SRS for the treatment of brain metastases has been published2. Our study adds to the breadth of data on the issue. This technique can be performed safely, with similar failure patterns and survival rates as photon-based radiosurgery and with low rates of toxicity, including radiation necrosis. Due to proton beam resulting in lower integral dose to the brain, this technology may confer a clinical benefit in selected patients requiring a high number of SRS treatments and merits further study.

07. RETROSPECTIVE ANALYSIS OF SALVAGE SURGERY FOR LOCAL PROGRESSION OF BRAIN METASTASIS PREVIOUSLY TREATED WITH STEREOTACTIC IRRADIATION: DIAGNOSTIC CONTRIBUTION, FUNCTIONAL OUTCOME, AND PROGNOSTIC FACTORS

BACKGROUNDStereotactic irradiation (STI) is a primary treatment for patients with newly diagnosed brain metastases. Some of these patients experience local progression, which is difficult to differentiate from radiation necrosis, and difficult to treat. Just a few studies have clarified the prognosis and effectiveness of salvage surgery after STI. We evaluated the diagnostic value and improvement of functional outcomes after salvage surgery.METHODSWe evaluated patients with brain metastases treated with salvage surgery for local progression from October 2002 to July 2019. These patients had undergone salvage surgery based on magnetic resonance imaging findings and/or clinical evidence of post-STI local progression and stable systemic disease. We employed two prospective strategies according to the eloquency of the lesions. Lesions in non-eloquent areas had been resected completely with a safety margin, utilizing a fence-post method; while lesions in eloquent areas had been treated with minimal resection and postoperative STI. Prognostic factors for survival were analyzed.RESULTSFifty-four salvage surgeries had been performed on 48 patients. The median age of patients was 64 years. The median diameter of the enhanced lesions was 35 mm (range 19–58 mm). The median overall survival was 20.2 months from salvage surgery and 37.5 months from initial STI. Primary cancers were lung 31, breast 9, and others 8. Local recurrence developed in 13 of 54 lesions (24%). Leptomeningeal dissemination occurred after surgery in 3 patients (5.6%). Primary breast cancer (breast vs. lung: HR: 0.17), (breast vs. others: HR: 0.08) and RPA class 1–2 (RPA 1 vs. 3, HR: 0.13), (RPA 2 vs 3, HR: 0.4) were identified as good prognostic factors for overall survival (OS) in multivariate analyses.CONCLUSIONWe insist that salvage surgery leads to rapid improvement of neurological function and clarity of histological diagnosis. Salvage surgery is recommended for large lesions especially with surrounding edema either in eloquent or non-eloquent areas.

Randomized phase II study of rituximab, methotrexate (MTX), procarbazine, vincristine, and cytarabine (R-MPV-A) with and without low-dose whole-brain radiotherapy (LD-WBRT) for newly diagnosed primary CNS lymphoma (PCNSL).

2501 Background: MTX-based chemoradiotherapy is effective in PCNSL, but carries a risk of severe neurotoxicity (NT), especially in the elderly. In a phase II single arm study, R-MPV-A chemotherapy was combined with substantially reduced doses of radiotherapy (23.4 Gy), achieving prolonged progression free survival (PFS) and overall survival (OS) with acceptable NT. Because R-MPV-A had never been tested without radiotherapy, we conducted a randomized study to determine if the low doses of radiation played a role in the observed disease control, and to characterize NT as compared to chemotherapy alone. Methods: Patients were stratified by MSK RPA class and randomized to receive R-MPV-A with LD-WBRT (chemoRT arm) versus R-MPV-A alone (chemo arm). MTX dose was 3.5g/m2 infused over 2 hours. Filgrastim and pegfilgrastim support was given to all patients. LD-WBRT dose was 23.4 Gy (1.8 Gy X 13). The primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63, with one-sided alpha level of 0.15. Results: A total of 91 patients were randomized, of whom 4 were ineligible. Among eligible patients, 43 were enrolled in the chemoRT arm and 44 in the chemo arm. Median age was 66 (chemoRT) and 59 (chemo). Median KPS was 80 for both arms. Response rates following R-MPV were 81% (chemoRT) and 83% (chemo). In the chemoRT arm, 37 patients (86%) received LD-WBRT. After median follow-up of 55 months (m), the median ITT PFS was 25 m in the chemo arm and not reached in the chemoRT arm (HR 0.51; 95% CI [0.27, 0.95]; p = 0.015). The 2-year PFS was 54% (chemo) and 78% (chemoRT). Salvage radiotherapy has been given to 11 patients in the chemo arm. Median OS was not reached in either arm, with data still maturing. In both arms, most common grades 3 or 4 toxicities were anemia (27%), lymphopenia (41%), neutropenia (35%), thrombocytopenia (26%), ALT (23%) and AST (13%). One patient died from sepsis (chemo arm). As per investigators’ assessment, the rate of clinically defined moderate to severe NT was 11.4% (chemo) and 14% (chemoRT), p = 0.75. Conclusions: The study met the primary endpoint, demonstrating the addition of LD-WBRT to R-MPV-A improves PFS in newly diagnosed PCNSL. As per investigator’s assessment, NT rates were not statistically significantly increased, but further neuropsychological testing and neuroimaging analyses are ongoing to characterize cognitive decline and how it compares to other consolidation treatments. Clinical trial information: NCT01399372 .