Upfront Radiotherapy Research Articles

OTHR-08. CLINICAL MANAGEMENT OF TWO PEDIATRIC CASES OF INTRACRANIAL MESENCHYMAL TUMORS WITH FET::CREB FUSIONS

Abstract BACKGROUND Intracranial mesenchymal tumors (IMTs) with FET::CREB fusion are a newly described provisional entity lacking standard management options. This group of neoplasms occur in children and young adults, and is molecularly characterized by a FET family gene (most commonly EWSR1, rarely FUS) fused with a CREB family transcription factor (ATF1, CREB1, or CREM). Histologically, the Ki-67 index is typically low (<5%) and only rarely elevated (15-20%). Treatment consists of surgical resection. Cases achieving gross total resection (GTR) are observed without adjuvant therapy, while subtotal resection (STR) is followed by radiation therapy. Regardless of resection status, patients are at risk for local recurrence. METHODS Case report. RESULTS We present two patients with IMTs harboring FET::CREB fusions. Patient 1 is a 12-year-old male with a known left choroid plexus lesion and hydrocephalus, who presented with acute loss of balance, headaches, and emesis. CT head revealed progression of the choroid plexus lesion with intraventricular hemorrhage and worsening hydrocephalus. Following GTR of the tumor, pathology revealed an IMT without high-grade features and a Ki-67 index of 5%. RNA-sequencing revealed an EWSR1::ATF1 fusion. In consideration of GTR and the tumor being low-grade, he is being followed with surveillance scans. Patient 2 is a 14-year-old male who presented with headaches and seizures and was found to have an enhancing left occipital lesion on MRI. Following GTR, pathology revealed an IMT with abundant mitotic figures (15 per 10 high power fields), increased Ki-67 index of 30-40%, and a FUS::CREM fusion. Due to the high-grade histopathology, he was treated with focal proton beam radiotherapy (5400 cGyRBE). An MRI three months post-therapy was negative for tumor recurrence. CONCLUSIONS We describe two adolescents with IMTs harboring FET::CREB fusions and their management, including one with high-grade histology managed with upfront radiation therapy, which has not been previously reported in the literature.

MDB-27. OUTCOMES FOR CHILDREN TREATED FOR MEDULLOBLASTOMA USING A RADIATION-SPARING APPROACH: A REPORT FROM THE CHILDREN’S BRAIN TUMOR NETWORK

Abstract OBJECTIVE To describe real-world outcomes in children with medulloblastoma treated with radiation-sparing chemotherapy in the USA. METHODS Clinical and molecular data were obtained from the Children’s Brain Tumor Network (CBTN), a multi-institutional collaboration to collect and freely share biological samples and longitudinal clinical data from consented patients. Patients with medulloblastoma treated with radiation-sparing regimens were included. Clinical data included patient demographics, stage, extent of resection, treatment regimen, and survival. Three-year overall survival (OS3) was calculated from diagnosis to death from any cause or last follow-up with log-rank p-value. RESULTS Eighty-one patients (56% male, median age 2.51 [range 0-7.44] years) with medulloblastoma (32% metastatic) were included. Molecular group was available for 36 (44%). Patients were treated according to protocols CCG99703 (n=26), ACNS0334 Arm A (n=13), ACNS0334 Arm B (n=30), PBTC026 (n=10), and ACNS1221 (n=2). Only 29 (36%) were enrolled on a therapeutic study. Seventy-two patients had median follow-up of 2.7 years (range 0.3-13 years). OS3 was 79+6; OS3 by molecular group was 90+9 in SHH (n=14), 55+14 in Group 3 (n=16), 56+25 in Group 4 (n=6). OS3 was 92+5 for 55 patients with localized disease versus 53+12 for 26 with metastasis (p=0.001); 86+6 for 55 patients with gross total resection versus 62+11 in 26 with partial resection or biopsy (p=0.03). OS3 was not associated with upfront radiation, 80+7 for 54 patients who received no radiation before relapse versus 78+9 for 27 who received radiation before relapse (21 focal, 6 craniospinal). OS3 was 87+8 for 30 patients on a methotrexate-containing regimen versus 74+7 for 51 without methotrexate (p=0.27). Five patients developed second malignancy. CONCLUSIONS CBTN data report real-world survival for young children treated with radiation-sparing approaches, most not enrolled on studies. Ongoing molecular characterization of the CBTN cohort will facilitate additional analysis to improve risk stratification and therapy selection for young children.

MDB-62. SUBGROUP AND SUBTYPE-SPECIFIC OUTCOMES IN METASTATIC INFANT MEDULLOBLASTOMA

Abstract BACKGROUND Metastatic infant medulloblastoma (MB) is a major challenge given the devastating long-term effects of craniospinal irradiation to the developing brain. However large cohorts of metastatic infant medulloblastoma have not been analysed to date. METHODS A multicentre molecularly informed international cohort of children <6 years old with metastatic medulloblastoma was assembled and analysed. RESULTS Eighty-four patients with a median age of 2.95 (0.66-6.58) years were identified. 48.8% were Group3-MB, 23.8% Group4-MB and 27.4% SHH-MB. 78% of Group3-MB were subtype II (40.4%) and IV (38.1%), 50% of Group 4 were subtype VII, and within SHH, SHHß and SHHγ were 52.2% and 43.5% respectively. 28.5% of all Group3-MB harboured MYC amplification. A multivariable analysis incorporating subgroup, MYC amplification and upfront craniospinal irradiation revealed that survival was superior for SHH patients compared to Group 3 irrespective of MYC status (Group3-veMYCamp: HR 3.05 95%-CI 1.05-8.87 p=0.04, Group3+veMYCamp HR 7.87 95%-CI 2.49-24.87 p=0.00044). Group 4 had a trend to a poor outcome (HR 2.63 95%-CI 0.82-8.39 p=0.1). SHH subjects had a superior outcome with 5-year PFS of 0.657 (95%-CI 0.47-0.92), without a significant difference between SHHß and SHHγ. High-dose chemotherapy regimens portended to a superior outcome for both subtypes of SHH-MB. 5-year PFS for non-radiated SHH-MB was 61% (95%-CI 40.8-91.4), compared to non-radiated Group3-MB (18.5%; 95%-CI 5.4-62.8) and Group4-MB (20%; 95%-CI 3.4-100). SHH-MB patients had more local than metastatic relapses compared to non-SHH-MB (p=0.01). CONCLUSIONS In the largest study dedicated to metastatic infant medulloblastoma assembled to date, outcomes for infants with Group 3- and 4-MB with metastatic disease treated with radiation sparing approaches is dismal despite intensified regimens. MYC amplification portends to a near uniformly fatal prognosis with current treatment irrespective of upfront radiotherapy. Novel radiation sparing approaches are urgently needed for this group. Infants with both metastatic SHHß and SHHγ benefit from intensified therapy.

QOL-38. PSYCHOSOCIAL OUTCOMES OF CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND HIGH-GRADE GLIOMA (HGG) –PROSPECTIVE, LONGITUDINAL PROMIS ASSESSMENTS OF PATIENTS ENROLLED ON CONNECT PHASE I CLINICAL TRIALS

Abstract INTRODUCTION Given poor prognoses, children with DIPG/HGG may experience psychosocial sequelae throughout their illness journey, negatively impacting quality of life (QOL). We prospectively assessed caregiver-proxy and patient-reported psychosocial outcomes of children with DIPG/HGG enrolled on two early-phase CONNECT trials. METHODS Patient-Reported Outcomes Measurement Information System (PROMIS) short forms were administered monthly to patients ≥8 years and caregivers of patients aged 5-17 years while enrolled on two phase I clinical trials for newly-diagnosed DIPG/HGG involving upfront radiotherapy (RT) and concurrent and/or adjuvant oral agents. T-scores (M=50, SD=10) were calculated relative to the general population for emotional distress (Anxiety and Depression) and relationship quality (Peer Relationships and Family Relationships). Linear mixed modeling compared scores at pre-RT, post-RT, 1 month pre-progression, and end of therapy (EOT). Spearman’s correlations were calculated. RESULTS Twenty-eight patients (median age=10 years; DIPG [n=23]; HGG [n=17]) and 40 caregivers participated. Patient and caregiver-proxy reports demonstrated comparable levels of emotional distress and relationship quality to norms and were stable over time. The proportion of patients endorsing mild or greater impairment in emotional distress (T-score >55) was relatively comparable at pre-RT (Anxiety & Depression=26%), post-RT (Anxiety=36%, Depression=23%), and 1 month pre-progression (Anxiety=23%, Depression=36%), with more patients endorsing impairment (Anxiety=58%, Depression=67%) at EOT, often corresponding to disease progression; though differences were not statistically significant. Caregiver-proxy and patient-reported scores were similar across all timepoints and domains, with a pattern of higher caregiver-reported versus patient-reported emotional distress (Spearman’s Rho range: 0.62-0.67;p<0.0001). CONCLUSIONS Children with DIPG/HGG and their caregivers reported comparable emotional functioning and relationship quality to the general population. Caregivers slightly overestimated psychological distress compared to youth self-reports. Findings may reflect resilience of this population when faced with adversity, while highlighting benefit of psychosocial supports and low therapy toxicity on QOL. Future analyses will compare psychosocial, physical, and functional symptoms.

DIPG-78. OSSEOUS METASTASIS IN DIFFUSE MIDLINE GLIOMA: A CASE REPORT AND REVIEW OF LITERATURE

Abstract BACKGROUND Diffuse midline glioma (DMG), H3K 27M-altered are uniformly fatal CNS tumors with 2-year overall survival of less than 10%. Neuroaxis dissemination with disease progression is well known. However, osseous metastasis is a rare occurrence. METHODS We report a patient with localized DMG at diagnosis with subsequent craniospinal and osseous metastasis. We also performed an updated literature review on DMG with extra-neural metastasis (ENM). RESULTS At 11 years of age, the patient presented with progressively worsening headache and vomiting and was found to have a tumor within the right thalamus with mild mass effect on the right lateral ventricle without hydrocephalus. The patient underwent stereotactic tumor biopsy with pathology consistent with DMG, H3K 27-altered. Whole exome sequencing revealed alterations in H3-3A, TP53 and PTPN11. Treatment consisted of upfront focal radiation therapy with subsequent stabilization of the thalamic lesion. However, within 1.5 months of completing radiotherapy, the patient developed drop metastasis, intracranial leptomeningeal dissemination, and diffuse osseous metastasis within the spine, bilateral iliac wings, and ribs. The patient died from disease progression within 2 months of metastatic progression, 6 months from initial diagnosis. Review of literature yielded 11 cases of ENM in pediatric patients with DMG, H3K 27M-altered. Four patients had ENM at diagnosis. The remaining seven patients developed extra CNS metastasis within 1-6 months of diagnosis. Eight patients received upfront radiotherapy with variation in adjuvant chemotherapy. All patients died with median overall survival of 9 months (range, 0.5-24) from diagnosis and 6 months (range, 0.5-22) from ENM occurrence. CONCLUSION ENM in DMG, H3K 27-altered is uncommon. Mechanisms for development of ENM in DMG is unclear. Biopsy and molecular testing for both primary site and ENM should be considered to help elucidate biologic mechanisms of ENM and potentially guide management.

DIPG-54. PREDICTING EARLY DEATH IN DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Diffuse midline glioma (DMG) is an invariably fatal diagnosis with a median survival of 9-11 months. While early death is uncommon, such cases do exist. Identification of children at risk of short-term survival can support clinicians to provide informed counselling to families regarding important treatment decisions. METHODS We identified patients with a radiological diagnosis of DMG at the Royal Children’s Hospital (Melbourne) and the Women’s and Children’s Hospital (Adelaide) between 2001-2023. Clinical, imaging, and histopathological data were abstracted and compared between short-term survivors (STSs) and longer survivors (LSs). RESULTS Among 89 patients included, 21 (24%) had an overall survival (OS) of < 6 months of which 7 (8%) had an OS < 3 months. 5 of these cases had dramatic early death with < 1 month since diagnosis. While neither the pattern nor presence of contrast enhancement were predictive of poor survival, STSs were found to have a larger volume of contrast enhancement on T1-weighted imaging compared to LSs (1.3 cm3 vs 0.2 cm3, p < 0.01). Evaluation of the presence and extent of intratumoural susceptibility signals (ITSS) on susceptibility weighted imaging (SWI) demonstrated higher grades of ITSS (> 5 foci) were strongly associated with poor survival (p = 0.01, median OS = 5.5 months). Furthermore, 50% (6/12) of STSs had ≥ 11 dot-like or fine linear ITSSs in a maximum tumour cross section. From a treatment standpoint, as expected, patients who did not receive upfront radiotherapy experienced significantly worse OS (3.4 months vs 10.4 months, p < 0.01). Notably, a number of STSs did not receive palliative therapy in the context of their rapid and unforeseen disease progression. CONCLUSIONS The preliminary findings from this multi-centre study provide the foundation for future exploratory analysis alongside international collaborators at the DMG/DIPG registry to improve prognostication for patients with high-risk features of early death.

LMIC-03. BRAINSTEM RADIATION NECROSIS IN A PATIENT WITH RECURRENT MEDULLOBLASTOMA. SUCCESFULL TREATMENT OF A HIGHLY FEARED COMPLICATION

Abstract BACKGROUND Medulloblastoma is the most common malignant brain tumor in pediatric population. Standard treatment combines surgery, risk-adapted craniospinal irradiation and chemotherapy. Given the well-known cognitive sequelae in young children associated to radiation, strategies in infants try to avoid upfront radiation. A significant number of patients treated during infancy will ultimately relapse. Re-irradition in relapse setting has proven to be effective in disease control (survival depending on several factors) although there is a concern in exceeding radiation tolerance and risk of toxicity. METHODS Herein, we describe the case of male patient that presented at 1 year of age with a non-metastatic anaplastic medulloblastoma that was completely resected. He received 3 cycles of adjuvant chemotherapy (as per Head Start II), local relapse was detected in tumor bed during evaluation and was completely resected, afterwards he received myeloablative chemotherapy with stem cell rescue and posterior fossa radiation therapy (54 Gy). At 8 months off therapy patient developed spinal relapse in imaging with negative cytology, then treated with spinal irradiation 36Gy without adjuvant chemotherapy. He remained disease free during 12 months, then tumor recur at the right cerebellopontine angle, surgery was complete and there was no evidence of distant disease. Patient received adjuvant local radiation with 30.6Gy followed by chemotherapy (bi weekly bevacizumab + irinotecan). Cumulative maximal dose to brainstem was 84Gy. 2 months after radiation patient presented with extreme sleepiness and imaging findings compatible with brainstem radiation necrosis, symptoms resolved promptly after scheduled bevacizumab. Patient is currently 6-year-old and remains free of disease after 3 years off therapy. CONCLUSION Medulloblastoma treatment in infants is challenging because survival is not the only goal. Future clinical trials will help to better tailored treatment based on molecular biology. Re-irradiation in medulloblastoma has been described as well tolerated but clinician should be aware of its complications and management.

Efficacy of chemotherapy followed by chemoradiation versus initial chemoradiation as part of the total neoadjuvant therapy for patients with locally advanced rectal cancer: An NCDB analysis.

e15629 Background: Results from multiple trials lead to modern management for locally advanced rectal cancer, with total neoadjuvant therapy (TNT) followed by surgery. However, the best sequence of different treatment modalities is unclear. Methods: We used the National Cancer Database (NCDB) to identify patients with locally advanced rectal adenocarcinoma. We divided patients into different categories based on the timing of chemo and radiation therapy relative to surgery. We used chi-square and Wilcoxon rank test for unadjusted comparison. To compare treatment efficacy with initial chemotherapy to concurrent chemoradiation in downstaging (clinical to pathological stage), we used a linear mixed effect model (LME) with adjustments on age, sex, race, facility type, and year of diagnosis. Also, we evaluated the probability of having positive lymph nodes in the pathological specimen (N+) in the multivariable logistic regression model with adjustment on the clinical stage in addition to the previously mentioned variables. All analyses were done using R 4.6.2. Results: A total of 100509 patients were identified. Only 695 patients received six cycles of neoadjuvant chemotherapy before concurrent chemoradiation (TNT chemotherapy), and 8677 patients received upfront radiation therapy with neoadjuvant chemotherapy administered within 12 weeks of neoadjuvant radiation therapy (TNT radiation). Patients whose start date of chemotherapy or radiation after surgery were excluded. The median age of participants was 63 (IQR = 54-63), and 83% were white. Patients who had TNT chemotherapy were younger (56.4 VS 59.5, P-value < 0.01), had clinically and pathologically advanced stage (IIIB, IIIC) compared to TNT radiation (64%VS 37% and 33%VS 29%, P-value < 0.01). Patients who received TNT radiation had an upgrade in their pathological stage compared to their clinical stage by 0.67 points in the LME (P value < 0.01). In multivariable logistic regression. TNT chemotherapy had a 17% lower risk of (N+) with an OR of 0.83 (0.95 CI 0.59-1.16). However, it was not statistically significant. The two groups had no difference in OS, with a median OS of 137 months (0.95 CI 110 -NR) and 143 (0.95 CI 137-151), respectively. Conclusions: Upfront chemotherapy before starting chemoradiation could be associated with more significant downstaging. Future trials to validate our finding is warranted. [Table: see text] [Table: see text]

Feasibility of induction chemoimmunotherapy (ID chemo-IO) followed by chemoradiation for locally advanced unresectable non-small cell lung cancer (NSCLC).

8071 Background: Data from the PACIFIC study demonstrated a 5-yr median progression free survival (PFS) and overall survival (OS) of 16.9 and 47.5 months respectively for patients with stage 3A and stage 3B NSCLC demonstrating a high risk of relapse. The 8th ed. of the IASLC staging project reports that the 60-month OS for stage 3A, B and C disease is 41%, 24% and 12% respectively, indicating that improved treatment options are needed for this patient population. Induction chemo-IO (ID chemo-IO) followed by concurrent chemo-radiation (CRT) has not been fully investigated due to concerns regarding the toxicity profile, but this may representant an important unexplored avenue for research. We aim to describe the outcomes of patients who received ID chemo-IO followed by CRT with or without maintenance IO. Methods: We conducted a retrospective study across all Mayo Clinic sites. Patients were included if they were diagnosed with Stage 3 NSCLC deemed ineligible for resection and/or requiring raditation over a large-field ] by a multidisciplinary team with plans for ID chemo-IO prior to CRT and maintenance IO. A total of 927 cases of stage 3 NSCLC patients were screened and those receiving ID chemo-IO followed by CRT were extracted (n = 36). Clinical endpoints are PFS, OS, overall response rate (ORR) and treatment related adverse events (TrAE) defined using CTCAE 5.0. Results: The median age was 67 years, 52.8% were female, all patients were past smokers and 97.2% identified as white. The tumor histologies were adenocarcinoma (66.67%), squamous (27.8%), mucinous adenocarcinoma (2.8%) and sarcomatoid (2.8%). Majority were Stage 3B (47.2%) followed by 3C (38.9%) and 3A (13.9%). N2 and N3 disease was noted in 36.1% and 55.6% of patients respectively. PD-L1 by IHC was > 1-49% (47.2%), > 50% (22.2%) and < 1% (19.4%). Patients received ID chemo-IO with pembrolizumab (83.3%), nivolumab (11.1%) and atezolizumab (2.78%). Average number of ID chemo-IO cycles were 3.67 cycles. The ORR to ID chemo-IO was 86.11%. The median PFS was 23.67 mths and the median OS was 32.07 months. About 94% of patients received CRT afterwards and 66.67% received maintenance IO with pembrolizumab (53.17%) or durvalumab (45.83%). Any grade TrAE occured in 58.33% of patients. Pneumonitis was the most common event (38.9%). Grade 3 -4 pneumonitis was noted in 28.5% (4/11) patients. Other toxicities included hepatitis (8.3%), colitis (11.1%) and myasthenia gravis (2.8%) and 22% of these TrAE’s were grade 3 or 4. Conclusions: Our results indicate that ID chemo-IO shows promise as a therapeutic approach for patients with unresectable stage III NSCLC, especially for patients deemed ineligible or high risk for upfront radiation. Further investigation is needed through a randomized clinical trial to systematically explore and validate the safety and efficacy of ID chemo-IO.

Anaplastic sarcoma of the kidney (DICER1-sarcoma of the kidney): A report from the International Pleuropulmonary Blastoma/DICER1 Registry.

Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p=.07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p=.20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively. ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.

1240 Assessing Survival Outcomes of PCV-Based and Temozolamide-Based Adjuvant Therapy in Oligodendroglioma Patients

INTRODUCTION: When treating oligodendroglioma patients, choosing between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV), with concurrent radiotherapy still poses a challenge. Given the commonality of tumor recurrence, optimizing progression-free survival while minimizing adverse effects is crucial to improving quality of life. METHODS: 87 patients treated for oligodendroglioma between 1994-2022 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) from initial resection were compared between PCV-based or TMZ-based treatment groups using Kaplan-Meier and multi-variable Cox survival analysis. RESULTS: The median age at diagnosis was 41 years and 62% were male. After initial resection, 42.8% received PCV-based treatment and 57.2% received TMZ-based treatment. Treatment groups were balanced in the following variables: age, tumor genetic profiling, the extent of resection, and KPS score. However, more patients in the TMZ-based group received concurrent radiation. The entire cohort had a 6.3-year PFS and 21.0-year OS. The median time to recurrence was significantly longer in those treated with PCV (12 years) compared to those treated with TMZ (4.7 years). PFS [HR = 0.46, p = 0.04] and OS [HR = 0.26, p = 0.04] were significantly longer in those receiving PCV-based treatment compared to TMZ-based treatment. After adjusting for previously mentioned variables, Cox regression analysis revealed no difference in OS between PCV- and TMZ-based treatment. The overall adverse effect rate did not significantly differ between PCV-based and TMZ-based treatment (25% vs. 28.1%, p > 0.99). CONCLUSIONS: PCV treatment confers longer progression-free survival than TMZ treatment for oligodendroglioma patients, noting that most patients in our series received concurrent radiation with TMZ, and those receiving PCV not having received upfront radiation. As we anticipate the results of the CODEL trial, our findings suggest PCV-based therapy warrants consideration as the preferred therapeutic option for oligodendroglioma patients.

PCV Adjuvant Therapy as a Preferred Treatment Option for Oligodendroglioma Patients: A Comparative Study With Temozolomide and Concurrent Radiotherapy

INTRODUCTION: When treating oligodendroglioma patients, choosing between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV), with concurrent radiotherapy still poses a challenge. Given the commonality of tumor recurrence, optimizing progression-free survival while minimizing adverse effects is crucial to improving quality of life. METHODS: 87 patients treated for oligodendroglioma between 1994-2022 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) from initial resection were compared between PCV-based or TMZ-based treatment groups using Kaplan-Meier and multi-variable Cox survival analysis. RESULTS: The median age at diagnosis was 41 years and 62% were male. After initial resection, 42.8% received PCV-based treatment and 57.2% received TMZ-based treatment. Treatment groups were balanced in terms of age, tumor genetic profiling, extent of resection, or KPS score, however, the TMZ-based group had more patients receiving concurrent radiation. The entire cohort had a 6.3-year PFS and 21.0-year OS. The median time to recurrence was significantly longer in those treated with PCV (12 years) compared to those treated with TMZ (4.7 years). PFS [HR = 0.46, p = 0.04] and OS [HR = 0.26, p = 0.04] were significantly longer for those receiving PCV-based treatment compared to TMZ-based treatment. After adjusting for factors mentioned above, Cox regression analysis revealed no difference in OS between PCV- and TMZ-based treatment. The overall adverse effect rate did not significantly differ between PCV-based and TMZ-based treatment (25% vs. 28.1%, p > 0.99). CONCLUSIONS: PCV confers improved progression-free survival than TMZ-based treatment for oligodendroglioma patients, noting that most patients in our series received concurrent radiation with TMZ, and those receiving PCV not having received upfront radiation. As we anticipate the results of the CODEL trial, our findings suggest PCV-based therapy warrants consideration as a preferred therapeutic option for oligodendroglioma patients.

Immunotherapy With Radiotherapy for Brain Metastases in Patients With NSCLC: NEJ060

IntroductionImmune checkpoint inhibitor (ICI)–based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo). MethodsThis study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores. ResultsPatients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29–0.72], OW-adjusted HR = 0.52 [95% CI: 0.35–0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70–1.48], OW-adjusted HR = 0.93 [95% CI: 0.65–1.33]). ConclusionsUpfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.

Long-term follow-up in high-grade meningioma and outcome analysis.

The determinants of progression-free survival (PFS) and overall survival (OS) for higher-grade meningiomas have not been clearly established and to summarize the long-term clinical outcome for patients with grade 2 or 3 meningioma and assess the PFS and OS factors. The study included all individuals, who had undergone surgical removal of cerebral meningiomas between 2005 and 2020 and whose histological results suggested a World Health Organization (WHO) grade 2 or grade 3 diseases. Kaplan-Meier curves are plotted to examine tumor control and OS after the follow-up. The reverse Wald logistic regression and Mantel-Cox test were used in multivariate analysis for tumor recurrence and mortality. There were 94 individuals enrolled with 82 having WHO grade 2 tumors and 12 having WHO grade 3 lesions. Gross total resection of the tumor was present in 73 patients (78%), and adjuvant radiotherapy (RT) was administered to 43 (45.7%) individuals. During the course of the study, 17 patients died. The WHO grade of the tumor, the extent of resection, and the absence of bone involvement were all independent predictors of better survival in a multivariate analysis. Furthermore, whereas adjuvant RT after surgery enhanced survival, it was not statistically significant (hazard ratios [95% confidence interval CI] = 1.91 [0.15-23.52] [P = 0.61]). The degree of tumor excision is the strongest predictor of PFS and OS. In the event of a recurrence, rather than opting for upfront radiation, a second surgery with the goal of maximum safe resection should be performed.

Analysis of the efficacy of upfront brain radiotherapy versus deferred radiotherapy for EGFR/ALK-positive non-small cell lung cancer with brain metastases: a retrospective study

BackgroundFor brain metastases (BMs) from EGFR/ALK-positive non-small cell lung cancer (NSCLC), the best time to administer tyrosine kinase inhibitors (TKIs) and brain radiotherapy (RT) has not been identified. This analysis was an attempt to solve this problem in part.MethodsA total of 163 patients with EGFR/ALK-positive NSCLC and brain metastasis (BM) who were diagnosed between January 2017 and July 2022 were included in this study. Ninety-one patients underwent upfront RT, and 72 patients received deferred RT. Comparing the clinical efficacy and safety in these two patient cohorts was the main goal of the study.ResultsThe average follow-up period was 20.5 months (range 2.0 to 91.9 months). The median overall survival (OS) was 26.5 months, and the median intracranial progression-free survival (iPFS) was 23.6 months. Upfront RT considerably increased the iPFS (26.9 vs. 20.2 months, hazard ratio [HR] = 5.408, P = 0.020) and OS (31.2 vs. 22.3 months, HR = 4.667, P = 0.031) compared to deferred RT. According to multivariate analysis, upfront RT was an independent risk factor for predicting iPFS (HR = 1.670, P = 0.021). Upfront RT (HR = 1.531, P = 0.044), TKI therapy (HR = 0.423, P < 0.001), and oligometastases (HR = 2.052, P = 0.021) were found to be independent risk factors for OS.ConclusionThis study showed that upfront RT combined with TKI treatment can significantly improve intracranial disease management and prolong survival in patients with EGFR/ALK mutations in BMs from NSCLC.

The efficacy of upfront craniocerebral radiotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors in patients with epidermal growth factor receptor-positive non-small cell lung cancer with brain metastases.

This is a retrospective study that involved 213 patients with EGFR-NSCLC and BMs, with the patients divided into two groups: the upfront cranial RT (ucRT) group (n = 96) and the non-ucRT group (n = 117). All patients were administered with osimertinib, and those in the ucRT group also underwent RT. The overall survival (OS), progression-free survival (PFS) and intracranial PFS (IPFS) of the two groups were compared. The ucRT group manifested a markedly higher IPFS than the non-ucRT group (29.65 months vs 21.8 months; P < 0.0001). The subgroup analysis revealed that patients with oligometastases (OLOGO-BMs; 1-3 BMs) demonstrated a notably longer OS (44.5 months vs 37.3 months; P < 0.0001), PFS (32.3 months vs 20.8 months; P = 0.6884) and IPFS (37.8 months vs 22.1 months; P < 0.0001) in the ucRT group than in the non-ucRT group. However, for patients with multiple BMs, there was no significant difference in OS (27.3 months vs 34.4 months; P = 0.0710) and PFS (13.7 months vs 13.2 months; P = 0.0516) between the ucRT group and the non-ucRT group; the ucRT group exhibited a higher IPFS (26.4 months vs 21.35 months; P = 0.0028). Cox's multivariate analysis of patients with OLOGO-BM indicated that the use of ucRT was linked to a better OS (heart rate [HR] = 0.392; 95% confidence interval [CI]: 0.178-0.863; P = 0.020) and PFS (HR = 0.558; 95% CI: 0.316-0.986; P = 0.044). Upfront cerebral cranial stereotactic radiosurgery can improve outcomes in EGFR-positive patients with NSCLC and OLOGO-BM. However, for patients with multiple BMs, the preferable strategy may be pre-treatment with EGFR-TKIs.

Prophylactic Radiotherapy Of MInimally Symptomatic Spinal Disease (PROMISSeD): study protocol for a randomized controlled trial

BackgroundEarly palliative/pre-emptive intervention improves clinical outcomes and quality of life for patients with metastatic cancer. A previous signal-seeking randomized controlled trial (RCT) demonstrated that early upfront radiotherapy to asymptomatic or minimally symptomatic high-risk osseous metastases led to reduction in skeletal-related events (SREs), a benefit driven primarily by subgroup of high-risk spine metastasis. The current RCT aims to determine whether early palliative/pre-emptive radiotherapy in patients with high-risk, asymptomatic or minimally symptomatic spine metastases will lead to fewer SREs within 1 year.MethodsThis is a single-center, parallel-arm, in-progress RCT in adults (≥ 18 years) with ECOG performance status 0–2 and asymptomatic or minimally symptomatic (not requiring opioids) high-risk spine metastases from histologically confirmed solid tumor malignancies with > 5 sites of metastatic disease on cross-sectional imaging. High-risk spine metastases are defined by the following: (a) bulkiest disease sites ≥ 2 cm; (b) junctional disease (occiput to C2, C7-T1, T12-L2, L5-S1); (c) posterior element involvement; or (d) vertebral body compression deformity > 50%. Patients are randomized 1:1 to receive either standard-of-care systemic therapy (arm 1) or upfront, early radiotherapy to ≤ 5 high-risk spine lesions plus standard-of-care systemic therapy (arm 2), in the form of 20–30 Gy of radiation in 2–10 fractions. The primary endpoint is SRE, a composite outcome including spinal fracture, spinal cord compression, need for palliative radiotherapy, interventional procedures, or spinal surgery. Secondary endpoints include (1) surrogates of health care cost, including the number and duration of SRE-related hospitalizations; (2) overall survival; (3) pain-free survival; and (4) quality of life. Study instruments will be captured pre-treatment, at baseline, during treatment, and at 1, 3, 6, 12, and 24 months post-treatment. The trial aims to accrue 74 patients over 2 years to achieve > 80% power in detecting difference using two-sample proportion test with alpha < 0.05.DiscussionThe results of this RCT will demonstrate the value, if any, of early radiotherapy for high-risk spine metastases. The trial has received IRB approval, funding, and prospective registration (NCT05534321) and has been open to accrual since August 19, 2022. If positive, the trial will expand the scope and utility of spine radiotherapy.Trial registrationClinicalTrials.Gov NCT05534321. Registered September 9, 2022.Trial statusVersion 2.0 of the protocol (2021-KOT-002), revised last on September 2, 2022, was approved by the WCG institutional review board (Study Number 1337188, IRB tracking number 20223735). The trial was first posted on ClinicalTrials.Gov on September 9, 2022 (NCT05534321). Patient enrollment commenced on August 19, 2022, and is expected to be completed in 2 years, likely by August 2024.

Radiotherapy dose escalation using pre-treatment diffusion-weighted imaging in locally advanced rectal cancer: a planning study.

Diffusion-weighted MRI (DWI) may provide biologically relevant target volumes for dose-escalated radiotherapy in locally advanced rectal cancer (LARC). This planning study assessed the dosimetric feasibility of delivering hypofractionated boost treatment to intra-tumoural regions of restricted diffusion prior to conventional long-course radiotherapy. Ten patients previously treated with curative-intent standard long-course radiotherapy (50 Gy/25#) were re-planned. Boost target volumes (BTVs) were delineated semi-automatically using 40th centile intra-tumoural apparent diffusion coefficient value with expansions (anteroposterior 11 mm, transverse 7 mm, craniocaudal 13 mm). Biased-dosed combined plans consisted of a single-fraction volumetric modulated arc therapy flattening-filter-free (VMAT-FFF) boost (phase 1) of 5, 7, or 10 Gy before long-course VMAT (phase 2). Phase 1 plans were assessed with reference to stereotactic conformality and deliverability measures. Combined plans were evaluated with reference to standard long-course therapy dose constraints. Phase 1 BTV dose targets at 5/7/10 Gy were met in all instances. Conformality constraints were met with only 1 minor violation at 5 and 7 Gy. All phase 1 and combined phase 1 + 2 plans passed patient-specific quality assurance. Combined phase 1 + 2 plans generally met organ-at-risk dose constraints. Exceptions included high-dose spillage to bladder and large bowel, predominantly in cases where previously administered, clinically acceptable non-boosted plans also could not meet constraints. Targeted upfront LARC radiotherapy dose escalation to DWI-defined is feasible with appropriate patient selection and preparation. This is the first study to evaluate the feasibility of DWI-targeted upfront radiotherapy boost in LARC. This work will inform an upcoming clinical feasibility study.

Upfront Radiation Therapy (RT) for Post-Stem Cell Transplant Multiple Myeloma (MM) Patients with Oligo-Relapse/Progressive Disease: Factors Associated with Favorable Outcomes

Introduction: Relapsed or refractory disease post-stem cell transplant (SCT) for Multiple Myeloma (MM) can be clinically challenging. For localized relapses, radiation therapy (RT) can represent an attractive treatment modality. However, data on outcomes with RT remains scarce. We investigated the impact of RT as a treatment modality in the setting of oligo-relapse and oligo-progressive plasmacytomas after SCT and explored prognostic factors associated with favorable long-term outcome Methods: In this single-institution retrospective analysis, we identified 31 MM patients who underwent upfront RT for oligo-relapse or oligo-progressive MM after SCT between 2000 and 2021. Patients were excluded if they had received systemic therapy for evidence of concurrent biochemical relapse prior to RT start. The treatment responses to stem cell transplantation (SCT) and RT were assessed following the response criteria established by the International Myeloma Working Group (IMWG), which includes the categories: complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) and progressive disease (PD). Additionally, we utilized the R-ISS staging system to classify patients into Standard-Risk (R-ISS I), Intermediate-Risk (R-ISS II), and High-Risk (R-ISS III) groups, to allow for a comprehensive evaluation of treatment efficacy and outcomes. Results: Disease and treatment characteristics for the cohort are summarized inFigure 1. Of the 27 patients with imaging available prior to SCT, 67% (18) were assessed with PET, 22% (6) with skeletal survey, 3.7% (1) with MRI/CT, 3.7% with CT, and 3.7% (1) with x-ray. Following SCT, 48% (13) of patients were noted to have radiographic progression, 23% (7) had sCR, 23% (7) had a CR, 10% had a serologic CR, and 45% (14) had a VGPR. Among the 18 patients with radiographic evaluation (in addition to bone marrow biopsy and/or labs) post-SCT, 67% (12) were in radiographic CR at time of re-staging. Median times from SCT to new site of oligo-relapsed disease (20, 64.5%) and pre-existing but inactive sites of oligo-relapsed MM (4, 12.9%) were 31 months (3.2-117.5) and 9 months (3.4-15.9), respectively. Oligo-progressive MM, defined as active sites of disease both pre- and post-SCT were present in 22.6% (7) of patients. Prior to RT, 94% (29) had PET/CT imaging, with a median SUV of 4.4 (2.6-7.2) for target lesions. Solitary bone (77%) and extramedullary (23%) disease were treated to median dose of 30 Gy (8-49 Gy). At first disease response assessment post-RT, 77% (24) of which was done with PET/CT imaging , 42% (13) achieved CR. Among the 18 patients that did not achieve CR, 15 subsequently achieved CR at a median time of 7 months (1.7-44.5). A majority of patients (87%) received systemic therapy post-RT, with a median number of lines of therapy post-RT of 3 (1-17). The remaining 13% (4) of patients did not receive additional systemic therapy post-RT and did not experience progression. Median overall survival for the full cohort was 38 months (3.5-37.9). Conclusions: Utilizing modern systemic therapies in combination with post-transplant RT for patients with limited refractory or relapsed MM is a promising therapeutic approach. For those that remain refractory or relapse in a single site RT local control merits consideration supported by our report. Further investigation to identify patients at highest risk of progression and who may therefore benefit most from RT would be valuable. We plan to conduct additional analyses on the radiographic characteristics that may portend high risk disease, with the ultimate goal of developing well-defined criteria for giving RT earlier.

NCMP-11. ASSESSING SURVIVAL OUTCOMES OF PCV-BASED AND TEMOZOLOMIDE-BASED ADJUVANT THERAPY IN OLIGODENDROGLIOMA PATIENTS

Abstract INTRODUCTION When treating oligodendroglioma, choosing between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV), with concurrent radiotherapy still poses a challenge. Given the commonality of tumor recurrence, optimizing progression-free survival while minimizing adverse effects is crucial to improving quality of life. We compare survival and adverse effects of patients treated for oligodendroglioma with PCV-based vs TMZ-based adjuvant therapy. METHODS 87 patients treated for oligodendroglioma between 1994-2022 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) from initial resection were compared between PCV-based or TMZ-based treatment groups using Kaplan-Meier and multi-variable Cox survival analysis. RESULTS The median age at diagnosis was 41 years and 62% were male. After initial resection, 42.8% received PCV-based treatment and 57.2% received TMZ-based treatment. Treatment groups were balanced in the following variables: age, tumor genetic profiling, extent of resection, and KPS score. However, more patients in the TMZ-based group received concurrent radiation. The entire cohort had a 6.3-year PFS and 21.0-year OS. The median time to recurrence was significantly longer in those treated with PCV (12 years) compared to those treated with TMZ (4.7 years). PFS [HR = 0.46, p = 0.04] and OS [HR = 0.26, p = 0.04] were significantly longer in those receiving PCV-based treatment compared to TMZ-based treatment (Fig. 1). After adjusting for aforementioned variables, Cox regression analysis revealed no difference in OS between PCV- and TMZ-based treatment. The overall adverse effect rate did not significantly differ between PCV-based and TMZ-based treatment (25% vs. 28.1%, p &amp;gt; 0.99). CONCLUSIONS PCV treatment confers longer progression-free survival than TMZ treatment for oligodendroglioma patients, noting that most patients in our series received concurrent radiation with TMZ, and those receiving PCV not having received upfront radiation. Pending clinical trial results, our findings suggest PCV-based therapy warrants consideration as the preferred therapeutic option for oligodendroglioma patients.