bluuebunny/crossref_metadata_2025 huggingface dataset:
RADT-45. INTEGRATION OF FUNCTIONAL MAGNETIC RESONANCE IMAGING INTO STEREOTACTIC RADIOSURGERY PLANNING TO REDUCE SYMPTOMATIC RADIATION NECROSIS
Authors: Gui Chengcheng , Jenabi Mehrnaz , Daly Jillian , Gillick Claire , Bradley Teresha , Sze Emily , Maldonado Ruth , Tiwari Akhil , Stember Joseph , Mankuzhy Nikhil , Yamada Yoshiya , Pike Luke , Pasquini Luca , Peck Kyung , Ballangrud-Popovic Åse , Holodny Andrei , Imber Brandon
Published: November 2024

BACKGROUND

Radiation necrosis (RN) is a common complication of stereotactic radiosurgery (SRS). Functional magnetic resonance imaging (fMRI) localizes eloquent cortical areas for neurosurgical planning but is seldom applied to SRS. We explored the relationship between symptomatic RN and functional neuroanatomy on fMRI. We evaluated the potential benefit of reducing radiation dose to functional areas.

METHODS

From 2011 to 2022, patients with an fMRI within 3 months of SRS for resected or unresected brain metastases (BM) were included. The BM nearest to the primary motor, language, or visual cortices was designated as the index BM. The functional area on fMRI nearest to the index BM was designated as the fOAR. Focally symptomatic RN (FSRN) was defined as radiographic RN alongside new or worsening focal neurologic symptoms consistent with the fOAR. Patients treated with 5-fraction SRS and modern planning techniques after 2013 were included in the dosimetric analysis. Associations between fOAR dose and FSRN were evaluated with logistic regression. SRS replanning was performed to determine if fOAR dose could be reduced without sacrificing target coverage.

RESULTS

Among 94 patients, 82% received SRS postoperatively, and 71% received 5-fraction SRS. fOARs included the primary motor (77%), language (19%), and visual (2%) cortices. Of 20 patients with radiographic RN, 20% were neurologically asymptomatic, 20% had anatomically unrelated neurologic symptoms, and 60% had FSRN. The dosimetric analysis included 39 patients. The fOAR volume receiving a single-fraction equivalent dose ≥14 Gy (V14Gy) was associated with FSRN at 18 months post-SRS (OR=6.8/mL, p=0.05). Replanning reduced fOAR V14Gy in all cases. The mean reduction was 28%.

CONCLUSION

Neurologic symptoms of SRS-induced RN reflect nearby functional neuroanatomy on fMRI. Dose reduction to functional areas while maintaining target coverage is consistently achievable and may mitigate symptomatic RN. Integrated fMRI-based SRS planning may protect neurologic function when treating tumors near eloquent areas.
RADT-47. CLINICAL OUTCOMES AFTER SURGICAL RESECTION OF BRAIN METASTASES IN SMALL CELL LUNG CANCER PATIENTS
Authors: Qureshi Tanya , Zureick Andrew , McCall Neal , Wilhite Tyler , Wilke Christopher , Burns Timothy , Hadjipanayis Costas , Burton Steven , Choi Serah
Published: November 2024

Small cell lung cancer (SCLC) has a high propensity to metastasize to the brain. Radiotherapy is the primary treatment for SCLC brain metastases. Whole brain radiotherapy (WBRT) has been the standard of care, but recent studies show similar overall survival (OS) in patients treated with upfront stereotactic radiosurgery (SRS). Surgery does not typically have a role in SCLC although it can provide relief of neurologic symptoms and pathologic diagnosis. We sought to determine the clinical outcomes of patients who underwent surgical resection of SCLC brain metastases. A retrospective chart review of SCLC patients treated at UPMC from 2010 – 2022 was performed. OS after resection was estimated using the Kaplan-Meier method with log-rank test. 4,213 patients were diagnosed with SCLC, of which 715 patients (17%) had synchronous brain metastases at initial diagnosis. Forty patients underwent resection of SCLC brain metastases, all of whom were symptomatic. The median diameter of the resected brain metastases was 3.8 cm (range 1.7 – 8 cm). Seventy-five percent (n=30) had resection of synchronous brain metastases and 25% (n=10) had resection of metachronous brain metastases. Median OS for the surgical cohort was 13.6 months (interquartile range (IQR), 3.4 – 21.9 months). Patients with metachronous and synchronous brain metastases had median OS of 6.8 months (IQR, 2.8 – 24.6 months) and 14.3 months (IQR, 3.6 – 20.4), respectively. Of patients with synchronous brain metastases (n=30), 53% (n=16) received post-operative WBRT, 40% (n=11) received post-operative SRS and 10% (n=3) died within 7 weeks of surgery. Median OS of patients with synchronous brain metastases treated with WBRT and SRS were 11.9 months (IQR, 3.8 – 21.7) and 19.0 months (IQR, 14.6 – 30.3), respectively, and the difference was not statistically significant (p=0.53). Surgery for SCLC brain metastases is uncommon. Patients who received SRS versus WBRT post-operatively for synchronous brain metastases had no difference in OS.
RADT-49. IMPACT OF SHORT COURSE RADIOTHERAPY IN REDUCING LYMPHOPENIA IN PATIENTS WITH GLIOBLASTOMA (SAGA STUDY)
Authors: Campian Jian , Zhang Chaocai , Porter Alyx , Johnson Derek , Trifiletti Daniel , Peterson Jennifer , Vora Sujay , Sener Ugur , Ruff Mike , Mahajan Anita , Sarkaria Jann N , Brown Paul , Laack Nadia , Kowalchuk Roman O , William G Breen
Published: November 2024

INTRODUCTION

Lymphopenia attributed to postoperative chemoradiotherapy (CRT) can accelerate tumor recurrence and contribute to poor prognosis in GBM. We hypothesize that short course (1-2 weeks) CRT can mitigate lymphopenia compared to standard course and may provide immune benefits for future combination therapy.

METHODS

GBM patients were randomized on a multi-site phase II study comparing short course (35Gy/5Fx or 40Gy/10Fx depending on target volume) (Arm A) versus standard dose fractionation (60Gy/30Fx or 40Gy/15Fx, Arm B). All patients received concurrent and adjuvant temozolomide (TMZ). This unplanned interim analysis evaluates changes of absolute lymphocyte count (ALC), CD4 and CD8 prospectively at 3-timepoints: baseline (prior to CRT), end of CRT, and 1-month post-CRT.

RESULTS

To date, 72 patients enrolled (34 Arm A, 38 Arm B). Median age 66 (35-86), ECOG 0-2. Patients characteristics as followed in Arm A vs. Arm B, respectively: female 47% vs. 42%, MGMT promotor methylated 31% vs. 34%, steroid use 46% vs. 45%, ALC 1310 cells/mm3 (330 –9730) vs. 1480 (750 –7750), CD4 531 cells/mm3 (86 –1368) vs. 662 (318 –1671), and CD8 151 cells/mm3 (56 –940) vs. 272 (68 –875). Lymphocytes data were collected in 49 patients (21 Arm A, 28 Arm B). There were signficantly fewer reductions of ALC, CD4 and CD8 in Arm A. Median ALC changes were 95% and 99% of baseline (Arm A) vs 52% and 61% of baseline (Arm B) at the end of CRT and 1-month post-CRT, respectively (p<0.01). Median CD4 changes 93% and 96% of baseline (Arm A) vs 51% and 49% (Arm B), and median CD8 changes 97% and 98% of baseline (Arm A) vs 57% and 71% (Arm B) at the end of CRT and 1-month post-CRT, respectively (p<0.05).

CONCLUSIONS

This interim analysis suggests that short course RT could reduce treatment-related lymphopenia and immune suppression compared to standard RT, thus could be potentially beneficial to combine with immunotherapy.
RADT-50. CLINICAL OUTCOME OF DAILY 5-FRACTIONATED GAMMA KNIFE RADIOSURGERY FOR LARGE BRAIN METASTASES
Authors: Jun Juhee , Kim Young-Hoon
Published: November 2024

INTRODUCTION

With the introduction of the Gamma Knife Icon, hypo-fractionated Gamma Knife radiosurgery (GKRS) for large brain metastases (LBMs) is beginning to be performed. This study aimed to assess the clinical outcome and risk of the daily 5-fractionated GKRS for LBMs.

METHODS

A total of 100 patients who underwent 5-fractionated GKRS for LBMs (> 14cm3) were enrolled. Forty-six were male patients, and the median age was 60 years. Most common primary cancer sites were lung (41 non-small cell cancers), breast (24), and kidney (14). The median tumor volume was 22cm3 (14 – 69cm3) and marginal dose was 35Gy (50% isodose line) in 5 fractions. Median follow-up duration was 18 months (3 – 72 months).

RESULTS

The last follow-up showed local tumor control in 74 cases. The cumulative 1, 2, and 3-year local tumor control rates were 73, 65, and 60%, respectively. Eighty-six tumors showed best MRI response in a year, and median tumor volume decrease rate was 80% (22 – 100%). Thirty patients experienced dramatically tumor volume decrease (> 95%). Median progression free and overall survival were 7 and 16 months, respectively. Radiation necrosis occurred in 24 patients, of which only 9 had neurological symptoms and treated with steroid and bevacizumab.

CONCLUSIONS

The daily 5-fractionated GKRS for very LBMs showed favorable local tumor control and acceptable radiation necrosis, but questionable survival benefit. In the future, prospective multi-center study is needed.
CTIM-15. LOCOREGIONAL ADMINISTRATION OF B7-H3-CAR T CELLS EXPRESSING 41BB LIGAND FOR PEDIATRIC PATIENTS WITH PRIMARY CNS TUMORS: PRELIMINARY RESULTS FROM A PHASE I STUDY
Authors: Bertrand Kelsey C , Kostecka Anna , Smith Kyle , Han Katie , Chiang Jason , Pinto Soniya , Tlais Dana , Selukar Subodh , Orr Brent , Hanzlik Emily , Langfitt Deanna , Metais Jean-Yves , Lockey Timothy , Willis Catherine , Fazio Frank , Shanmugam Raghu , Tian Liqing , Walhart Tara , Wang Yu , Allmon Patricia , Perry Scott , Schell Sarah , Adams Polly , Ward Meghan B , Meehl Michaela , Akel Salem , Poston Leigh , Bag Asim , Mack Stephen C , Leggas Markos , Klimo Paul , Gajjar Amar , Thomas Paul , Robinson Giles W , Park Julie R , Crawford Jeremy Chase , Gottschalk Stephen , Northcott Paul A , Krenciute Giedre , DeRenzo Christopher
Published: November 2024

Outcomes for pediatric patients with diffuse midline glioma (DMG) and relapsed/refractory CNS malignancies remain poor. Loc3CAR is an ongoing, first-in-human, phase I clinical trial (NCT05835687) evaluating intracranial delivery of B7-H3-CAR T cells expressing 41BB ligand (B7-H3-CAR-T) for patients ≤21 years old with i) relapsed/refractory B7-H3+ CNS tumors (Cohort A), or ii) DMG post-radiation (Cohort B). Treatment included 6 intracerebroventricular B7-H3-CAR-T infusions administered over 7 weeks. Primary and secondary outcomes were safety and disease response, respectively. To date, 84% (21/25) of tumors screened were B7-H3+ (median H-score 200; range 0-300). CAR-T products were successfully manufactured for all patients enrolled on the collection/manufacture phase of the trial (n=11). Eight patients (7 cohort A; 1 cohort B) were treated with a total of 42 infusions on dose level 1 (1x107/3x107 CAR+ T cells/dose). Post-infusion, multiple participants exhibited neurologic findings suggestive of on-tumor CAR-T activation, including seizure, dysphasia, and localized pain. One patient, with a large tumor burden and high B7-H3 expression (H-score = 300), experienced a dose limiting toxicity with unresponsiveness and decorticate posturing approximately 16 hours post-infusion #1. Their clinical status rapidly improved following CSF removal and intravenous dexamethasone. Common adverse events attributable to B7-H3-CAR-T included headache (8/8), fever (7/8), and nausea/vomiting (5/8). Two of 7 (29%) evaluable patients achieved clinical benefit with stable disease at week 8. B7-H3-CAR-T and inflammatory cytokines were detected in the CSF from all patients evaluated. Circulating tumor DNA (ctDNA) was measured using a novel DNA methylation-based sequencing pipeline and detected in the CSF from 6/8 patients. For 2 patients, ctDNA abundance increased post-infusion, followed by clearance, suggesting subclinical antitumor activity. Single cell RNAseq of immune cells in the CSF from 1 patient analyzed to date, demonstrated abundant Tregs post-infusion #4, suggesting B7-H3-CAR-T may induce local anti-inflammatory responses. Overall, intracranially administered B7-H3-CAR-T have an acceptable safety profile and warrant continued exploration for pediatric patients with CNS tumors.
CTIM-21. FIRST-IN-HUMAN PHASE I CLINICAL TRIAL USING 8R-70CAR T CELLS FOR NEWLY DIAGNOSED ADULT GLIOBLASTOMA
Authors: Ghiaseddin Ashley , Tao Haipeng , Deleyrolle Phuong , Rahman Maryam , Rinonos Serendipity Zapanta , Kresak Jesse , Massini Tara , Hiemenz John , robinson Christopher , Hsu Jack , Lin Tuo , Wynne Kristine , King Jennifer , Hodik Marcia , Lybarger John , Manso Eugenio Simon , Wang Anqi , Sekora David , McKibben Kathryn , Dechkovskaia Anjelika , Castillo Paul , Ligon John , Sayour Elias , Deleyrolle Loic , Mitchell Duane , Huang Jianping
Published: November 2024

BACKGROUND

To address the challenges of chimeric antigen receptor (CAR) T cell therapy in GBM, we utilized IL-8 release from tumor cells as a ‘GPS homing signal’ to enhance T-cell trafficking with a novel CD70-specific CAR design (8R-70CAR) that targets GBM. The 8R-70CAR offers several advantages: 1) Improved CAR T-cell trafficking, enhancing antitumor efficacy; 2) Reduced CD70, reshaping the tumor microenvironment (TME) and boosting endogenous immunity; 3) Utilized CD27 as the CAR, a co-stimulatory molecule that enhances T-cell functions; 4) Enabled CAR T cells to act as a sink to neutralize or remove IL-8, a pro-cancer chemokine, from the TME; and 5) Required only 120 ml of whole blood (not leukapheresis) for CAR T cell production. Preclinically, 8R-70CAR significantly enhanced CAR-T cell tumor migration and persistence, leading to complete tumor regression and sustained immune memory in a chemo/radiation/PD-1-blockade-resistant GBM model. These findings led to a phase-I trial (IMPACT trial: FDA-IND#23881, NCT05353530) using 8R-70CAR T cells for CD70 -positive newly diagnosed adult GBM.

METHODS

We aim to recruit 18 adult patients (3 + 3 dose-escalation design) with CD70-positive (>20%) tumors. The CAR T cells will be given intravenously after completing standard-of-care (SOC) therapy. Primary endpoints: Evaluate safety, tolerability, and dose-limiting toxicities (DLTs) to determine the maximum tolerated dose. Secondary endpoints: Assess preliminary efficacy. Immune monitoring and correlative studies will also be conducted.

RESULTS

To date, four patients have been enrolled in the IMPACT trial, with 2 eligible patients participating in treatment at dose level 1 (1x10^6/kg). One patient has completed treatment with 8R-70CAR T cells, experienced no DLTs, and is currently in follow-up. The remaining patient is under SOC therapy before receiving CAR T cell treatment.

CONCLUSIONS

This study aims to address current therapeutic gaps and offers options for implementing a novel CAR design for the development of a more effective therapeutic modality for GBM.
CTIM-23. A PHASE II STUDY OF RETIFANLIMAB (PD-1 INHIBITOR) AND EPACADOSTAT (IDO1 INHIBITOR) IN COMBINATION WITH BEVACIZUMAB AND HYPOFRACTIONATED RADIOTHERAPY FOR RECURRENT GLIOBLASTOMA: NCT03532295
Authors: Butt Abeer , Luo Jingqin , Tao Yu , Butt Omar , Etter Kelsey , Nehring Leslie , Hissim Deanna , McKean Cole , Ansstas George , Kim Albert , Abraham Christopher , Kizilbash Sani , Strowd Roy , Johanns Tanner , Huang Jiayi , Ciorba Matthew , Campian Jian , Chheda Milan
Published: November 2024

INTRODUCTION

Immunotherapy has not improved survival in recurrent GBM (rGBM). Indoleamine 2,3 dioxygenase 1 (IDO1), highly expressed in ~90% of patients with malignant glioma, is a rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn) and enables immune escape.

METHODS

We hypothesized combining therapies targeting immunosuppressive pathways with cytotoxic and antiangiogenic therapies would overcome tumor-related immunosuppression. This was an open-label Phase II study of two regimens: Arm A consisted of retifanlimab (anti-PD1, 500mg IV Q4W) + bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x 10) in patients with IDH1/2-WT rGBM. Regimen B added the IDO inhibitor, epacadostat (400mg po BID), initiated prior to HFRT. Key inclusion criteria included dexamethasone ≤ 4 mg/day. The primary endpoint was overall survival (OS) at 9 months (OS-9). 24 evaluable patients were required to detect an OS-9 of 60% with 80% power, compared to 38% in historical controls (bevacizumab alone) by 1-sided 1-sample log rank test at alpha=0.1.

RESULTS

We previously reported Arm A. Here, we present results from Arm B. 25 of the 27 patients enrolled to regimen B were evaluable: median age 58years (23-71); 28% female; 23% MGMT promotor methylated; median KPS 90 (70 - 100); a median of 6 cycles of epacadostat as of May 2024 (1 - 13). 18 of 25 died with a median follow up 9.23 months. Median PFS was 7.52 months (95%CI: 5.52-9.43). Median OS was 9.5 months (95%CI 8.08-11.96). Regimen B met its primary endpoint with OS-9 of 61.07% (95%CI: 38.23-77.65%). There were 5 possible immune-related grade 3+ toxicities to date (2 ALT/AST increase; 3 rash).

CONCLUSIONS

Retifanlimab, epacadostat, HFRT, and bevacizumab in rGBM is well-tolerated, with encouraging OS and PFS at the time of submission. Arm B met its primary endpoint. Further studies are warranted to identify biomarkers to predict long-term responders.
CTIM-25. PHASE2B/3 STUDY OF NEOANTIGEN-SPECIFIC T CELL IMMUNOTHERAPY IN NEWLY DIAGNOSED O6 – METHYLGUANINE METHYLTRANSFERASE UNMETHYLATED (MGMT -) GLIOBLASTOMA
Authors: Tuncer Tolga , Salacz Michael , Milligan Brian , Sloan Andrew , Mammoser Aaron , Yu John , Aguiar Jean , Skikne Barry , Carter Wayne , Wood Gary
Published: November 2024

MGMT- glioblastoma (GBM) is the most common malignant primary brain tumor, yet outcomes have not improved in decades despite intensive investigations. TVI-AST-008 is a randomized clinical trial of a novel neoantigen-specific T cell immunotherapy regimen proven invariably curative in rodent models and clinically effective in trials of patients with relapsed/resistant GBM. TVAX neoantigen-specific T cell immunotherapy exploits the fact that cancer cells express neoantigens, and adoptive transfer can bypass the immunosuppressive milieu near the resection cavity. In this manner, TVAX effector T cells initiate apoptosis in any residual GBM. After pathologic confirmation, autologous GBM tumor tissue sent to the TVAX GMP manufacturing facility is irradiated and utilized for proprietary vaccine production. Patients are vaccinated with a series of two intradermal injections and the resulting cancer neoantigen-specific T cells are harvested by leukapheresis. These T cells are activated and proliferated ex vivo by TVAX manufacturing to generate effector T cells. These are re-infused following standard radio-chemotherapy, followed by low-dose interleukin-2 to further stimulate T cell proliferation. In the study, MGMT- GBM patients are randomly assigned to treatment or control arms. Patients in the treatment arm undergo vaccination, then standard concurrent IMRT-chemotherapy, followed by re-infusion of TVAX autologous effector T cells. Patients in the control arm undergo standard IMRT-chemotherapy followed by adjuvant chemotherapy with temozolomide. TVI-AST-008 is an ongoing, randomization-controlled study with Fast Track designation from the FDA. The primary end point is overall survival. Additional end points include progression free survival, safety and immune response. Patients are followed with physical exams and surveillance MRI for evidence of disease progression. The trial is targeted for 15 centers in the US.
CTIM-26. PHASE II STUDY OF AZELIRAGON IN COMBINATION WITH RADIATION THERAPY IN NEWLY DIAGNOSED PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Huang Jiayi , Ahluwalia Manmeet , Boockvar John , Batiste James , Jaboin Jerry , Thotala Dinesh , Halasz Lia , Rammohan Nikhil , Ney Douglas , Malani Rachna , Chinnaiyan Prakash , Kotecha Rupesh R , Mehta Minesh , Marcus Stephen
Published: November 2024

BACKGROUND

Myeloid-derived suppressor cells (MDSCs) exacerbate immunosuppression and immune exhaustion in glioblastoma (GBM) and promote resistance to chemoradiotherapy. Preclinical data demonstrate that inhibiting the receptor for advanced glycation end-products (RAGE) pathway using azeliragon, when combined with radiation therapy (RT), can modulate MDSC accumulation in the tumor microenvironment and improve tumor control. CAN-401 is a phase II study evaluating the safety and preliminary clinical efficacy of combining azeliragon with RT for newly diagnosed IDH-wildtype MGMT-unmethylated glioblastoma (GBM).

METHODS

This multi-institutional, single-arm, open-label phase II study combines azeliragon with RT (60 Gy/30 fractions). Azeliragon is administered orally with a loading dose of 30 mg twice daily for 6 days before RT, followed by 20 mg daily during and after RT. If more than one dose-limiting toxicity occurs during the safety run-in of 6 patients, additional patients will be treated at de-escalated dose levels using the rolling six design. The study hypothesizes that azeliragon and RT will improve median progression-free survival (PFS) to 9.7 months compared to historical control of 5.7 months, corresponding to a hazard ratio of 0.58. The study aims to enroll 30 evaluable patients.

RESULTS

From December 2023 to May 2024, 10 patients were enrolled and treated with 20 mg of azeliragon daily, including 6 patients in the safety run-in. No dose-limiting toxicity was observed, hence no dose de-escalation was needed. The most common treatment-related adverse events (AEs) were grade 1, including fatigue and lymphopenia. There were no dose modifications or discontinuations due to treatment-related AEs. Enrollment is ongoing, and updated clinical outcomes will be reported.

CONCLUSIONS

Azeliragon at 20 mg per day with concurrent RT is well tolerated in patients with GBM. The phase II study is currently enrolling across 8 institutions in the United States (NCT05986851).
CTNI-01. INTERVENTION OUTCOMES OF ENHANCED RECOVERY AFTER SURGERY PROTOCOL VERSUS STANDARD CARE FOR GLIOMA PATIENTS IN SELECTED HOSPITALS IN DEMOCRATIC REPUBLIC OF THE CONGO: RANDOMIZATION AND STRATIFICATION OF PROVIDERS AND HOSPITALS
Authors: Kamabu Larrey Kasereka
Published: November 2024

BACKGROUND

Enhanced Recovery after Surgery (ERAS) protocols have shown promise in improving perioperative care and patient outcomes in various surgical specialties. Aim: This study will aim to assess the efficacy of ERAS compared to the current standard of care (SOC) for glioma patients in DRC hospitals.

METHODS

A pragmatic, multicenter, randomized controlled trial will be designed to evaluate the outcomes of glioma patients treated with ERAS protocols versus SOC in selected hospitals in DRC.

EXPECTED RESULTS

A total of 100 glioma patients will be included in this study, with 50 patients in the ERAS group and 50 in the SOC group. The primary analysis will reveal that the ERAS group will have significantly fewer post-operative complications (p < 0.05) and a shorter length of hospital stay (p < 0.05) compare to the SOC group. Patient satisfaction scores will also higher in the ERAS group. Subgroup analyses by hospital center will indicate consistent trends in favor of the ERAS protocol. Randomization of providers and stratification by hospital will aim to mitigate the influence of individual provider practices and hospital-specific factors on the study outcomes. This approach will be expected to enhance the validity of the results and ensure equitable representation across hospitals.

CONCLUSIONS

The unique design of randomizing providers and stratifying by hospital will be a critical component of this multicenter trial, which seeks to provide valuable insights into the potential benefits of ERAS protocols for glioma patients in DRC. The findings will guide clinical practice and healthcare policy in resource-constrained settings, ultimately improving the care and outcomes of glioma patients
CTNI-02. FLUORESCEIN-STAINED CONFOCAL LASER ENDOMICROSCOPY VERSUS CONVENTIONAL FROZEN SECTION FOR INTRAOPERATIVE HISTOPATHOLOGICAL ASSESSMENT OF INTRACRANIAL TUMORS
Authors: Wagner Arthur , Brielmaier Maria Charlotte , Kampf Charlotte , Baumgart Lea , Aftahy Amir Kaywan , Meyer Hanno-Sebastian , Kehl Victoria , Höhne Julius , Schebesch Karl-Michael , Schmidt Nils Ole , Zoubaa Saida , Riemenschneider Markus , Ratliff Miriam , Enders Frederik , von Deimling Andreas , Liesche-Starnecker Friederike , Delbridge Claire , Schlegel Jürgen , Meyer Bernhard , Gempt Jens
Published: November 2024

BACKGROUND

The aim of this clinical trial was to compare Fluorescein-stained intraoperative confocal laser endomicroscopy (CLE) of intracranial lesions and evaluation by a neuropathologist with routine intraoperative frozen section (FS) assessment by Neuropathology.

METHODS

In this phase II non-inferiority, prospective, multicenter, non-randomized, off-label clinical trial (Eudra-CT: 2019-004512-58), patients above the age of 18 years with any intracranial lesion scheduled for elective resection were included. The diagnostic accuracies of both CLE and FS referenced with the final histopathological diagnosis were statistically compared in a non-inferiority analysis, representing the primary endpoint. Secondary endpoints included the safety of the technique and time expedited for CLE and FS.

RESULTS

210 patients were included by 3 participating sites between November 2020 and June 2022. Most common entities were high grade gliomas (37.9%), metastases (24.1%), and meningiomas (22.7%), A total of 6 serious adverse events in 4 (2%) patients were recorded. For the primary endpoint, the diagnostic accuracy for CLE was inferior with.87 versus.91 for FS, resulting in a difference of.04 (95% confidence interval -.10;.02; p=.367). The median time expedited until intraoperative diagnosis was 3 minutes for CLE and 27 minutes for FS, with a mean difference of 27.5 minutes (standard deviation 14.5; p<.001).

CONCLUSION

CLE allowed for a safe and time-effective intraoperative histological diagnosis with a diagnostic accuracy of 87% across all intracranial entities included. The technique achieved histological assessments in real-time with a tenfold reduction of processing time compared to FS, which may invariably impact surgical strategy on the fly.
CTNI-04. DECODING GLIOBLASTOMA SURVIVAL: UNRAVELING THE PROGNOSTIC POTENTIAL OF OLFACTORY FUNCTION IN A PROSPECTIVE OBSERVATIONAL STUDY
Authors: Oster Christoph , Matyar Aylin , Hummel Thomas , Hattingen Elke , Schmidt Teresa , Jokisch Martha , Jokisch Daniel , Ahmadipour Yahya , Sure Ulrich , Stuschke Martin , Tertel Tobias , Giebel Bernd , Kleinschnitz Christoph , Scheffler Björn , Deuschl Cornelius , Kebir Sied , Glas Martin
Published: November 2024

BACKGROUND

Olfactory impairment is a common neurologic deficit among glioblastoma patients.We have previously shown that glioblastoma patients with reduced smell sensitivity had lower overall survival rates compared to those with normal olfactory function.A notable limitation in that study was the unequal distribution of prognostic factors between the two groups,and the absence of continuous olfactory assessments during treatment to investigate if therapy-associated neurotoxicity could be a contributing factor to diminished olfactory acuity.In this trial olfactory function will be evaluated in glioblastoma patients as a prognostic marker with regard to overall survival,neurocognition and quality of life.

METHODS

This prospective,multicenter study is set to recruit 64 glioblastoma patients alongside 64 healthy controls.Stratification of participants is based on prognostically relevant variables such as resection status,MGMT-promoter-methylation-status,radiographic involvement of olfactory brain areas,olfactory function,age,and Karnofsky performance status scale.We utilize Sniffin´ Sticks to evaluate olfactory function through identification and threshold tests,and this assessment is carried out longitudinally throughout the therapy starting from tumor diagnosis.Infiltration of the olfactory nerves or olfactory brain are scrutinized using a high-resolution coronal T2-weighted sequence which is added to a dedicated brain tumor protocol.MRI images are independently reviewed by two board-certified radiologists from distinct institutions,who are blinded to the patients’ olfactory function status.Furthermore,quality of life data,neuropsychological testing,and psychosomatic screening are performed at specific intervals throughout the study.Also,we examine next-generation-sequencing results to investigate potential genetic associations with hyposmia in glioblastoma patients.

RESULTS

The first participant was enrolled in May 2023.Currently,16 patients and three controls are already enrolled(May 2024).Plans are underway to open a second study site in 2024,with the aim to complete recruitment by December 2025.Follow-up assessments will continue until December 2027.We anticipate that the final results of the study will be available in 2028.

CONCLUSIONS

In the process,this study is the first prospective study which investigates the olfactory function systematically as prognostic factor in glioblastoma patients.
CTNI-13. 18-FET-PET ENHANCED DIAGNOSIS OF PSEUDOPROGRESSION IN GLIOBLASTOMA IS AN INDEPENDENT PROGNOSTIC FACTOR FOR OVERALL SURVIVAL
Authors: Schmidt Teresa , Oezdemir Zeynep , Oster Christoph , Sure Ulrich , Hermann Ken , Stuschke Martin , Deuschl Cornerlius , Kleinschnitz Christoph , Müther Michael , Glas Martin , Kebir Sied
Published: November 2024

INTRODUCTION

Detecting pseudoprogression (PSP) in glioblastoma during first-line treatment remains challenging and has significant clinical implications for patient management. The detection of PSP has been shown feasible using FET-PET. The prognostic impact of FET-PET diagnosed PSP on overall survival is still uncertain, as retrospective studies provide limited insights due to the substantial differences in the distribution of prognostic factors between tumor progression (TP) and PSP groups. This study aims to address these uncertainties by leveraging advanced analysis techniques.

METHODS

Patients with newly diagnosed glioblastoma (WHO 2021) who underwent chemoradiation and contrast-enhanced MRI suspected for TP and subsequent FET-PET scan at Essen University Hospital were retrospectively evaluated. The modified Response Assessment in Neuro-Oncology (RANO) criteria were used to diagnose PSP. FET-PET analysis included mean (TBRmean) and maximum tumor-to-brain ratios (TBRmax). The two groups (TP/PSP) were balanced using a propensity score analysis including age at diagnosis, extent of resection, Karnofsky-Performance-Status Scale (KPS) and MGMT methylation status. Overall survival was predicted using Kaplan-Meier and multivariate analysis as well as conventional FET-PET parameters, PET/MRI volumetry, and FET/MRI-derived radiomics. An independent cohort was used for validation.

RESULTS

Out of the 165 patients analysed in this study, 38 were diagnosed with PSP. Following balancing analysis, our study cohort consisted of 40 patients (20 TP/20 PSP). Patients with PSP had a significantly longer mean overall survival (mOS) compared to those with TP (mOS TP 20.24 months; mOS PSP 33.25 months; p=0.0023). The multivariate Cox-Regression analysis confirmed PSP as a significant prognostic marker for overall survival (p=0.0153). Confirmation of these results on an independent validation cohort is pending and will be presented at the meeting.

CONCLUSION

This study shows that PSP is an independent prognostic factor for overall survival in newly diagnosed glioblastoma patients.
CTNI-14. RADIOTHERAPY VERSUS TMZ FOR HIGH-RISK LOW-GRADE GLIOMA. FINAL RESULTS AFTER MEDIAN FOLLOW-UP OF 13 YEARS OF PHASE III EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033) STUDY
Authors: Baumert Brigitta G , Hegi Monika E , Van den Bent Martin , von Deimling Andreas , Gorlia Thierry , Hoang-Xuan Khe , Brandes Alba A , Sargos Paul , Taphoorn Martin , Vauleon Elodie , Phillips Claire , Kros Johan M , Bady Pierre , Wick Wolfgang , Enting Roelien , Reni Michele , Thiessen Brian , Dhermain Frederic , Bromberg Jacoline , Jacob Julian , Reijneveld Jaap C , Chinot Olivier , Gijtenbeek Anja , Rossiter John , Lentz Marie-Ange , Balana Carmen , Azevedo Ana Luisa Silva , Clement Paul M , Berghoff Anna , Tzuk Tzahala , Weller Michael , Nordal Robert , Rees Jeremy , Lacombe Denis , Mason Warren P , Stupp Roger
Published: November 2024

BACKGROUND

We previously reported on progression-free survival of our randomized phase 3 trial [Lancet Oncol. 2016;17:1521-1532]. Here we report results of long-term follow-up (FU) including overall survival (OS) and molecular subgroup analyses.

METHODS

487 patients were randomized between 2005-2012 to either standard radiotherapy (RT, 50.4 Gy/ 28 fractions) or primary dose-dense temozolomide [TMZ] chemotherapy (75 mg/m² daily x 21/28 days, up to 12 cycles). Treatment at progression was at investigators discretion and commonly included cross-over to the alternative treatment modality.

RESULTS

At a median follow-up of 13 years, 68% of patients had died. Median age at inclusion was 45 years (range 18-75), 96% had a performance status of 0-1. There was no significant difference in PFS nor OS: PFS was 3.6 years (95% CI: 3.0-4.1) and 3.1 years (95% CI: 2.7-3.6), HR 1.12 (95% CI: 0.92-1.36); OS 6.6 years (95% CI: 5.8-7.5) and 8.0 years (95% CI: 6.9-9.1), HR 0.87 (95% CI: 0.69-1.09), for RT or TMZ, respectively. Subgroup analyses were performed for patients when available tissue allowed for molecular analyses (n=351/487,73%). In astrocytoma, IDHmt/1p/19q non-codeleted (n = 178), median OS with RT was 6.6 years (95% CI: 5.3-7.6) and with TMZ was 6.7 years (95% CI: 5.7-8.0); HR 0.98 (95% CI: 0.67-1.44). For oligodendroglioma, IDHmt/codeleted (n = 109) median OS with RT was 12.9 years (95% CI: 9.4 - NE) and with TMZ 14.9 years (95% CI: 10.1 - NE); HR 1.01 (95% CI: 0.56-1.81). For a heterogenous group of IDHwt tumors (n = 64), median OS with RT was 2.5 years (95% CI: 1.8-3.3) and with TMZ 4.7 years (95% CI: 2.2-7.2); HR 0.37 (95% CI: 0.18-0.77).

CONCLUSIONS

Primary treatment with RT or TMZ provided comparable PFS and OS. Choice of primary treatment can be tailored to individual tumor characteristics and patient preference.
CTNI-23. DIFFERENT GUT MICROBIOTA COMPOSITION IS ASSOCIATED WITH CHEMOTHERAPY EFFICACY IN PATIENTS WITH DIFFERENT TYPES OF CENTRAL NERVOUS SYSTEM CANCER
Authors: Guo Chengcheng , Zhai Shijia , Chen Zhongping , Yin Lin , Zheng Yilin , Huang Guoxin
Published: November 2024

BACKGROUND

The relationship between central nervous system cancers and the gut microbiota (GM) is not well understood. The purpose of this study is to retrospective analyze the differences between the composition of the gut microbiota in patients with different neurologic tumors and their correlation with chemotherapy efficacy.

METHODS

A total of 44 patients participated in the study and were divided into four groups: gliocytoma (GA), medulloblastoma (MB), germ cell tumors (GT), and diffuse large B-cell lymphoma (DB) based on their pathological diagnosis. Fecal samples were collected from patients for 16S amplicon sequencing to analyze GM composition. Moreover, all the patients were classified into completed response (CR), stable disease (SD), and progressive disease (PD) groups based on the clinical outcomes of chemotherapy. PLS-DA analysis and heatmap analysis were used to reveal the correlation between GM composition and outcomes of chemotherapy.

RESULTS

Phyla taxa comparison showed the detailed GM composition among these four groups. The phylum of Bacteroidetes was higher in GA group when compared to the other groups. And the phylum of Fusobacteria could only be found in GA and MB groups while the phylum of Verrucomicrobia showed a significant accumulation in DB group. the genera of Ruminococcus, Gemmiger, and Parasutterella were accumulated in the patients with the completed response of chemotherapy. Besides, patients in SD group had higher abundance of the genera of Prevotella, Tyzzerella, and Odoribacter. While patients in PD group showed the higher abundance of Streptcoccus, Fusobacterium, Lachnospira, and Holemanella.

CONCLUSION

We firstly drew the GM composition profile of the patients with GA, MB, GT, and DB to show the different GM composition of the diseases. Moreover, the gut microbiota composition correlates with chemotherapy outcomes in central nervous system cancer patients so may serve as a potential biomarker for predicting chemotherapy efficacy.
CTNI-24. WF-1801: SINGLE ARM PILOT STUDY OF RAMIPRIL FOR PREVENTION OF RADIATION-INDUCED COGNITIVE DECLINE IN GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIOTHERAPY
Authors: Cramer Christina , Dressler Emily , Smith Sydney , Page Brandi , Wefel Jeffrey , Gilbert Mark , Rapp Stephen , Ip Edward , Pugh Stephanie , Summrall Ashley , Weaver Kathryn , Lesser Glenn , Chan Michael
Published: November 2024

BACKGROUND

Patients with glioblastoma (GBM) experience cognitive decline after chemoradiation. Radiation therapy (RT) to the brain creates chronic inflammation believed to contribute to cognitive decline. Ramipril counteracts neuroinflammatory changes in pre-clinical models when given during RT.

METHODS

This prospective single arm study (WF-1801) coordinated by the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base assessed feasibility, tolerability, and potential efficacy of using ramipril in patients with GBM. Eligibility and treatment paradigms mirrored NRG/RTOG 0825 allowing for outcomes from the placebo arm to be used for comparison. Participants took ramipril during 6 weeks of chemoradiation with temozolomide and for 3 months after RT. Patients completed cognitive testing (HVLT-R, TMT, and COWA) and patient-reported outcomes at baseline, RT completion, and 1 and 4 months after RT. Co-primary endpoints were retention rate (compliance with 75% doses and completion of cognitive testing) and change in cognitive composite score 1 month after RT.

RESULTS

75 participants were accrued between 3/25/2019 and 11/14/23: 65% were male, 89% White, median age 63 years. The NRG/RTOG 0825 placebo cohort (n=247) was younger (median 57, p<0.0001) with more White participants (95%, p=0.04). The overall retention rate in WF-1801 was 48% (one-sided 95% CI: 38%-100%); 61% completed >=75% of doses; 57% completed cognitive testing at all time points. The median (range) change in cognitive composite score 1 month after RT was 0.01 (-82.6, 13.0) reflecting an improvement from baseline. However, this was not significantly different from the NRG/RTOG 0825 placebo group median of 0.10 (-48.2, 8.6); p=0.49.

CONCLUSION

The overall retention rate fell short of our pre-specified endpoint of > 65%; however, medication compliance was high and well-tolerated in retained patients. Future investigations could identify patient subsets who may benefit more from concurrent ramipril. WF-1801 (NCT03475186) funded by UG1CA189824. NRG/RTOG-0825 (NCT00884741) funded by U10CA180868 and U10CA021661.
CTNI-27. SYSTEMIC DELIVERY OF LOW ENERGY RADIOFREQUENCY ELECTROMAGNETIC FIELDS FOR THE TREATMENT OF PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Feher Olavo , Chaul Caroline , Xavier Camila Bragança , de Sousa Micelange Carvalho , Testagrossa Leonardo , de Medeiros Maria Fernanda Barbosa , Sampaio Luana Alencar Fernandes , Gansl Rene , Tuma Rogerio , Meireles Sibele , Zanesco Tatiana , Iemma Antonio , Costa Tiago , Wiedenmann Bertram , Tuszynski Jack , Costa Frederico Perego
Published: November 2024

BACKGROUND

Tumor Treating Fields plus maintenance temozolomide (mTMZ) showed a survival advantage in the first-line glioblastoma (GBM) treatment. The survival benefit remains limited in patients with unmethylated MGMT gene promoter. The AutEMsys device emits low-energy amplitude modulated systemic electromagnetic fields (EMF) at patient specific frequencies. It is an outpatient procedure that can be integrated with mTMZ.

METHODS

This study involved a prospective compassionate access program targeting adult GBM patients using an intrabuccal EMF exposure via AutEMsys in addition to chemoRT+mTMZ. The program explored the effects on survival and patients’ reported quality-of-life (QOL) by EORTC-QL-C30. Patients underwent a 90-minute session of EMF exposure therapy repeated every 2 weeks until progression, deterioration in QOL or death. All patients had pathological specimens for diagnosis, IDH mutation status through NGS techniques, and MGMT promoter region methylation status.

RESULTS

31 participants were enrolled, including 29 with GBM and 2 with diffuse midline glioma. 14 patients (45%) received EMF+chemoRT followed by EMF+mTMZ and 17 patients (55%) received EMF+mTMZ (post chemoRT). Survival time was measured from the start of mTMZ to the date of the last follow-up. The median overall survival (mOS) for all 31 patients was 26.0 months (95% CI: 14.4 – 37.2 months). Specifically for 21 patients with unmethylated MGMT, the mOS was 25.0 months (95% CI: 15.9 – 34.1 months). Similarly, for the 28 patients with IDH wildtype status, the mOS remained 26.0 months (95% CI: 9.6 – 42.4 months). The addition of AutEMsys with chemoRT+mTMZ demonstrated an improved role functioning in 79% of patients with 25% of these with >10-point score.

CONCLUSION

The AutEMsys device has shown promising initial results when added to chemoRT+mTMZ treatment of GBM. These findings warrant further prospective investigation and validation in a multicenter clinical trial setting.
CTNI-28. IN VITRO GLIOMA STEMLIKE CELL-BASED SCREENING TO PREDICT DRUG SENSITIVITY IN RECURRENTGLIOBLASTOMA: A CLINICAL SERIES AND SYSTEMATIC LITERATURE REVIEW
Authors: Buccarelli Mariachiara , Offi Martina , Chiesa Silvia , Mazzarella Ciro , Falchetti Maria Laura , Ceccarelli Giovanni Maria , Bartoli Francesco Beghella , Silvia Silvia , Bonaventura Rina Di , Pepa Giuseppe Maria Della , Shetty Sohum Rajesh , Monaco Giuliano Di , Doglietto Francesco , Pallini Roberto , Olivi Alessandro , Lauretti Liverana , Ricci-Vitiani Lucia , D’Alessandris Quintino Giorgio
Published: November 2024

INTRODUCTION

There is no standard care for recurrent glioblastoma (GBM) after surgery and radiochemotherapy. Lomustine is commonly used in clinical trials, while regorafenib, a multikinase inhibitor, has shown a survival benefit in the randomized multicentric REGOMA trial, becoming the standard treatment in several countries, including Italy. However, due to nonnegligible toxicity, early identification of likely responders is crucial for personalized treatment. Various studies have explored putative molecular predictors of response with conflicting results. Glioma stem-like cells (GSCs), the most treatment-resistant subpopulation, are believed to drive GBM recurrence post-chemoradiotherapy. Thus, GSCs might provide valuable insights into the drug sensitivity of recurrent GBM.

MATERIALS AND METHODS

Between 2020 and 2022, nine patients enrolled in a prospective study to obtain GSC cultures from tumor tissue obtained at first surgery were treated with regorafenib upon tumor recurrence. Four patients underwent reoperation before starting regorafenib. GSC cultures were exposed to increasing regorafenib doses in vitro to determine sensitivity (IC50).

RESULTS

The median progression-free survival (PFS) was 3 months, consistent with REGOMA data. Only one patient achieved 6-month PFS (11.1%). GSCs from this patient were the only ones with an IC50 below the plasma range of regorafenib during treatment (IC50 4.6 μM, range 5.2-8.1 μM). Additionally, this patient had not undergone reoperation before starting regorafenib. Systematic literature review showed few but promising studies in which therapy personalization was based on in vitro drug screening.

CONCLUSIONS

Although preliminary, these findings suggest a potential paradigm shift in personalized treatment for recurrent GBM, utilizing a GSC-based approach rather than molecular profiling. Further evaluation of GSCs from recurrent tumor tissue is necessary to determine their utility.
CTNI-29. A PHASE 1B STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND OBJECTIVE RESPONSE OF LP-184 ALONE AND IN COMBINATION WITH SPIRONOLACTONE IN IDH WILD TYPE GLIOBLASTOMA AT FIRST PROGRESSION
Authors: Schreck Karisa , Laterra John , Kulkarni Aditya , Bhatia Kishor , Ewesuedo Reginald , Chamberlain Marc
Published: November 2024

LP-184 is a fully synthetic small molecule alkylator of the acylfulvene therapeutics class that induces DNA double-strand breaks and improves survival in orthotopic GBM xenograft models. In preclinical studies, LP-184 is brain penetrant with a brain tumor/plasma concentration ratio of 0.2. DNA damage induced by acylfulvenes is repaired via transcription-coupled nucleotide excision repair (TC-NER) mediated by ERCC complexes. GBM with intrinsic or pharmacologically induced DNA Damage Repair deficiency (dDDR) may preferentially respond to LP-184, independent of MGMT status. LP-184 is currently under investigation in a first-in-human Phase 1a dose-escalation safety study (NCT05933265) in adult patients with advanced solid tumors including GBM, with no dose-limiting toxicities to date at dose level 6. Following determination of the Maximum Tolerated Dose and/or Recommended Phase 2 Dose from Phase 1a, the selected expansion dose will be assessed in a Phase 1b study to evaluate the safety, pharmacokinetics, and objective response of LP-184 alone and in combination with spironolactone in IDH wild type glioblastoma at first progression. Spironolactone is a brain penetrant FDA approved agent that proteolytically degrades the TC-NER component ERCC3, thereby creating dDDR. Two rGBM cohorts will be enrolled according to a Simon’s 2-stage optimal design: (i) LP-184 alone (days 1 and 8 in a 21-day cycle, as intravenous infusion over 30 minutes) and (ii) combination of LP-184 and spironolactone (200 mg orally daily in conjunction and before the LP-184 infusion). In the first stage, 10 response evaluable subjects will be enrolled. If 1 or more of the first 10 response evaluable subjects achieve an objective response, 19 further subjects may be accrued in the second stage. In each cohort, at least 5 subjects will undergo planned tumor resection and will be treated with LP-184 or the combination the day prior to surgery to evaluate PK/PD.
CTNI-52. EXPEDITED CHEMORADIATION AFTER LASER INTERSTITIAL THERMAL THERAPY (LITT) IS FEASIBLE AND SAFE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Yu Jennifer , Meade Seth , Zhao Ran , Wei Wei , Dashora Himanshu , Prayson Richard , Grabowski Matthew , Stevens Glen , Murphy Erin , Suh John , Chao Samuel , Barnett Gene , Peereboom David , Ahluwalia Manmeet , Mohammadi Alireza
Published: November 2024

BACKGROUND

High-grade gliomas (HGG) are incurable primary brain tumors. Laser Interstitial Thermal Therapy (LITT) has emerged as an alternative to surgery for select patients. Hyperthermia can improve the efficacy of radiation and chemotherapy. Shortening the time between LITT and chemoradiation may maximize their biological and clinical benefits. This clinical trial evaluated the safety and feasibility of expediting chemoradiation after biopsy and LITT in patients with newly-diagnosed HGG.

METHODS

Patients with suspected HGG were enrolled. Those with pathologic confirmation of HGG and deemed appropriate candidates for LITT and chemoradiation were considered evaluable. Participants underwent 6 weeks of adjuvant chemoradiation within seven days of LITT. Endpoints were assessed until the completion of radiation, and included the occurrence of wound dehiscence; new, treatment-refractory seizures; cerebral edema; and completion of planned radiotherapy.

RESULTS

Fifteen patients with suspected HGG were enrolled and ten were considered evaluable. All ten patients were diagnosed with glioblastoma (GBM, IDHwt). Five patients were deemed unevaluable: four patients with other CNS tumors and one GBM patient who developed grade 4 postoperative edema. Of ten evaluable patients, the median age was 60.2 years (IQR: 51.0, 69.4), and median preoperative KPS was 90 (IQR: 90, 80). The median time between LITT and the initiation of chemoradiation was seven days. There were no occurrences of significant protocol-related adverse events.

CONCLUSIONS

Accelerated initiation of chemoradiation after biopsy and LITT is safe and feasible for patients with newly diagnosed HGG. A larger study is needed to assess potential synergy of hyperthermia and chemoradiation to improve survival.