To treat or not to treat? A retrospective multicenter assessment of survival in patients with IDH-mutant low-grade glioma based on adjuvant treatment

2020 ◽  
Vol 133 (2) ◽  
pp. 273-280 ◽  
Author(s):  
Andrej Paľa ◽  
Jan Coburger ◽  
Moritz Scherer ◽  
Hajrullah Ahmeti ◽  
Constantin Roder ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Therapy ◽  
Adjuvant Treatment ◽  
Low Grade Glioma ◽  
Histopathological Diagnosis ◽  
Low Grade ◽  
Who Grade ◽  
High Risk Patients ◽  
Risk Patients ◽  
Grade Ii

OBJECTIVEThe level of evidence for adjuvant treatment of diffuse WHO grade II glioma (low-grade glioma, LGG) is low. In so-called “high-risk” patients most centers currently apply an early aggressive adjuvant treatment after surgery. The aim of this assessment was to compare progression-free survival (PFS) and overall survival (OS) in patients receiving radiation therapy (RT) alone, chemotherapy (CT) alone, or a combined/consecutive RT+CT, with patients receiving no primary adjuvant treatment after surgery.METHODSBased on a retrospective multicenter cohort of 288 patients (≥ 18 years old) with diffuse WHO grade II gliomas, a subgroup analysis of patients with a confirmed isocitrate dehydrogenase (IDH) mutation was performed. The influence of primary adjuvant treatment after surgery on PFS and OS was assessed using Kaplan-Meier estimates and multivariate Cox regression models, including age (≥ 40 years), complete tumor resection (CTR), recurrent surgery, and astrocytoma versus oligodendroglioma.RESULTSOne hundred forty-four patients matched the inclusion criteria. Forty patients (27.8%) received adjuvant treatment. The median follow-up duration was 6 years (95% confidence interval 4.8–6.3 years). The median overall PFS was 3.9 years and OS 16.1 years. PFS and OS were significantly longer without adjuvant treatment (p = 0.003). A significant difference in favor of no adjuvant therapy was observed even in high-risk patients (age ≥ 40 years or residual tumor, 3.9 vs 3.1 years, p = 0.025). In the multivariate model (controlled for age, CTR, oligodendroglial diagnosis, and recurrent surgery), patients who received no adjuvant therapy showed a significantly positive influence on PFS (p = 0.030) and OS (p = 0.009) compared to any other adjuvant treatment regimen. This effect was most pronounced if RT+CT was applied (p = 0.004, hazard ratio [HR] 2.7 for PFS, and p = 0.001, HR 20.2 for OS). CTR was independently associated with longer PFS (p = 0.019). Age ≥ 40 years, histopathological diagnosis, and recurrence did not achieve statistical significance.CONCLUSIONSIn this series of IDH-mutated LGGs, adjuvant treatment with RT, CT with temozolomide (TMZ), or the combination of both showed no significant advantage in terms of PFS and OS. Even in high-risk patients, the authors observed a similar significantly negative impact of adjuvant treatment on PFS and OS. These results underscore the importance of a CTR in LGG. Whether patients ≥ 40 years old should receive adjuvant treatment despite a CTR should be a matter of debate. A potential tumor dedifferentiation by administration of early TMZ, RT, or RT+CT in IDH-mutated LGG should be considered. However, these data are limited by the retrospective study design and the potentially heterogeneous indication for adjuvant treatment.

scholarly journals Radiotherapy versus radiotherapy combined with temozolomide in high-risk low-grade gliomas after surgery: study protocol for a randomized controlled clinical trial

Trials ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Jingjing Wang ◽  
Ying Wang ◽  
Yan He ◽  
Hui Guan ◽  
Ling He ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
World Health ◽  
Controlled Clinical Trial ◽  
Low Grade ◽  
Who Grade ◽  
Low Grade Gliomas ◽  
High Risk Patients ◽  
Randomized Controlled ◽  
Risk Patients

Abstract Background It has been reported that radiation therapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy could improve progression-free survival (PFS) and overall survival (OS) in patients with high-risk World Health Organization (WHO) grade 2 gliomas after surgery. However, procarbazine is not available in China. In clinical practice, Chinese doctors often use radiotherapy combined with temozolomide (TMZ) to treat these patients, although large-scale prospective studies are lacking. This trial aims to confirm whether RT combined with temozolomide can improve PFS and OS in high-risk patients with low-grade gliomas (LGGs). Methods/design This is a two-group, randomized controlled trial (RCT) enrolling patients who have LGGs (WHO grade 2) and are aged 40 years or older without regard to the extent of resection or are aged younger than 40 years old with subtotal resection or biopsy. An estimated 250 patients will be enrolled. Eligible participants will be randomly assigned to receive RT alone or RT plus TMZ chemotherapy in a 1:1 ratio. The same RT will be given to all eligible participants regardless of whether they are randomly assigned to the RT group or the chemoradiotherapy (CRT) group. While in the CRT group, patients will receive adjuvant TMZ with or without concurrent radiochemotherapy. The primary outcome of this trial is PFS, and it will be analyzed by the intention-to-treat approach. Secondary outcomes include OS, adverse events, and cognitive function. Discussion The objective of our research is to assess the effect of radiotherapy coupled with TMZ in high-risk patients with LGGs after surgery, compared with RT alone. Different histological types and molecular subtypes will be examined, and a corresponding subgroup analysis will be conducted. Our data can provide evidence for postoperative adjuvant therapy in patients with high-risk LGGs in China. Trial registration Chinese Clinical Trial Registry, ChiCTR1800015199. Registered on 13 March 2018.

scholarly journals Dynamic 18F-FET PET in Newly Diagnosed Astrocytic Low-Grade Glioma Identifies High-Risk Patients

2013 ◽  
Vol 55 (2) ◽  
pp. 198-203 ◽  
Author(s):  
N. L. Jansen ◽  
B. Suchorska ◽  
V. Wenter ◽  
S. Eigenbrod ◽  
C. Schmid-Tannwald ◽  
...  
Keyword(s):  
High Risk ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Fet Pet ◽  
High Risk Patients ◽  
Risk Patients

scholarly journals Prognostic Factors for Survival in Adult Patients With Cerebral Low-Grade Glioma

2002 ◽  
Vol 20 (8) ◽  
pp. 2076-2084 ◽  
Author(s):  
Francesco Pignatti ◽  
Martin van den Bent ◽  
Desmond Curran ◽  
Channa Debruyne ◽  
Richard Sylvester ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Scoring System ◽  
Low Grade Glioma ◽  
Low Risk ◽  
Adult Patients ◽  
Low Grade ◽  
High Risk Patients ◽  
Risk Patients ◽  
Validation Set

PURPOSE: To identify prognostic factors for survival in adult patients with cerebral low-grade glioma (LGG), to derive a prognostic scoring system, and to validate results using an independent data set. PATIENTS AND METHODS: European Organization for Research and Treatment of Cancer (EORTC) trial 22844 and EORTC trial 22845 are the largest phase III trials ever carried out in adult patients with LGG. The trials were designed to investigate the dosage and timing of postoperative radiotherapy in LGG. Cox analysis was performed on 322 patients from EORTC trial 22844 (construction set), and the results were validated on 288 patients from trial 22845 (validation set). Patients with pilocytic astrocytomas were excluded from this prognostic factor analysis. RESULTS: Multivariate analysis on the construction set showed that age ≥ 40 years, astrocytoma histology subtype, largest diameter of the tumor ≥ 6 cm, tumor crossing the midline, and presence of neurologic deficit before surgery were unfavorable prognostic factors for survival. The total number of unfavorable factors present can be used to determine the prognostic score. Presence of up to two of these factors identifies the low-risk group, whereas a higher score identifies high-risk patients. The validity of the multivariate model and of the scoring system was confirmed in the validation set. CONCLUSION: In adult patients with LGG, older age, astrocytoma histology, presence of neurologic deficits before surgery, largest tumor diameter, and tumor crossing the midline were important prognostic factors for survival. These factors can be used to identify low-risk and high-risk patients.

scholarly journals RTID-05. INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF VORASIDENIB (AG-881) VS PLACEBO IN PATIENTS WITH RESIDUAL/RECURRENT GRADE II GLIOMA WITH AN ISOCITRATE DEHYDROGENASE 1/2 (IDH1/2) MUTATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii194-ii194
Author(s):  
Ingo Mellinghoff ◽  
Martin van den Bent ◽  
Jennifer Clarke ◽  
Elizabeth Maher ◽  
Katherine Peters ◽  
...  
Keyword(s):  
High Risk ◽  
Dose Escalation ◽  
Objective Response ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
High Risk Population ◽  
Low Grade ◽  
Who Grade ◽  
Free Survival ◽  
Grade Ii

Abstract BACKGROUND Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study. METHODS Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).

scholarly journals The Kaiser score reliably excludes malignancy in benign contrast-enhancing lesions classified as BI-RADS 4 on breast MRI high-risk screening exams

2020 ◽  
Vol 30 (11) ◽  
pp. 6052-6061 ◽  
Author(s):  
Ruxandra Iulia Milos ◽  
Francesca Pipan ◽  
Anastasia Kalovidouri ◽  
Paola Clauser ◽  
Panagiotis Kapetas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Diagnostic Accuracy ◽  
Breast Mri ◽  
Histopathological Diagnosis ◽  
Risk Screening ◽  
High Risk Patients ◽  
Risk Patients ◽  
Malignant Lesions ◽  
High Risk Screening

Abstract Objectives MRI is an integral part of breast cancer screening in high-risk patients. We investigated whether the application of the Kaiser score, a clinical decision-support tool, may be used to exclude malignancy in contrast-enhancing lesions classified as BI-RADS 4 on breast MRI screening exams. Methods This retrospective study included 183 consecutive, histologically proven, suspicious (MR BI-RADS 4) lesions detected within our local high-risk screening program. All lesions were evaluated according to the Kaiser score for breast MRI by three readers blinded to the final histopathological diagnosis. The Kaiser score ranges from 1 (lowest, cancer very unlikely) to 11 (highest, cancer very likely) and reflects increasing probabilities of malignancy, with scores greater than 4 requiring biopsy. Receiver operating characteristic (ROC) curve analysis was used to evaluate diagnostic accuracy. Results There were 142 benign and 41 malignant lesions, diagnosed in 159 patients (mean age, 43.6 years). Median Kaiser scores ranged between 2 and 5 in benign and 7 and 8 in malignant lesions. For all lesions, the Kaiser score’s accuracy, represented by the area under the curve (AUC), ranged between 86.5 and 90.2. The sensitivity of the Kaiser score was high, between 95.1 and 97.6% for all lesions, and was best in mass lesions. Application of the Kaiser score threshold for malignancy (≤ 4) could have potentially avoided 64 (45.1%) to 103 (72.5%) unnecessary biopsies in 142 benign lesions previously classified as BI-RADS 4. Conclusions The use of Kaiser score in high-risk MRI screening reliably excludes malignancy in more than 45% of contrast-enhancing lesions classified as BI-RADS 4. Key Points • The Kaiser score shows high diagnostic accuracy in identifying malignancy in contrast-enhancing lesions in patients undergoing high-risk screening for breast cancer. • The application of the Kaiser score may avoid > 45% of unnecessary breast biopsies in high-risk patients. • The Kaiser score aids decision-making in high-risk breast cancer MRI screening programs.

scholarly journals NCOG-30. ADJUVANT VERSUS SALVAGE MANAGEMENT FOR IDH-MUTANT LOW GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii135-ii135
Author(s):  
Martin Tom ◽  
Deborah Park ◽  
Surabhi Tewari ◽  
Wei Wei ◽  
Samuel Chao ◽  
...  
Keyword(s):  
Adjuvant Treatment ◽  
Salvage Treatment ◽  
Low Grade Glioma ◽  
Postoperative Treatment ◽  
Management Approach ◽  
Low Grade ◽  
Free Survival ◽  
Grade Ii ◽  
Postoperative Observation

Abstract PURPOSE Timing of postoperative treatment in low-grade glioma (LGG) remains controversial. We sought to evaluate outcomes between adjuvant versus salvage management among patients with IDH-mutant molecularly-defined LGG. METHODS We analyzed a single-institutional database of adults diagnosed with LGG (grade II) with an IDH-mutation and either 1p19q-codeletion (oligodendroglioma) or 1p19q-intact (astrocytoma). Cox multivariable analysis (MVA) accounting for age, sex, and extent-of-resection, was used to compare adjuvant versus salvage approaches on overall survival (OS), progression free survival (PFS), next-intervention free survival (NIFS, defined as intervention subsequent to either adjuvant or salvage treatment), and malignant-transformation free survival (MTFS). Adjuvant treatment was defined as immediate postoperative treatment with radiotherapy (RT) and/or temozolomide (TMZ) prior to progression. Salvage management was defined as postoperative observation followed by surgery or RT and/or TMZ at progression. RESULTS Of 162 patients with oligodendroglioma, median follow-up was 8.5 years (range, 0.03-25.7). Adjuvant treatment was given to 97 (59.9%) patients, with 65 (40.1%) undergoing a salvage approach. On MVA, adjuvant treatment was not associated with OS, PFS, NIFS, or MTFS (p > 0.05 each). Among 82 patients with astrocytoma, median follow-up was 6.1 years (range, 0.5–25.7), and adjuvant treatment was administered to 41 (50.0%) patients, while 41 (50.0%) received salvage management. On MVA, adjuvant treatment was associated with improved PFS (HR 0.42, 95% CI 0.24-0.73, p < 0.001) and NIFS (HR 0.35, 95% CI 0.18–0.65, p < 0.001), but was not associated with OS or MTFS (p > 0.05 each). CONCLUSIONS Among grade II, IDH-mutant oligodendrogliomas, initial postoperative observation followed by salvage treatment at progression may be appropriate, as immediate adjuvant therapy was not associated improved outcomes. However, a more individualized postoperative management approach is required for grade II, IDH-mutant astrocytomas, as adjuvant treatment was associated with improved PFS and NIFS, but not OS. Further validation and prospective studies are required.

scholarly journals A SEER population analysis of stage IB resected gastric cancer: Who can benefit from adjuvant therapy?

2019 ◽  
Vol 5 (suppl) ◽  
pp. 122-122
Author(s):  
Yue Wang
Keyword(s):  
Gastric Cancer ◽  
High Risk ◽  
Adjuvant Therapy ◽  
Clinical Decision Making ◽  
Family Income ◽  
Population Analysis ◽  
Low Risk ◽  
High Risk Patients ◽  
Stage Ib ◽  
Risk Patients

122 Background: The benefit of adjuvant therapy (AT) remains controversial in stage IB gastric cancer (GC). This study aimed to offer a reference for the rational indications of AT. Methods: We retrospectively included 1935 stage IB GC patients who experienced curative surgery from the SEER database between 2004 and 2015. These patients were allocated into two groups: Group AT and Group surgery alone (Group SA). Risk factors associated with AT were examined using univariate/multivariate analyses. A nomogram to project overall survival (OS) of AT was established and internally validated. Results: Five variables, which were significantly related with OS of AT, were incorporated in the nomogram. These variables were sex, age, examined lymph nodes, tumor site, and family income. The C-index of the model was 0.636 and the calibration curve showed that the anticipated values were in accordance with the actual values. The decision curve demonstrated that the optimal clinical impact was achieved when the threshold possibility was 0-47%. Then the entire cohort was separated into low-risk (≤107 points) as well as high-risk ( > 107 points) groups based on the projected 5-year OS. Group SA revealed a significantly poorer OS than Group AT for high-risk patients (P < 0.001); on the other hand, there was a comparable OS for low-risk patients (P = 0.067). Conclusions: We have developed an effective, intuitional and applied prognostic tool based on nomogram to clinical decision-making. For stage IB GC after surgical resection, AT was only recommended for high-risk patients. However, AT may be dispensable for low-risk patients.

scholarly journals Sustained Donor Chimerism and Rapid Immune Cell Reconstitution Following Familial Haploidentical (FHI) CD34 Enriched Stem Cell Transplantation with Pbmnc Addback in Patients with High Risk Sickle Cell Disease (SCD) (IND 14359)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1990-1990
Author(s):  
Yaya Chu ◽  
Julie-An Talano ◽  
Lee Ann Baxter-Lowe ◽  
Carolyn A. Keever-Taylor ◽  
Erin Morris ◽  
...  
Keyword(s):  
High Risk ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Depletion ◽  
High Risk Patients ◽  
Donor Chimerism ◽  
Cd34 Cells ◽  
Risk Patients ◽  
Grade Ii ◽  
Nk Cytotoxicity

Background: Allogeneic stem cell transplantation (AlloSCT) from an HLA-matched sibling donor is the only known curative therapy in patients with high-risk SCD (Talano/Cairo, EJH, 2015). Unfortunately only about 15% of high risk patients with SCD have an HLA-matched unaffected sibling donor. T cell depletion has been employed to reduce AGVHD e.g., CD3/CD19 cell depletion (Barfiled RC, et al, Cytotherapy, 2004), αβ T-cell/CD19 cell depletion (Locatelli F, et al, Blood, 2017), CD34+ positive selection (Aversa F, et al, NEJM, 1998). MUD transplantation in high-risk SCD recipients has shown unexpectedly high rates of CGVHD (Shenoy et al, Blood, 2016). We reported a very low incidence of acute and chronic GVHD in pediatric recipients receiving CD34 enriched HPC products with PB MNC addback with 2 x 105 CD3/kg from MUD donors (Geyer/Cairo et al, BJH, 2012). Furthermore, rapid NK cell reconstitution after AlloSCT is associated with a significant improvement in 1yr OS (Pical-Izard, BBMT, 2015; Dunbar et al, Hematologica, 2008). Recently, we reported promising results for high-risk SCD patients at 1 year follow-up after FHI CD34 enriched/PBMNC with addback AlloSCT with the probability of 1-year overall survival (OS) n=17; 88.2% (CI95: 60.6-96.9) (Talano/Cairo, ASH, 2017), expanding the donor pool and hopefully improving outcomes for high-risk patients with SCD. Objective: To investigate donor chimerism, immune cell reconstitution and NK cell function in high-risk patients with SCD following AlloSCT using FHI CD34 enrichment/PBMNC (2 x 105 CD3/kg) addback. Methods: Twenty-one eligible SCD patients (2-<21 yrs) were enrolled. Nineteen patients received hydroxyurea, azathioprine, fludarabine, busulfan, thiotepa, cyclophosphamide, R-ATG, and TLI followed by FHI AlloSCT to date (Talano/Cairo, ASH, 2017). CD34 cells were enriched using the CliniMACS® system, kindly provided by Miltenyi Biotec, with a target dose of 10 x 106 CD34+ cells/kg with a PBMNC addback dose of 2x10*5 CD3/kg in the final product. Whole blood and RBC chimerism (estimated using CD71 to isolate an eythroid lineage-enriched fraction) were determined by STR. Immune cell and subset reconstitution was assessed by flow cytometry as previously described (Geyer/Cairo et al. BJH, 2012). NK function was determined by cytotoxic activity against K562 tumor targets at 10:1 E:T ratio by europium release assay and intracellular LAMP-1 (CD107a) and granzyme B expression by flow cytometry as previously described (Chu/Cairo et al, Can Imm Res, 2015). Results: There was 100% engraftment of neutrophils and platelets. The median day post-HISCT to neutrophil and platelet engraftment was +9 and +19, respectively. Whole blood donor chimerism (mean±SEM) at 1-year, 2-year, and 3-year post-HISCT was 97±1%, 97±1%, 97±1%, respectively (Fig.1). Donor chimerism for CD71+ RBCs (mean±SEM) at 1-year, 2-year, 3-year post-HISCT was 97±2%, 98±1%, 98±1%, respectively (Fig.1). Immune reconstitution of CD3, CD4, CD8, and CD19 was evaluated. The time to recovery of minimally normal levels post-HISCT of CD3 (800 cells/ul), CD4 (400 cells/ul), CD8 (200 cells/ul), and CD19 (200 cells/ul), was approximately 365, 365, 270, and 60 days post-HISCT (Fig.2), respectively. Probability of Grade II-IV AGVHD, CGVHD and 1 year EFS/OS was 6.2%, 6.7% and 90%, respectively. NK reconstitution was rapid and peaked at d+30 (36±9%, 2710cells/ml). NK cytotoxicity against K562 at a E:T=10:1 peaked at d+30 (26±3%) and d+180 (28±3%) vs at pre-t (16±2%) (p<0.01) (Fig. 3A). Consistent with increased NK cytotoxicity, CD56dimCD3- subset was increased at d+30 vs pre- HISCT (p<0.05). The NK activation marker, CD107a peaked at d+30 (38±9%) and d+180 (41±6%) (Fig.3B). More over, reconstituted NK cells expressed higher level of activating receptors NKp46 (24±9%), NKG2D (32±9%) and KIR2DS (8±3%) and inhibitory receptors NKG2A (33±9%), CD94 (28±9%) and KIR2DL2/3 (11±2%) at d+30 compared to other time points. Conclusion: Despite a 5 log depletion of T cells, the PBMNC addback (fixed at 2 x 105 CD3/kg) facilitated rapid donor chimerism and immune reconstitution with a low probability of Grade II-IV AGVHD. The rapid NK reconstitution may have in part contributed to the excellent 1yr OS in the FHI study. (Supported by FDA R01FD004090 (MSC)). Disclosures Cairo: Jazz Pharmaceuticals: Other: Advisory Board, Research Funding, Speakers Bureau; Osuka: Research Funding; Miltenyi: Other: MTA.

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