scholarly journals MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

2016 ◽  
Vol 23 (8) ◽  
pp. 625-633 ◽  
Author(s):  
J Cros ◽  
O Hentic ◽  
V Rebours ◽  
M Zappa ◽  
N Gille ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Stable Disease ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Tumor Response ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Pancreatic Neuroendocrine Tumors ◽  
Mgmt Expression

Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). LowO6-methylguanine-DNA methyltransferase (MGMT) expression andMGMTpromoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression andMGMTpromoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0–300) andMGMTpromoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27–84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15–0.81),P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. HighMGMTpromoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29–1.08),P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50–100) seems to be associated with prolonged stable disease.

Subgroup analysis by Ki-67 and baseline CgA of the randomized, placebo-controlled phase 3 study of surufatinib in advanced well-differentiated pancreatic neuroendocrine tumors (SANET-p).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4111-4111
Author(s):  
Xianjun Yu ◽  
Jianming Xu ◽  
Lin Shen ◽  
Chunmei Bai ◽  
Jie Li ◽  
...  
Keyword(s):  
Partial Response ◽  
Neuroendocrine Tumors ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Pancreatic Neuroendocrine Tumors ◽  
Phase 3 ◽  
Ki 67 ◽  
Meaningful Improvement ◽  
Well Differentiated

4111 Background: In the phase 3 SANET-p trial (NCT02589821), surufatinib significantly increased progression-free survival (PFS) compared with placebo in patients with progressive, well-differentiated (grade 1 or 2), advanced pancreatic neuroendocrine tumors (NETs). Here we report the relationship of Ki-67 and baseline Chromogranin A (CgA) on efficacy outcomes. Methods: A total of 172 patients with advanced pancreatic NETs were randomized to surufatinib or placebo in a 2:1 ratio. Investigator-assessed PFS and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 were used for the analysis. The post-hoc subgroup analyses were performed on Ki-67 subcategory: < 5% (n = 40 vs 21), 5-10% (n = 57 vs 31), > 10% (n = 16 vs 7), and baseline CgA subcategory: ≤ 2 times of upper limit of normal (ULN) (n = 59 vs 31), > 2 × ULN (n = 44 vs 24). Results: In the intent-to-treat population, surufatinib was superior to placebo, median PFS (mPFS) of 10.9 vs 3.7 months (mo) ( p = 0.0011), with a stratified hazard ratio (HR) of 0.491 (95% confidence interval [CI]: 0.319, 0.755). mPFS was statistically significantly longer in the surufatinib arm versus that in the placebo arm in subgroups of Ki-67 5-10% (11.0 vs 3.7 mo, HR = 0.33, p= 0.0002), Ki-67 > 10% (11.1 vs 2.8 mo, HR = 0.04, p = 0.0003) and CgA > 2 × ULN (11.0 vs 3.7 mo, HR = 0.36, p = 0.0036). There was numerical PFS improvement with surufatinib compared to placebo in subgroup of Ki-67 < 5% (9.3 vs 5.6 mo, HR = 0.91, p = 0.8015) and CgA ≤ 2 × ULN (9.4 vs 3.7 mo, HR = 0.61, p = 0.0809). ORRs in the subgroups of Ki-67 < 5%, 5-10%, and > 10% with surufatinib were 15.8%, 24.0% and 12.5% respectively. There was only one partial response in the placebo arm (with Ki-67 < 5%). ORRs in the subgroups of CgA ≤ 2 × ULN and > 2 × ULN with surufatinib were 18.9% and 21.4%, while also only one partial response in the placebo arm with CgA ≤ 2 × ULN. Conclusions: Surufatinib showed statistically significant and clinically meaningful improvement in PFS compared to placebo in patients with advanced, progressive, well-differentiated pancreatic NETs. From this exploratory analysis, surufatinib demonstrated benefit irrespective of Ki-67 expression levels or baseline CgA. Clinical trial information: NCT02589821.

scholarly journals Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors

2016 ◽  
Vol 23 (9) ◽  
pp. 759-767 ◽  
Author(s):  
M Cives ◽  
M Ghayouri ◽  
B Morse ◽  
M Brelsford ◽  
M Black ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Proliferative Activity ◽  
Dna Methyltransferase ◽  
Predictive Biomarkers ◽  
Pancreatic Neuroendocrine Tumors ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase ◽  
Response Predictors ◽  
Alternative Lengthening ◽  
Pathway Activation

The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O6-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.

scholarly journals Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after 177Lu-octreotate

2013 ◽  
Vol 20 (6) ◽  
pp. 825-831 ◽  
Author(s):  
Kimberly Kamp ◽  
Brenda Gumz ◽  
Richard A Feelders ◽  
Dik J Kwekkeboom ◽  
Gregory Kaltsas ◽  
...  
Keyword(s):  
Adverse Events ◽  
Neuroendocrine Tumors ◽  
Safety Profile ◽  
Tumor Response ◽  
Evaluation Criteria ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Safety And Efficacy ◽  
Develop Disease Progression

Although 177Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with 177Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5–21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.

scholarly journals Phase II Study of Carboplatin and Paclitaxel in Advanced Thymoma and Thymic Carcinoma

2011 ◽  
Vol 29 (15) ◽  
pp. 2060-2065 ◽  
Author(s):  
Girum L. Lemma ◽  
Ju-Whei Lee ◽  
Seena C. Aisner ◽  
Corey J. Langer ◽  
William J. Tester ◽  
...  
Keyword(s):  
Stable Disease ◽  
Objective Response Rate ◽  
Thymic Carcinoma ◽  
Response Rate ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Area Under The Curve ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
The Impact

Purpose The purpose of this study was to evaluate the impact of carboplatin and paclitaxel in patients with advanced previously untreated thymoma and thymic carcinoma. Patients and Methods We conducted a prospective multicenter study in patients with unresectable thymoma (n = 21) or thymic carcinoma (n = 23). Patients were treated with carboplatin (area under the curve, 6) plus paclitaxel (225 mg/m2) every 3 weeks for a maximum of six cycles. The primary end point of this trial was to evaluate the objective response rate. Results From February 2001 through January 2008, 46 patients were enrolled. Thirteen patients had grade 4 or greater toxicity, mostly neutropenia. Using RECIST (Response Evaluation Criteria in Solid Tumors) 1.0 criteria, three complete responses (CRs) and six partial responses (PRs; objective response rate [ORR], 42.9%; 90% CI, 24.5% to 62.8%) were observed in the thymoma cohort; 10 patients had stable disease. For patients with thymic carcinoma, no CRs and five PRs (ORR, 21.7%; 90% CI, 9.0% to 40.4%) were observed; 12 patients had stable disease. Progression-free survival (PFS) was 16.7 (95% CI, 7.2 to 19.8) and 5.0 (95% CI, 3.0 to 8.3) months for thymoma and thymic carcinoma cohorts, respectively. To date, only seven patients (33.3%) with thymoma have died, compared with 16 patients (69.6%) with thymic carcinoma. Median survival time was 20.0 months (95% CI, 5.0 to 43.6 months) for patients with thymic carcinoma, but it has not been reached for patients with thymoma. Conclusion Carboplatin plus paclitaxel has moderate clinical activity for patients with thymic malignancies, but this seems less than expected with anthracycline-based therapy. Patients with thymic carcinoma have poorer PFS and overall survival than patients with thymoma.

scholarly journals Real Life Prospective Evaluation of New Drug-Eluting Platform for Chemoembolization of Patients with Hepatocellular Carcinoma: PARIS Registry

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3405
Author(s):  
Thierry de Baere ◽  
Boris Guiu ◽  
Maxime Ronot ◽  
Patrick Chevallier ◽  
Géraldine Sergent ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Response ◽  
Objective Response ◽  
Survival Rates ◽  
Evaluation Criteria ◽  
Real Life ◽  
Progression Free Survival ◽  
Mri Scans ◽  
Drug Eluting ◽  
Grade 3

Background and aim: Transarterial chemoembolization with drug-eluting microspheres (DEM-TACE) is recommended for patients with BCLC stage B hepatocellular carcinoma (HCC) and stage 0-A unsuitable for curative treatments. We assessed efficacy and safety along with hepatobiliary toxicities (HBT) of DEM-TACE using a novel microsphere, LifePearlTM, loaded with anthracyclines. Materials and methods: 97 patients diagnosed with HCC were prospectively enrolled and treated using LifePearlTM loaded with doxorubicin (77%) or idarubicin (23%). Safety and tolerability were assessed using CTCAE, HBT by CT/MRI scans, and tumor response by applying modified Response Evaluation Criteria in Solid Tumors (mRECIST). Follow-up was after 2 years. Results: Adverse events (AE) were reported in 73.2% of patients, majority being Grade 1–2. Grade ≥ 3 AE reported in 13.4% of patients were mainly related to postembolization syndrome. HBT were observed after 15.5% (29/187) of the DEM-TACEs. Objective response and disease control rates were 81% and 99%, respectively, as the best responses. Survival rates at one and two years were 81% and 66%, respectively, while the median overall survival (OS) was not reached. Median progression free survival was 13.7 months (95% CI: 11.3; 15.6) and median time to TACE untreatable progression was 16.7 months (95% CI: 12.7; not estimable (n.e.)). Conclusions: DEM-TACE using LifePearlTM provides a high tumor response rate in HCC patients. HBT rates within or below previously reported results for cTACE and DEM-TACE indicate a good safety profile for LifePearlTM. The trial was registered in National Library of Medicine (ID: NCT03053596).

Efficacy and safety of aranoza-based therapy in neuroendocrine neoplasms. Prognostic role of O6-methylguanine DNA methyltransferase expression in tumor tissue

2016 ◽  
Vol 21 (6) ◽  
pp. 293-299
Author(s):  
Svetlana A. Polozkova ◽  
V. A Gorbunova ◽  
V. V Delektorskaya ◽  
N. F Orel ◽  
N. A Kozlov ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Tumor Tissue ◽  
Objective Response ◽  
Chemotherapy Resistance ◽  
Progression Free Survival ◽  
Neuroendocrine Neoplasms ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase ◽  
Tumor Focus ◽  
The Impact

Aranoza (3-a-L-arabinopyranosyl-1-methyl-nitrosourea) is nitrosourea derivative, as streptozotocin STZ. O6-methylguanine DNA methyltransferase (MGMT) is an enzyme involved in chemotherapy resistance to alkalyting agents. Material and methods. There were observed 117patients with neuroendocrine neoplasms (NENs) received Aranoza-based therapy. They included 52 cases with pancreatic neuroendocrine tumors (P-NETs), 52 patients with non-pancreatic (notP-NETs, 13 NET patients with metastases without revealed primary tumor focus). There was investigated the radiologic response to the treatment according to Response Evaluation Criteria In Solid Tumors (RECIST) Score, version 1.0), biochemical response, median progression-free survival (PFS) by Kaplan-Meier estimator), toxicity (according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0) and the impact of MGMT expression (immunohistochemistry method) in tumor tissue on the efficacy of the treatment. Results. Objective response rate (ORR) in PNET cases accounted for 39% (20/52) whereas in nonP-NETpatients - 12% (6/52) (p = 0.0032). Median PFS accounted for 15.3 months in PNET patients and 16.6 months in non-PNET cases (p = 0.78). The most common types of the toxicity grade III-IV included thrombocytopenia (17from 871 courses) and neutropenia (11 from 871 courses). In samples of the tumor tissue the lack of MGMT expression was observed in 29 out of 35 P-NET cases, 12 out of 31 non-PNET cases (p = 0,0006). Objective response was recorded in 20 of 44 patients with MGMT-deficient tumors and in 1 out of 27patients with MGMT intact tumors (p = 0.0001). In the lack and presence of the MGMT expression in the tumor tissue median PFS accounted for 20.6 months and 14.4 months correspondingly (p = 0,022). Conclusion. Aranoza-based therapy demonstrated an antitumor activity and good safety profile in NENpatientss. MGMT deficiency in PNETs was more common than in non-PNETs and explained the susceptibility of some PNETs to treatment.

scholarly journals Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial

2017 ◽  
Vol 35 (29) ◽  
pp. 3315-3321 ◽  
Author(s):  
Maria E. Cabanillas ◽  
Jonas A. de Souza ◽  
Susan Geyer ◽  
Lori J. Wirth ◽  
Michael E. Menefee ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Multikinase Inhibitor

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

scholarly journals FAS and Subsequent Therapies in Pancreatic Neuroendocrine Tumors

2021 ◽  
Author(s):  
Jane E. Rogers ◽  
Michael Lam ◽  
Daniel M. Halperin ◽  
Cecile G. Dagohoy ◽  
James C. Yao ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Pancreatic Neuroendocrine Tumors ◽  
Free Survival ◽  
Prior Therapy ◽  
Well Differentiated ◽  
Grade 3 ◽  
Line Of Therapy

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.

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