scholarly journals Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

2015 ◽  
Vol 23 (3) ◽  
pp. R173-R183 ◽  
Author(s):  
Maria Chiara Zatelli ◽  
Giuseppe Fanciulli ◽  
Pasqualino Malandrino ◽  
Valeria Ramundo ◽  
Antongiulio Faggiano ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Neuroendocrine Tumours ◽  
Somatostatin Analogs ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Free Survival ◽  
Development Of Resistance ◽  
Imaging Markers ◽  
Intensive Investigation ◽  
Recent Demonstration

Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for therapeutic response are under intensive investigation, aiming at a tailored patient management and more appropriate resource utilization. This review summarizes the available data on the tissue, circulating and imaging markers that are potentially predictive of rapalog efficacy in NETs.

Evaluation of safety and efficacy of somatuline autogel in combination with molecular targeted therapies (MTT) in patients with neuroendocrine tumors (NETs): Data from one Spanish cohort.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14671-e14671
Author(s):  
Jaume Capdevila ◽  
Isabel Sevilla ◽  
Vicente Alonso ◽  
Luis Anton Aparicio ◽  
Paula Jimenez ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Synergistic Effects ◽  
Somatostatin Analogs ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Hormonal Control ◽  
Phase Iii ◽  
Free Survival ◽  
Phase Iii Studies ◽  
Spanish Cohort

e14671 Background: Analysis of the mechanisms of action of somatostatin analogs (SSAs) and mTOR inhibitors or tyrosine kinase inhibitors suggest that they may provide synergistic effects when used in combination for the treatment of pts with NETs. Methods: This is a Spanish multicenter cohort of pts with NETs treated with the SSAs lanreotide (LAN) and MTTs at 35 Spanish referral centers. Data of 159 combined treatments (133 pts) was retrospectively collected in order to evaluate the efficacy and safety of such combinations. Results: 133 pts (52,6% M) with a median age of 59,9 years; ECOG 0/1/2/3: 34%/49%/16%/1%; Lung/Pancreas/Gastrointestinal//Unknown(UK) origin: 9%/48% /32%/11%; G1/G2/G3/UK: 41%/32%/1%/26%; Non Functioning/ Functioning (69%/31%) received treatment with MTT + LAN for synergistic antiproliferative purpose in 85% of the cases, hormonal control (13,5%) or both objectives (1,5%). 115 pts received one combination treatment and 18 pts received between 2 (12 pts) and 5 (1 pt). LAN was administrated in combination with sunitinib (61), everolimus (73), bevazucimab (9), sorafenib (8) and pazopanib (8). The reported toxicity was determined by the MTT profile with no significant additional severe adverse events related to the combination with LAN. The probability of progression-free survival (PFS) at 6, 12 and 18months was 89%, 73% and 67% respectively for those pts who received LAN and sunitinib (n=50) and 78%, 69% and 57%, respectively for those pts who received LAN and everolimus (n=56). Median PFS was not reached at the time of analysis. Conclusions: The combination of LAN and MTT, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities. Median PFS will be higher than data observed in phase III studies with sunitinib and everolimus, raising the hypothesis of enhanced efficacy combining SSAs and MTT that should be confirmed in randomized prospective clinical trials. [Table: see text]

scholarly journals Kinase Inhibitors and Ovarian Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1357 ◽  
Author(s):  
Katopodis ◽  
Chudasama ◽  
Wander ◽  
Sales ◽  
Kumar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Phase Iii ◽  
Free Survival ◽  
Gynecological Malignancy ◽  
Phase Iii Trials ◽  
Chemotherapy Agents ◽  
Multiple Signaling

Ovarian cancer is fifth in the rankings of cancer deaths among women, and accounts for more deaths than any other gynecological malignancy. Despite some improvement in overall-(OS) and progression-free survival (PFS) following surgery and first-line chemotherapy, there is a need for development of novel and more effective therapeutic strategies. In this mini review, we provide a summary of the current landscape of the clinical use of tyrosine kinase inhibitors (TKIs) and mechanistic target of rapamycin (mTOR) inhibitors in ovarian cancer. Emerging data from phase I and II trials reveals that a combinatorial treatment that includes TKIs and chemotherapy agents seems promising in terms of PFS despite some adverse effects recorded; whereas the use of mTOR inhibitors seems less effective. There is a need for further research into the inhibition of multiple signaling pathways in ovarian cancer and progression to phase III trials for drugs that seem most promising.

Alkylating agent rechallenge in metastatic pancreatic neuroendocrine tumours

2021 ◽  
Author(s):  
Ophelie De Rycke ◽  
Thomas Walter ◽  
Marine Perrier ◽  
Olivia Hentic ◽  
Catherine Lombard-Bohas ◽  
...  
Keyword(s):  
Neuroendocrine Tumours ◽  
Objective Response ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Tumor Control ◽  
Free Survival ◽  
Mgmt Expression ◽  
Pancreatic Neuroendocrine Tumours

A rechallenge is common after initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET. Secondly, to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (Cohort A). Primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (Cohort B). We foud that cohort A included 62 patients (median Ki67 8%), for which ALK1 followed by pause achieved an objective response rate of 55%, and a PFS1 of 23.7 months (95% IC, 19.8-27.6). ALK2 achieved no objective response, and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1-11.3). At multivariable analysis, a hormonal syndrome (p=0.032) and a pause longer than 12 months (p=0.041) were associated with a longer PFS2. In the cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18-105) before ALK, to 100 (IQR 56-180) after ALK (p=0.003). We conclude that after initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain low efficacy of ALK rechallenge.

scholarly journals Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 434 ◽  
Author(s):  
Ming-Ju Tsai ◽  
Jen-Yu Hung ◽  
Mei-Hsuan Lee ◽  
Chia-Yu Kuo ◽  
Yu-Chen Tsai ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
First Line ◽  
Free Survival ◽  
Younger Patients ◽  
Epidermal Growth

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) “a single sensitizing uncommon mutation”, 7 (12%) “multiple sensitizing mutations”, 5 (9%) “a sensitizing mutation and a resistant uncommon mutation”, and 18 (32%) “other resistant uncommon mutations”. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings.

Pancreatic endocrine disorders and multiple endocrine neoplasia

2020 ◽  
pp. 2449-2463
Author(s):  
B. Khoo ◽  
T.M. Tan ◽  
S.R. Bloom
Keyword(s):  
Kinase Inhibitors ◽  
Neuroendocrine Tumours ◽  
Mammalian Target Of Rapamycin ◽  
Peptide Receptor Radionuclide Therapy ◽  
Mtor Inhibitors ◽  
Somatostatin Analogues ◽  
Endocrine Disorders ◽  
Pancreatic Neuroendocrine Tumours ◽  
Islet Cell Tumours ◽  
Cancer Syndromes

Pancreatic neuroendocrine tumours (islet-cell tumours) are rare and usually sporadic, but they may be associated with complex familial endocrine cancer syndromes. Recognized types of pancreatic neuroendocrine tumours are those that are non-functioning (often advanced at diagnosis and presenting with mass effects due to the absence of symptoms attributable to hormone hypersecretion), insulinoma (the most frequent type), and others including gastrinoma, VIPoma, and glucagonoma. The following should be considered in addition to the symptomatic treatments: surgical resection—the only curative treatment, but not possible in many cases; tyrosine kinase inhibitors which inhibit specific kinases involved in tumour cell proliferation, growth, and angiogenesis; mammalian Target of Rapamycin (mTOR) inhibitors; peptide-receptor radionuclide therapy (radiolabelled somatostatin analogues).

scholarly journals Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study

2019 ◽  
Vol 37 (28) ◽  
pp. 2571-2580 ◽  
Author(s):  
Alberto Carmona-Bayonas ◽  
Paula Jiménez-Fonseca ◽  
Ángela Lamarca ◽  
Jorge Barriuso ◽  
Ángel Castaño ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Failure Time ◽  
Somatostatin Analogs ◽  
Progression Free Survival ◽  
Accelerated Failure Time Model ◽  
Endocrine Tumors ◽  
First Line ◽  
Ki 67 ◽  
Free Survival ◽  
Well Differentiated

PURPOSE Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.

scholarly journals More than a Decade of Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors: What We Have Learned and What the Future Holds

2015 ◽  
Vol 10s3 ◽  
pp. BMI.S22436 ◽  
Author(s):  
Maria Vergoulidou
Keyword(s):  
Tyrosine Kinase ◽  
Small Molecules ◽  
Solid Tumors ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Free Survival ◽  
Free Treatment

The use of tyrosine kinase inhibitors (TKIs) in the treatment of solid tumors is the expected standard of care for many types of tumors. Since the description of signal transduction pathways, followed by the development of small molecules designed to inhibit those pathways, there has been significant improvement not only in progression-free survival and overall survival but also in aiming toward chemotherapy-free treatment of solid tumors to maximize quality of life. This article reviews available TKIs and discusses toxicity, dosing, and resistance.

Correlation of hypothyroidism with survival in metastatic renal cancer patients treated with sorafenib or sunitinib.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 379-379
Author(s):  
L. Riesenbeck ◽  
S. Bierer ◽  
I. Hoffmeister ◽  
T. Koepke ◽  
L. Hertle ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Prognostic Markers ◽  
Progression Free Survival ◽  
Response To Therapy ◽  
Metastatic Renal Cancer ◽  
Free Survival ◽  
Normal Limits ◽  
Serum T3 ◽  
Univariate Analyses ◽  
Serum Tsh

379 Background: To investigate prognostic markers in patients with metastatic renal cell carcinoma (mRCC) undergoing treatment with the tyrosine kinase inhibitors (TKIs) sorafenib (So) or sunitinib (Su). Methods: Eighty-three patients with mRCC, who were treated at our institution between 2006 and 2009, were evaluated prospectively. Clinical and laboratory parameters were investigated, as well as, treatment-related adverse events. Subclinical hypothyroidism was characterized by serum TSH above the upper limit of normal and both total triiodtyronine (T3) and thyroxine (T4) within normal limits. Clinical hypothyroidism was defined as low serum T3 and T4 together with elevated TSH. Results: Thirty-one (37.3%) patients received So, and 52 (62.7%) were treated with Su. In univariate analyses, a poor ECOG status was associated with an unfavorable progression-free survival (PFS) (p<0.0001); similarly high risk MSKCC criteria correlated with a worse PFS (p=0.003). Furthermore, response to therapy was a surrogate parameter (p<0.0001). Twenty-one of 66 (31.8%) patients developed hypothyroidism during treatment, which was associated with a positive prognosis (p=0.032). In multivariate analyses, only the ECOG status (ECOG 0/1 vs. ECOG 2, p=0.018) and hypothyroidism (p=0.01) were independent prognostic parameters. Conclusions: The development of hypothyroidism during treatment might be useful as a clinical predictor of PFS for mRCC patients undergoing treatment with targeted agents. No significant financial relationships to disclose.

Bronchial neuroendocrine tumors: A retrospective review of management and outcomes in 116 patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17543-e17543
Author(s):  
Marinos Pericleous ◽  
Heather Lumgair ◽  
Johnathan Reiner ◽  
Laura Marelli ◽  
Martyn Caplin ◽  
...  
Keyword(s):  
Neuroendocrine Tumours ◽  
Survival Rates ◽  
Treatment Algorithm ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
Large Cell ◽  
Diagnostic Features ◽  
Free Survival ◽  
Histopathological Classification

e17543 Background: Bronchial neuroendocrine tumours, represent 1–3% of all primary lung tumours and 25% of all neuroendocrine tumours (NETs). They are classified into: typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC) and small cell lung carcinomas (SCLC). The aim of our study was to assess diagnostic features, management and outcome, focusing on the differences between TC and AC. Methods: 116 patients were identified from our NET database. WHO histopathological classification was used. Follow-up was complete in all patients (mean follow-up 59.8 months). Disease-free survival (DFS), and progression-free survival (PFS) were evaluated for each therapy. Results: The average age of presentation was 55.30 years (range 16-85 years, M:F ratio=1:1.5). The commonest presenting symptom was cough (19%) followed by haemoptysis (18%). 36% were TC, 45% AC, and 19% LCNEC/SCLC. 16% TC and 28% AC patients had metastases at diagnosis. Octreoscan was positive in 76% TC and 66% AC. In 2 patients with TC and negative Octreoscan, Ga-68 Octreotate PET showed avid uptake in lung lesions. 46 patients had surgery. In 35 of AC, the disease relapsed (DFS=29.8 months) compared to 24% TC (DFS=48months). 12 patients received somatostatin analogues (SSTA) with PFS for TC 60 months and AC 21 months. 16 patients received systemic chemotherapy with PFS for TC 72 months and AC 21 months. 4/5 patients achieved disease stability with 90Yttrium-DOTAoctreotate. 5-years survival after surgery, chemotherapy or SSTA, was 91%, 86% and 81% respectively. Overall five year survival was 91% (100 % TC, 75% AC). Conclusions: AC and SCLC/LCLC more often present with metastatic disease with shorter DFS and PFS compared to TC. Molecular imaging is helpful for staging and predicting appropriateness for SSTA or radionuclide targeted therapy. Surgery confers the best survival rates. AC have higher relapse rates and metastatic potential. Further clinical trials are required to define the best treatment algorithm.

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