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Cheng S, Jin Z, Xue H. Assessment of Response to Chemotherapy in Pancreatic Cancer with Liver Metastasis: CT Texture as a Predictive Biomarker. Diagnostics (Basel) 2021; 11:diagnostics11122252. [PMID: 34943489 PMCID: PMC8700536 DOI: 10.3390/diagnostics11122252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/21/2021] [Accepted: 11/26/2021] [Indexed: 11/16/2022] Open
Abstract
In this paper, we assess changes in CT texture of metastatic liver lesions after treatment with chemotherapy in patients with pancreatic cancer and determine if texture parameters correlate with measured time to progression (TTP). This retrospective study included 110 patients with pancreatic cancer with liver metastasis, and mean, entropy, kurtosis, skewness, mean of positive pixels, and standard deviation (SD) values were extracted during texture analysis. Response assessment was also obtained by using RECIST 1.1, Choi and modified Choi criteria, respectively. The correlation of texture parameters and existing assessment criteria with TTP were evaluated using Kaplan-Meier and Cox regression analyses in the training cohort. Kaplan-Meier curves of the proportion of patients without disease progression were significantly different for several texture parameters, and were better than those for RECIST 1.1-, Choi-, and modified Choi-defined response (p < 0.05 vs. p = 0.398, p = 0.142, and p = 0.536, respectively). Cox regression analysis showed that percentage change in SD was an independent predictor of TTP (p = 0.016) and confirmed in the validation cohort (p = 0.019). In conclusion, CT texture parameters have the potential to become predictive imaging biomarkers for response evaluation in pancreatic cancer with liver metastasis.
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Fusco R, Granata V, Mazzei MA, Meglio ND, Roscio DD, Moroni C, Monti R, Cappabianca C, Picone C, Neri E, Coppola F, Montanino A, Grassi R, Petrillo A, Miele V. Quantitative imaging decision support (QIDS TM) tool consistency evaluation and radiomic analysis by means of 594 metrics in lung carcinoma on chest CT scan. Cancer Control 2021; 28:1073274820985786. [PMID: 33567876 PMCID: PMC8482708 DOI: 10.1177/1073274820985786] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Objective: To evaluate the consistency of the quantitative imaging decision support (QIDSTM) tool and radiomic analysis using 594 metrics in lung carcinoma on chest CT scan. Materials and Methods: We included, retrospectively, 150 patients with histologically confirmed lung cancer who underwent chemotherapy and baseline and follow-ups CT scans. Using the QIDSTM platform, 3 radiologists segmented each lesion and automatically collected the longest diameter and the density mean value. Inter-observer variability, Bland Altman analysis and Spearman’s correlation coefficient were performed. QIDSTM tool consistency was assessed in terms of agreement rate in the treatment response classification. Kruskal Wallis test and the least absolute shrinkage and selection operator (LASSO) method with 10-fold cross validation were used to identify radiomic metrics correlated with lesion size change. Results: Good and significant correlation was obtained between the measurements of largest diameter and of density among the QIDSTM tool and the radiologists measurements. Inter-observer variability values were over 0.85. HealthMyne QIDSTM tool quantitative volumetric delineation was consistent and matched with each radiologist measurement considering the RECIST classification (80-84%) while a lower concordance among QIDSTM and the radiologists CHOI classification was observed (58-63%). Among 594 extracted metrics, significant and robust predictors of RECIST response were energy, histogram entropy and uniformity, Kurtosis, coronal long axis, longest planar diameter, surface, Neighborhood Grey-Level Different Matrix (NGLDM) dependence nonuniformity and low dependence emphasis as Volume, entropy of Log(2.5 mm), wavelet energy, deviation and root man squared. Conclusion: In conclusion, we demonstrated that HealthMyne quantitative volumetric delineation was consistent and that several radiomic metrics extracted by QIDSTM were significant and robust predictors of RECIST response.
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Affiliation(s)
- Roberta Fusco
- Radiology Division, "Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli", Naples, Italy
| | - Vincenza Granata
- Radiology Division, "Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli", Naples, Italy
| | - Maria Antonietta Mazzei
- Department of Radiological Sciences, Diagnostic Imaging Unit, "Azienda Ospedaliera Universitaria Senese," Siena, Italy
| | - Nunzia Di Meglio
- Department of Radiological Sciences, Diagnostic Imaging Unit, "Azienda Ospedaliera Universitaria Senese," Siena, Italy
| | - Davide Del Roscio
- Department of Radiological Sciences, Diagnostic Imaging Unit, "Azienda Ospedaliera Universitaria Senese," Siena, Italy
| | - Chiara Moroni
- Division of Radiodiagnostic, 18561"Azienda Ospedaliero-Universitaria Careggi," Firenze, Italy
| | - Riccardo Monti
- Division of Radiodiagnostic, "Università degli Studi della Campania Luigi Vanvitelli," Naples, Italy
| | - Carlotta Cappabianca
- Division of Radiodiagnostic, "Università degli Studi della Campania Luigi Vanvitelli," Naples, Italy
| | - Carmine Picone
- Radiology Division, "Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli", Naples, Italy
| | - Emanuele Neri
- Division of Radiodiagnostic, 9257"Azienda Ospedaliera Universitaria Pisana," Pisa, Italy
| | - Francesca Coppola
- Radiology Unit, Department of Specialized, Diagnostic and Experimental Medicine (DIMES), "S. Orsola Hospital, University of Bologna," Bologna, Italy
| | - Agnese Montanino
- Thoracic Medical Oncology, "Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli," Naples, Italy
| | - Roberta Grassi
- Division of Radiodiagnostic, "Università degli Studi della Campania Luigi Vanvitelli," Naples, Italy
| | - Antonella Petrillo
- Radiology Division, "Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli", Naples, Italy
| | - Vittorio Miele
- Division of Radiodiagnostic, 18561"Azienda Ospedaliero-Universitaria Careggi," Firenze, Italy
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Rallabandi HR, Ganesan P, Kim YJ. Targeting the C-Terminal Domain Small Phosphatase 1. Life (Basel) 2020; 10:life10050057. [PMID: 32397221 PMCID: PMC7281111 DOI: 10.3390/life10050057] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 05/05/2020] [Accepted: 05/07/2020] [Indexed: 12/15/2022] Open
Abstract
The human C-terminal domain small phosphatase 1 (CTDSP1/SCP1) is a protein phosphatase with a conserved catalytic site of DXDXT/V. CTDSP1’s major activity has been identified as dephosphorylation of the 5th Ser residue of the tandem heptad repeat of the RNA polymerase II C-terminal domain (RNAP II CTD). It is also implicated in various pivotal biological activities, such as acting as a driving factor in repressor element 1 (RE-1)-silencing transcription factor (REST) complex, which silences the neuronal genes in non-neuronal cells, G1/S phase transition, and osteoblast differentiation. Recent findings have denoted that negative regulation of CTDSP1 results in suppression of cancer invasion in neuroglioma cells. Several researchers have focused on the development of regulating materials of CTDSP1, due to the significant roles it has in various biological activities. In this review, we focused on this emerging target and explored the biological significance, challenges, and opportunities in targeting CTDSP1 from a drug designing perspective.
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Well differentiated neuroendocrine tumors, a single center experience. JOURNAL OF ONCOLOGICAL SCIENCES 2018. [DOI: 10.1016/j.jons.2018.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Advances and Current Concepts in the Medical Management of Gastroenteropancreatic Neuroendocrine Neoplasms. BIOMED RESEARCH INTERNATIONAL 2017; 2017:9856140. [PMID: 29349087 PMCID: PMC5733630 DOI: 10.1155/2017/9856140] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 10/02/2017] [Indexed: 02/07/2023]
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare and heterogeneous group of tumors presenting as localised or metastatic disease and in a subset with distinct clinical syndromes. Treatment is aimed at controlling the functional syndrome, eradicating the tumor, and/or preventing further tumor growth. Surgery is the treatment of choice in removing the primary tumor and/or reducing tumor burden but cannot be applied to all patients. Somatostatin analogs (SS-analogs) obtain control of functional syndromes in the majority of GEP-neuroendocrine tumors (NETs); phase III trials have shown that SS-analogs can be used as first-line antiproliferative treatment in patients with slow-growing GEP-NETs. The role of the recently approved serotonin inhibitor, telotristat ethyl, and gastrin receptor antagonist, netazepide, is evolving. Streptozotocin-based chemotherapy has been used for inoperable or progressing pancreatic NENs but the orally administered combination of capecitabine/temozolomide is becoming more popular due to its better tolerability and potential effect in other GEP-NENs. Phase III trials have shown efficacy of molecular targeted therapies in GEP-NETs and of radionuclide treatment in patients with midgut carcinoid tumors expressing somatostatin receptors. Most patients will develop disease progression necessitating further therapeutic options. A combination of currently available treatments along with the molecular signature of each tumor will guide future treatment.
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Luo Y, Chen J, Huang K, Lin Y, Chen M, Xu L, Li ZP, Feng ST. Early evaluation of sunitinib for the treatment of advanced gastroenteropancreatic neuroendocrine neoplasms via CT imaging: RECIST 1.1 or Choi Criteria? BMC Cancer 2017; 17:154. [PMID: 28231773 PMCID: PMC5324282 DOI: 10.1186/s12885-017-3150-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 02/21/2017] [Indexed: 12/14/2022] Open
Abstract
Background The aim of this study was to assess and compare the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and the Choi criteria in evaluating the early response of advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) treated with sunitinib. Methods Eighteen patients with pathologically proven advanced GEP-NENs treated with sunitinib were enrolled in the study. Pre- and post-treatment CT scans (plain, biphasic enhanced CT scan) were performed on all patients. Changes in the target tumor size and density from pre-treatment to 1.4–3.1 months after treatment were measured and recorded for each patient. Tumor responses were identified using RECIST 1.1 and Choi criteria. The time to tumor progression (TTP) for each patient was measured and compared between groups using the Kaplan-Meier method. Results Among the 18 patients, 4 (22%) exhibited a partial response (PR), 9 (50%) exhibited stable disease (SD), and 5 (28%) experienced progressive disease (PD), using RECIST 1.1. However, based on the Choi criteria, 8 (44%) patients exhibited a PR, 4 (22%) exhibited SD, and 6 (33%) experienced PD. According to RECIST 1.1, the median TTP of PR, SD and PD group were 16.6, 10.8 and 2.3 months, respectively. The TTP of the PR group was significantly longer than that of the PD group (P = 0.007) but insignificant when compared to the SD group (P = 0.131). According to Choi criteria, the median TTP of PR, SD and PD group were not reached, 10.8 and 2.3 months, respectively. The TTP of the PR group was significantly longer than that of the SD (P = 0.026) and PD groups (P < 0.001). Conclusion The Choi criteria appear to be more sensitive and more precise than RECIST 1.1 in assessing the early response of advanced GEP-NENs treated with sunitinib.
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Affiliation(s)
- Yanji Luo
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58th, The Second Zhongshan Road, Guangzhou, Guangdong, 510080, China
| | - Jie Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58th, The Second Zhongshan Road, Guangzhou, Guangdong, 510080, China
| | - Kun Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58th, The Second Zhongshan Road, Guangzhou, Guangdong, 510080, China
| | - Yuan Lin
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, 58th, The Second Zhongshan Road, Guangzhou, Guangdong, 510080, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58th, The Second Zhongshan Road, Guangzhou, Guangdong, 510080, China
| | - Ling Xu
- Faculty of Medicine and Dentistry, University of Western Australia, Perth, Australia
| | - Zi-Ping Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58th, The Second Zhongshan Road, Guangzhou, Guangdong, 510080, China.
| | - Shi-Ting Feng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58th, The Second Zhongshan Road, Guangzhou, Guangdong, 510080, China.
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Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, Borbath I, Lombard-Bohas C, Metrakos P, Smith D, Chen JS, Ruszniewski P, Seitz JF, Patyna S, Lu DR, Ishak KJ, Raymond E. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol 2017; 28:339-343. [PMID: 27836885 DOI: 10.1093/annonc/mdw561] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib. PATIENTS AND METHODS In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses. RESULTS Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib. CONCLUSIONS BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib. TRIAL REGISTRATION NUMBER NCT00428597.
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Affiliation(s)
- S Faivre
- Medical Oncology and Gastroenterology Department, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon and Paris Diderot University, Clichy
| | - P Niccoli
- Cancer Care, Institut Paoli-Calmettes, and RENATEN Network, Marseille, France
| | - D Castellano
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - J W Valle
- Medical Oncology Department, The University of Manchester/The Christie NHS Foundation Trust, Manchester, UK
| | - P Hammel
- Medical Oncology and Gastroenterology Department, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon and Paris Diderot University, Clichy
| | - J-L Raoul
- Translational Medicine - Digestive Cancers, Institut Paoli-Calmettes and RENATEN Network, Marseille, France
| | - A Vinik
- Eastern Virginia Medical School Streilitz Diabetes Research Center and Neuroendocrine Unit, Norfolk, USA
| | - E Van Cutsem
- Digestive Oncology Unit, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | - Y-J Bang
- Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - S-H Lee
- Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - I Borbath
- Hepato-Gastroenterology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - C Lombard-Bohas
- Medical Oncology Department, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - P Metrakos
- McGill University Hospital Centre, Montreal, Canada
| | - D Smith
- Oncology Department, University Hospital, Bordeaux, France
| | - J-S Chen
- Linkou Chang Gung Memorial Hospital and Chang Gung University, Tao-Yuan, Taiwan
| | - P Ruszniewski
- Medical Oncology and Gastroenterology Department, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon and Paris Diderot University, Clichy
| | - J-F Seitz
- Centre Hospitalier Universitaire Timone, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille Université, and RENATEN Network, Marseille, France
| | | | - D R Lu
- Pfizer Oncology, La Jolla, USA
| | - K J Ishak
- Department of Evidera, St-Laurent, Canada
| | - E Raymond
- Medical Oncology and Gastroenterology Department, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon and Paris Diderot University, Clichy
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Berardi R, Morgese F, Torniai M, Savini A, Partelli S, Rinaldi S, Caramanti M, Ferrini C, Falconi M, Cascinu S. Medical treatment for gastro-entero-pancreatic neuroendocrine tumours. World J Gastrointest Oncol 2016; 8:389-401. [PMID: 27096034 PMCID: PMC4824717 DOI: 10.4251/wjgo.v8.i4.389] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Revised: 01/18/2016] [Accepted: 02/14/2016] [Indexed: 02/05/2023] Open
Abstract
Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) represents a various family of rare tumours. Surgery is the first choice in GEP-NENs patients with localized disease whilst in the metastatic setting many other treatment options are available. Somatostatin analogues are indicated for symptoms control in functioning tumours. Furthermore they may be effective to inhibit tumour progression. GEP-NENs pathogenesis has been extensively studied in the last years therefore several driver mutations pathway genes have been identified as crucial factors in their tumourigenesis. GEP-NENs can over-express vascular endothelial growth factor (VEGF), basic-fibroblastic growth factor, transforming growth factor (TGF-α and -β), platelet derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1) and their receptors PDGF receptor, IGF-1 receptor, epidermal growth factor receptor, VEGF receptor, and c-kit (stem cell factor receptor) that can be considered as potential targets. The availability of new targeted agents, such as everolimus and sunitinib that are effective in advanced and metastatic pancreatic neuroendocrine tumours, has provided new treatment opportunities. Many trials combing new drugs are ongoing.
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Basu B, Basu S. Correlating and Combining Genomic and Proteomic Assessment with In Vivo Molecular Functional Imaging: Will This Be the Future Roadmap for Personalized Cancer Management? Cancer Biother Radiopharm 2016; 31:75-84. [PMID: 27093341 DOI: 10.1089/cbr.2015.1922] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Bhakti Basu
- Molecular Biology Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Sandip Basu
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Mumbai, India
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Wolin EM. Treatment options for advanced pancreatic neuroendocrine tumors: what is on the horizon? INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2015. [DOI: 10.2217/ije.14.30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract: Treatment options for patients with advanced or metastatic pancreatic tumors (pNET) have expanded greatly in recent years. These treatments include resection, ablation or embolization of liver metastases and systemic therapy with everolimus or sunitinib and cytotoxic agents. New investigational approaches include the use of inhibitors of multiple downstream effectors in the PI3K/Akt/mTOR pathway, novel antiangiogenics, somatostatin analogues, new tyrosine kinase inhibitors and peptide receptor radionuclide therapy. The treatment horizon for pNET patients may offer improved duration of tumor control and survival and more effective symptom control.
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Raymond E, García-Carbonero R, Wiedenmann B, Grande E, Pavel M. Systemic therapeutic strategies for GEP-NETS: what can we expect in the future? Cancer Metastasis Rev 2013; 33:367-72. [DOI: 10.1007/s10555-013-9467-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Vinik AI, Raymond E. Pancreatic neuroendocrine tumors: approach to treatment with focus on sunitinib. Therap Adv Gastroenterol 2013; 6:396-411. [PMID: 24003340 PMCID: PMC3756637 DOI: 10.1177/1756283x13493878] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are relatively rare malignancies. With secretory tumors such as insulinomas, vasoactive intestinal peptideomas, and gastrinomas, the hormone produced causes the symptom complex (e.g. hypoglycemia, peptic ulcer disease). With nonsecretory NETs, the clinical condition is determined by tumoral growth and metastasis. The course of metastatic pNETs may be indolent for several years but progression is often more rapid at later stages, leading to significant disability and a markedly negative impact on quality of life. Until recently, there were few effective systemic treatments for pNETs. Standard chemotherapy produces limited responses and has considerable toxicity. Somatostatin analogues control symptoms in some types of pNETs, but have not yet demonstrated antitumor activity. The recent introduction of targeted therapies, including the tyrosine kinase inhibitor sunitinib and the mammalian target of rapamycin inhibitor everolimus, yielded new opportunities for patients with advanced/metastatic pNETs. These drugs, which target key pathways in tumor proliferation and angiogenesis, provided clear clinical benefits in phase III clinical trials, including delayed tumor progression. The pivotal sunitinib phase III trial was discontinued prematurely due to higher rates of death and serious adverse events with placebo and greater progression-free survival (PFS) with sunitinib. In this trial, sunitinib demonstrated encouraging long-term responses as well as PFS and overall survival benefits, and an acceptable safety profile that allowed patients to preserve their quality of life. In every patient subgroup, including secretory and nonsecretory tumors, the hazard ratio for progression or death favored sunitinib. Circulating biomarkers are being investigated for the prediction and monitoring of responses to sunitinib. Although not fully evaluated in pNETs, biomarkers associated with response to sunitinib in several tumor types include soluble vascular endothelial growth factor receptor 2 and 3, interleukin 8, and stromal cell-derived factor 1α. Based on recent data, treatment algorithms have been updated for advanced and metastatic pNETs.
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Affiliation(s)
- Aaron I. Vinik
- Director of Research and Neuroendocrine Unit, EVMS Strelitz Diabetes Research Center, Eastern Virginia Medical School, 855 West Brambleton Avenue, Norfolk, VA 23510-1001, USA
| | - Eric Raymond
- Beaujon University Hospital, Assistance Publique, Hôpitaux de Paris, Clichy, France
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Role of 18FDG PET/CT in patients treated with 177Lu-DOTATATE for advanced differentiated neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2013; 40:881-8. [PMID: 23443937 DOI: 10.1007/s00259-013-2369-z] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Accepted: 02/07/2013] [Indexed: 02/06/2023]
Abstract
PURPOSE The prognostic value of FDG PET for neuroendocrine tumours (NETs) has been reported. In this study we evaluated the role of FDG PET in predicting response and progression-free survival (PFS) after (177)Lu-DOTATATE peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced well-differentiated grade 1/2 NETs. METHODS We retrospectively evaluated 52 patients with progressive advanced NETs overexpressing somatostatin receptors and treated with Lu-PRRT with a cumulative activity up to 27.7 GBq divided into five courses. According to WHO 2010/ENETS classification, patients were stratified into two groups: those with grade 1 tumour (Ki-67 index ≤2 %, 19 patients), and those with grade 2 tumour (Ki-67 index >3 % to <20 %, 33 patients). On the basis of the FDG PET scan, 33 patients were classified as PET-positive (PET+) and 19 as PET-negative (PET-). RESULTS FDG PET was positive in 57 % of patients with grade 1 NET and in 66 % of patients with grade 2 NET, and the rates of disease control (DC, i.e. complete response + partial response + stable disease) in grade 1 and grade 2 patients were 95 % and 79 %, respectively (P = 0.232). In PET- and PET+ patients, the DC rates were 100 % and 76 % (P = 0.020) with a PFS of 32 and 20 months, respectively (P = 0.033). Of the PET+ patients with grade 1 NET, 91 % showed disease control, whereas about one in three PET+ patients with grade 2 NET (32 %) progressed after Lu-PRRT (DC rate 68 %). CONCLUSION These results suggest that FDG PET evaluation is useful for predicting response to Lu-PRRT in patients with grade 1/2 advanced NETs. Notably, none of PET- patients had progressed at the first follow-up examination after Lu-PRRT. Grade 2 NET and PET+ (arbitrary SUV cutoff >2.5) were frequently associated with more aggressive disease. PET+ patients with grade 2 NET, 32 % of whom did not respond to Lu-PRRT monotherapy, might benefit from more intensive therapy protocols, such as the combination of chemotherapy and PRRT.
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Nagasawa T, Hye Khan MA, Imig JD. Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib. Clin Exp Pharmacol Physiol 2013; 39:454-61. [PMID: 22443474 DOI: 10.1111/j.1440-1681.2012.05699.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Vascular endothelial growth factor inhibitors (VEGFi) are known to cause hypertension and renal injury that severely limits their use as an anticancer therapy. We hypothesized that the angiotensin-converting enzyme inhibitor captopril not only prevents hypertension, but also decreases renal injury caused by the VEGFi sorafenib. Rats were administered sorafenib (20 mg/kg per day) alone or in combination with captopril (40 mg/kg per day) for 4 weeks. Sorafenib administration increased blood pressure, which plateaued by day 10. Concurrent treatment with captopril for 4 weeks resulted in a 30 mmHg decrease in blood pressure compared with sorafenib alone (155 ± 5 vs 182 ± 6 mmHg, respectively; P < 0.05). Furthermore, concurrent captopril treatment reduced albuminuria by 50% compared with sorafenib alone (20 ± 8 vs 42 ± 9 mg/day, respectively; P < 0.05) and reduced nephrinuria by eightfold (280 ± 96 vs 2305 ± 665 μg/day, respectively; P < 0.05). Glomerular injury, thrombotic microangiopathy and tubular cast formation were also decreased in captopril-treated rats administered sorafenib. Renal autoregulatory efficiency was determined by evaluating the afferent arteriolar constrictor response to ATP. Sorafenib administration attenuated the vasoconstriction to ATP, whereas concurrent captopril treatment improved ATP reactivity. In conclusion, captopril attenuated hypertension and renal injury and improved renal autoregulatory capacity in rats administered sorafenib. These findings indicate that captopril treatment, in addition to alleviating the detrimental side-effect of hypertension, decreases the renal injury associated with anticancer VEGFi therapies such as sorafenib.
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Affiliation(s)
- Tasuku Nagasawa
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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15
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Ito T, Igarashi H, Jensen RT. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances. J Gastroenterol 2012; 47:941-960. [PMID: 22886480 PMCID: PMC3754804 DOI: 10.1007/s00535-012-0642-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 06/23/2012] [Indexed: 02/08/2023]
Abstract
Neuroendocrine tumors (NETs) [carcinoids, pancreatic neuroendocrine tumors (pNETs)] are becoming an increasing clinical problem because not only are they increasing in frequency, but they can frequently present with advanced disease that requires diagnostic and treatment approaches different from those used in the neoplasms that most physicians are used to seeing and treating. In the past few years there have been numerous advances in all aspects of NETs including: an understanding of their unique pathogenesis; specific classification systems developed which have prognostic value; novel methods of tumor localization developed; and novel treatment approaches described. In patients with advanced metastatic disease these include the use of newer chemotherapeutic approaches, an increased understanding of the role of surgery and cytoreductive methods, the development of methods for targeted delivery of cytotoxic agents, and the development of targeted medical therapies (everolimus, sunitinib) based on an increased understanding of the disease biology. Although pNETs and gastrointestinal NETs share many features, recent studies show they differ in pathogenesis and in many aspects of diagnosis and treatment, including their responsiveness to different therapies. Because of limited space, this review will be limited to the advances made in the management and treatment of patients with advanced metastatic pNETs over the past 5 years.
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Affiliation(s)
- Tetsuhide Ito
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hisato Igarashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Building 10, Room 9C-103, Bethesda, MD 20892, USA
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Faivre S, Ronot M, Dreyer C, Serrate C, Hentic O, Bouattour M, Bruno O, Couvelard A, Vilgrain V, Raymond E. Imaging response in neuroendocrine tumors treated with targeted therapies: the experience of sunitinib. Target Oncol 2012; 7:127-133. [PMID: 22585430 DOI: 10.1007/s11523-012-0216-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2012] [Accepted: 04/24/2012] [Indexed: 12/11/2022]
Abstract
Among neuroendocrine carcinomas of the gut, well-differentiated tumors are highly vascularized, featuring specific characteristics on contrast-enhanced imaging. Well-differentiated neuroendocrine tumors spontaneously harbor hypervascular enhancement, coexisting with areas of necrosis mainly located at the center of tumor lesions. When exposed to vascular endothelial growth factor (VEGFR) inhibitors such as sunitinib, target lesions display few if any variation in tumor size, but rather detectable modifications in tumor density. In several patients treated with targeted therapy, a significant decrease of tumor density at first tumor evaluation can be detected as compared to baseline. Consistently, the two randomized trials leading to approval of sunitinib and everolimus in pancreatic neuroendocrine tumors report objective response rate below 10%, emphasizing that Response Evaluation Criteria in Solid Tumors (RECIST), that focus only on the largest diameters of target lesions, may be insufficient to capture the full benefit of targeted therapies. Alternative criteria, such as those developed by Choi et al., consider both the size and the density of the tumor as parameters for response evaluation. Choi criteria have been recently proposed as a surrogate endpoint for efficacy and to identify patients that are good responders to VEGFR inhibitors such as sunitinib and sorafenib in advanced hepatocellular carcinoma, another disease highly addicted to angiogenesis. Preliminary data generated from patients included in the sunitinib phase III trial suggest that Choi criteria might also be considered as an alternative to RECIST to evaluate the effects of sunitinib in patients with advanced well-differentiated neuroendocrine tumors.
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Affiliation(s)
- Sandrine Faivre
- Department of Medical Oncology, Beaujon University Hospital (AP-HP-Paris 7 Diderot), Clichy, France.
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Karpathakis A, Caplin M, Thirlwell C. Hitting the target: where do molecularly targeted therapies fit in the treatment scheduling of neuroendocrine tumours? Endocr Relat Cancer 2012; 19:R73-92. [PMID: 22474226 DOI: 10.1530/erc-12-0050] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Neuroendocrine tumours (NETs) are a rare and heterogeneous group of tumours whose incidence is increasing and their prevalence is now greater than that of any other upper gastrointestinal tumour. Diagnosis can be challenging, and up to 25% of patients present with metastatic disease. Following the recent FDA approval of two new molecularly targeted therapies for the treatment of advanced pancreatic NETs (pNETs), the first in 25 years, we review all systemic therapies and suggest where these newer targeted therapies fit in the treatment schedule for these challenging tumours. Clinical trial data relating to the routine use of sunitinib and everolimus in low-intermediate-grade pNETs are summarised alongside newer molecularly targeted agents undergoing clinical assessment in NETs. We particularly focus on the challenge of optimal scheduling of molecularly targeted treatments around existing systemic and localised treatment such as chemotherapy or radiotargeted therapy. We also discuss application of current evidence to subgroups of patients who have not so far been directly addressed such as those with poorer performance status or patients receiving radical surgery who may benefit from adjuvant treatment.
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Affiliation(s)
- Anna Karpathakis
- University College London Cancer Institute, Paul O'Gorman Building, Huntley Street, London WC1E 6BT, UK
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18
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de Wilde RF, Edil BH, Hruban RH, Maitra A. Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nat Rev Gastroenterol Hepatol 2012; 9:199-208. [PMID: 22310917 PMCID: PMC3544293 DOI: 10.1038/nrgastro.2012.9] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Well-differentiated pancreatic neuroendocrine tumors (PanNETs) comprise ∼1-3% of pancreatic neoplasms. Although long considered as reasonably benign lesions, PanNETs have considerable malignant potential, with a 5-year survival of ∼65% and a 10-year survival of 45% for resected lesions. As PanNETs have a low incidence, they have been understudied, with few advances made until the completion of their exomic sequencing in the past year. In this Review, we summarize some of the latest insights into the genetics of PanNETs, and their probable implications in the context of prognosis and therapy. In particular, we discuss two genes (DAXX and ATRX) that have collectively been identified as mutated in >40% of PanNETs, and the biological and prognostic implications of these novel mutations. The identification of recurrent somatic mutations within the mTOR signaling pathway and the therapeutic implications for personalized therapy in patients with PanNETs are also discussed. Finally, this Review outlines state-of-the-art advances in the biology of PanNETs that are of emerging translational importance.
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Alexandraki KI, Kaltsas G. Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy. Endocrine 2012; 41:40-52. [PMID: 22124940 DOI: 10.1007/s12020-011-9562-2] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 10/12/2011] [Indexed: 01/22/2023]
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare and heterogenous malignancies. Recent advances in histopathological classification according to the anatomical site of origin, proliferation rate, and extend of the disease have created a valid and powerful tool for the prognostic stratification of GEP-NETs. Chromogranin A is still the best available marker used for the biochemical confirmation of these tumors, but new more sensitive markers are urgently required. Although scintigraphy with (111)In-octreotide has widely been applied for the localization and staging of GEP-NETs, newer imaging modalities based on the functional characteristics of these tumors are evolving aiming not only to facilitate the diagnosis but also prognosis and evaluation of treatment. Somatostatin receptors are the primary therapeutic targets through somatostatin analogs and peptide receptor radionuclide therapy (PRRT) producing symptomatic, biochemical and to a lesser extent antiproliferative effects. Due to the relatively limited and erratic response to chemotherapy, new molecular targeted therapies exploiting some of the biological properties of GEP-NETs such as increased vascularity and inhibition of pathways involved in downstream signal transduction have evolved. Some of these therapies, the mTOR inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have been recently validated in phase III studies producing practice changing outcomes. In addition, two oral chemotherapeutic agents temozolomide and capecitabine, show promising effects and may replace streptozotocin-based regimens whereas combination therapies with the angiogenesis inhibitor bevacizumab are being investigated. Although progression free survival is used as a feasible primary end point due to the long survival of patients even in the presence of extensive disease prolongation of overall survival following the introduction of new therapies needs to be established.
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Pavlidis TE, Psarras K, Symeonidis NG, Pavlidis ET, Sakantamis AK. Current surgical management of pancreatic endocrine tumor liver metastases. Hepatobiliary Pancreat Dis Int 2011; 10:243-247. [PMID: 21669565 DOI: 10.1016/s1499-3872(11)60040-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The management of metastatic disease in pancreatic endocrine tumors (PETs) demands a multidisciplinary approach and the cooperation of several medical specialties. The role of surgery is critical, even when a radical excision cannot always be achieved. DATA SOURCES A PubMed search of relevant articles published up to February 2011 was performed to identify current information about PET liver metastases regarding diagnosis and management, with an emphasis on surgery. RESULTS The early diagnosis of metastases and their accurate localization, most commonly in the liver, is very important. Surgical options include radical excision, and palliative excision to relieve symptoms in case of failure of medical treatment. The goal of the radical excision is to remove the primary tumor bulk and all liver metastases at the same time, but unfortunately it is not feasible in most cases. Palliative excisions include aggressive tumor debulking surgeries in well-differentiated carcinomas, trying to remove at least 90% of the tumor mass, combined with other additional destructive techniques such as hepatic artery embolization or chemoembolization to treat metastases or chemoembolization to relieve symptoms in cases of rapidly growing tumors. The combination of chemoembolization and systemic chemotherapy results in better response and survival rates. Other local destructive techniques include ethanol injection, cryotherapy and radiofrequency ablation. CONCLUSION It seems that the current management of PETs can achieve important improvements, even in advanced cases.
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Affiliation(s)
- Theodoros E Pavlidis
- Second Surgical Propedeutical Department, Hippocration Hospital, Medical School, Aristotle University of Thessaloniki, Konstantinopoulos 49, 54642 Thessaloniki, Greece.
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