Clinical trial NCT03513198: Perfusion Assessment With Contrast-Enhanced EUS in Locally Advanced and Metastatic Pancreatic Cancer
Official title: Changes in Tumor Vascularity Depicted by Contrast-Enhanced Endoscopic Ultrasonography as a Predictor of Treatment Efficacy in Patients With Locally Advanced and Metastatic Pancreatic Cancer (PEACE)
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Pancreas Cancer
Keywords: contrast-enhanced endoscopic ultrasound
endoscopic ultrasound elastography
tumor vascularity
prognostic
Lead sponsor: University of Medicine and Pharmacy Craiova
Sponsor class: OTHER
Collaborators: name: Copenhagen University Hospital at Herlev
name: Iuliu Hatieganu University of Medicine and Pharmacy
name: Central Military Hospital Bucharest
name: Ponderas Regina Maria Hospital Bucharest
name: Caritas-Krankenhaus Bad Mergentheim
name: Helios Kliniken Meiningen
name: University of Santiago de Compostela
name: Hospital Märkisch Oderland Wriezen/ Strausberg
name: Institut Paoli-Calmettes
name: Ospedale San Raffaele
name: University College London Hospitals
name: Newcastle-upon-Tyne Hospitals NHS Trust
name: M.D. Anderson Cancer Center
name: Shengjing Hospital
name: Asan Medical Center
name: Tokyo Medical University
name: Singapore General Hospital
First posted: 2018-05-01
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with a confirmed diagnosis of locally advanced/metastatic pancreatic cancer (both adenocarcinoma and neuroendocrine tumors will be included)

Brief summary: Patients with non-resectable pancreatic cancer have a poor prognosis.The analysis of prognostic factors before treatment may be helpful in selecting appropriate candidates for chemotherapy and determining treatment strategies.

The aim of the PEACE study is to assess the vascularity of pancreatic malignant tumors using contrast-enhanced endoscopic ultrasonography and to clarify the prognostic value of tumor vascularity in patients with locally advanced and metastatic pancreatic cancer.

Detailed description: Introduction and rationale:

Pancreatic cancer (PC) is one of the most lethal and therapeutically resistant malignancies, with a grim prognosis that is attributed to the late clinical presentation and the relative chemoresistance of the disease.

Even with identical chemotherapy regimens, some patients experience improvements in survival and tumor response, whereas other patients only experience inconvenience and increased toxicity. It has been suggested that the burden of treatment should not be added to the suffering of those with advanced pancreatic cancer. Therefore, understanding prognostic factors before treating patients with antitumoral agents may be helpful in selecting those patients predicted to have an improved survival and tumor response after treatment.

Studies have shown that angiogenesis is an important factor that influences the prognostic of solid tumors, including pancreatic tumors. Contrast-enhanced imaging methods can offer detailed information on tumor vascularity. Contrast-enhanced endoscopic ultrasound (CE-EUS) is a new method which allows detailed characterization of focal pancreatic masses. CE-EUS offers high-resolution images of the pancreas that far surpass those achieved by computed tomography, ultrasound, or magnetic resonance imaging. CE-EUS can detect intratumoral vessels in the pancreatic lesions. One of the fluoro-gas-containing contrast agents used in CE-EUS is Sonovue®, which is isotonic, stable and resistant to pressure, with a viscosity similar to blood. It does not diffuse into the extravascular compartment remaining within the blood vessels until the gas dissolves and is eliminated in the expired air (blood pool contrast agent). The safety profile of SonoVue showed a very low incidence of side effects; it is not nephrotoxic and the incidence of severe hypersensitivity is similar to other magnetic resonance imaging contrast agents. Moreover, Sono-Vue is approved for clinical use in European Union countries.

The hypothesis that tumors with intratumoral vessels are chemosensitive appears to be reasonable because drugs penetrate tumors through vessels. Therefore, it is possible that hypoxic condition in tumor tissue leads to chemoresistance and poor prognosis in patients with pancreatic carcinoma who received systemic chemotherapy. However, whether low vascularized tumors correlate with the chemoresistance and poor prognosis is still unclear. Patients with non-resectable pancreatic cancer have an especially poor prognosis and have many severe symptoms.The analysis of prognostic factors before treatment may be helpful in selecting appropriate candidates for chemotherapy and determining treatment strategies. For example, patients who have a poor prognosis may be treated best with only supportive care because of their short survival. Consequently, the aim of the PEACE study is to assess the vascularity of pancreatic malignant tumors with CE-EUS and to clarify the prognostic value of tumor vascularity in patients with advanced PC.

Moreover, studies have shown that angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels. Chauchan et al. demonstrated that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production. Consequently, losartan reduces solid stress in tumors resulting in increased vascular perfusion. Through this physical mechanism, it can improve drug and oxygen delivery to tumors, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Accordingly, another aim of our study will be to examine the correlation between tumor vascularity and angiotensin inhibitors use in patients using these drugs to control arterial hypertension.

Objectives:

Primary Objective:

• to register time-intensity curve (TIC) analysis-derived parameters, obtained from post-processing of CE-EUS recordings with a commercially available software, before and after chemotherapy and to describe tumor changes in vascularity after treatment.

Secondary Objectives:

* to prospectively determine whether the CE-EUS parameters can be used to predict response to treatment in patients with locally advanced and metastatic pancreatic cancer. Tumor response will be assessed by contrast-enhanced computed tomography, according to the Response Evaluation Criteria in Solid Tumors (RECIST)
* to determine the correlation between CE-EUS parameters before treatment and overall survival and progression-free survival
* to determine the correlation between changes in tumor vascularity and progression-free survival and overall survival
* to assess quantitative elastography parameters during EUS, before and after systemic treatment and determine their correlation with overall survival and progression-free survival
* to examine the correlation between tumor vascularity and angiotensin inhibitors use.

Study design:

This is a prospective, non-randomized, single-arm, observational, multicenter study aiming to assess changes in tumor vascularity using CE-EUS before and after systemic treatment in patients with locally advanced and metastatic pancreatic cancer and to examine the correlation between vascular changes and treatment response, progression-free survival and overall survival.

All patients with a suspicion of pancreatic masses will undergo EUS (including endoscopic ultrasound-fine needle aspiration for confirmation of diagnosis), with sequential elastography EUS (EG-EUS) and CE-EUS. A positive cytological diagnosis will be taken as a final proof of malignancy of the pancreas mass. The diagnoses obtained by EUS-fine needle aspiration will be further verified during a clinical follow-up of at least 6 months. Contrast-enhanced computed tomography (CT) will be performed as pretreatment staging study to assess the diagnosis of pancreatic cancer, local extension of the tumor, and presence of distant and lymph node metastasis.

Patients with a confirmed diagnosis of pancreatic cancer (both adenocarcinomas and neuroendocrine tumors will be included) will undergo systemic treatment. Selection of the specific treatment regimen will be according to individual physicians' choice.

Two months after the first course of systemic chemotherapy, CT and EUS (with sequential EG-EUS and CE-EUS) will be repeated. CT will be performed in order to evaluate the tumor response. Tumor response will be assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST).

CE-EUS will be performed during usual EUS examinations, with the whole movie (T0-T120s) recorded in a DICOM format on the embedded HDD of the ultrasound system, for later analysis. In order to minimize human bias, all post-processing and computer analysis of digital movies will be performed within the coordinating IT Center, with all programmers and statisticians being blinded to the clinical, imaging and pathological data. Off-line analysis of time-intensity curves will be performed using Vue-Box, which yields the following quantitative parameters: Peak Enhancement (PE), Wash-in Area Under the Curve (Wi-AUC), Rise Time (RT), mean Transit Time (mTT), Time To Peak (TTP), Wash-in Rate (WiR) and Wash-in Perfusion Index (WiPI). The software also provides referenced values (expressed in percentages), aligning the set of values for the tumor Region of interest (ROI) to the parenchymal ones.

EUS-EG will also be performed during usual EUS examinations, with two movies of 10 seconds recorded on the embedded Hard Disk Drive (HDD) in order to minimize variability and to increase repeatability of acquisition. Strain Ratio (SR) and SH (Strain Histogram) will be measured; with three measurements made and recorded on the embedded HDD.

The patients will be followed-up for at least six months through clinical examination, biological exams and transabdominal ultrasound, eventually with a repeat spiral CT / EUS after six months.

For each patient, the following information will be recorded and uploaded to http://oncobase.umfcv.ro/ (this website aims to provide hosting and support for multicentric studies; all registered users can access the project and submit the data or upload files through a form defined and controlled by the project's coordinator):

* Age
* Gender
* Primary tumor location (pancreatic head or pancreatic body and tail)
* Primary tumor size
* Tumor status (metastatic or locally advanced)
* Site of metastasis
* Histologic grade
* Serum carcinoembryonic antigen (CEA) level
* Serum carbohydrate antigen 19-9 (CA19-9) level
* Prior biliary drainage (presence or absence).
* Antitumoral agent (chemotherapy regimen).
* Angiotensin inhibitors (drug, dose).
* Parameters of the pancreatic cancer CT reporting template
* EUS, CE-EUS, EG-EUS parameters (echogenicity, echostructure, size, presence/absence of power Doppler signals, Strain Ratio, Strain Histogram, Peak Enhancement (PE), Wash-in Area Under the Curve (Wi-AUC), Rise Time (RT), mean Transit Time (mTT), Time To Peak (TTP), Wash-in Rate (WiR) and Wash-in Perfusion Index (WiPI)).

Eligibility criteria: Inclusion Criteria:

* Age 18 to 90 years old, men or women
* Signed informed consent for CE-EUS, EG-EUS and FNA biopsy
* The diagnosis of pancreatic cancer histologically confirmed by fine needle aspiration (FNA) with EUS
* Both pancreatic adenocarcinoma and pancreatic neuroendocrine tumors will be included
* Unresectable, locally advanced and/or metastatic disease.

Exclusion Criteria:

* Previous chemotherapy or radiotherapy
* Resectable pancreatic tumors

Primary outcomes:
measure: Change of Peak Enhancement (PE) from baseline to 2 months after the first course of treatment
timeFrame: baseline and 2 months after the first course of treatment
measure: Change of Wash-in Area Under the Curve (Wi-AUC) from baseline to 2 months after the first course of treatment
timeFrame: baseline and 2 months after the first course of treatment
measure: change of Rise Time (RT) from baseline to 2 months after the first course of treatment
timeFrame: baseline and 2 months after the first course of treatment
measure: change of mean Transit Time (mTT) from baseline to 2 months after the first course of treatment
timeFrame: baseline and 2 months after the first course of treatment
measure: Change of Time To Peak (TTP) from baseline to 2 months after the first course of treatment
timeFrame: baseline and 2 months after the first course of treatment
measure: Change of Wash-in Rate (WiR) from baseline to 2 months after the first course of treatment
timeFrame: baseline and 2 months after the first course of treatment
measure: Change of Wash-in Perfusion Index (WiPI) from baseline to 2 months after the first course of treatment
timeFrame: baseline and 2 months after the first course of treatment
Secondary outcomes:
measure: Overall survival
timeFrame: 1 year
measure: Progression-free survival
timeFrame: 1 year
measure: Tumor response to treatment
timeFrame: 2 months after the first course of treatment
Other outcomes:
Locations:
Study officials:
affiliation: University of Medicine and Pharmacy Craiova
name: Adrian Saftoiu, MD PhD FASGE
role: PRINCIPAL_INVESTIGATOR
References:
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