Contrast Enhanced Harmonic Endoscopic Ultrasound (CEH-EUS) in Focal Pancreatic Masses

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Brief Title

Contrast Enhanced Harmonic Endoscopic Ultrasound (CEH-EUS) in Focal Pancreatic Masses

Official Title

Contrast Enhanced Harmonic Endoscopic Ultrasound (CEH-EUS) Used in the Differentiation of Focal Pancreatic Masses

Brief Summary

      The aim of the study is to assess the accuracy of real-time perfusion imaging pattern of
      pancreatic focal lesions visualized by contrast-enhanced harmonic endoscopic ultrasound
      (CEH-EUS) for the differential diagnosis between chronic pseudotumoral pancreatitis and
      pancreatic cancer in a prospective multicenter design.

      The study will include patients with focal pancreatic masses evaluated by CEH-EUS and
      EUS-FNA. The diagnosis is usually unknown in the moment of the initial evaluation, the
      patients being included based on a suspicion of focal pancreatic masses after transabdominal
      ultrasound, CT or MR examinations. However, after a complete evaluation, a final diagnosis
      will be reached based on the combination of EUS-FNA cytology/pathology, surgical pathology
      and minimum 12 months follow-up.
    

Detailed Description

      Ultrasound contrast agents in conjunction with contrast specific imaging techniques are
      increasingly accepted in clinical use for diagnostic imaging. The study of the pancreas is a
      new and promising application of contrast-enhanced ultrasound (CE-US), including
      contrast-enhanced endoscopic ultrasound (CE-EUS). The technique is not indicated to improve
      the detection of pancreatic lesions, but to improve the delineation and differential
      diagnosis of pancreatic lesions. One of the fluoro-gas-containing contrast agents used in
      CE-US and CE-EUS is Sonovue®, which consists of phospholipids-stabilized bubbles of
      sulfurhexafluoride (SF6). Sonovue® 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 EU countries. The blood supply of the pancreas is entirely arterial, making
      contrast-enhanced examinations feasible and readily available. Based on the European
      Federation Societies of Ultrasound in Medicine and Biology guidelines and recommendations,
      updated in 2008, two phases were defined for CE-US and CE-EUS of the pancreas: an
      early/arterial phase (starting from 10 to 30 seconds) and a venous/late phase (from 30 to 120
      seconds).

      Distinguishing pancreatic adenocarcinoma from other pancreatic masses remains challenging
      with current imaging techniques. The specificity of the discrimination between benign and
      malignant focal pancreatic lesions was found to be 93.3% using power Doppler
      contrast-enhanced EUS (PD-CE-EUS) compared with 83.3% for conventional EUS. The hypovascular
      aspect of lesions under PD-CE-EUS seemed highly sensitive and specific (higher than 90%) for
      adenocarcinoma in several published studies. During PD-CE-EUS examinations the ultrasound
      frequency returned to the transducer is the same with that transmitted, but the method is
      associated with artifacts resulting from turbulent flow (flash and overpainting). At CE-EUS,
      ductal adenocarcinoma is typically hypoenhanced compared to the adjacent pancreatic tissue in
      all phases. Furthermore, the lesion size and margins are better visualized, as well as the
      relationship with peripancreatic arteries and veins. Focal lesions in chronic pancreatitis
      are reported to have similar or hyper enhancement features as compared to the normal
      pancreatic parenchyma.

      Dedicated contrast-enhanced harmonic EUS techniques (based on a low mechanical index) are
      recently available in new EUS systems. The harmonic frequencies returned during CEH-EUS are
      different from those transmitted by the transducer and are the result of non-linear
      oscillations of the microbubbles. The image obtained is an addition of the signal created by
      the distortion of the microbubbles and the tissue-derived signal. This can be optimized by
      using low MI, which allows minimum bubble destruction and complete "subtraction" of the
      tissue derived signal, obtaining a high resolution continuous real-time assessment of the
      microvascularization during the contrast uptake period (real-time perfusion imaging). CEH-EUS
      allows a more precise location of vascular structures within the parenchyma and focal
      abnormalities, with better delineation of pancreatic lesions than EUS, especially in the
      cases where air or fat causes artifacts and insufficient visualization of the pancreatic
      parenchyma. An initial pilot study described an experimental technique of CEH-EUS based on a
      linear prototype EUS scope, a low mechanical index (0.08 - 0.25) and a 2nd generation
      contrast agent (Sono-Vue), which allowed the visualization of early arterial phase and late
      parenchymal phase enhancement of the pancreas. Another pilot study demonstrated both
      real-time continuous images of finely branching vessels of the pancreas and intermittent
      homogenous parenchymal perfusion images, by using a radial prototype EUS scope, a low
      mechanical index (0.4) and a 2nd generation contrast agent (Sono-Vue). Several other research
      groups already reported the feasibility of CEH-EUS with low mechanical index. The
      sensitivity, specificity and accuracy for diagnosing pancreatic adenocarcinoma were 88%, 89%,
      and 88.5% in one study and 80%, 91.7%, and 86% in the other study. However, the data is still
      limited and a prospective, multicentric blinded study would certainly be necessary.

      The study design is prospective, blinded and multi-center, comparing contrast-enhanced
      harmonic endoscopic ultrasound (CEH-EUS) results for the detection and characterization of
      focal pancreatic masses, in comparison with the gold standard represented by pathology. The
      study will be performed with the approval of the institutional board review of each center.
      The study protocol will be uploaded on ClinicalTrials.gov, the registry of federally and
      privately supported clinical trials conducted in the United States and around the world.

      The study is already approved by the ethical committee of the University of Medicine and
      Pharmacy Craiova, Romania (attached). According to EFSUMB (European Federation Societies for
      Ultrasound in Medicine and Biology) guidelines published in 2008, second-generation contrast
      agents are also approved in the E.U. for ultrasound examinations, including liver and
      pancreas examinations.

      All patients with a suspicion (clinical, US, CT/MR) of pancreatic masses should undergo EUS,
      contrast-enhanced harmonic EUS and EUS-elastography, as well as EUS-FNA

      EUS with EUS-guided FNA

        -  Protocol of EUS with EUS-FNA should include linear EUS instruments with complete
           examinations of the pancreas.

        -  Tumor characteristics (echogenicity, echostructure, size) will be described as well as
           presence / absence of power Doppler signals.

        -  EUS-FNA will be performed in all pancreatic masses with at least three passes

        -  All examiners should be blinded for the results of pathology

      CEH-EUS procedure

        -  A two panel image with the usual conventional gray-scale B-mode EUS image on the right
           side and with the contrast harmonic image on the left side will be used, according to
           pre-established presets.

        -  A low mechanical index procedure (dynamic wide-band contrast harmonic imaging mode) will
           be used, with a mechanical index of 0.08-0.25 and corresponding powers.

        -  The starting point of the timer will be considered the moment of intravenous contrast
           injection (Sonovue 4.8 mL).

        -  CEH-EUS will be performed during usual EUS examinations, with the whole movie (T0-T120s)
           recorded 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.

      EUS-elastography procedures

        -  An additional EUS elastography movie of 30 seconds should be saved on the embedded HDD.

        -  The following settings will be used for EUS elastography: examination frequency is
           usually set at 7.5 MHz, while preinstalled system settings are used in all patients:
           reject (2), E-smoothing (2), persistence (3), and E-dynamic range (4).

      Final diagnosis The diagnosis of chronic pancreatitis will be based on the clinical
      information (history of alcohol abuse, previous diagnosis of chronic pancreatitis or diabetes
      mellitus), as well as a combination of imaging methods (ultrasound, CT and EUS). At least
      four criteria of chronic pancreatitis during EUS will be considered for the positive
      diagnosis. The diagnosis of chronic pseudotumoral pancreatitis will always be confirmed by
      surgery or by a follow-up of at least six months used to exclude malignancy in the patients
      that will not be operated on.

      A positive cytological diagnosis will be taken as a final proof of malignancy of the pancreas
      mass. The diagnoses obtained by EUS-FNA will be further verified either by surgery or during
      a clinical follow-up of at least 6 months.

      Pathology samples obtained from duodeno-pancreatectomies or caudal pancreatectomies done with
      curative intent, as well as microhistological fragments obtained through EUS-FNA biopsy will
      be processed by paraffin embedding with usual colorations (haematoxylin-eosin), with
      subsequent immune-histochemistry at the discretion of the participating centers pathologists
      in order to exclude neuroendocrine tumors / pancreatic metastases.

      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.

      Statistical analysis All results will be expressed as mean ± standard deviation (SD).
      Differences between the patients with pancreatic cancer and chronic pancreatitis will
      performed by the two-sample t-test (two independent samples). Since this parametric method
      makes assumptions about normality and similar variances, we will initially perform both the
      Kolmogorov-Smirnov and Shapiro-Wilk W normality tests and verify the equality of variances
      assumption with the F test. In the case of the two-sample t-test, we will also perform the
      non-parametric alternative given by the Mann-Whitney U test, since in some instances it may
      even offer greater power to reject the null hypothesis than the t-test.

      Since with more than two groups of observations it is far better to use a single analysis
      that enables us to look at all the data in the same time, we will also perform the one-way
      analysis of variance (ANOVA) method with the same baseline assumptions. A p-value less than
      0.05 will be considered as statistically significant.

      Sensitivity, specificity, positive predictive value, negative predictive value and accuracy
      of CEH-EUS +/- will be determined in comparison with the final diagnosis.

      The estimated number of patients included is at least 210, based on at least 10 centers with
      at least 20 patients each, which will be enrolled in an 18 months period. The power analysis
      was based on the following assumption: in order to use the powerful t-test for independent
      samples, a sample size equaling 105 patients in each group is sufficient to provide 95%
      statistical power to detect a difference of 5% in mean, for a type I error alpha = 0.05, and
      the population standard deviation = 10%. The difference in mean was based on previously
      published data which report an accuracy of approximately 80-85% for EUS-FNA, and 90% for
      contrast-enhanced EUS.
    


Study Type

Observational


Primary Outcome

Contrast enhanced harmonic endoscopic ultrasound


Condition

Adenocarcinoma Pancreas


Study Arms / Comparison Groups

 Pancreatic adenocarcinoma
Description:  Patients diagnosed with solid pancreatic adenocarcinoma masses, with cytological / histologicalconfirmation

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

210

Start Date

March 2011

Completion Date

December 2012

Primary Completion Date

April 2012

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with suspicion of solid pancreatic tumor masses by previous cross-sectional
             imaging techniques (US, CT, MR)

          -  Age 18 to 90 years old, men or women

          -  Signed informed consent for EUS with contrast-enhancement, elastography and EUS-FNA

        Exclusion Criteria:

          -  Prior surgical treatment with curative intent or chemo-radiotherapy

          -  Patients diagnosed with mucin producing tumors, pancreatic cystic tumors, etc.
      

Gender

All

Ages

18 Years - 90 Years

Accepts Healthy Volunteers

No

Contacts

Adrian Săftoiu, Professor, , 

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT01315548

Organization ID

CEH-EUS-001

Secondary IDs

CEH-EUS-UMFCV-RO

Responsible Party

Sponsor

Study Sponsor

University of Medicine and Pharmacy Craiova

Collaborators

 Copenhagen University Hospital, Denmark

Study Sponsor

Adrian Săftoiu, Professor, Study Director, University of Medicine and Pharmacy Craiova, Romania


Verification Date

January 2018