<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03022188</url>
  </required_header>
  <id_info>
    <org_study_id>CAL-201557</org_study_id>
    <nct_id>NCT03022188</nct_id>
  </id_info>
  <brief_title>Nonfunctioning Small (≤2 cm) Neuroendocrine Pancreatic Incidentaloma</brief_title>
  <official_title>Nonfunctioning Small (≤2 cm) Neuroendocrine Pancreatic Incidentaloma: Clinical and Morphological Findings, and Therapeutic Options (IPANEMA)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Société Française d'Endoscopie Digestive</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Société Française d'Endoscopie Digestive</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Neuroendocrine tumors (NETs) and carcinomas account for 10-15 % of all pancreatic&#xD;
      incidentalomas. The management of pancreatic NETs depends on tumor stage and on presence or&#xD;
      not of hormonal syndrome. The therapeutic approach for hormonally functional tumor, or large&#xD;
      tumor (&gt; 2 cm) with local, vascular or lymph nodes invasion, highly suggestive of malignancy,&#xD;
      or in presence of metastasis, is well admitted: surgery is indicated or should be discussed.&#xD;
      However, the attitude is less consensual for small (≤ 2 cm) non-functioning (NF) and&#xD;
      non-metastatic lesions. In English, American or French recommendations, systematic surgical&#xD;
      resection with lymphadenectomy is currently recommended in all medically fit patients. The&#xD;
      follow-up (FU) is possible for tumors &lt;2 cm (T1) located in the pancreatic head and for which&#xD;
      enucleation is not feasible. Several recently published retrospective studies discuss the&#xD;
      &quot;non- surgical&quot; management of the small NF incidentally detected pancreatic NETs (IPNETs) and&#xD;
      highlight the necessity of developing guidelines for management of these patients. A strict&#xD;
      correlation between tumor size and malignancy of these tumors was demonstrated in the&#xD;
      single-center retrospective Italian study of Bettini and col., which included all patients&#xD;
      with NF PNETs who underwent curative (R0) resection during 18 years. In the group of 51&#xD;
      patients with small size of T (2 cm or less), incidentally discovered, the majority of lesion&#xD;
      was benign, and the authors concluded that follow-up can be proposed in patients with&#xD;
      incidentally discovered NF PNETs ≤ 2 cm. However in despite of small size and asymptomatic&#xD;
      character of the tumor, the rate of malignancy of NF IPNETs ≤ 2 cm was estimated to be 24 %&#xD;
      (in 18% and 6% of cases, uncertain behaviour and carcinoma were present). Given the inherent&#xD;
      morbidities associated with pancreatic surgery, a risk-benefit calculation may favour&#xD;
      surveillance rather than surgery in highly selected patients. Thus, a better understanding of&#xD;
      NF IPNETs and identification of their prognostic factors can be of help to select a subgroup&#xD;
      of patients who could benefit from a long-term surveillance rather than a systematic surgical&#xD;
      resection. Clearly, large prospective trials are needed to validate this approach.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      With increasing use of high-resolution conventional imaging, pancreatic incidentalomas are&#xD;
      being diagnosed more frequently. In two recent surgical series, neuroendocrine tumors (NETs)&#xD;
      and carcinomas account for 10-15 % of all pancreatic incidentalomas, the majority ( 75-90 %&#xD;
      of cases) well differentiated. The factors affecting the behaviour of pancreatic NETs are&#xD;
      differentiation, histological grade, staging, size and intratumoral microvascular density. In&#xD;
      updated World Health Organization (WHO) classification, the grading system is based on tumor&#xD;
      differentiation, the rate of proliferation and Ki-67 index. The management of pancreatic NETs&#xD;
      depends on tumor stage and on presence or not of hormonal syndrome. By definition, the&#xD;
      incidentally discovered pancreatic NETs (PNETs) are unassociated with hormonal syndromes&#xD;
      (nonfunctioning) and detected in patients who undergo diagnostic evaluations for unrelated&#xD;
      conditions.&#xD;
&#xD;
      The therapeutic approach for hormonally functional tumor, or large tumor (&gt; 2 cm) with local,&#xD;
      vascular or lymph nodes invasion, highly suggestive of malignancy, or in presence of&#xD;
      metastasis, is well admitted: surgery is indicated or should be discussed.&#xD;
&#xD;
      However, the attitude is less consensual for small (≤ 2 cm) non-functioning (NF) and&#xD;
      non-metastatic lesions. There is a paucity of literature reporting pancreatic neuroendocrine&#xD;
      incidentalomas and their characteristics. However, given their increased incidence, they are&#xD;
      an emerging problem and require changes in treatment guidelines. In English, American or&#xD;
      French recommendations, systematic surgical resection with lymphadenectomy is currently&#xD;
      recommended in all medically fit patients. The follow-up (FU) is possible for tumors &lt;2 cm&#xD;
      (T1) located in the pancreatic head and for which enucleation is not feasible. This&#xD;
      therapeutic approach has two limitations: 1) the significant incidence of these tumors,&#xD;
      because of the widespread use of routine imaging, and the improved technology of multi&#xD;
      detector CT scan, the fortuitous discovery of small pancreatic incidentalomas is becoming&#xD;
      more common. 2) Pancreatic surgery carries significant postoperative morbidity even in&#xD;
      high-volume tertiary centers and even in parenchyma-preserving resection. This may results in&#xD;
      many pancreatic resections for tumors with unknown natural history. On the other hand, the&#xD;
      follow-up may be a factor of considerable anxiety, and carries the risk, actually difficult&#xD;
      to assess, to let the tumor grow between two monitoring controls, with the possible evolution&#xD;
      to the irreversible metastatic stage of the disease.&#xD;
&#xD;
      As a result, the investigators are unceasingly facing a dilemma: how to manage asymptomatic&#xD;
      patients with small incidentally detected, potentially benign NETs? Several recently&#xD;
      published retrospective studies discuss the &quot;non- surgical&quot; management of the small NF&#xD;
      incidentally detected pancreatic NETs (IPNETs) and highlight the necessity of developing&#xD;
      guidelines for management of these patients. A strict correlation between tumor size and&#xD;
      malignancy of these tumors was demonstrated in the single-center retrospective Italian study&#xD;
      of Bettini and col. , which included all patients with NF PNETs who underwent curative (R0)&#xD;
      resection during 18 years. In the group of 51 patients with small size of T (2 cm or less),&#xD;
      incidentally discovered, the majority of lesion was benign, and the authors concluded that&#xD;
      follow-up can be proposed in patients with incidentally discovered NF PNETs ≤ 2 cm. However&#xD;
      in despite of small size and asymptomatic character of the tumor, the rate of malignancy of&#xD;
      NF IPNETs ≤ 2 cm was estimated to be 24 % (in 18% and 6% of cases, uncertain behaviour and&#xD;
      carcinoma were present).&#xD;
&#xD;
      Given the inherent morbidities associated with pancreatic surgery, a risk-benefit calculation&#xD;
      may favour surveillance rather than surgery in highly selected patients. Thus, a better&#xD;
      understanding of NF IPNETs and identification of their prognostic factors can be of help to&#xD;
      select a subgroup of patients who could benefit from a long-term surveillance rather than a&#xD;
      systematic surgical resection. Clearly, large prospective trials are needed to validate this&#xD;
      approach.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 10, 2017</start_date>
  <completion_date type="Anticipated">December 2022</completion_date>
  <primary_completion_date type="Anticipated">July 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>rate of malignancy among nonfunctioning (NF) small (≤ 2 cm) pancreatic neuroendocrine incidentalomas (PNEI).</measure>
    <time_frame>36 months</time_frame>
    <description>any G3 tumor *&#xD;
G2 * or G1 * tumor with lymph node metastases and / or distant metastasis&#xD;
G2 or G1 tumor with recurrence during the clinical and morphological surveillance after surgical treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>progression rate among NF-PNEI ≤ 2cm in case of non-surgical management</measure>
    <time_frame>36 months</time_frame>
    <description>- significant increase of tumor size within one year &gt; 20% on radiological examination or &gt; 2 mm at endoscopic ultrasound ; - appearance of metastatic lymph nodes and / or distant metastases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>determination of Ki67 value</measure>
    <time_frame>36 months</time_frame>
    <description>determination of Ki67 value on cytological samples obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and on surgical specimen</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>performance of contrast harmonic endoscopic ultrasound (CH-EUS) for the diagnosis of malignancy</measure>
    <time_frame>36 months</time_frame>
    <description>assessment of sensibility (Se), specificity (Spe), positive predictive value (PPV), negative predctive value (NPV) and accuracy of CH-EUS for the diagnosis of malignancy, appreciated by tumor microvascularisation assessment during CH-EUS procédures and correlation with tumor microvascular density appreciated on surgical specimen</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>rate of surgical treatment, delay from diagnosis to surgery and rationale</measure>
    <time_frame>36 months</time_frame>
    <description>number of patients having undergone surgical treatment / total number of patients included in the study ; - number of days between diagnosis and surgical treatment ,</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the rate of non-surgical management and the reasons that determined the choice of this therapeutic option</measure>
    <time_frame>36 months</time_frame>
    <description>- number of patients with non- surgical management (monitoring) / total number of patients included in the study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>to assess the morbidity among the patients with surgical treatment</measure>
    <time_frame>36 months</time_frame>
    <description>-Morbidity defined as all complication occurring after surgical resection until discharge and/or readmission, and will be grade according to the Clavien-Dindo classification. Postoperative pancreatic fistula, haemorrhage, and delayed gastric emptying were defined according to the International Study Group of Pancreatic Surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>to assess the mortality among the patients with surgical treatment</measure>
    <time_frame>36 monts</time_frame>
    <description>Perioperative mortality is death in relation to surgery, defined as death after surgical resection until discharge and/or readmission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>to assess the overall survival (OS) among the patients with surgical treatment</measure>
    <time_frame>36 months</time_frame>
    <description>OS defined as the time from diagnosis to death of any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>disease specific survival (DSS) among the patients with surgical treatment</measure>
    <time_frame>36 months</time_frame>
    <description>DSS defined as the time from diagnosis to disease-related death and censored at the last follow-up date if no events had occurred.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>to assess the progression-free survival (PFS) among the patients with surgical treatment</measure>
    <time_frame>36 months</time_frame>
    <description>PFS is the period during and after treatment in which a participant is living with a disease that does not get worse defined and is defined as the time from diagnosis until 1) loco-regional or systemic recurrence, 2) second malignancy, or 3) death from any cause; late deaths not related to cancer or its treatment are excluded</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>to assess the morbidity among the patients with non-surgical treatment</measure>
    <time_frame>36 months</time_frame>
    <description>morbidity defined as all complication occurred after endoscopic ultrasound procedures until discharge and/or readmission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>to assess the mortality among the patients with non-surgical treatment</measure>
    <time_frame>36 months</time_frame>
    <description>mortality defined as death in relation to endoscopic ultrasound procedure, occured until discharge and/or readmission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>to assess the overal survival (OS) among the patients with non-surgical treatment</measure>
    <time_frame>36 months</time_frame>
    <description>OS defined as the time from diagnosis to death of any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>to assess the disease free survival (DSS) among the patients with non-surgical treatment</measure>
    <time_frame>36 months</time_frame>
    <description>DSS defined as the time from diagnosis to disease-related death and censored at the last follow-up date if no events had occurred.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>to assess the progression-free survival (PFS) among the patients with non-surgical treatment</measure>
    <time_frame>36 months</time_frame>
    <description>PFS is the period during and after treatment in which a participant is living with a disease that does not get worse defined and is defined as the time from diagnosis until 1) loco-regional or systemic recurrence, 2) second malignancy, or 3) death from any cause; late deaths not related to cancer or its treatment are excluded</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life assessment at baseline, 12, 24 and 36 months</measure>
    <time_frame>baseline, 12, 24 and 36 months</time_frame>
    <description>The quality of life will be assessed using the 12-item Short-Form Health Survey (SF12) self- questionnaire</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Neuroendocrine Tumors</condition>
  <arm_group>
    <arm_group_label>Observational</arm_group_label>
    <description>Observational</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Patient with pancreatic tumors &lt;2cm (stage 1 discovered incidentally.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients older than 18 years old&#xD;
&#xD;
          -  with a small size ≤ 2 cm (stage I) non-functioning pancreatic neuroendocrine&#xD;
             incidentaloma, cytologically and/or histologically proved or, in case of impossibility&#xD;
             to obtain a cyto-histological specimen, with highly suggested diagnosis by imaging&#xD;
             (early, homogenous enhancement at computerized tomography (CT- scan) and/or magnetic&#xD;
             resonance Imaging (MR)I and positivity at somatostatin receptor scintigraphy (SRS))&#xD;
&#xD;
          -  patient ASA 1-2 (assessed according to ASA physical status classification system of&#xD;
             American Society of Anesthesiology)&#xD;
&#xD;
          -  after geriatric evaluation for the patients older than 75 y.o&#xD;
&#xD;
          -  affiliated to a social security system&#xD;
&#xD;
          -  with signed consent for study enrolment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients &lt; 18 years old&#xD;
&#xD;
          -  Patients with NET with size &gt; 2 cm ( stage II-IV) or NEC and/or with presence of signs&#xD;
             suspicious of malignancy&#xD;
&#xD;
          -  Patients with a functioning NET or NEC (clinical syndrome caused by excess hormonal&#xD;
             secretion, as insulinoma or Zollinger -Ellison syndrome)&#xD;
&#xD;
          -  Patients with multiple pancreatic neuroendocrine tumors&#xD;
&#xD;
          -  Patients with multiple endocrine neoplasia type 1 (MEN1)&#xD;
&#xD;
          -  Patients with suspicion of non- neuroendocrine tumor&#xD;
&#xD;
          -  Patient ASA 3-4 (assessed according to ASA physical status classification system of&#xD;
             American Society of Anesthesiology)&#xD;
&#xD;
          -  Patients with other malignant disease under treatment or with under 5 years remission,&#xD;
             except in situ or intramucosal carcinoma.&#xD;
&#xD;
          -  Pregnant or breastfeeding women&#xD;
&#xD;
          -  Patients judged not able to perform the monitoring&#xD;
&#xD;
          -  Absence of signed consent for study enrolment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rodica Gincul, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Société Française d'Endoscopie Digestive</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clinique Universitaire Saint Luc</name>
      <address>
        <city>Louvain</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Sud</name>
      <address>
        <city>Amiens</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Angers</name>
      <address>
        <city>Angers</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU Jean Minjoz</name>
      <address>
        <city>Besançon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital du Haut Leveque</name>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Beaujon</name>
      <address>
        <city>Clichy</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Bocage central</name>
      <address>
        <city>Dijon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Lyon Sud</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Edouard Herriot</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Privé Jean Mermoz</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital de la Timone</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Nord</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Privé Européen</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Saint Joseph</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Paoli Calmette</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hotel Dieu</name>
      <address>
        <city>Nantes</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital de l'archet 2</name>
      <address>
        <city>Nice</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinique du Trocadero</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Cochin</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Européen George Pompidou</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Robert Debré</name>
      <address>
        <city>Reims</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Rangueil</name>
      <address>
        <city>Toulouse</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>France</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>January 10, 2017</study_first_submitted>
  <study_first_submitted_qc>January 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 16, 2017</study_first_posted>
  <last_update_submitted>October 8, 2021</last_update_submitted>
  <last_update_submitted_qc>October 8, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 11, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Société Française d'Endoscopie Digestive</investigator_affiliation>
    <investigator_full_name>Gincul Rodica</investigator_full_name>
    <investigator_title>Medical Doctor, Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>pancreatic incidentaloma</keyword>
  <keyword>pancreatic neuroendocrine tumor</keyword>
  <keyword>EUS-guided fine-needle aspiration</keyword>
  <keyword>contrast-enhanced endoscopic ultrasound</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroendocrine Tumors</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03022188
org study id: CAL-201557
nct id: NCT03022188
lead sponsor: 
has dmc: No
Neuroendocrine tumors (NETs) and carcinomas account for 10-15 % of all pancreatic
      incidentalomas. The management of pancreatic NETs depends on tumor stage and on presence or
      not of hormonal syndrome. The therapeutic approach for hormonally functional tumor, or large
      tumor (> 2 cm) with local, vascular or lymph nodes invasion, highly suggestive of malignancy,
      or in presence of metastasis, is well admitted: surgery is indicated or should be discussed.
      However, the attitude is less consensual for small (≤ 2 cm) non-functioning (NF) and
      non-metastatic lesions. In English, American or French recommendations, systematic surgical
      resection with lymphadenectomy is currently recommended in all medically fit patients. The
      follow-up (FU) is possible for tumors <2 cm (T1) located in the pancreatic head and for which
      enucleation is not feasible. Several recently published retrospective studies discuss the
      "non- surgical" management of the small NF incidentally detected pancreatic NETs (IPNETs) and
      highlight the necessity of developing guidelines for management of these patients. A strict
      correlation between tumor size and malignancy of these tumors was demonstrated in the
      single-center retrospective Italian study of Bettini and col., which included all patients
      with NF PNETs who underwent curative (R0) resection during 18 years. In the group of 51
      patients with small size of T (2 cm or less), incidentally discovered, the majority of lesion
      was benign, and the authors concluded that follow-up can be proposed in patients with
      incidentally discovered NF PNETs ≤ 2 cm. However in despite of small size and asymptomatic
      character of the tumor, the rate of malignancy of NF IPNETs ≤ 2 cm was estimated to be 24 %
      (in 18% and 6% of cases, uncertain behaviour and carcinoma were present). Given the inherent
      morbidities associated with pancreatic surgery, a risk-benefit calculation may favour
      surveillance rather than surgery in highly selected patients. Thus, a better understanding of
      NF IPNETs and identification of their prognostic factors can be of help to select a subgroup
      of patients who could benefit from a long-term surveillance rather than a systematic surgical
      resection. Clearly, large prospective trials are needed to validate this approach.
With increasing use of high-resolution conventional imaging, pancreatic incidentalomas are
      being diagnosed more frequently. In two recent surgical series, neuroendocrine tumors (NETs)
      and carcinomas account for 10-15 % of all pancreatic incidentalomas, the majority ( 75-90 %
      of cases) well differentiated. The factors affecting the behaviour of pancreatic NETs are
      differentiation, histological grade, staging, size and intratumoral microvascular density. In
      updated World Health Organization (WHO) classification, the grading system is based on tumor
      differentiation, the rate of proliferation and Ki-67 index. The management of pancreatic NETs
      depends on tumor stage and on presence or not of hormonal syndrome. By definition, the
      incidentally discovered pancreatic NETs (PNETs) are unassociated with hormonal syndromes
      (nonfunctioning) and detected in patients who undergo diagnostic evaluations for unrelated
      conditions.

      The therapeutic approach for hormonally functional tumor, or large tumor (> 2 cm) with local,
      vascular or lymph nodes invasion, highly suggestive of malignancy, or in presence of
      metastasis, is well admitted: surgery is indicated or should be discussed.

      However, the attitude is less consensual for small (≤ 2 cm) non-functioning (NF) and
      non-metastatic lesions. There is a paucity of literature reporting pancreatic neuroendocrine
      incidentalomas and their characteristics. However, given their increased incidence, they are
      an emerging problem and require changes in treatment guidelines. In English, American or
      French recommendations, systematic surgical resection with lymphadenectomy is currently
      recommended in all medically fit patients. The follow-up (FU) is possible for tumors <2 cm
      (T1) located in the pancreatic head and for which enucleation is not feasible. This
      therapeutic approach has two limitations: 1) the significant incidence of these tumors,
      because of the widespread use of routine imaging, and the improved technology of multi
      detector CT scan, the fortuitous discovery of small pancreatic incidentalomas is becoming
      more common. 2) Pancreatic surgery carries significant postoperative morbidity even in
      high-volume tertiary centers and even in parenchyma-preserving resection. This may results in
      many pancreatic resections for tumors with unknown natural history. On the other hand, the
      follow-up may be a factor of considerable anxiety, and carries the risk, actually difficult
      to assess, to let the tumor grow between two monitoring controls, with the possible evolution
      to the irreversible metastatic stage of the disease.

      As a result, the investigators are unceasingly facing a dilemma: how to manage asymptomatic
      patients with small incidentally detected, potentially benign NETs? Several recently
      published retrospective studies discuss the "non- surgical" management of the small NF
      incidentally detected pancreatic NETs (IPNETs) and highlight the necessity of developing
      guidelines for management of these patients. A strict correlation between tumor size and
      malignancy of these tumors was demonstrated in the single-center retrospective Italian study
      of Bettini and col. , which included all patients with NF PNETs who underwent curative (R0)
      resection during 18 years. In the group of 51 patients with small size of T (2 cm or less),
      incidentally discovered, the majority of lesion was benign, and the authors concluded that
      follow-up can be proposed in patients with incidentally discovered NF PNETs ≤ 2 cm. However
      in despite of small size and asymptomatic character of the tumor, the rate of malignancy of
      NF IPNETs ≤ 2 cm was estimated to be 24 % (in 18% and 6% of cases, uncertain behaviour and
      carcinoma were present).

      Given the inherent morbidities associated with pancreatic surgery, a risk-benefit calculation
      may favour surveillance rather than surgery in highly selected patients. Thus, a better
      understanding of NF IPNETs and identification of their prognostic factors can be of help to
      select a subgroup of patients who could benefit from a long-term surveillance rather than a
      systematic surgical resection. Clearly, large prospective trials are needed to validate this
      approach.
observational model: Cohort
time perspective: Prospective
measure: rate of malignancy among nonfunctioning (NF) small (≤ 2 cm) pancreatic neuroendocrine incidentalomas (PNEI).
time frame: 36 months
description: any G3 tumor *
G2 * or G1 * tumor with lymph node metastases and / or distant metastasis
G2 or G1 tumor with recurrence during the clinical and morphological surveillance after surgical treatment
measure: progression rate among NF-PNEI ≤ 2cm in case of non-surgical management
time frame: 36 months
description: - significant increase of tumor size within one year > 20% on radiological examination or > 2 mm at endoscopic ultrasound ; - appearance of metastatic lymph nodes and / or distant metastases
measure: determination of Ki67 value
time frame: 36 months
description: determination of Ki67 value on cytological samples obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and on surgical specimen
measure: performance of contrast harmonic endoscopic ultrasound (CH-EUS) for the diagnosis of malignancy
time frame: 36 months
description: assessment of sensibility (Se), specificity (Spe), positive predictive value (PPV), negative predctive value (NPV) and accuracy of CH-EUS for the diagnosis of malignancy, appreciated by tumor microvascularisation assessment during CH-EUS procédures and correlation with tumor microvascular density appreciated on surgical specimen
measure: rate of surgical treatment, delay from diagnosis to surgery and rationale
time frame: 36 months
description: number of patients having undergone surgical treatment / total number of patients included in the study ; - number of days between diagnosis and surgical treatment ,
measure: the rate of non-surgical management and the reasons that determined the choice of this therapeutic option
time frame: 36 months
description: - number of patients with non- surgical management (monitoring) / total number of patients included in the study
measure: to assess the morbidity among the patients with surgical treatment
time frame: 36 months
description: -Morbidity defined as all complication occurring after surgical resection until discharge and/or readmission, and will be grade according to the Clavien-Dindo classification. Postoperative pancreatic fistula, haemorrhage, and delayed gastric emptying were defined according to the International Study Group of Pancreatic Surgery
measure: to assess the mortality among the patients with surgical treatment
time frame: 36 monts
description: Perioperative mortality is death in relation to surgery, defined as death after surgical resection until discharge and/or readmission
measure: to assess the overall survival (OS) among the patients with surgical treatment
time frame: 36 months
description: OS defined as the time from diagnosis to death of any cause
measure: disease specific survival (DSS) among the patients with surgical treatment
time frame: 36 months
description: DSS defined as the time from diagnosis to disease-related death and censored at the last follow-up date if no events had occurred.
measure: to assess the progression-free survival (PFS) among the patients with surgical treatment
time frame: 36 months
description: PFS is the period during and after treatment in which a participant is living with a disease that does not get worse defined and is defined as the time from diagnosis until 1) loco-regional or systemic recurrence, 2) second malignancy, or 3) death from any cause; late deaths not related to cancer or its treatment are excluded
measure: to assess the morbidity among the patients with non-surgical treatment
time frame: 36 months
description: morbidity defined as all complication occurred after endoscopic ultrasound procedures until discharge and/or readmission
measure: to assess the mortality among the patients with non-surgical treatment
time frame: 36 months
description: mortality defined as death in relation to endoscopic ultrasound procedure, occured until discharge and/or readmission
measure: to assess the overal survival (OS) among the patients with non-surgical treatment
time frame: 36 months
description: OS defined as the time from diagnosis to death of any cause
measure: to assess the disease free survival (DSS) among the patients with non-surgical treatment
time frame: 36 months
description: DSS defined as the time from diagnosis to disease-related death and censored at the last follow-up date if no events had occurred.
measure: to assess the progression-free survival (PFS) among the patients with non-surgical treatment
time frame: 36 months
description: PFS is the period during and after treatment in which a participant is living with a disease that does not get worse defined and is defined as the time from diagnosis until 1) loco-regional or systemic recurrence, 2) second malignancy, or 3) death from any cause; late deaths not related to cancer or its treatment are excluded
measure: Quality of life assessment at baseline, 12, 24 and 36 months
time frame: baseline, 12, 24 and 36 months
description: The quality of life will be assessed using the 12-item Short-Form Health Survey (SF12) self- questionnaire
arm group label: Observational
description: Observational
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rodica Gincul, MD
role: Principal Investigator
affiliation: Société Française d'Endoscopie Digestive
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country: Belgium
country: France
responsible party type: Principal Investigator
investigator affiliation: Société Française d'Endoscopie Digestive
investigator full name: Gincul Rodica
investigator title: Medical Doctor, Principal Investigator
mesh term: Neuroendocrine Tumors
sharing ipd: No