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Nonfunctioning Small (≤2 cm) Neuroendocrine Pancreatic Incidentaloma

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ClinicalTrials.gov Identifier: NCT03022188
Recruitment Status : Recruiting
First Posted : January 16, 2017
Last Update Posted : July 12, 2018
Sponsor:
Information provided by (Responsible Party):
Gincul Rodica, Société Française d'Endoscopie Digestive

Brief Summary:
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.

Condition or disease
Neuroendocrine Tumors

Detailed Description:

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.


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Study Type : Observational
Estimated Enrollment : 100 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Nonfunctioning Small (≤2 cm) Neuroendocrine Pancreatic Incidentaloma: Clinical and Morphological Findings, and Therapeutic Options (IPANEMA)
Actual Study Start Date : January 10, 2017
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2022


Group/Cohort
Observational
Observational



Primary Outcome Measures :
  1. rate of malignancy among nonfunctioning (NF) small (≤ 2 cm) pancreatic neuroendocrine incidentalomas (PNEI). [ Time Frame: 36 months ]
    • 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


Secondary Outcome Measures :
  1. progression rate among NF-PNEI ≤ 2cm in case of non-surgical management [ Time Frame: 36 months ]
    - 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

  2. determination of Ki67 value [ Time Frame: 36 months ]
    determination of Ki67 value on cytological samples obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and on surgical specimen

  3. performance of contrast harmonic endoscopic ultrasound (CH-EUS) for the diagnosis of malignancy [ Time Frame: 36 months ]
    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

  4. rate of surgical treatment, delay from diagnosis to surgery and rationale [ Time Frame: 36 months ]
    number of patients having undergone surgical treatment / total number of patients included in the study ; - number of days between diagnosis and surgical treatment ,

  5. the rate of non-surgical management and the reasons that determined the choice of this therapeutic option [ Time Frame: 36 months ]
    - number of patients with non- surgical management (monitoring) / total number of patients included in the study

  6. to assess the morbidity among the patients with surgical treatment [ Time Frame: 36 months ]
    -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

  7. to assess the mortality among the patients with surgical treatment [ Time Frame: 36 monts ]
    Perioperative mortality is death in relation to surgery, defined as death after surgical resection until discharge and/or readmission

  8. to assess the overall survival (OS) among the patients with surgical treatment [ Time Frame: 36 months ]
    OS defined as the time from diagnosis to death of any cause

  9. disease specific survival (DSS) among the patients with surgical treatment [ Time Frame: 36 months ]
    DSS defined as the time from diagnosis to disease-related death and censored at the last follow-up date if no events had occurred.

  10. to assess the progression-free survival (PFS) among the patients with surgical treatment [ Time Frame: 36 months ]
    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

  11. to assess the morbidity among the patients with non-surgical treatment [ Time Frame: 36 months ]
    morbidity defined as all complication occurred after endoscopic ultrasound procedures until discharge and/or readmission

  12. to assess the mortality among the patients with non-surgical treatment [ Time Frame: 36 months ]
    mortality defined as death in relation to endoscopic ultrasound procedure, occured until discharge and/or readmission

  13. to assess the overal survival (OS) among the patients with non-surgical treatment [ Time Frame: 36 months ]
    OS defined as the time from diagnosis to death of any cause

  14. to assess the disease free survival (DSS) among the patients with non-surgical treatment [ Time Frame: 36 months ]
    DSS defined as the time from diagnosis to disease-related death and censored at the last follow-up date if no events had occurred.

  15. to assess the progression-free survival (PFS) among the patients with non-surgical treatment [ Time Frame: 36 months ]
    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

  16. Quality of life assessment at baseline, 12, 24 and 36 months [ Time Frame: baseline, 12, 24 and 36 months ]
    The quality of life will be assessed using the 12-item Short-Form Health Survey (SF12) self- questionnaire



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patient with pancreatic tumors <2cm (stage 1 discovered incidentally.
Criteria

Inclusion Criteria:

  • patients older than 18 years old
  • with a small size ≤ 2 cm (stage I) non-functioning pancreatic neuroendocrine incidentaloma, cytologically and/or histologically proved or, in case of impossibility to obtain a cyto-histological specimen, with highly suggested diagnosis by imaging (early, homogenous enhancement at computerized tomography (CT- scan) and/or magnetic resonance Imaging (MR)I and positivity at somatostatin receptor scintigraphy (SRS))
  • patient ASA 1-2 (assessed according to ASA physical status classification system of American Society of Anesthesiology)
  • after geriatric evaluation for the patients older than 75 y.o
  • affiliated to a social security system
  • with signed consent for study enrolment.

Exclusion Criteria:

  • Patients < 18 years old
  • Patients with NET with size > 2 cm ( stage II-IV) or NEC and/or with presence of signs suspicious of malignancy
  • Patients with a functioning NET or NEC (clinical syndrome caused by excess hormonal secretion, as insulinoma or Zollinger -Ellison syndrome)
  • Patients with multiple pancreatic neuroendocrine tumors
  • Patients with multiple endocrine neoplasia type 1 (MEN1)
  • Patients with suspicion of non- neuroendocrine tumor
  • Patient ASA 3-4 (assessed according to ASA physical status classification system of American Society of Anesthesiology)
  • Patients with other malignant disease under treatment or with under 5 years remission, except in situ or intramucosal carcinoma.
  • Pregnant or breastfeeding women
  • Patients judged not able to perform the monitoring
  • Absence of signed consent for study enrolment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03022188


Contacts
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Contact: Rodica Gincul, MD +33 4 78 75 67 43 rodica_h13@yahoo.fr
Contact: Thomas Walter, MD,PhD +33 4 72 11 73 98 thomas.walter@chu-lyon.fr

Locations
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Belgium
Clinique Universitaire Saint Luc Recruiting
Louvain, Belgium
Contact: Ivan Borbath, MD,PhD         
Principal Investigator: Ivan Borbath, MD,PhD         
France
Hopital Sud Active, not recruiting
Amiens, France
CHU Angers Active, not recruiting
Angers, France
CHRU Jean Minjoz Active, not recruiting
Besançon, France
Hopital du Haut Leveque Active, not recruiting
Bordeaux, France
Hopital Beaujon Recruiting
Clichy, France
Contact: Maxime Palazzo, MD         
Principal Investigator: Maxime Palazzo, MD         
Hopital Bocage central Active, not recruiting
Dijon, France
Centre Hospitalier Lyon Sud Active, not recruiting
Lyon, France
Hopital Edouard Herriot Recruiting
Lyon, France
Contact: Thomas Walter, Dr         
Principal Investigator: Thomas Walter, Dr         
Hopital Privé Jean Mermoz Recruiting
Lyon, France
Contact: Rodica Gincul, Dr         
Principal Investigator: Rodica Gincul, Dr         
Hopital de la Timone Active, not recruiting
Marseille, France
Hopital Nord Active, not recruiting
Marseille, France
Hopital Privé Européen Active, not recruiting
Marseille, France
Hopital Saint Joseph Recruiting
Marseille, France
Contact: Arthur Laquiere, MD         
Principal Investigator: Arthur Laquiere, MD         
Institut Paoli Calmette Active, not recruiting
Marseille, France
Hotel Dieu Active, not recruiting
Nantes, France
Hopital de l'archet 2 Active, not recruiting
Nice, France
Clinique du Trocadero Recruiting
Paris, France
Contact: Laurent Palazzo, MD         
Principal Investigator: Laurent Palazzo, MD         
Hopital Cochin Active, not recruiting
Paris, France
Hopital Européen George Pompidou Recruiting
Paris, France
Contact: Camille Lorenceau-Savale, MD         
Principal Investigator: Camille Lorenceau-Savale, MD         
Hopital Robert Debré Recruiting
Reims, France
Contact: Guillaume Cadiot, MD-PHD         
Principal Investigator: Guillaume Cadiot, MD-PHD         
CHU Rangueil Active, not recruiting
Toulouse, France
Sponsors and Collaborators
Société Française d'Endoscopie Digestive
Investigators
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Principal Investigator: Rodica Gincul, MD Société Française d'Endoscopie Digestive

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Responsible Party: Gincul Rodica, Medical Doctor, Principal Investigator, Société Française d'Endoscopie Digestive
ClinicalTrials.gov Identifier: NCT03022188     History of Changes
Other Study ID Numbers: CAL-201557
First Posted: January 16, 2017    Key Record Dates
Last Update Posted: July 12, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Gincul Rodica, Société Française d'Endoscopie Digestive:
pancreatic incidentaloma
pancreatic neuroendocrine tumor
EUS-guided fine-needle aspiration
contrast-enhanced endoscopic ultrasound
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue