Clinical trial NCT03022188: Nonfunctioning Small (≤2 cm) Neuroendocrine Pancreatic Incidentaloma
Official title: Nonfunctioning Small (≤2 cm) Neuroendocrine Pancreatic Incidentaloma: Clinical and Morphological Findings, and Therapeutic Options (IPANEMA)
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Neuroendocrine Tumors
Keywords: pancreatic incidentaloma
pancreatic neuroendocrine tumor
EUS-guided fine-needle aspiration
contrast-enhanced endoscopic ultrasound
Lead sponsor: Société Française d'Endoscopie Digestive
Sponsor class: OTHER
First posted: 2017-01-16
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patient with pancreatic tumors \<2cm (stage 1 discovered incidentally.

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.

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.

Eligibility 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

Primary outcomes:
measure: rate of malignancy among nonfunctioning (NF) small (≤ 2 cm) pancreatic neuroendocrine incidentalomas (PNEI).
timeFrame: 36 months
Secondary outcomes:
measure: progression rate among NF-PNEI ≤ 2cm in case of non-surgical management
timeFrame: 36 months
measure: determination of Ki67 value
timeFrame: 36 months
measure: performance of contrast harmonic endoscopic ultrasound (CH-EUS) for the diagnosis of malignancy
timeFrame: 36 months
measure: rate of surgical treatment, delay from diagnosis to surgery and rationale
timeFrame: 36 months
measure: the rate of non-surgical management and the reasons that determined the choice of this therapeutic option
timeFrame: 36 months
measure: to assess the morbidity among the patients with surgical treatment
timeFrame: 36 months
measure: to assess the mortality among the patients with surgical treatment
timeFrame: 36 monts
measure: to assess the overall survival (OS) among the patients with surgical treatment
timeFrame: 36 months
measure: disease specific survival (DSS) among the patients with surgical treatment
timeFrame: 36 months
measure: to assess the progression-free survival (PFS) among the patients with surgical treatment
timeFrame: 36 months
measure: to assess the morbidity among the patients with non-surgical treatment
timeFrame: 36 months
measure: to assess the mortality among the patients with non-surgical treatment
timeFrame: 36 months
measure: to assess the overal survival (OS) among the patients with non-surgical treatment
timeFrame: 36 months
measure: to assess the disease free survival (DSS) among the patients with non-surgical treatment
timeFrame: 36 months
measure: to assess the progression-free survival (PFS) among the patients with non-surgical treatment
timeFrame: 36 months
measure: Quality of life assessment at baseline, 12, 24 and 36 months
timeFrame: baseline, 12, 24 and 36 months
Other outcomes:
Locations:
city: Louvain
country: Belgium
facility: Clinique Universitaire Saint Luc
city: Amiens
country: France
facility: Hopital Sud
city: Angers
country: France
facility: CHU Angers
city: Besançon
country: France
facility: CHRU Jean Minjoz
city: Bordeaux
country: France
facility: Hopital du Haut Leveque
city: Clichy
country: France
facility: Hopital Beaujon
city: Dijon
country: France
facility: Hopital Bocage central
city: Lyon
country: France
facility: Centre Hospitalier Lyon Sud
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Lyon
country: France
facility: Hopital Privé Jean Mermoz
city: Marseille
country: France
facility: Hopital de la Timone
city: Marseille
country: France
facility: Hopital Nord
city: Marseille
country: France
facility: Hopital Privé Européen
city: Marseille
country: France
facility: Hopital Saint Joseph
city: Marseille
country: France
facility: Institut Paoli Calmette
city: Nantes
country: France
facility: Hotel Dieu
city: Nice
country: France
facility: Hopital de l'archet 2
city: Paris
country: France
facility: Clinique du Trocadero
city: Paris
country: France
facility: Hopital Cochin
city: Paris
country: France
facility: Hopital Européen George Pompidou
city: Reims
country: France
facility: Hopital Robert Debré
city: Toulouse
country: France
facility: CHU Rangueil
Study officials:
affiliation: Société Française d'Endoscopie Digestive
name: Rodica Gincul, MD
role: PRINCIPAL_INVESTIGATOR
References: