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Patients randomized in this arm will undergo a robotic pancreaticoduodenectomy.

Patients randomized in this arm will undergo a routine open pancreaticoduodenectomy.

Patients in this arm will undergo a pancreaticoduodenectomy with robotic-assisted techonology.

Robotic pancreaticoduodenectomy

Patients in this arm will undergo an open pancreaticoduodenectomy which is the standard surgical approach.

Open pancreaticoduodenectomy

Jiabin JIN, PhD

Georgios Gemenetzis, MD

jiabin JIN, PhD

Baiyong Shen, PhD

This multicenter randomized trial aims to primarily assess and compare the functional recovery of patients who undergo open versus robotic pancreaticoduodenectomy for benign and malignant lesions of the head of the pancreas.

The PORTAL trial is a Phase 3 multicenter non-inferiority randomized controlled trial that aims to address the question of feasibility and efficacy of the robotic minimally invasive approach in pancreaticoduodenectomy.

In the past 10 years there has been an increasing number of retrospective series from major centers for pancreatic surgery worldwide, that demonstrate similar and occasionally improved postoperative outcomes in patients who undergo a robotic pancreaticoduodenectomy (Whipple). The benefits of this minimally invasive approach appear to be decreased intraoperative estimated blood loss, lower postoperative pain levels and smaller length of hospital stay, whereas postoperative complications rates are comparable with the standard open approach.

This trial is conducted in multiple major centers for pancreatic surgery (open and robotic) in China and aims to address these questions in a prospective fashion. All eligible patients who present to these centers within the study period will be randomized in a 1:1 ratio to either of the two arms (open vs. robotic). Patients enrolled in the study will be blinded regarding the type of the procedure by application of identical wound dressings at the trocar sites and the open incision. Patients will be followed up closely and will be evaluated routinely for quality of life parameters for a period of at least 2 years postoperatively. Additionally, patients who undergo surgery in either arm for pancreatic adenocarcinoma will also be evaluated for time to adjuvant chemotherapy postoperatively, as well as recurrence and survival data.

Robotic Versus Open Pancreaticoduodenectomy for Pancreatic and Periampullary Tumors

Robotic Versus Open Pancreaticoduodenectomy for Pancreatic and Periampullary Tumors: A Multicenter Phase III Non-Inferiority Randomized Controlled Trial

Daily evaluation of patient postoperative course will take place by the nursing and medical staff and will be documented by the study coordinators. Postoperative criteria that need to be fulfilled independently to achieve functional recovery status are the following:

* Discontinuation of intravenous or subcutaneous analgesia and preservation of adequate control levels (pain score)
* Early ambulation and restoration of mobility to an independent level (or to preoperative level if previously impaired)
* Ability to maintain sufficient oral caloric intake as defined by institutional dietitian services, without intravenous fluid support
* No clinical signs of active abdominal infection affecting the patient's performance status: absence of fever, white cell count and C-reactive protein decreasing towards normalization. The patient can be in oral antibiotics.

The number of patients who are fit and well to initiate adjuvant chemotherapy at the 8-week mark after the operation will be documented and compared between the two arms

Comparison of estimated blood loss (in ml)

Comparison of operative time (in minutes, from first incision to skin closure)

Comparison of post-pancreatectomy morbidity between the two surgical approaches, that focus on:

* Pancreatic fistula
* Bile leak
* Chyle leak
* Delayed gastric emptying
* Surgical site infection
* Postoperative pancreatitis
* Postoperative hemorrhage
* Surgical site infections
* Other complications Additional documentation of re-intervention (radiological, endoscopic, or surgical) and re-admission rates, as well as postoperative hospital and ICU length of stay (time to discharge)

Comparison of mortality rates as a result of the pancreaticoduodenectomy in each arm

For assessment of postoperative quality of life (QoL) improvement, patients will be evaluated with the established EuqoQol EQ-5D-5L questionnaire, which is a self-reported assay focusing on five parameters: Pain/discomfort, anxiety/depression, usual activities, self-care, and mobility. Each of the five aforementioned parameters is scored from 0 to 5 (no issue, slight problem, moderate problem, severe problem, unable); patients also score independently their health status on a scale numbered from 0 to 100; 100 means the best health they can imagine, and 0 the worst.

Answered questionnaires will be collected on postoperative days 1, 3, 5, 7, and afterwards every week until day 30. QoL evaluation will terminate at Day 90.

In a sub-cohort of patients with pancreatic adenocarcinoma, the margin resection status (R) will be assessed and compared: R0 is defined as presence of tumor \>1mm from the resection margin, R1 as presence of tumor ≤1mm from the resection margin.

* Number of harvested lymph nodes
* Number of positive lymph nodes (infiltrated by tumor)
* Tumor size, degree of differentiation, perineural and lymphovascular invasion

In a sub-cohort of patients with pancreatic adenocarcinoma, the number of harvested and positive lymph nodes (infiltrated by tumor) will be assessed and compared between the two groups.

Patients with pancreatic adenocarcinoma who undergo resection in each arm will be followed postoperatively to document disease recurrence, defined as the re-presentation of measurable tumor after resection.

Patients with pancreatic adenocarcinoma who undergo resection in each arm will be followed postoperatively to document overall survival, defined as the time between date of operation and date of death.

Comparison of cost between the two groups, defined as the combination of intraoperative and postoperative costs, measured in US Dollars.

Enrolled patients in the study will be consented for peripheral blood draws in multiple time-points to assess the amount of circulating tumor DNA (ctDNA) and assess potential differences between the two groups in patients with pancreatic adenocarcinoma. The blood draws will occur: 1. immediately pre-operatively, 2. Postoperative days 2, 7, and 30.

Patients C-reactive protein (CRP, measured in ng/L) will be assessed with peripheral blood draws on the day of operation, and postoperative days 1, 3, and 7.

Patients neutrophil-to-lymphocyte ratio (NLR, defined as the division of absolute neutrophil number to absolute lymphocyte number) will be assessed with peripheral blood draws on the day of operation, and postoperative days 1, 3, and 7.

Patients Interleukin 6 (IL-6, measured in pg/mL) will be assessed with peripheral blood draws on the day of operation, and postoperative days 1, 3, and 7.

Intuitive Surgical

Ruijin Hospital

Attending Surgeon, Pancreatic Disease Center

all patients treated for ampullary adenocarcinoma (particularly survival without recurrence and prognostic indicators for excised tumours and the duration of disease control for tumours treated with palliative chemotherapy).

treatment for ampullary adenocarcinoma

Julien TAIEB, Pr

JOEL BUTEL

NATHALIE BAIZE

ROMAN COMBES

FRANCK AUDEMAR

CHABRUN

BALHADERE

MICHAEL HUMMELSBERGER

DENIS PEZET

LAURIANNE PLASTARAS

CAMARA

BREYSACHER

SAMY LOUAFI

SYLVAIN MANFREDI

ANTOINE DROUILLARD

JEAN LOUIS JOUVE

MORGAN AMIL

RAME

LALY

Stéphane BENOIST

christophe MARIETTE

GUILLAUME PIESSEN

STEPHANE BOUVIER

YOUNES ZEKRI

MARIELLE GUILLET

MUSTAPHA ADHAM

GRAILLOT

OLIVIER GLEHEN

MARINE BARRAUD BLANC

HERVE PERRIER

CHRISTOPHE LOCHER

MARIE MARTIN BELLECOSTE

CLAIRE PHILIPPE

BRAHIM OUAHRANI

THOMAS APARICIO

ROMAIN CORIAT

CROMBE

JEAN BAPTISTE BACHET

ORIANNE COLUSSI

PERKINS

FAIZA KHEMISSA AKOUZ

David TOUGERON

KARINE BIDEAU

Olivier BOUCHE

ROMAIN DESGRIPPES

YOUSSEF TAZI

DENIS GRASSET

Julien TAIEB

A Vater's ampulloma is a rare digestive tumour which accounts for under 1% of all digestive tumours. The only curative treatment is complete excision (surgical or endoscopic) of the lesions which is possible in 80% of cases , with or without adjuvant treatment. The reference radical treatment is cephalic duodenopancreatectomy (CDP). The indication for adjuvant treatment is still debated: in view of the aggressive nature of the disease and the high recurrence rate, it would appear appropriate to offer adjuvant treatment, although several studies have failed to find any benefit on survival with post-operative radio-chemotherapy, the most widely studied treatment at present, compared to excision alone. At present there are no phase II studies specifically examining medical treatment of degenerated, inoperable Vater's ampullomas. Some groups propose chemotherapies with 5-FU or gemcitabine, analogous to the treatments used for intestinal, pancreatic or biliary tumours, although neither one has been shown to date to be superior to the other, nor have decision-making criteria been clearly established.In conclusion, a national cohort study is proposed to undertake a prospective analysis of the outcome of all patients treated for ampullary adenocarcinoma (particularly survival without recurrence and prognostic indicators for excised tumours and the duration of disease control for tumours treated with palliative chemotherapy). The treatment methods will be left to the free choice of the investigator and all patients may be included, regardless of stage of their disease. In this study, freezing of tumour fragments is encouraged, as this cohort will be supplemented by a later biological study. In order to recruit sufficient patient numbers, the study will be based on participation of the cooperative groups involved in the management of digestive cancers.

A Vater's ampulloma is a rare digestive tumour which accounts for under 1% of all digestive tumours. In terms of incidence, it is the 3rd most common biliary tract tumour after gallbladder cancer and common bile duct cancer. The incidence of ampullary adenocarcinoma is not well known although it is estimated to be around 0.49 per 100,000 people. The known risk factors are familial adenomatous polyposis (FAP) and Gardner's syndrome, HNPCC (Hereditary Non-Polyposis Colorectal Cancer) syndrome, Peutz-Jeghers syndrome, Crohn's disease and coeliac disease.

Except in its highly localised forms, ampulla of Vater carcinoma carries a poor prognosis. It is a highly lymphophilic disease which commonly metastasises, particularly to the lymph nodes and liver. The prognosis is however considerably better than that of pancreatic adenocarcinoma. In one study which compared 71 ampullomas with 144 adenocarcinomas of pancreatic head, the 5-year survival was 60% for the ampullary carcinomas compared to 20% for pancreatic adenocarcinomas.

More generally, the 5-year survival rate in the literature is between 40-60% and, depending on the study, 10-year survival is approximately 38% .

The only curative treatment is complete excision (surgical or endoscopic) of the lesions which is possible in 80% of cases , with or without adjuvant treatment. The reference radical treatment is cephalic duodenopancreatectomy (CDP). The 5-year survival rate in cases of adenocarcinoma excised by CPD is in the region of 50%, rising to 60-70% if no lymph node invasion is present, compared to 30% when lymph nodes are invaded and median survival is approximately 4.5 years .

The indication for adjuvant treatment is still debated: in view of the aggressive nature of the disease and the high recurrence rate, it would appear appropriate to offer adjuvant treatment, although several studies have failed to find any benefit on survival with post-operative radio-chemotherapy, the most widely studied treatment at present, compared to excision alone . There is only one single randomised study comparing these two forms of management, which shows no benefit in terms of 2 and 5-year survival, although only a small number of patients had an ampullary tumour in this study . The conclusions of several retrospective studies are more subtle, showing results in favour of adjuvant treatment in patients with lymph node disease or a large tumour (T3/T4) .

Some groups have tested the merits of peroperative irradiation. It would appear that this technique does not improve survival, although data on this subject are extremely patchy .

Administration of exclusive adjuvant chemotherapy has been examined in a single randomised study. In this phase III study (ESPAC 3), median overall survival of patients who received adjuvant chemotherapy with FUFOL Mayo for 6 months (n=101) or gemcitabine (n=98) was not significantly improved compared to survival in patients undergoing surgery and not receiving complementary treatment (57.1 versus 43 months, HR= 0.85, p=0.32). A subgroup analysis suggested that the benefit of chemotherapy could be greater in the subgroup of patients with RO resection (p= 0.057, 91% of cases).

Mean survival in patients suffering inoperable tumours is between 9 and 20.4 months depending on the study .

It should be noted however that most of these studies have included tumours other than ampullomas (particularly small bowel adenocarcinomas), making it more difficult to interpret these results, and also that many are old results dating from before the era of modern chemotherapies.

At present there are no phase II studies specifically examining medical treatment of degenerated, inoperable Vater's ampullomas. Some groups propose chemotherapies with 5-FU or gemcitabine, analogous to the treatments used for intestinal, pancreatic or biliary tumours, although neither one has been shown to date to be superior to the other, nor have decision-making criteria been clearly established. One phase II study published in 2009 proposed CAPOX as the reference treatment in light of the promising results obtained. Patients suffering from ampullary cancer in this study however were combined with patients who were suffering from small bowel adenocarcinoma.

In conclusion, a national cohort study is proposed to undertake a prospective analysis of the outcome of all patients treated for ampullary adenocarcinoma (particularly survival without recurrence and prognostic indicators for excised tumours and the duration of disease control for tumours treated with palliative chemotherapy). The treatment methods will be left to the free choice of the investigator and all patients may be included, regardless of stage of their disease. In this study, freezing of tumour fragments is encouraged, as this cohort will be supplemented by a later biological study. In order to recruit sufficient patient numbers, the study will be based on participation of the cooperative groups involved in the management of digestive cancers.

Survival and Description of Care for Patients With Degenerate Vaterian Ampulloma

Study of Survival and Description of Care for Patients With Degenerate Vaterian Ampulloma

The time interval between the date of diagnosis of the disease and date of death (all causes). Patients who are alive will be censured at the date of last news.

The time interval between the date of diagnosis of the disease and the date of the recurrence or death (all causes). Patients who are alive without recurrence will be censured at the date of last news.

Time interval between the date of starting treatment and the date of first progression (local or remote, clinical or radiological) or death (all causes). Patients who are alive without progression will be censured at the date of last news. Radiological progression will be defined according to RECIST version 1.1 criteria.

Federation Francophone de Cancerologie Digestive

Fistula

Pancreatic Fistula

Pathological Conditions, Anatomical

Pharmaceutical Solutions

All Drugs and Chemicals

Gastrointestinal Agents

Pancrelipase

Pancreatin

Patients benefited from total pancreatectomy for resectable adenocarcinoma of the cephalic region at high risk of postoperative pancreatic fistula, with intaportal/intramuscular islet autotransplantation

The total pancreatectomy will be performed in two steps: The pancreatectomy will begin by a standard pancreaticoduodenectomy procedure.

The section margin will be sent for intraoperative histological analysis to confirm the absence of invasion of the left remnant pancreas.

When absence of tumor invasion is confirmed and the high-risk of postoperative pancreatic fistula is validated intraoperatively, the extended left distal pancreatectomy will be performed, with splenic preservation when possible.

Then, the left side of the pancreas will be resected and cooled (4-6°) in the preservation solution and shipped to Lille Biotherapy platform to perform islet isolation and purification. The reconstruction after total pancreatectomy will be done as usually performed by center expert surgeon.

total pancreatectomy

The final islet preparation will be cultured and shipped 48 hours after total pancreatectomy from the Lille laboratory to the surgical center, and finally transplanted into the patient through a venous catheter placed in the portal trunk (91% of the total islet mass) and at the same time, a small fraction of the isolated islet (5% of the total islet mass) will be transplanted into the forearm muscle.

intraportal islet autotransplantation

François PATTOU, MD,PhD

Curative management of locally resectable invasive adenocarcinomas located in the cephalic region of the pancreas (pancreas, duodenum and ampulla of Vater) requires a pancreaticoduodenectomy followed by adjuvant chemotherapy. Pancreaticoduodenectomy is a major surgery that often leads to major complications including approximately 20% of relevant clinical postoperative pancreatic fistula.

Postoperative complications following pancreaticoduodenectomy can lead to early discontinuation of the complete oncologic strategy, i.e., chemotherapy for malignancy is performed in only about a third of patients who experienced a grade C fistula.

A total pancreatectomy rather than a pancreaticoduodenectomy is an alternative procedure that involves the complete and definitive resection of all pancreatic tissue, eliminating any risk of postoperative pancreatic fistula but is associated with unavoidable endocrine insufficiency and potentially severe metabolic complications, such as "brittle diabetes".

Total Pancreatectomy following by intraportal Islet AutoTransplantation (TPIAT) can prevent "brittle diabetes" and improve the quality of life. The endocrine islets can be isolated from the pancreatic surgical specimen with standardized procedures and transplanted in the liver through intraportal infusion, in absence of immunosuppression and allow adequate control of glucose metabolism with a reduced need for exogenous insulin and an effective graft function in 70% of cases at 3 years Thereby, the investigators hypothesize that total pancreatectomy with intraportal Islet autotransplantation rather than classical pancreaticuduodenectomy, in patients with high-risk of postoperative fistula will increase the rate of complete access to adjuvant chemotherapy, while maintaining an adequate metabolic control.

Curative management of locally resectable invasive adenocarcinomas located in the cephalic region of the pancreas (pancreas, duodenum and ampulla of Vater) requires a pancreaticoduodenectomy followed by adjuvant chemotherapy. Pancreaticoduodenectomy is a major surgery that often leads to major complications including approximately 20% of relevant clinical postoperative pancreatic fistula. Severe postoperative pancreatic fistulas (grade C) require reoperation or lead to organ failure and/or mortality. In an extensive international registry study of pancreaticoduodenectomy procedures, chemotherapy for malignancy was performed in only about 33% (on time in 7% and delayed in 25.6 % of patients) and never delivered in about 67,4 % of patients who experienced a grade C fistula. Therefore, postoperative complications following pancreaticoduodenectomy can lead to early discontinuation of the complete oncologic strategy.

A total pancreatectomy rather than a pancreaticoduodenectomy is an alternative procedure that involves the complete and definitive resection of all pancreatic tissue, eliminating any risk of postoperative pancreatic fistula.

Total pancreatectomy could represent a major shift in the surgical management of patients with a high-risk of postoperative fistula by eliminating the life-threatening risk associated with fistula and by increasing the opportunity to initiate and to complete adjuvant chemotherapy without delay.

However, total pancreatectomy is associated with unavoidable endocrine insufficiency and potentially severe metabolic complications, such as "brittle diabetes".

Total Pancreatectomy with intraportal Islet AutoTransplantation (TPIAT) is currently performed in patients with chronic pancreatitis under chronic pain failing endoscopic treatment and dependent on long-term opioid treatment.

Therefore, islet autotransplantation following total pancreatectomy can prevent "brittle diabetes" and improve the quality of life.

The endocrine islets can be isolated from the pancreatic surgical specimen with standardized procedures and transplanted in the liver through intraportal infusion, in absence of immunosuppression and allow adequate control of glucose metabolism with a reduced need for exogenous insulin and an effective graft function in 70% of cases at 3 years

Thereby, the investigators hypothesize that total pancreatectomy with intraportal Islet autotransplantation rather than classical pancreaticuduodenectomy, in patients with high-risk of postoperative fistula will increase the rate of complete access to adjuvant chemotherapy, while maintaining an adequate metabolic control.

Efficacy and Safety of TPIAT for Resectable Adenocarcinoma of the Pancreas Region at High Risk of Postoperative Fistula

Efficacy and Safety of Total Pancreatectomy With Intraportal Islet Autotransplantation for Resectable Adenocarcinoma of the Cephalic Region of the Pancreas at High-risk of Postoperative Fistula and Requiring Systemic Adjuvant Chemotherapy

success is defined when patients treated with TPIAT will have completed the adjuvant systemic chemotherapy initially approved and planned by the local multidisciplinary expert team according to current international guidelines

postoperative complication will be evaluated with Dindo Clavien classification

complications related to islet transplantation will be reported according to CTCAE v5.0.

the time in weeks between TPIAT procedure and the adjuvant systemic chemotherapy will be reported

The cancer recurrence will be assessed according standard of care imaging (Thorax multi-detection Computed Tomography, Abdomino-pelvis imaging : Mutli-detection Computed Tomography OR Magnetic Resonance Imaging) through the follow up using the Recist 1.1 criteria

Postopeartive diabetes and exocrine insufficiency will be evaluated with clinical examination (symptoms, Pancreatic enzyme replacement therapy dosage, Diabetes medication : non insulin medication, insulin (daily insuline dosage UI/kg); blood samples (Fasting C-peptide and glycemia, Post-prandial C-peptide and glycemia, HbA1C (%))

EORTC QLQ-C30 and QLQ -PAN26 are self-completion questionnaires specific to cancer patients quality of life and pancreatic cancer patients quality of life

adverse events will be reported according to CTCAE v5.0 and classified according to their suspected or confirmed reason (i.e. chemotherapy, intraportal islet transplantation, pancreatic surgery)

Islet transplantation succes status is defined by HbA1C \< 7% AND no severe hypoglycemic event

Islet transplantation succes status is defined by HbA1C \< 7% AND no severe hypoglycemic event AND C-peptide ≥ 0.2 ng/mL

Defined by the Beta 2 score calculated at 1 month post TPIAT using blood sample with fasting C peptide and glycemic, HbA1c and exogenous insuline requirement

Serious Hypoglycemic Event is defined as one requiring third-party assistance or resulting in hospitalization in an intensive care unit

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Robotic Versus Open Pancreaticoduodenectomy for Pancreatic and Periampullary Tumors	NCT04400357	Pancreatic Aden... Pancreatic Cyst... Pancreatic Endo... Chronic Pancrea... Cholangiocarcin... Ampullary Adeno... Duodenal Adenoc...	Robotic pancrea... Open pancreatic...	18 Years -	Ruijin Hospital
Robotic Versus Open Pancreaticoduodenectomy for Pancreatic and Periampullary Tumors	NCT04400357	Pancreatic Aden... Pancreatic Cyst... Pancreatic Endo... Chronic Pancrea... Cholangiocarcin... Ampullary Adeno... Duodenal Adenoc...	Robotic pancrea... Open pancreatic...	18 Years -	Ruijin Hospital
Survival and Description of Care for Patients With Degenerate Vaterian Ampulloma	NCT03800212	Ampullary Adeno...	treatment for a...	18 Years -	Federation Francophone de Cancerologie Digestive
Efficacy and Safety of TPIAT for Resectable Adenocarcinoma of the Pancreas Region at High Risk of Postoperative Fistula	NCT05116072	Adenocarcinoma ... Adenocarcinoma ... Ampullary Adeno...	total pancreate... intraportal isl...	18 Years -	University Hospital, Lille
Efficacy and Safety of TPIAT for Resectable Adenocarcinoma of the Pancreas Region at High Risk of Postoperative Fistula	NCT05116072	Adenocarcinoma ... Adenocarcinoma ... Ampullary Adeno...	total pancreate... intraportal isl...	18 Years -	University Hospital, Lille

Spots Global Cancer Trial Database for ampullary adenocarcinoma