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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Процедура total pancreatectomy
  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 possi
• Биопрепарат intraportal islet autotransplantation
  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.

Первичные конечные точки

• the rate of patients who have completed the chemotherapy planned [Срок оценки: at postoperative month 12 following surgery.]

Вторичные конечные точки (12)

• Rate of postoperative complications related to total pancreatectomy. [Срок оценки: At 3 months following surgery.]
• Rate of complications related to islet transplantation during the study [Срок оценки: through study completion, at 36 months following surgery.]
• Mean time (in weeks) between TPIAT and adjuvant systemic chemotherapy. [Срок оценки: through study completion, at 36 months following surgery.]
• Rate of patients with cancer recurrence [Срок оценки: at 3, 6, 9, 12, 24, and 36 months following surgery.]
• Postoperative diabetes and pancreatic endocrine insufficiency following pancreatic surgery as recommended by the best standard care will be evaluated [Срок оценки: functions before surgery and at day 7 and at 3, 12, 24 and 36 months following surgery.]
• EORTC QLQ-C30 core with it specific pancreatic module QLQ -PAN26 [Срок оценки: at 3, 12, 24 and 36 months following surgery.]
• Rate of adverse events [Срок оценки: through study completion, at 36 months following surgery.]
• Mortality rate [Срок оценки: at day 7 and at 3, 12, 24 and 36 months following surgery.]
• islet transplantation success rate defined by CIT criteria [Срок оценки: at 3, 12, 24 and 36 months following surgery.]
• islet transplantation success rate defined by IGLS 2.0 criteria [Срок оценки: at 3, 12, 24 and 36 months following surgery.]
• Primary islet Graft Function [Срок оценки: at 1 month following TPIAT.]
• mean number of Serious Hypoglycemic Event (SHE) since last visit [Срок оценки: at day 7 and months 3, 12, 24 and 36 following surgery.]

Критерии участия

Критерии включения

Inclusion criteria are composed of preoperative conditions validated by intraoperative confirmation to plan an exit of the protocol if the pancreas does not finally appear with a high-risk of CR-POPF.

• Age ≥ 18 years
• Locale resectable invasive adenocarcinomas located in the cephalic region of the pancreas documented by endoscopic ultrasonography with fine-needle aspiration biopsy
• pancreatic adenocarcinoma;
• duodenal adenocarcinoma;
• ampullary adenocarcinoma;
• and IPMNs with adenocarcinoma degeneration;
• A potentially curative strategy with primary tumor resection approved by a multidisciplinary expert team
• A high-risk of CR-POPF

• Suspected during preoperative evaluation by the presence of 2 or more of the following criteria (screening criteria of inclusion) : sex male;an obesity (BMI ≥ 30 kg/m2);a main pancreatic duct diameter ≤ 3 mm on preoperative endoscopic ultrasonography a visceral obesity (i.e. a visceral fat area > 84 cm2) ; a sarcopenia (i.e. a skeletal muscle index < 43 cm2/m2 in men with a BMI of <25 kg/m2 or <53 cm2/m2 in men with a BMI of ≥25 kg2/m2, and <41 cm2/m2 in women)
• and validated during intraoperative evaluation (finale inclusion) by a probability score above or equal to 20% on the validated updated alternative Fistula Risk Score ua-FRS for pancreaticoduodenectomy (ua-FRS) based of pancreas texture, duct size, BMI, sex .
• Women of childbearing potential should only be included after a confirmed menstrual period, and a negative highly sensitive urine or serum pregnancy test and must agree to be subjected to a monthly pregnancy test (urine or blood) until the end of the relevant systemic exposure to chemotherapy agents, in accordance with current CTFG recommendations (Recommendations related to contraception and pregnancy testing in clinical trials);
• Women of child-bearing potential and male subjects must agree to use a birth control methods which may be considered as highly effective (failure rate of less than 1% per year ) as recommended by the CTFG (Cinical Trials Facilitation and Coordination Group, version 1.1). These recommandations related to contraception and pregnancy testing in clinical trials suggested such method (see below) that will be use during chemotherapy exposure for included women of child-bearing potential and woman of child-bearing potential when partner of included male : combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal) ; progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable) ; intrauterine device (IUD) ; intrauterine hormone-releasing system ( IUS) ; bilateral tubal occlusion; vasectomised partner ;sexual abstinence For included male partner of a women of child-bearing potential, contraception with condom.

Contraception will be perform during the relevant systemic exposure to chemotherapy agents and will be extended by 6 months for women of childbearing potential and by 1 month for men included as recommended by the CTFG

• Patient covered by a health insurance system
• Patient who provides a written informed consent to participate to the study

Критерии исключения

• Patient will be screened and excluded if they present a preoperative diabetes defined by a stimulated C-peptide < 0.5 ng/mL relative to blood glucose > 2 g/dL, at 2 hours in post prandial
• Patients with a known or highly suspected genetic syndrome associated with a risk of pancreatic adenocarcinoma: familial pancreatic cancer, multiple familial melanoma, Peutz-Jeghers syndrome, hereditary chronic pancreatitis, cystic fibrosis, familial breast Ovarian Cancer, Lynch syndrome, adenomatous polyposis family, Li Fraumeni syndrome, Multi-endocrine disorder type I;
• Multifocal pancreatic adenocarcinomas identified during preoperative evaluation;
• Performance status and comorbidity profile inappropriate for a major abdominal surgery;
• Contraindication for autologous islet intraportal transplantation
• Current or indicated/scheduled neoadjuvant chemotherapy;
• Extra pancreatic metastasis identified during preoperative evaluation (high-definition cross-sectional imaging with thorax-abdomen-pelvis multi-detection computed tomography or abdominal MRI with T1, T2 and diffusion weighted sequences) or during intraoperative assessment (clinical examination and ultrasonography);
• Need for complex vascular reconstructions (endovascular treatment or release of the arcuate ligament will be not considered as complex vascular reconstructions), major vein reconstructions will exclude the patients because of the over-risk of portal thrombosis following islet intraportal infusion.
• evident macroscopically or biologically proved post biliary drainage pancreatitis that jeopardize islet isolation
• Known infection or positive serology performed at screening for human immunodeficiency virus (HIV) infection, Hepatitis B or C virus infection, HTLV infection or syphilis infection.
• Active infection for SARS-CoV-2 virus (positive PCR), which will require rescheduling of the intervention 30 days later.
• Pregnant or breastfeeding woman
• Dihydropyrimidine dehydrogenase total deficiency
• Ethics / regulatory criteria :

• Person unable to understand purposes, benefits and risks of the study and/or unable to provide a written informed consent.
• Person unable to comply with the whole study schedule.
• Person not covered by a health insurance system.
• Person kept in detention and/or receiving psychiatric medical care and/or patients admitted in a social or medical sanatorium.
• Person in an emergency situation.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 1 центр

• Hop Claude Huriez Chu Lille — Lille

Идентификаторы

NCT: NCT05116072 · 2019_27 · 2021-A00136-35

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗