Total Pancreatectomy or High-risk Pancreatic Anastomosis After Pancreatoduodenectomy (TETRIS): a Randomized Controlled Trial
Phase: NA
Conditions: Pancreatic Fistula
Sponsor: Azienda Ospedaliera Universitaria Integrata Verona

Total pancreatectomy or high-risk pancreatic anastomosis 
after pancreatoduodenectomy (TETRIS): 
a randomized controlled trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 3, 04/10/21 
Trial: TETRIS (Total pancrEaTectomy or high-Risk anastomosIS) 
Sponsor: Università degli Studi di Verona 
Clinical Center: Department of General and Pancreatic Surgery 
Coordinator: Giovanni Marchegiani 
Principal investigator: Roberto Salvia 
 
 

ABBREVIATIONS 
DGE= delayed gastric emptying 
ETS= external transanastomotic stent   
FRS= fistula risk score 
HR-PD= high-risk pancreatoduodenectomy 
IPMN= intraductal papillary mucinous neoplasm 
NGT= nose gastric tube 
PD= pancreatoduodenectomy 
PDAC= pancreatic ductal adenocarcinoma 
PJ= pancreaticojejunostomy 
POD= postoperative day 
POPF= postoperative pancreatic fistula 
PPH= post-pancreatectomy hemorrhage 
QoL= quality of life  
TP= total pancreatectomy 
 
 
 
 
 
 

INTRODUCTION 
 
Postoperative pancreatic fistula (POPF) is the main driver of surgical morbidity after pancreatoduodenectomy 
(PD).  
Several score systems have been proposed in order to intraoperatively stratify patients based on their risk of 
developing POPF, allowing a risk-adjusted approach to the reconstructive phase of PD.1 2 The fistula risk score 
(FRS) is the most used and extensively validated, and it is based on predictors such as pancreatic parenchyma 
texture, presumed pathology, main pancreatic duct diameter and estimated intraoperative blood loss (EBL). 
This prognostic score is able to identify a high-risk cohort (FRS 7-10) representing about 10% of all PDs and 
having an increased rate of POPF (around 30% and up to  40% in the FRS 10 patients) and consequently worse 
postoperative outcomes with a major postoperative morbidity around 35%.3,4 Recently, a large multi-
institutional retrospective study and  a randomized controlled trial both identified  an optimal combination 
of  therapeutic strategies able to mitigate the incidence and the burden of POPF in high-risk patients. Those 
“mitigation strategies” were the use of externalized trans-anastomotic stent (ETS), pancreatico-jejunal 
anastomosis (PJ), drains placement and the omission of prophylactic octreotide. 4 5 However, both morbidity 
and mortality rates after high-risk PD (HR-PD) remain extremely high, even after the implementation of the 
above-mentioned strategies.5 Due to its clinical burden, POPF is still associated with delays (> 8 weeks) or 
omission of adjuvant therapy in two-thirds of complication-bearing patient. 4 
Given the increased postoperative burden of high-risk PDs, total pancreatectomy (TP) might be advocated 
for those who are at a high-risk for POPF, especially after recent studies showing improved postoperative 
outcomes of TP at high-volume centers. Stoop et al. found that the historic major postoperative morbidity of 
34%  after TP decreases to 23% when considering only the most recent years, similarly to another bicentric 
study including patients undergoing TP from 2000 to 2014.6 7 A more recent multicenter snapshot study, 
including TP performed at both high- and low- volume centers between 2018 and 2019, showed a major 
morbidity of 25% and an in-hospital mortality of 5%.8 Moreover, recent studies have reported improved 
postoperative quality of life (QoL) after TP compared to the past, presumably due to centralization at high-
volume centers and development of long-acting insulin and modern pancreatic enzyme preparations.6 9 10 7  
Given the encouraging postoperative outcomes after TPs at high-volume centers, we conducted a 
retrospective analysis of all PDs and TPs performed at the Verona Pancreas Institute from July 2017 to 
December 2019 to evaluate TP as an alternative to PD in patients at high risk for POPF development.11 Albeit 
the extensive application of the currently recognized mitigation strategies in the HR-PD group, including the 
use of externalized pancreatic stent and jejunostomy, patients who underwent TP exhibited comparable 
mortality (3% vs 4%, p= 0,6) and strikingly better postoperative outcomes. In the HR-PD group, the rates of 
abdominal fluid collection, PPH, DGE, and LOS were nearly doubled, and the rate of sepsis was three times 
higher than those in the TP group. Major morbidity defined as Clavien-Dindo ≥ 3 was 1,5-fold higher in the 
HR-PD group (19% vs 31%; p= 0,05). Additionally, cancer- and pancreas- specific QoL seemed to be 
comparable, while endocrine insufficiency and insulin-dependent diabetes occurred in the totality of patients 
after TP and TP was associated with worse diabetes-specific QoL. Furthermore, we identified a small cohort 
of patients (FRS 9-10) at extremely high-risk for POPF (60%) and major morbidity (55%).  
This retrospective analysis suggests a role for TP after PD in selected patients at extremely high-risk for POPF 
after adequate counselling. For the sake of making progress in the management of the pancreatic remnant 
in high-risk scenario, we firmly believe that these findings need to be confirmed in a randomized fashion.  
 
 
 
 

AIM OF THE STUDY  
In patients at extremely high risk for POPF and related severe complications, TP may represent a potential 
rescue strategy to avoid the morbidity related to the pancreatic anastomosis.  
The aim of the present study is to compare TP and primary pancreatic anastomosis (PA) in a cohort of 
extremely high-risk patients. 
 
OBJECTIVES 
 
PRIMARY OBJECTIVE 
To evaluate whether TP is superior to PA in reducing major morbidity, defined as Clavien-Dindo ≥3, in patients 
with extremely high-risk pancreas. 
 
SECONDARY OBJECTIVES  
- To evaluate the incidence and severity of general and pancreas-specific (POPF, postoperative pancreatitis, 
DGE, PPH, sepsis) postoperative complications and mortality in each group 
- To evaluate time to functional recovery and length of hospital stay (days) in each group 
- To evaluate the incidence and severity of postoperative endocrine and exocrine insufficiency in each group 
- To evaluate the access to adjuvant chemotherapy (when indicated) 
- To evaluate cancer-specific, pancreas-specific, and diabetes-related QoL in each group 
 
MATERIAL AND METHODS  
The study will be organized as a multicentric randomized controlled trial. When a patient will be considered 
eligible preoperatively, he or she will be enrolled in the present study.  
The patient’s risk will be allocated intraoperatively after the demolitive time and before pancreatic 
anastomosis, according to the following criteria:  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Table 1 Eligible patients will have two major and one or more minor criteria confirmed by at least two 
surgeons 
 
Major Criteria 
Main pancreatic duct diameter ≤3mm 
Soft pancreas 
Minor Criteria 
Bleeding stump 
Friable stump 
Posterior/Eccentric duct 
Invisible duct 
Deep pancreas 
Intraoperative acute pancreatitis 
FRS 9-10 
Interobserver agreement 
≥2 Surgeons 
 

Patients presenting with all major criteria (stage D according to Schuh et al.12) and at least one among the 
minor criteria will be considered eligible. At least two surgeons must confirm eligibility, according to 
interobserver agreement regarding the above-mentioned criteria and ethical applicability of randomization 
(ethical “guarantor”). Eligible patients will be randomized to receive PA or TP. 
Pre-operative, intra-operative and post-operative data will be recorded prospectively by the P.I. and by his 
collaborators. 
 
Population 
 
Inclusion criteria  
Preoperative  
- 
Patients older than 18 years 
- 
All patients scheduled for PD for all kind of pancreatic diseases 
- 
Patients able to give their informed consent 
Intraoperative  
- 
Patients undergoing PD (Kausch-Whipple or Longmire-Traverso) 
- 
Patients presenting two major and at least one minor criteria (Table 1) 
- 
Two or more surgeons confirming eligibility 
- 
PA or TP with or without spleen preservation (Kimura technique). These techniques are consistent 
with clinical practice; any other procedure will be a deviation from the protocol 
 
Surgical techniques different from those mentioned in the section “procedures” will be considered as a 
violation of the current protocol. 
 
Drop-out criteria  
Preoperative  
- 
Informed consent withdrawal 
- 
Impossibility to undergo surgery for any reason 
- 
Main pancreatic duct of the pancreatic neck/body >3mm at preoperative imaging (CT scan or MRI) 
Intraoperative  
- 
PD not performed for any reason 
- 
Absence of two major criteria 
- 
Absence of at least one minor criteria 
- 
Absence of interobserver agreement between at least 2 surgeons 
- 
More than 1 extension of resection to pancreatic neck due to pancreatic margin positivity  
Postoperative  
- 
Wrong randomization 
 
Procedures  
 
Preoperative care  
Preoperative care will follow institutional standards, according to each center involved. After obtaining the 
informed consent for elective pancreatic resection and after adequate counselling, the study will be proposed 
to the patient. Patients with a main pancreatic duct of the pancreatic neck/body >3mm at preoperative 
imaging (CT scan or MRI) will be excluded. If the patient will accept, the informed consent will be obtained. 
The physician who will get the informed consent for the procedure will also be responsible for the consent 

to the study. Randomization lists will be provided for each Center and for each randomized group. All patients 
will be preoperatively checked for diabetes by measuring fasting blood glucose (FBG) and Hb1Ac, C- peptide, 
and for pancreatic exocrine insufficiency by associated clinical criteria and fecal elastase-1 (FE-1) 
determination. 
 
Intraoperative setting 
The resection phase will be carried out according to clinical practice at each participating center. At the time 
of pancreatic anastomotic reconstruction, the risk will be calculated on the basis of the presence of major 
and minor criteria (see Table 1):  
- 
The operating surgeon will assess pancreatic texture by manual palpation (only the distinction 
between “hard” and “soft” is allowed; the expert pancreatic surgeon manual palpation represents 
the gold standard for pancreatic texture assessment)13 
- 
The operating surgeon will precisely measure the main pancreatic duct caliber in millimeters 
- 
The operating surgeon will assess other risk features related to the pancreatic remnant such as: 
presence of bleeding, friable or deep pancreatic stump14 ; presence of invisible, eccentric or posterior 
main pancreatic duct; presence of intraoperative pancreatitis; FRS 9 or 101 
- 
The operating surgeon will confirm the presumed pathology and estimated blood losses will be 
assessed in order to calculate the FRS 
The operating surgeon will decide whether the patient can be included in the study or must be excluded for 
the presence of any drop-out criteria (see above). The interobserver agreement of at least another surgeon 
will serve as a confirmation for the inclusion in the trial (ethical “guarantor”). According to the presence of 
two major and one or more minor criteria patients will be included in the study and randomized in two 
groups. A picture of the pancreatic remnant will be taken intraoperatively before anastomosis/totalization. 
Both patients undergoing open and minimally invasive surgery can be considered eligible. 
 
PA Group 
PA will be carried out according to the techniques adopted by the participating Centre, either pancreatico-
jejunostomy (PJ) (i.e. dunking PJ, Cattel-Warren duct-to-mucosa PJ, Blumgart PJ) or pancreatico-gastrostomy 
(PG) will be considered eligible. Any mitigation strategy (i.e. ETS, use of glues/biological matrices to protect 
the anastomosis, surgical feeding jejunostomy, prophylactic hydrocortisone/somatostatin administration) 
can be used according to the Center practice. The other two anastomosis, hepaticojejunostomy and 
duodenojejunostomy (in case of Longmire-Traverso PD) or gastrojejunostomy (in case of Kausch-Whipple 
PD), will be carried out as usual according to each Institution’s operative standards.15  
At least one surgical drain will be placed in the retroperitoneum in all patients. 
 
TP Group 
TP will be carried out according to each Institution’s operative standards. Preservation of the spleen will be 
considered whenever possible according to Kimura technique. Either ligation or preservation of gastric 
vessels (right/left gastric artery/vein) will be allowed according to clinical necessity but will be recorded and 
correlated with postoperative outcomes.16  
The reconstruction phase will be carried out according to each Institution’s operative standards. One or more 
surgical drains can be left in place according to surgeon’s preference. 
 
Postoperative care 
After the procedure, the patient will be admitted to the ICU or in the ward. The management of intravenous 
fluids, nasogastric tube, bladder catheter and postoperative analgesia will take place as usual according to 

each Institution’s standards of care. In the PJ Group, the amylase value of drain fluids will be checked on 
POD1, POD3 and at any POD if it will help to diagnose a still undiscovered POPF. Surgical drain will be 
managed according to clinical judgment and each Institution’s clinical standards. During hospitalization, all 
patients will receive specialistic evaluation to assess and possibly treat the occurrence of new onset diabetes 
or the worsening of pre-existing diabetes. Pancreatic exocrine insufficiency will be treated with oral 
supplementation of pancreatic enzymes if needed. Patients in the TP Group will be vaccinated 1 month after 
complete functional recovery against Pneumococcus, Hemophilus influenzae group B, and Meningococcus 
to minimize the likelihood of developing post-splenectomy sepsis. All patients will receive an outpatient 
follow-up, 1 month after discharge and every 6 months for 2 years. During follow-up, glycemic control, 
nutritional status, and possible symptoms of exocrine insufficiency will be assessed, and patients will receive 
specialistic assistance if needed. QoL will be registered using specific questionnaires. An oncologic evaluation 
will determine the indication for administration of adjuvant therapy, in case of malignancy. 
 
 
Questionnaires 
All patients who will be alive after at least 12 months of follow-up will be enrolled in the cross-sectional study 
of quality of life. All the eligible patients who are not able to attend outpatient visits will be contacted by 
telephone before receiving the 5 questionnaires by mail. Patients who will not respond within 1 month will 
be contacted again by telephone. Four questionnaires will be administered: (1) the EuroQoL Group 
questionnaire (EQ-5D); (2) the European Organization for Research and Treatment of Cancer (EORTC) QLQ-
C30 questionnaire; (3) the European Organization for Research and Treatment of Cancer (EORTC) QLQ-PAN26 
questionnaire; and (4) the Problem Areas in Diabetes (PAID) questionnaire.17 18 19 20 The comprehensive 
assessment will consist of a total of 116 questions.   
 
ENDPOINTS 
Primary endpoint 
For each study group the primary endpoint is the rate of postoperative major morbidity, defined as Clavien-
Dindo≥ 3.   
 
Secondary endpoints 
For each study group secondary endpoints are: 
- 
Incidence of In-hospital, 30-days and 90-days postoperative mortality. Beyond these time-limits, the 
mortality that may be related to the operation will be considered and discussed in each case. 
- 
Incidence, severity, and overall average complication burden for PPH and DGE 
- 
Incidence of other postoperative morbidity (see below) 
- 
Time-to-functional recovery (functional recovery is defined by all of the following criteria: adequate 
pain control with only oral analgesia (no intravenous or epidural analgesia necessary); independent 
mobility; ability to maintain more than 50% of the daily required caloric intake; no need for 
intravenous fluid administration; and no signs of infection)21 
- 
Length of hospital stay 
- 
Postoperative endocrine insufficiency (new onset diabetes, worsening of pre-existent diabetes, 
insulin dependency). The definition of postoperative new onset of diabetes will be based on the 
reporting of a normal preoperative FBG/HbA1c and postoperatively by measured glucose 
metabolism including FBG/HbA1c level and/or insulin medication. 
- 
Postoperative exocrine insufficiency (incidence of diarrhea, prescription of pancreatic enzymes, 
number of capsules). The definition of postoperative exocrine insufficiency will be based on FE-1 

determination, the presence of steatorrhea and necessity of enzyme treatment with 
cessation/mitigation of diarrhea after enzyme supplementation. 
- 
Access to adjuvant chemotherapy (when indicated) 
- 
Delay in starting adjuvant chemotherapy, calculated as the time between surgery and the beginning 
of adjuvant chemotherapy (when indicated) 
- 
General, cancer-specific, pancreas-specific and diabetes-related QoL (EQ-5D; EORTC QLQ C30 and 
PAN26; PAID) 17 18 19 20 
 
The observation period for postoperative morbidity will last until the complete recovery from surgery. 
Morbidity will include: 
- 
PPH as defined by ISGPS 22 
- 
DGE as defined by ISGPS 23 
- 
Bile leakage as defined by ISGLS24 
- 
Enteric fistula defined as presence of enteric fluid from drains, possibly confirmed by sinogram or 
plain radiography with oral contrast study 
- 
Abdominal fluid collection defined as any intraabdominal fluid collections larger than 5cm confirmed 
at imaging 
- 
Abdominal abscess defined as an intraabdominal fluid collection containing gas bubbles and 
producing clinically relevant signs of infection 
- 
Wound infection as defined by CDC 25 
- 
Blood transfusions defined as the number of packed red blood cells unit transfused after the 
procedure  
- 
Sepsis 26 
- 
Chyle leak as defined by ISGPS 27 
- 
Gastric venous congestion 16 
- 
Postoperative liver failure 
- 
Myocardial infarction 
- 
Acute kidney injury 
- 
Pulmonary embolism 
- 
Pneumonia 
- 
Respiratory distress (defined as the need for mechanic ventilation after surgery) 
- 
Urinary tract infection  
- 
Neurological morbidity (cerebrovascular accidents, hemorrhage) 
- 
Re-operation 
- 
Re-admission within 30, 60 and 90 days 
 
For PA Group additional secondary endpoints are:  
- 
Incidence and severity of POPF 28 
- 
Incidence of biochemical leak 28 
- 
Overall average complication burden for POPF 
- 
Incidence of postoperative pancreatitis 29 
 
SAMPLE SIZE CALCULATION 
A recent metanalysis by Schuh et al. reported a POPF rate around 23% in stage D patients (main pancreatic 
duct diameter ≤3mm, soft pancreas) but no data were available regarding major morbidity12. Patients that 
will be considered eligible for the present trial will have further features increasing their risk of POPF and 

related major morbidity, compared to stage D patients. Based on the current literature and on a recent 
retrospective study by the Verona group, considering only a cohort of patients with extremely high FRS (FRS 
9-10), the rate of major morbidity can be estimated around 55% after PD and 19% after TP.11 
The original risk score proposed in this trial is extrapolated based on previous literature and expert opinions. 
For this reason, there are no data directly available for estimation of major morbidity in this rare subset of 
patients, for which we estimate a rate of Clavien-Dindo ≥3 of around 40%. 
Considering a 1:1 allocation between the groups, a sample size of 49 patients per group would allow a two-
sides, two-sample test for binomial proportions to detect a difference in Clavien-Dindo ≥3 of 25% (40% vs 
15%) with 80% power (1-β) and an error α of 0,05.  The study has a group sequential design allowing for 
interim analyses at pre-specified timepoints with possible early stopping for efficacy or futility in case of an 
overwhelming large or small effect, respectively. Considering that extremely high-risk cases represent around 
7% of the total amount of PDs performed and that the fistula risk can only be assessed intraoperatively, we 
expect to approach preoperatively around 1300 patients.  
 
STATISTICAL ANALYSIS 
Continuous variables will be expressed as the means and standard deviation values or as median values with 
ranges and will be compared using the Student t-test or the Mann-Whitney test as appropriate. Categorical 
variables will be analyzed by Chi-square or Fisher’s exact test in case of expected small frequencies. All the 
tests will be 2-tailed. P values < 0.05 will be considered statistically significant. All endpoints will require the 
above-mentioned statistical analysis, comparing the two study arms. Statistical analyses will be performed 
using STATA14 for Windows. 
 
DURATION AND END OF THE STUDY 
Since the Department of General and Pancreatic Surgery performs about 250 PD per year and the study will 
be proposed to at least other 2 international referral centers, the primary endpoint will be reached after 25 
months: 22 months of patients’ enrollment and 3 months of follow-up. Long term analysis of QoL and 
pancreatic insufficiency will require additional 24 month of follow-up. Time for data analysis must be 
considered negligible. All the patients undergoing PD will be enrolled for the study if inclusion and exclusion 
criteria will be respected. The study will be discontinued in case of reaching the statistical significance of the 
primary endpoint, or in case of suspension by the coordinators or by the authorities. 
 
PROCEDURES RELATED TO REGISTRATION AND DATA MANAGEMENT 
To ensure the confidentiality of data, each patient will be registered and de-identified by an identification 
code. 
Each subject will be identified by a code consisting of: 
- 
Code Protocol: TETRIS 
- 
Number of the institution: (e.g. Patient recruited at the Verona Pancreas Institute will be coded as 
TETRIS_C1) 
- 
Number of recruitment (e.g. the third patient recruited at the Verona Pancreas Institute will be coded 
as TETRIS_C1_3). 
The P.I. of the study will be responsible for data protection and privacy of study participants by treating the 
data solely for statistical purposes and scientific research, and he will not communicate them if not 
anonymously. The manager of data processing is the principal investigator. 
All data of enrolled patients collected during the study will be recorded in a computerized case report form 
(CRF) and transferred automatically into a specific database protected by passwords. These data will be kept 
confidential and will be treated in full compliance with the Legislative Decree 196/03. 

 
ETHICAL CONSIDERATIONS 
Each patient will be included in the study only after providing his/her written informed consent, which may 
be withdrawn at any time. Personal data will be processed according to Legislative Decree 196/2016. The 
procedures relating to the conduct of the study and documentation of the results shall comply with ethical 
principles set out in the Declaration of Helsinki, in the Oviedo Convention and Good Clinical Practice. The 
study will be conducted in compliance with following documents: European Directive 91/507 / EEC, Decree 
211/03, D.M. December 21, 2007, AIFA Determination March 20, 2008, D.L. 189 of 08/09/2012, European 
Directive 2011 / C172 / 01 and Decree 196/2016. The evaluation of the study is responsibility of the Ethics 
Committee and its implementation will be possible only after its approval. Any amendment to the Protocol 
will follow the same approval process. 
 
QUALITY OF THE STUDY, GOOD CLINICAL PRACTICE AND ETHICS COMMITTEE 
The procedures relating to management, implementation and documentation of the study will be in 
accordance with the ethical principles set out in the Helsinki Declaration and its revisions, the Oviedo 
Convention, the GCP (Good Clinical Practice). The evaluation of this study is responsibility of the Ethics 
Committee that will be informed of any possible subsequent revision of the protocol. After the approval of 
the local Ethics Committee, the study will be entered in the international registers (clinicaltrials.gov). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FLOWCHART  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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