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. 2012 Nov 19;15(5):392–399. doi: 10.1111/j.1477-2574.2012.00608.x

Prospective randomized trial of the effect of octreotide on pancreatic juice output after pancreaticoduodenectomy in relation to histological diagnosis, duct size and leakage

Laureano Fernández-Cruz 1,✉, Enrique Jiménez Chavarría 2, Pilar Taurà 2, Daniel Closa 3, Miguel-Angel López Boado 1, Joana Ferrer 1
PMCID: PMC3633042  PMID: 23557411

Abstract

Background Octreotide is generally administered based on the surgeon's interpretation of perceived risk for pancreatic fistula at the time of pancreaticoduodenectomy (PD).

Methods A single-institution, prospective randomized trial was conducted between April 2009 and December 2011 involving 62 PD patients who were randomized to receive octreotide (100 μg subcutaneously every 8 h; n = 32) or placebo (n = 30). Pancreatic juice output was measured after the operation using a catheter inserted into the pancreatic duct. Postoperative complications were recorded.

Results No significant differences in median output were found between the octreotide (82.5 ml) and placebo (77.5 ml) groups (P = 0.538). Median total output was significantly lower in patients with adenocarcinoma compared with those with periampullary tumours (P = 0.004) and in patients with a duct diameter of >5 mm compared with those with a duct diameter of <5 mm (P = 0.001). There were no significant differences in overall morbidity between the octreotide and placebo groups (P = 0.819). Grade B pancreatic fistula (International Study Group for Pancreatic Fistula) was observed in two and three patients in the octreotide and placebo groups, respectively.

Conclusions Morbidity did not differ significantly between the groups. This study did not demonstrate an inhibitory effect of octreotide on exocrine pancreatic secretion. Based on these results, the routine use of octreotide after PD cannot be recommended.

Introduction

Although mortality rates after pancreaticoduodenectomy (PD) have fallen, morbidity remains as high as 28–58%.1,2 Incidences of postoperative pancreatic fistula (POPF) in patients undergoing PD lie in the range of 5–35%.3 Clinically relevant POPF is the major contributor to postoperative morbidity and is usually caused by leakage from the pancreatoenteric anastomosis.4,5 If it is not controlled, POPF may lead to secondary septic and haemor rhagic complications, organ failure and death. Although attempts have been made to decrease the incidence of POPF by improving techniques for reconstructing the pancreatoenteric anastomosis or optimizing its placement, no effective strategy for the prevention of POPF has yet been found.6–8

Somatostatin and its analogues are known to have an inhibitory effect on the exocrine secretion of the pancreas.9 These drugs had been presumed to reduce the rate of pancreatic fistula. The concept originated in 1979, when Klempa et al.10 first reported that somatostatin reduced the incidence of complications after PD. Somatostatin has a short half-life of 1–2 min and must be administered by continuous i.v. infusion. This can decrease the patient's mobility. By contrast, octreotide has a half-life of 120 min, which allows intermittent subcutaneous dosing schedules. Several double-blinded multicentre randomized controlled trials (RCTs) have suggested a statistically significant decrease in overall postoperative complications after pancreatectomy with the use of perioperative octreotide.11–13 The majority of these studies included patients with chronic pancreatitis who would be expected to show a lower incidence of pancreatic fistula.14 Other studies reported no statistically significant benefit of the perioperative use of octreotide.15–20 A study by a pancreatic surgery group failed to show a decrease in postoperative complications after major pancreatectomy with the use of vapreotide.21 The results of meta-analyses are also conflicting.22–26 A recent meta-analysis concluded that the use of somatostatin and its analogues does not significantly reduce postoperative complications after PD.27 Therefore, despite 20 years of the clinical use of somatostatin and its analogues to prevent pancreatic fistula, evidence of the benefit of its use is still lacking and is required to establish clear recommendations or guidelines.

Other studies have attempted to clarify the effect of somatostatin on remnant exocrine secretion and related morbidity in patients undergoing PD for malignancy.28,29 In both studies, somatostatin administered i.v. reduced the incidence and severity of pancreas-related complications, but its effect on the amount of pancreatic secretion was difficult to demonstrate.

Despite the contradictory results, octreotide is generally administered according to the surgeon's interpretation of perceived risk for fistula development at the time of operation.

The aim of this study was to evaluate the effect of octreotide on exocrine secretion of the pancreatic remnant after PD and to assess the efficacy of this drug in the prevention of pancreas-specific complications in patients undergoing PD for pancreatic and periampullary lesions, excluding chronic pancreatitis.

Materials and methods

Patients undergoing elective PD between April 2009 and December 2011 in the Biliopancreatic Unit, Department of Surgery at the Clinic Hospital of Barcelona were eligible to participate in this trial (Fig. 1). Patients found to have unresectable disease and those in whom surgery was converted to a different procedure after laparotomy were excluded. Enrolled patients were randomized to either the octreotide or the placebo group. The randomization process was carried out during the operation by means of a randomly generated number pattern. Patients in the octreotide group received 100 μg subcutaneously during the operation (immediately after PD) and every 8 h after surgery for 10 days. Patients in the placebo group received 31 perioperative doses of saline administered in a similar manner.

Figure 1.

Figure 1

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Selection of the study sample according to the CONSORT (consolidated standards of reporting trials) template

Surgical technique

All procedures were performed by a team of surgeons specializing in biliopancreatic surgery. All patients underwent pylorus-preserving PD. The resection included division of the pancreas to the left of the superior mesenteric and portal veins. In all patients pancreatogastrostomy with an invagination anastomosis was performed according to the gastric-partition technique (PG-GP).30 External drainage of the pancreatic duct with a silastic tube was applied in all patients. The stent tube was secured to the mucosa of the Wirsung duct using an anchoring stitch (PDS 3/0; Ethicon, Inc., Somerville, NJ, USA) to prevent catheter migration. A small gastrotomy was made in the anterior gastric antrum to allow the catheter to be externalized through a stab incision in the anterior abdominal wall. A purse-string suture was used to close the gastrotomy site through which the catheter exited. The external end of the tube was connected to a bottle on the floor to facilitate the gravitational drainage of pancreatic juice. After PG-GP, the remaining anastomoses (hepaticojejunostomy and gastrojejunostomy) were performed on the jejunal limb. Two peritoneal drainage tubes (Jackson–Pratt silicone flat drain; Fortune Medical Instrument Corp., Taipei Hsien, Taiwan) were placed so that one was anterior and the other posterior to the pancreaticogastrostomy anastomosis. Another suction close drain (Jackson–Pratt) was positioned posterior to the hepaticojejunostomy anastomosis.

Assessment of pancreatic characteristics

After the division of the pancreas, removal of the specimen and mobilization of the pancreatic remnant, pancreatic consistency and the diameter of the main pancreatic duct were assessed. The pancreatic duct diameter was assessed according to a three-grade classification system: pancreatic duct diameter grade 1 (<3 mm) was assigned when a silastic tube of 2 mm in diameter precisely fit in the duct; grade 2 (3–5 mm) was assigned when a silastic tube of 3 mm in diameter precisely fit in the duct but a silastic tube of 5 mm in diameter could be inserted with significant pressure, and grade 3 (>5 mm) was assigned when a silastic tube of 5 mm in diameter precisely fit in the duct. The assessment of pancreatic consistency (hard or soft) was subjective and was based on visual and tactile information gathered over the period of pancreatic manipulation, and the placement of sutures during the pancreaticogastrostomy reconstruction.

Data collection and perioperative management

Perioperative demographic and clinical data and details of the operation, including information on pancreatic texture and duct diameter, pathological diagnosis, postoperative course and complications were collected prospectively. Clinically relevant POPF was graded as B or C according to the International Study Group on Pancreatic Fistula (ISGPF) grading system.32

Nasogastric tubes were removed at 5 days after surgery. For the purpose of the study all patients were fasted for the first 10 days after the operation. Oral solid diet was then resumed gradually if there was no evidence of clinical POPF, delayed gastric emptying (DGE) or other intra-abdominal complications.

Amylase levels in serum and drainage fluid were measured on days 1, 3 and 5 after the operation and every week thereafter if persistent clinical POPF was apparent. Intraperitoneal drainage tubes were removed on day 5 if there was no evidence of anastomotic leakage.

Daily pancreatic juice output was measured for 10 days during the postoperative period. Total daily lipase output in the pancreatic juice measured on postoperative day 3 was calculated by multiplying the concentration of the enzyme by the volume collected in 24 h. Pancreatic lipase was determined by using commercial turbidimetric assay kits (Randox Laboratories Ltd, Crumlin, UK), according to the supplier's specifications.

Study endpoints and definition

The primary study endpoint was the effect of perioperative octreotide given at the time of operation and subsequently every 8 h for 10 days, at a dose of 100 μg subcutaneously, on pancreatic remnant exocrine secretion and the rate of development of POPF in patients undergoing PD for pancreatic and periampullary lesions. Clinically relevant POPF (grade B or C) was defined according to ISGPF criteria32 as the presence of amylase-rich fluid (more than three times the upper limit of normal serum levels) of any measurable volume on or after day 3. Secondary endpoints included overall morbidity, hospital mortality and duration of postoperative hospital length of stay (LoS).

Statistical analysis

Previous studies predicted that somatostatin would decrease mean pancreatic juice output from 200 ml to 50 ml per 24 h.29 It was calculated that each group would be required to comprise 24 evaluable patients to give α and β errors of 5% each (95% power).28,29 To ensure an adequate number of patients for all analyses, the trial aimed to recruit a minimum of 30 patients to each treatment group.

Patient demographic and clinical characteristics were compared between the octreotide and placebo groups using X2 test or Fisher's exact test, as appropriate, for categorical variables and the Mann–Whitney rank sum test for continuous variables. A P-value of <0.05 was considered to indicate statistical significance. Statistical analysis was performed using spss Version 19 (SPSS, Inc., Chicago, IL, USA).

Results

A total of 71 patients were scheduled for PD during the study period (Fig. 1). Seven patients with an inflammatory mass of the head of the pancreas for chronic pancreatitis and two patients requiring conversion to a different operation (total pancreatectomy) were excluded from the study. A total of 62 patients who successfully underwent PD were finally randomized into the octreotide (n = 32) and placebo (n = 30) groups. Table 1 shows baseline demographic data for both patient groups. Table 2 shows the distribution of duct diameters in relation to pancreatic texture. Patients with pancreatic duct diameters of <3 mm (grade 1) and 3–5 mm (grade 2) were found to have a soft pancreas in 75.0% and 54.1% of cases, respectively (Table 2). Patients with a pancreatic duct diameter of >5 mm (grade 3) were found to have a hard pancreas in 72.7% of cases (grade 3 versus grades 1 and 2; P < 0.01). Most patients with periampullary tumours (65.6%) were found to have a soft pancreas, whereas most patients with adenocarcinoma (66.6%) had a hard pancreas.

Table 1.

Baseline demographics and diagnoses in the study sample

Octreotide group (n = 32) Placebo group (n = 30) P-value
Age, years, median (range) 69 (31–84) 69 (31–84) .950
Sex ratio, male : female 17:15 17:13 .448
Body mass index, kg/m2, median (range) 23.8 (18.3–3.24) 23.6 (19.2–31.3) .928
Comorbid illness, n 15 16 1.000
Diagnosis, n
Pancreatic carcinoma 17 15 .714
Ampullary carcinoma 4 6 .617
Intraductal papillary mucinous neoplasm 2 3 1.000
Cholangiocarcinoma 3 1 .617
Neuroendocrine tumour 2 1 .617
Metastatic tumour 1 1
Duodenal cancer 1 1
Pseudopapillary solid tumour 1 1
Serous cystoadenoma 1 1
Biliary stenting, n 10 9 .802
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Table 2.

Diameter of main pancreatic duct and pancreatic consistency in the study sample

Duct diameter Pancreatic adenocarcinoma (n = 30) Periampullary tumours (n = 32)
Pancreatic texture Pancreatic texture
All, n Soft, n Hard, n All, n Soft, n Hard, n
Grade 1 (< 3 mm) 5 3 2 11 9 2
Grade 2 (3–5 mm) 9 3 6 15 10 5
Grade 3 (> 5 mm)a 16 4 12 6 2 4
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a

Hard pancreas in grade 3 compared with grades 1 and 2 (P < 0.01).

Changes in exocrine secretion during treatment

Output of pancreatic juice increased steadily up to 3 days after the operation; median total output during this early period was 40 ml (range: 10–50 ml) in the octreotide group and 55 ml (range: 30–60 ml) in the placebo group. No significant differences in median output during a relatively stable period (postoperative days 4–10) emerged between the octreotide and placebo groups (Table 3). When the patients were stratified according to pathological diagnosis (adenocarcinoma versus periampullary tumour) no significant differences in total output emerged between the octreotide and placebo groups. However, adenocarcinoma patients showed significantly less output (P < 0.004) compared with patients with periampullary tumours in both the octreotide and placebo groups. Table 4 shows that daily output did not exceed 100 ml in the majority of adenocarcinoma patients, but was higher in patients with periampullary tumours (P < 0.05). When patients were categorized according to the diameter of the main pancreatic duct, no significant differences in subgroups emerged between the octreotide and placebo groups, but significant differences (P < 0.001) emerged between patients with large and small ducts, respectively (Table 5).

Table 3.

Pancreatic juice output in the study sample

Pancreatic juice output, ml/24 h, median (range)
Octreotide group (n = 32) Placebo group (n = 30) P-value
All patients (n = 62) 82 (50–250) 77 (50–250) .538
Pancreatic adenocarcinoma (n = 30) 50 (50–250) 46 (50–250) .401
Periampullary tumour (n = 32) 100 (50–250) 106 (50–250) .821
Pancreatic adenocarcinoma versus periampullary tumour .004
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Table 4.

Daily output of pancreatic juice during postoperative days 1–10

Output, ml/day All patients Adenocarcinoma Periampullary tumour
Octreotide group Placebo group Octreotide group Placebo group Octreotide group Placebo group
(n = 32) (n = 30) (n = 17) (n = 15) (n = 15) (n = 15)
–50 9 7 7 5 2 2
51–100 11 9 7 5 4 4
101–150 8 7 1 2 7 5
151–200 3 4 2 2 1 2
201–250 1 3 – 1 1 2
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Table 5.

Pancreatic juice output categorized according to main pancreatic duct diameter

Duct diameter Pancreatic juice output, ml/24 h, median (range) P-value
Octreotide group (n = 32) Placebo group (n = 30)
Grade 1 (< 3 mm) (n = 16) 90 (50–250) 93 (50–250) .880
Grade 2 (3–5 mm) (n = 24) 85 (50–250) 75 (50–250) .435
Grade 3 (> 5 mm) (n = 22) 46 (50–250) 48 (50–250) .813
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Postoperative outcomes

Postoperative mortality was nil. Complications occurred in 21 patients. No significant differences were identified between the two groups (Table 6). The most frequent complication was DGE, which occurred in eight patients. The incidence of clinical POPF was similar in both groups and occurred in patients with a soft pancreas and a Wirsung duct size of < 3 mm. Hospital LoS was similar in both groups (Table 6). Median lipase output (U/24 h) on day 3 was lower in patients with adenocarcinoma in both the octreotide [13 472 U (range: 2239–45 400 U)] and placebo [14 452 U (range: 0–100 678 U)] groups than in patients with periampullary tumours in the octreotide [119 318 U (range: 4075–399 420 U)] and placebo [121 909 U (range: 7422–229 333 U)] groups. However, the great variability of results precluded the finding of any significant differences between the octreotide and placebo groups in either patients with adenocarcinoma or those with periampullary tumours (P = 0.683).

Table 6.

Postoperative outcomes in the study sample

Octreotide group (n = 32) Placebo group (n = 30) P-value
Mortality, n
Morbidity, n 10 11 .819
POPF Grade B, n 2 3 .769
POPF Grade C, n – –
Biliary fistula, n 1 1 .907
Delayed gastric emptying, n 4 4 .918
Intra-abdominal abscess, n 1 1 1.000
Surgical site infection, n 2 2 1.000
Postoperative hospital stay, days 11.5 12.1 .871
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POPF, postoperative pancreatic fistula.

Discussion

Somatostatin and its analogues decrease exocrine and endocrine pancreatic secretion by binding the somatostatin receptors on the exocrine and endocrine cells, and decrease the secretion of cells.33 It is assumed that decreasing the volume of pancreatic secretion may decrease the incidence of pancreatic leak or fistula. The prophylactic use of somatostatin and its analogues during and after pancreatic surgery remains controversial. The role of somatostatin delivered by i.v. infusion was investigated by Gouillat et al.28 and Shan et al.29 in RCTs on the prevention of pancreas-related complications after PD and changes in exocrine secretion during treatment. In the study by Gouillat et al.,28 the analysis failed to demonstrate a significant decrease in pancreatic juice output and enzyme production, and therefore pancreatic exocrine secretion following somatostatin infusion. In a similar study, Shan et al.29 found that: ‘… during the period of infusion of somatostatin, the amount of exocrine secretion decreased to about 50% in the somatostatin group in comparison to the placebo group within the first 7 days with marginal significance (P = 0.0605).’

Early RCTs of somatostatin analogues favoured the use of octreotide and found a decrease in pancreatic anastomotic leaks.11–14 However, other studies reported no statistical benefit of the perioperative use of octreotide.15–20 A recent meta-analysis of RCTs on the efficacy of somatostatin and its analogues in the prevention of postoperative complications after PD showed that the use of pharmacological prophylaxis did not significantly reduce incidences of pancreatic fistula, total pancreas-specific complications, DGE, mortality or hospital LoS.27 These findings are supported by a recent Cochrane review,24 which found no differences in outcomes between the somatostatin analogue and control groups and thus indicated a lack of effect.

The current study showed octreotide to lack efficacy in reducing the exocrine secretion of the remnant pancreas by collecting and measuring the amount of diverted pancreatic juice. Pancreatic exocrine secretion was significantly lower in patients with adenocarcinoma compared with patients with periampullary tumours. In both groups of patients, total pancreatic juice output was not influenced by the presence or absence of octreotide. Furthermore, the current results support the findings of several RCTs that did not show a clinically beneficial effect of octreotide prophylaxis in terms of mortality, morbidity and postoperative hospital stay in patients undergoing PD.15–20 This is of particular interest as cost considerations become increasingly important in the management of such patients.34

In the current study, the presence of pancreatic adenocarcinoma was associated with a significant decrease in exocrine pancreatic volume compared with periampullary tumours. The present report also observed that pancreatic adenocarcinoma was associated more frequently with a hard (66.6%) than a soft pancreatic texture. Matsumoto and Traverso35 found exocrine pancreatic insufficiency to be common (33%) in patients who require PD. Further, 68% of patients with pancreatic adenocarcinoma showed an abnormal secretory function based on stool elastase.35 Patients with pancreatic adenocarcinoma are considered to be at low risk for pancreatic complications.

It has been suggested that the prophylactic use of octreotide may have a particular benefit in patients at high risk for the occurrence of pancreatic complications after PD.34 These high-risk patients are typically considered to be those lacking parenchymal fibrosis, specifically patients with a soft pancreatic texture, undergoing resection for duodenal cancer, ampullary tumours, cystic neoplasms or islet cell tumours.36–38 A recent RCT39 comparing pancreaticojejunostomy with invagination versus duct-to-mucosa anastomosis in patients stratified by pancreatic texture showed that soft texture was an independent risk factor for POPF. A soft parenchyma is often associated with a small, non-dilated pancreatic duct and well-preserved exocrine pancreatic function.40 Several studies have shown that normal pancreatic exocrine function is a risk factor for anastomotic leakage according to the objective assessment of pancreatic function.41–45 Hamanake et al.46 described a higher risk for pancreatic anastomotic leakage and a greater amount of pancreatic juice from pancreatic ductal drainage in patients with a pancreas of intermediate or normal consistency compared with those with a pancreas of hard consistency.

The classification of pancreatic texture is relatively subjective and lacks objective criteria.47 In the present investigation, the size of the pancreatic duct was also used to stratify patients. Duct size was found to correlate strongly with pancreatic texture. Duct diameters of <3 mm (grade 1) and 3–5 mm (grade 2) were associated with a soft pancreas in the majority of patients. However, a grade 3 duct diameter (>5 mm) was associated significantly more strongly with a hard pancreas (P < 0.01). To the authors' knowledge, this is the first study to report the relationship between the diameter of the Wirsung duct and pancreatic juice output. Outputs of pancreatic juice were similar in patients with duct diameters of grades 1 and 2. However, total output was significantly lower in patients with grade 3 duct diameters compared with those with grade 1 or 2 duct diameters. In all duct diameter grade groups, total pancreatic juice output was not influenced by the presence or absence of octreotide.

Conclusions

The current study demonstrates the lack of efficacy of octreotide in reducing the exocrine secretion of the remnant pancreas after PD. In addition, it confirms the correlation between pathological diagnosis and exocrine pancreatic function after PD. Pancreaticoduodenectomy for pancreatic adenocarcinoma was significantly associated with greater dilatation of the pancreatic duct and a harder pancreas, as well as with a lower output of pancreatic juice compared with PD for periampullary tumours. Therefore, the assumption that pancreatic cancer increases the risk for fistula is probably not justified because it appears to offer a protective effect. A soft parenchyma and non-dilated pancreatic duct are shown to be associated with well-preserved exocrine pancreatic secretion and represent important risk factors for POPF.

This study corroborates the findings of previous studies that similarly reported a lack of efficacy of octreotide in patients undergoing PD.15–21 Prophylactic octreotide use does not decrease rates of POPF or overall morbidity, or postoperative hospital LoS.

Conflicts of interest

None declared.

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