Abstract
Purpose
Radical gastrectomy with D2 lymphadenectomy can trigger a high incidence of postoperative pancreatic fistula (POPF), which produces a poor clinical prognosis. We sought to evaluate the effect of somatostatin analogs (SSA) on POPF and clinical prognosis after radical gastrectomy.
Methods
A total of 123 patients with a high risk of POPF after radical gastrectomy (drainage fluid amylase concentration on a postoperative day [POD] 1 > 3 times the upper limit of normal serum amylase value) were randomly divided into the SSA group (n = 61) and the control group (n = 62). The former received continuous intravenous SSA (0.3 mg/8 h) for 3 days from POD1, and the latter normal saline. The primary outcome was the incidence of POPF.
Results
The incidence of POPFs in the SSA group was significantly lower than that in the control group (3.3% vs. 14.5%, P = 0.029). The incidence of short-term postoperative complications was significantly lower in the SSA group than in the control group (9.8% vs. 24.2%, P = 0.034). The median white blood cell counts, neutrophil counts, and the percentage of neutrophils on POD4 were significantly lower in the SSA group than in the control group (all P < 0.05). The SSA group had a shorter mean time to the first liquid diet (87.33 ± 17.92 h vs. 93.97 ± 17.29 h, P = 0.039). And the SSA group had less median daily drainage volume (96.33 mL vs. 119.67 mL, P = 0.025) and shorter drainage duration (7.0 days vs. 10.0 days, P = 0.013).
Conclusion
Postoperative treatment with a somatostatin analog reduced the incidence of POPF and short-term complications after radical gastrectomy. (TRN: ChiCTR2200056201, Reg. Date: 2022/2/1).
Supplementary Information
The online version contains supplementary material available at 10.1007/s00432-023-04584-7.
Keywords: Gastric cancer, Radical gastrectomy, Somatostatin analog, Postoperative pancreatic fistula, Complications
Introduction
Gastric cancer is the fifth most common cancer and a fourth most common cause of cancer-related deaths worldwide (Sung et al. 2021). For resectable gastric cancer, radical gastrectomy combined with D2 lymphadenectomy is the main treatment method (Japanese Gastric Cancer Association 2021). Parenchymal and thermal injury to the pancreas caused by the operator during lymph node dissection and “blunt injury” caused by the assistant during exposure lead to the occurrence of postoperative pancreatic fistula (POPF) (Irino et al. 2016; Ida et al. 2018). Severe POPF can lead to abdominal bleeding, infection, and anastomotic leakage (Nobuoka et al. 2008; Nakanishi et al. 2020).
According to previous studies, the incidence of POPF after radical gastrectomy varies widely from 19.5 to 55.8%, and the incidence of grade B and C POPF requiring clinical intervention can reach 2.2–22.1% (Miki et al. 2011; Jiang et al. 2012; Komatsu et al. 2013; Kung et al. 2014; Hiki et al. 2017). Owing to the high incidence of POPF after radical gastrectomy, the prevention and treatment of POPF have become an important issue.
Previous studies focused on the prevention of pancreatic fistula after pancreatic surgery (Allen et al. 2014; Li et al. 2020; Cao et al. 2021) but ignored the high incidence of pancreatic fistula after gastric cancer surgery. There is a lack of large-scale clinical trials for the prevention of pancreatic fistulas after radical gastrectomy.
Somatostatin is a naturally occurring tetradecapeptide that inhibits pancreatic exocrine, bile and small intestinal secretions and increases water and electrolyte absorption (Gans et al. 2012). Octreotide is an octapeptide analog of somatostatin. Compared to natural somatostatin, octreotide has a longer half-life and greater potency, which can inhibit the exocrine function of the pancreas and protect pancreatic cells (Jenkins and Berein 1995). So far, there is no consensus on the routine use of somatostatin analogs (SSA) after radical gastrectomy.
A randomized controlled trial (Song et al. 2014) reported that the use of somatostatin analogs after radical gastrectomy did not reduce the incidence of pancreatic fistula. However, this trial included all patients undergoing gastric cancer surgery, including those with a low risk of POPF, which may mask the effect of somatostatin analogs in patients with a high risk of POPF. Several studies (Iwata et al. 2010; De Sol et al. 2015; Kanda et al. 2016) have reported that a high level of drainage fluid amylase content on postoperative day (POD) 1 is an independent risk factor for pancreatic fistula. Therefore, we enrolled patients with a high risk of POPF (drainage fluid amylase content on POD1 > 3 times the upper limit of normal [ULN] serum amylase value) to confirm the effect of somatostatin analogs on pancreatic fistula after radical gastrectomy.
Methods
Study design and patient eligibility
This study was approved by the Ethics Committee of Shandong Provincial Hospital (SWYX: NO. 2021-1013), and registered in the Chinese Clinical Trial Register (http://www.chictr.org.cn, ChiCTR2200056201). All patients understood and signed the informed consent. And this study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Moher et al. 2012).
Because the reported incidence of POPF varies greatly among centers, sample sizes calculated based on previous studies have a high risk of bias. Therefore, before starting a multicenter randomized controlled trial, we conducted this pilot study to evaluate the sample size and identify and resolve potential issues in the implementation of the project. This pilot study was designed to enroll 60 patients per group.
The inclusion criteria were as follows: (1) age 18–80 years, (2) had undergone radical gastrectomy, (3) drainage fluid amylase concentration on POD1 > 3 times ULN serum amylase value, and (4) the patients or their legal representatives signed the informed consent. The exclusion criteria of the trial included: (1) history of pancreatitis, (2) tumor invasion into the pancreas, (3) use of somatostatin or analogs in the preceding week, (4) intolerance to somatostatin analogs, and (5) severe liver or kidney function abnormalities.
Randomization and intervention
Randomly assigned sequences were generated in silico. Distribution concealment was achieved using sequentially numbered, sealed, opaque envelopes. All patients who met the inclusion and exclusion criteria after radical gastrectomy were randomly assigned to the SSA group and the control group. Besides the conventional treatment, patients in the SSA group received continuous intravenous somatostatin analogue (0.3 mg/8 h) for 3 days from POD1, and the control group received the same volume of normal saline. The patients were unaware of their group assignments. Surgical treatment, postoperative management, and follow-up assessments were performed by physicians and nurses who were unaware of the study protocol.
Primary and secondary outcomes
The primary outcome was the overall incidence of POPF. Secondary outcomes included the occurrence of short-term postoperative complications within 30 days, drainage fluid and serum amylase concentration, postoperative inflammatory markers, gastrointestinal function recovery, peritoneal drainage volume and duration, postoperative hospital stay, and hospitalization expenses.
Surgical procedure
All operations were performed according to the Japanese Gastric Cancer Treatment Guidelines (Japanese Gastric Cancer Association 2021) by surgeons with sufficient experience in radical gastrectomy. Surgeons chose reconstruction from Billroth I, Billroth II, Roux-en-Y, or Double-tract according to their preference. The gastric, nasointestinal, and abdominal drainage tubes were placed selectively according to the surgeon’s judgment.
Postoperative management
All patients were administered prophylactic antibiotics for 0.5 h preoperatively and 24 h postoperatively, according to the Enhanced Recovery After Surgery (ERAS) Society guidelines (Mortensen et al. 2014) for diet and activity. Laboratory tests were performed on POD1 and POD4, including routine blood tests, biochemistry, and liver function, as well as serum amylase content. Two milliliters of fluid were collected from each abdominal drainage tube every morning to measure the concentration of amylase, and taking the highest value as the representative one. The daily abdominal drainage volume was recorded, and the drainage tube was removed when the drainage was normal with a volume < 50 mL/day. Patients were required to meet the following criteria for discharge: stable vital signs, ability to eat a soft diet to meet daily needs, no complications according to clinical and laboratory examinations, and good physical strength.
Definition of POPF
The definition and grading of POPF were formulated and updated by the International Study Group of Pancreatic Fistula (ISGPF). Using the ISGPF criteria (Bassi et al. 2005, 2017), patients with any measurable drainage amylase content on or after POD3 > 3 times ULN normal serum amylase value were defined as having POPF. The grades of POPF are as follows: grade A POPF has no special clinical impact; grade B POPF requires a change in the management of the expected postoperative development; grade C POPF leads to organ failure or clinical instability and requires reoperation.
Statistical analysis
Normally distributed continuous variables are presented as mean ± standard deviation and non-normally distributed continuous variables are reported as median (interquartile range). The differences between groups were compared using the independent sample Student’s t test or Whitney U test. Categorical variables were presented as numbers and percentages, and the chi-squared or Fisher’s exact test was used appropriately to calculate differences between groups. Statistical significance was set at P < 0.05. All analyses were performed using the SPSS 24.0 statistical software (IBM Corporation).
Results
Patient recruitment and characteristics
From February 2022 to July 2022, 278 patients underwent radical gastrectomy in Shandong Provincial Hospital. Among them, 148 patients did not meet the inclusion criteria because the drainage fluid amylase concentration on POD1 was < 3 times ULN serum amylase value, four patients were excluded because of tumor invasion to the pancreas, and three patients declined to participate in the trial. Finally, 123 patients were divided into the SSA group (n = 61) and control group (n = 62) following a random allocation principle (Fig. 1).
Fig. 1.
CONSORT flow diagram. AMY amylase concentration, ULN the upper limit of normal level, SSA somatostatin analog
The baseline characteristics were found to be well-balanced between the two groups (Table 1). The distribution of the operative approach, extent of resection, reconstruction method, intraoperative blood loss, operation time, and s number of lymph nodes dissected were also similar between the two groups (Table 2).
Table 1.
Patient clinical and pathology characteristics at baseline
| SSA group (n = 61) | Control group (n = 62) | P | |
|---|---|---|---|
| Age, year, (mean ± SD) | 57.1 ± 12.8 | 59.7 ± 10.1 | 0.206 |
| Sex (n, %) | 0.381 | ||
| Male | 43 (70.5) | 48 (77.4) | |
| Female | 18 (29.5) | 14 (22.6) | |
| BMI, kg/m2, (mean ± SD) | 24.4 ± 3.1 | 23.9 ± 3.2 | 0.433 |
| ASA score (n, %) | 0.306 | ||
| I | 6 (9.8) | 6 (9.7) | |
| II | 46 (75.4) | 40 (64.5) | |
| III | 9 (14.8) | 16 (25.8) | |
| Comorbidity (n, %) | 20 (32.8) | 21 (33.9) | 0.899 |
| Previous abdominal surgery, (n, %) | 5 (8.2) | 3 (4.8) | 0.697 |
| Neoadjuvant therapy (n, %) | 11 (18) | 10 (16.1) | 0.779 |
| Tumor location (n, %) | 0.783 | ||
| Upper | 18 (29.5) | 14 (22.6) | |
| Middle | 7 (11.5) | 7 (11.3) | |
| Lower | 35 (57.4) | 39 (62.9) | |
| Whole | 1 (1.6) | 2 (3.2) | |
| Tumor differentiation (n, %) | 0.623 | ||
| Well | 25 (41.0) | 30 (48.4) | |
| Moderate | 18 (29.5) | 18 (29.0) | |
| Poor | 18 (29.5) | 14 (22.6) | |
| Pathological T stage (n, %) | 0.361 | ||
| T1 | 28 (45.9) | 27 (43.5) | |
| T2 | 5 (8.2) | 10 (16.1) | |
| T3 | 7 (11.5) | 10 (16.1) | |
| T4 | 21 (34.4) | 15 (24.2) | |
| Pathological N stage (n, %) | 0.647 | ||
| N0 | 31 (50.8) | 38 (61.3) | |
| N1 | 14 (23.0) | 10 (16.1) | |
| N2 | 8 (13.1) | 8 (12.9) | |
| N3 | 8 (13.1) | 6 (9.7) | |
| Pathological TNM stage (n, %) | 0.517 | ||
| I | 28 (45.9) | 30 (48.4) | |
| II | 14 (23.0) | 18 (29.0) | |
| III | 19 (31.1) | 14 (22.6) |
SSA somatostatin analog, ASA American Society of Anesthesiologists, BMI body mass index, SD standard deviation
Table 2.
Surgical results
| SSA group (n = 61) | Control group (n = 62) | P | |
|---|---|---|---|
| Operative approach (n, %) | 0.928 | ||
| LG | 30 (49.2) | 31 (50.0) | |
| RG | 31 (50.8) | 31 (50.0) | |
| Extent of resection (n, %) | 1.000 | ||
| Proximal | 5 (8.2) | 4 (6.5) | |
| Distal | 39 (63.9) | 40 (64.5) | |
| Total | 17 (27.9) | 18 (29.0) | |
| Reconstruction (n, %) | 1.000 | ||
| Double-tract | 4 (6.6) | 4 (6.5) | |
| Billroth II | 40 (65.6) | 40 (64.5) | |
| Roux-en-Y | 17 (27.9) | 18 (29.0) | |
| Tumor size, cm, (mean ± SD) | 2.2 ± 1.1 | 2.3 ± 1.1 | 0.509 |
| Surgical time, min, (mean ± SD) | 235.6 ± 41.3 | 232.2 ± 42.0 | 0.652 |
| Blood loss, mL, (mean ± SD) | 47.9 ± 34.3 | 50.1 ± 35.5 | 0.726 |
| Number of lymph nodes, (mean ± SD) | 26.7 ± 10.7 | 29.0 ± 9.7 | 0.223 |
SSA somatostatin analog, LG laparoscopic gastrectomy, RG robotic gastrectomy, SD standard deviation
Incidence of POPFs
Two patients (3.3%) in the SSA group and six patients (9.7%) in the control group had grade A POPF. Three patients (4.8%) in the control group developed grade B POPF with postoperative abdominal pain, fever, increased WBC count, and fluid accumulation around the pancreas, as shown by abdominal ultrasonography or computed tomography scans. Among them, two underwent ultrasound-guided intra-abdominal puncture and one had original drain tubes that were kept for more than 3 weeks. There was no grade C POPF in either group. The overall incidence of POPFs (grades A, B, and C) in the SSA group was significantly lower than that in the control group (2/61 [3.3%] vs. 9/62 [14.5%]; risk difference, 11.2%; 95% confidence interval [CI], 1.4% to 21.1%; P = 0.029). No statistically significant difference was found in the occurrence of grade B and C POPF (0/61 [0%] vs. 3/62 [4.8%]; risk difference, 4.8%; 95% CI − 0.5% to 10.2%; P = 0.248) (Table 3).
Table 3.
Postoperative pancreatic fistula in the two groups
| SSA group (n = 61) | Control group (n = 62) | Absolute difference (95% CI) | P* | |
|---|---|---|---|---|
| Total POPF (n, %) | 2 (3.3) | 9 (14.5) | 11.2 (1.4–21.1) | 0.029 |
| POPF grade (ISGPF) | ||||
| Grade A | 2 (3.3) | 6 (9.7) | 6.4 (− 2.2–15.0) | 0.283 |
| Grade B | 0 (0) | 3 (4.8) | 4.8 (− 0.5–10.2) | 0.248 |
| Grade C | 0 (0) | 0 (0) | 0.0 (0.0–0.0) | NA |
NA not applicable, CI confidence interval, POPF postoperative pancreatic fistula, ISGPF International Study Group of Pancreatic Fistula
*Chi-squared test
Short-term postoperative complications
No significant difference was observed in the postoperative complications within 30 days, including anastomotic leakage, chylous fistula, abdominal infection, bleeding, ileus, abdominal effusion or abscess, and pneumonia (P > 0.05). However, the overall incidence of postoperative complications was significantly lower in the SSA group than that in the control group (6/61 [9.8%] vs. 15/62 [24.2%]; risk difference, 14.4%; 95% CI 1.3–27.4%; P = 0.034) (Table 4). One patient in the SSA group had readmissions due to postoperative intra-abdominal bleeding, and five patients in the control group had readmissions (one for anastomotic leakage, one for ileus, and three for abdominal infection).
Table 4.
Postoperative complications and drug-related adverse effects in the two groups
| SSA group (n = 61) | Control group (n = 62) | Absolute difference (95% CI) | P | |
|---|---|---|---|---|
| Total numbera (n, %) | 6 (9.8) | 15 (24.2) | 14.4 (1.3–27.4) | 0.034* |
| Grade B and C POPFb (n, %) | 0 (0) | 3 (4.8) | 4.8 (− 0.5–10.2) | 0.248** |
| Anastomotic leakage (n, %) | 0 (0) | 1 (1.6) | 1.6 (− 1.5–4.8) | 1.000*** |
| Chylous fistula (n, %) | 2 (3.3) | 0 (0) | − 3.3 (− 7.8–1.2) | 0.244*** |
| Intra-abdominal infection (n, %) | 1 (1.6) | 5 (8.1) | 6.4 (− 1.1–13.9) | 0.217** |
| Intraluminal bleeding (n, %) | 1 (1.6) | 0 (0) | − 1.6 (− 4.8–1.6) | 0.496*** |
| Intra-abdominal bleeding (n, %) | 1 (1.6) | 2 (3.2) | 1.6 (− 3.8–7.0) | 1.000** |
| Ileus (n, %) | 0 (0) | 3 (4.8) | 4.8 (− 0.5–10.2) | 0.248** |
| Abdominal effusion/abscess (n, %) | 2 (3.3) | 4 (6.5) | 3.2 (− 4.4–10.8) | 0.690** |
| Pneumonia (n, %) | 1 (1.6) | 3 (4.8) | 3.2 (− 3.0–9.4) | 0.623** |
| Clavien–Dindo classification (n, %) | 0.210*** | |||
| I | 2 (3.3) | 2 (3.2) | − 0.1 (− 6.3–6.2) | |
| II | 2 (3.3) | 8 (12.9) | 9.6 (0.2–19.1) | |
| III | 1 (1.6) | 2 (3.2) | 1.6 (− 3.8–7.0) | |
| IV | 1 (1.6) | 3 (4.8) | 3.2 (− 3.0–9.4) | |
| V | 0 (0) | 0 (0) | 0.0 (0.0–0.0) | |
| Readmission | 1 (1.6) | 5 (8.1) | 6.4 (1.1–13.9) | 0.217** |
| Drug-related adverse effectc (n, %) | 2 (3.3) | 0 (0) | − 3.3 (− 7.8–1.2) | 0.244*** |
SSA somatostatin analog, POPF postoperative pancreatic fistula
aThere were 8 complications in 6 patients in the SSA group and 21complications in 15 patients in the control group
bGrade A POPF is not an actual postoperative complication according to ISGPF criteria
cTwo patients in the SSA group had drug-related adverse effects, manifested as mild nausea during the intervention
*Chi-squared test
**Adjusted chi-squared test
***Fisher’s exact test
In addition, two patients in the SSA group had drug-related adverse effects that manifested as mild nausea during the intervention. No statistically significant difference was found in the occurrence of drug-related adverse effects between the two groups. (2/61 [3.3%] vs. 0/62 [0%]; risk difference, − 3.3%; 95% CI − 7.8–1.2%; P = 0.244) (Table 4).
Postoperative laboratory data
The median drainage fluid amylase concentration on POD4 in the SSA group tended to be lower than that of the control group (92.0 [40.00, 190.50] U/L vs. 119.00 [49.75, 258.75] U/L, P = 0.083). There was no significant difference in serum amylase concentrations between the two groups. The median white blood cell count (7.35 [5.60, 8.86] × 109/L vs. 8.35 [6.74, 9.87] × 109/L, P = 0.023), neutrophil count (5.55 [3.83, 6.86] × 109/L vs. 6.66 [5.30, 8.14] × 109/L, P = 0.010), and percentage of neutrophils (75.50 [69.95, 79.75] % vs. 77.40 [75.20, 81.95] %, P = 0.014) on POD 4 were significantly lower in the SSA group than in the control group (Table 5). And the proportion of patients with white blood cell counts (11/61 [18.0%] vs. 20/62 [32.3%], P = 0.069), the neutrophil counts (18/61 [29.5] vs. 36/62 [58.1], P = 0.001) and neutrophil percentages (31/61 [50.8%] vs. 47/62 [75.8%], P = 0.004) above the ULN level on POD4 were significantly lower in the SSA group (Table S1 in supplement material). The median levels of procalcitonin (PCT), interleukin-6 (IL-6), C-reactive protein (CRP), and the percentage of these values above ULN level on POD4 did not differ significantly between the two groups (P > 0.05).
Table 5.
Postoperative Laboratory Data
| SSA group (n = 61) | Control group (n = 62) | P* | |
|---|---|---|---|
| AMY of drainage (U/L) | |||
| POD1 | 807.00 (563.50, 1259.00) | 699.00 (531.75, 1271.00) | 0.634 |
| POD4 | 92.00 (40.00, 190.50) | 119.00 (49.75, 258.75) | 0.083 |
| AMY of serum (U/L) | |||
| POD1 | 67.00 (43.00, 93.50) | 53.00 (42.00, 93.50) | 0.411 |
| POD4 | 56.00 (38.50, 84.00) | 51.50 (40.75, 66.25) | 0.386 |
| PCT (ng/mL) | |||
| POD1 | 0.38 (0.20, 0.66) | 0.30 (0.16, 0.53) | 0.314 |
| POD4 | 0.30 (0.17, 0.45) | 0.28 (0.16, 0.48) | 0.937 |
| IL-6 (pg/mL) | |||
| POD1 | 30.40 (16.92, 59.62) | 24.32 (13.58, 37.31) | 0.140 |
| POD4 | 17.60 (12.01, 28.19) | 18.73 (12.25, 31.49) | 0.556 |
| CRP (mg/L) | |||
| POD1 | 33.20 (18.75, 57.15) | 34.75 (22.30, 50.60) | 0.802 |
| POD4 | 66.40 (36.55, 116.20) | 64.35 (35.32, 98.90) | 0.361 |
| WBC (× 109/L) | |||
| POD1 | 11.16 (9.38, 13.40) | 10.85 (9.03, 13.46) | 0.583 |
| POD4 | 7.35 (5.60, 8.86) | 8.35 (6.74, 9.87) | 0.023 |
| NEUT (× 109/L) | |||
| POD1 | 9.39 (7.82, 12.16) | 9.35 (7.93, 11.84) | 0.602 |
| POD4 | 5.55 (3.83, 6.86) | 6.66 (5.30, 8.14) | 0.010 |
| NEUT% (%) | |||
| POD1 | 86.80 (83.30, 90.30) | 86.45 (83.67, 90.90) | 0.779 |
| POD4 | 75.50 (69.95, 79.75) | 77.40 (75.20, 81.95) | 0.014 |
| LY (× 109/L) | |||
| POD1 | 0.80 (0.60, 1.04) | 0.75 (0.57, 1.11) | 0.512 |
| POD4 | 1.06 (0.84, 1.31) | 1.08 (0.78, 1.25) | 0.643 |
| LY% (%) | |||
| POD1 | 7.10 (4.80, 10.00) | 7.15 (4.95, 9.65) | 0.907 |
| POD4 | 14.50 (10.75, 20.25) | 12.35 (9.70, 14.40) | 0.018 |
SSA somatostatin analog, AMY amylase concentration, PCT procalcitonin, IL-6 interleukin-6, CRP C-reaction protein, WBC white blood cell count, NEUT neutrophil count, NEUT% neutrophil percentage, LY lymphocyte count, LY% lymphocyte percentage, IQR interquartile range
*Data were described as median (IQR) and compared using Mann–Whitney U test
Postoperative recovery course
The time to first liquid diet was significantly shorter in the SSA group than in the control group (87.33 ± 17.92 h vs. 93.97 ± 17.29 h, P = 0.039). There were no significant differences in the time to first flatus or postoperative hospital stay (P > 0.05). No significant difference was found in actual hospitalization expenses (78,461.11 ± 11,328.30 ¥ vs. 77,702.18 ± 11,849.00 ¥, P = 0.717), even when the cost of somatostatin was added to the total hospitalization expenses (80,794.11 ± 11,328.30 ¥ vs 77,702.18 ± 11,849.00 ¥, P = 0.142) (Table 6).
Table 6.
Postoperative recovery course and peritoneal drainage volume
| SSA group (n = 61) | Control group (n = 62) | P | |
|---|---|---|---|
| First flatus (h) | 54.10 ± 15.78 | 56.53 ± 20.69 | 0.465* |
| First liquid diet (h) | 87.33 ± 17.92 | 93.97 ± 17.29 | 0.039* |
| Postoperative hospital stays (days) | 5.0 (5.0, 6.0) | 5.0 (5.0, 6.0) | 0.453** |
| Hospitalization expenses (¥)a | 78,461.11 ± 11,328.30 | 77,702.18 ± 11,849.00 | 0.717* |
| Hospitalization expenses (¥)b | 80,794.11 ± 11,328.30 | 77,702.18 ± 11,849.00 | 0.142* |
| Drainage volume (mL) | |||
| POD1 | 111.00 (75.00, 138.50) | 138.50 (87.25, 197.00) | 0.015** |
| POD2 | 90.00 (53.00, 121.00) | 107.00 (70.00, 140.00) | 0.057** |
| POD3 | 80.00 (46.00, 130.50) | 92.00 (58.75, 180.00) | 0.075** |
| Mean (daily) | 96.33 (70.00, 123.50) | 119.67 (80.25, 168.75) | 0.025** |
| Drainage duration (days) | 7.0 (5.0, 9.5) | 10.0 (6.0, 12.0) | 0.013** |
SSA somatostatin analog, POD postoperative day
aSSA was provided to the SSA group free of charge
bThe cost of SSA was added to the total hospitalization costs (a market price of 2,333 ¥/patient was used)
*Student’s t test
**Mann–Whitney U test
Peritoneal drainage volume and duration
During the intervention period, the median average daily drainage volume of the SSA group was significantly lower than that of the control group (96.33 [70.00, 123.50] mL vs. 119.67 [80.25, 168.75] mL, P = 0.025). The duration of indwelling drainage tube placement in the SSA group was significantly shorter than that in the control group (7.0 [5.0, 9.5] days vs. 10.0 [6.0, 12.0] days, P = 0.013) (Table 6).
Discussion
To confirm the effect of somatostatin analogs on pancreatic fistulas after radical gastrectomy, we planned to conduct a multicenter, prospective, randomized controlled clinical trial. Before beginning the multicenter trial, we conducted this pilot study to verify the effectiveness and safety of the trial.
Previous studies have mostly focused on the prevention of pancreatic fistula after pancreatic surgery, and clinical trials have demonstrated that somatostatin analogs can reduce the incidence of pancreatic fistula after pancreatic surgery (Allen et al. 2014; Li et al. 2020; Cao et al. 2021). However, for patients who undergo radical gastrectomy, especially those with a high risk of POPF after surgery, there are no clear reports on whether somatostatin analogs can reduce the incidence of POPF. Considering that a high drainage fluid amylase concentration on POD1 was an independent risk factor for pancreatic fistula after radical gastrectomy, we selected patients with drainage fluid amylase concentration > 3 times ULN serum amylase level on POD1, which is different from previous studies.
The incidence of POPF was 3.3% (2/61) in the SSA group and 14.5 (9/62) in the control group. This pilot study suggested that for patients with drainage fluid amylase concentration on POD1 > 3 times ULN serum value, postoperative treatment with somatostatin analog reduced the incidence of POPF (3.3% vs. 14.5%, P = 0.029). And a decreasing trend in the SSA group was observed in grades B and C POPF; however, the difference was not statistically significant (0/61 vs. 3/62, p = 0.248). The small sample size in our pilot study and the low incidence of grade B and C POPF influenced our statistical results.
However, a previous clinical trial (Song et al. 2014) showed that somatostatin analogs did not reduce the occurrence of POPF after radical gastrectomy. There are two reasons for this discrepancy. First, the population included in this trail was different from the previous trial, which included all patients after radical gastrectomy, whereas in our trial, patients at risk of POPF were screened for intervention. In this study, 53.2% (148/278) of the patients did not meet the inclusion criteria (drainage fluid amylase concentration on POD1 > 3 times ULN serum value), and the incidence of POPF in this population was low. Thus, the use of somatostatin analogs in all populations after radical gastrectomy could mask the effect of somatostatin analogs in patients with a high risk of POPF. Second, the duration of our intervention was shorter than that of the previous trial (3 days vs. 5–7 days). We found that even in patients at high risk of POPF, the incidence of grade A POPF was much higher than that of grade B and C POPF. Grade A POPF are self-healing, and we found that drainage fluid amylase concentrations in patients with grade A POPF gradually normalized with time after surgery. It is possible that grade A POPF, which should have been detected, was masked by prolonged intervention.
In this study, the overall incidence of postoperative complications was 17.1% (of 21/123). In previous retrospective studies, the incidence of postoperative complications after laparoscopy-assisted radical gastrectomy ranged from 8.0 to 24.2% (Hwang et al. 2009; Hamabe et al. 2012; Kim et al. 2012; Park et al. 2012; Shinohara et al. 2013), consistent with our results. Recent high-quality clinical trials in some East Asian countries have shown that the incidence of postoperative complications after laparoscopic-assisted radical gastrectomy is closer to our data: CLASS-01 (15.2%) (Hu et al. 2016), KLASS-01 (13.0%) (Kim et al. 2016), KLASS-02 (16.6%) (Lee et al. 2019). In this trial, the overall rate of postoperative complications was significantly lower in the SSA group than in the control group (6/61 [9.8%] vs. 15/62 [24.2%], P = 0.034). However, the incidence of each complication did not differ between the two groups because the incidence of each complication was too low to produce a positive result with a small sample size.
Intra-abdominal infection is a common complication of radical gastrectomy, leading to a prolonged postoperative hospital stay and increased mortality. After gastrectomy, abdominal infectious complications mainly include anastomotic leakage, pancreatic fistula, and abdominal abscess (Fujiya et al. 2021). Some studies have reported that pancreatic fistula is an independent risk factor for abdominal infection (Fujiya et al. 2021). When pancreatic fistula and anastomotic leakage occur, leakage of digestive fluid can lead to secondary abdominal infections. In the SSA group, somatostatin analogs reduced the secretion and exudation of digestive fluid and abdominal inflammation, which also explained the lower blood inflammatory markers, such as white blood cell counts, neutrophil counts, and the neutrophil percentage in the SSA group than in the control group (P < 0.05).
Notably, the median amylase concentration in the drainage fluid on POD4 in the SSA group tended to be lower than that in the control group; however, the difference was not statistically significant (P = 0.083). In this study, we found that amylase concentration in drainage fluid showed a large degree of variation and non-normal distribution, which may have affected the statistical effect.
We observed that the average daily abdominal drainage volume in the SSA group was significantly lower than that in the control group. This study provides preliminary evidence that somatostatin analogs can significantly reduce the postoperative abdominal drainage volume, thereby reducing the indwelling time of the drainage tube. This is also consistent with the ERAS guidelines for gastric cancer (Mortensen et al. 2014), in where the drainage tube should be removed as soon as the abdominal drainage fluid is reduced to a certain extent to reduce the occurrence of drainage tube complications.
Our study bore several limitations. First, this trial was a pilot study with small sample size, and a multicenter, large-sample trial shall further explore its results. Second, we selected the overall incidence of POPF as the primary outcome and obtained expected results. The incidence of grade B and C POPF in the SSA group was lower than that in the control group; however, the difference was not statistically significant as the low incidence of grade B and C POPF. Third, this trial was highly selective, and patients enrolled in the trial were required to have drainage fluid amylase concentration on POD1 > 3 times ULN serum value, increasing the difficulty of screening patients. Therefore, it should be emphasized that this trial demonstrated a good preventive effect of somatostatin analogs on POPF in patients with a high risk of POPF (drainage fluid amylase concentration on POD1 > 3 times ULN serum value), and it is not applicable to the entire population after radical gastrectomy.
Conclusions
In this pilot randomized control trial, we confirmed that postoperative treatment with a somatostatin analog reduced the incidence of POPF and complications after radical gastrectomy in patients with drainage fluid amylase concentration on POD1 > 3 times ULN serum value. Somatostatin analogs may shorten the time to the first liquid diet, reduce abdominal drainage volume, shorten the duration of the indwelling drainage tube, and reduce serum inflammatory markers in patients after radical gastrectomy. Due to the small sample size of this study, a multicenter clinical trial with a large sample size is deemed necessary to confirm these findings.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors gratefully acknowledge the patients who participated in the trial and the team members for their contributions to the trial.
Author contributions
All authors contributed to the study conception and design. Financial and administrative support were performed by CJ and FT. Provision of study materials or patients were performed by GL, YC, LP and LL. Date collection and follow-up of the patients were performed by RF and JW. Data analysis and interpretation were performed by SS and WQ. The first draft of the manuscript was written by SS and all authors commented on previous versions of the manuscript.
Funding
This study was supported by the [National Natural Science Foundation of China] under Grant [81900524]; the [Natural Science Foundation of Shandong Province] under Grant [ZR2020MH252; ZR2020MH205; ZR2022MH085]; the China Postdoctoral Science Foundation under Grant [2020M672102]; the [Science and Technology Development Program of Jinan] under Grant [202134027].
Data availability
Data are available from the corresponding author upon reasonable request.
Declarations
Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
Ethical approval
This study was performed in line with the principles of the Declaration of Helsinki. Study protocol was approved by the Ethics Committee of Shandong Provincial Hospital (SWYX: NO.2021–1013), and registered in the Chinese Clinical Trial Register (http://www.chictr.org.cn, ChiCTR2200056201).
Consent to participate
Informed consent was obtained from all individual participants included in the study.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Shengxu Sha, Wenhao Qiao and Renxiang Feng contributed equally to this work.
Contributor Information
Feng Tian, Email: tianfeng_nju@163.com.
Changqing Jing, Email: jingchangqing@sdfmu.edu.cn.
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Data Availability Statement
Data are available from the corresponding author upon reasonable request.