Abstract
Background/Aim: Staging laparoscopy (SL) for pancreatic cancer (PC) is considered useful to improve accuracy of staging and resectability. However, given the current accuracy of preoperative imaging, the routine application of SL remains unclear. Therefore, we aimed to investigate the importance of SL in patients with PC without radiological distant metastasis. Patients and Methods: This was a prospective, cohort, observational study. SL was performed in all patients with PC without radiological distant metastasis before pancreatectomy or chemotherapy at the Yamaguchi University Hospital. Results: Between July 2020 and March 2023, 55 patients underwent SL with peritoneal cytology. The median age was 71, with 53% male patients. SL revealed occult metastasis in six (11%) patients including positive peritoneal cytology (n=6), and peritoneal dissemination (n=1). The resectability of unresectable locally advanced (UR-LA) was associated with a significantly increased risk of occult metastasis (p=0.0211). The median operative time was 40 min, and the median volume of blood loss was 3 ml. There were no severe complications (Clavien-Dindo III or higher). Conclusion: SL with peritoneal cytology regardless of previous abdominal surgery is safe and effective to determine accurate staging. Therefore, SL with peritoneal cytology should be considered for patients with PC without radiological distant metastasis, especially in those with UR-LA.
Pancreatic cancer (PC), one of the most lethal malignancies, is the seventh leading cause of cancer death worldwide and accounted for 500,000 patients with newly diagnosed PC in 2020 (1). Patients with PC show poor prognosis with a five-year survival rate, less than 10%, due to difficulties in early diagnosis, including non-specific symptoms and anatomic features. Moreover, PC easily invades major vessels, and >80% of patients are diagnosed with an unresectable stage (2, 3). Although preoperative imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are available to assess the spread of PC, some patients with occult metastasis are diagnosed only during laparotomy (4, 5).
The usefulness of staging laparoscopy (SL) has been reported for improving accuracy of PC staging and resectability (6). Recent studies have reported that SL demonstrated the presence of peritoneal metastases or liver metastases undetected by the preoperative images in approximately 15-40% of patients with PC (6-9). These results indicated that SL can avoid unnecessary surgical exploration and allow for rapid introduction of systemic therapy in patient with occult metastasis. However, there were few prospective studies have investigated the accuracy, thus, the routine application of SL remains controversial due to increased sensitivity of preoperative imaging (7, 8).
In this study, we aimed to investigate the importance of SL in patients with PC without distant metastasis after preoperative imaging.
Patients and Methods
Patients. This study was a single-center prospective cohort study including patients with PC without distant metastasis at the Yamaguchi University Hospital (Ube, Japan) (UMIN000043376). All 55 patients had pathological evidence of PC before or during SL. Preoperative resectability was evaluated with triple-phase helical CT, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), and fluorodeoxyglucose-positron emission tomography (FDG-PET). SL was performed in all patients with PC with no radiological distant metastasis before they underwent pancreatic resection or chemotherapy. This study protocol was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Boards of Yamaguchi University Hospital (H2020-041). Informed consent was obtained from all patients.
Data collection. Preoperative data included age, sex, tumor location, tumor size, carbohydrate antigen 19-9 (CA19-9), FDG-PET maximum standardized uptake value (SUV-max) in the primary tumor, preoperative resectability, and previous surgical history. The perioperative and postoperative data included operative time, blood loss, morbidity, and length of hospital stay. Postoperative morbidities, including surgical site infection and delirium, were defined according to the classification system of the Clavien-Dindo (C-D) classification of surgical complications (10).
Surgical procedure. With the patient in the supine position under general anesthesia, a 12 mm trocar was inserted at the umbilical site. A flexible laparoscope was inserted followed by two additional 5 mm trocars. First, the entire abdominal cavity and liver were inspected. Second, peritoneal washing cytology with 50 ml of normal saline was aspirated from the Pouch of Douglas and the right subphrenic space. Any suspicious metastatic lesion was biopsied and sent to frozen sections and permanent specimens.
When occult metastasis was detected in SL, patients were treated with systemic chemotherapy. When occult metastasis was not detected in SL, patients were treated with either neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy or pancreatectomy on another day.
Statistical analysis. Quantitative data are expressed as median (range), and qualitative data are expressed as percentages. Univariable logistic regression analysis was performed to identify risk factors for occult metastasis, with the results expressed as odds ratios with 95% confidence intervals. The cut-off values of age, tumor size, CA19-9, and SUV-max were determined by receiver operating characteristic analysis. Statistical analyses were performed using JMP Pro15 (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at p<0.05.
Results
Clinical characteristics of patients. Between July 2020 and March 2023, 55 patients were enrolled in the study. The median age was 71 years (range=37-85 years), and 29 out of 55 (53%) patients were male. Based on the resectability status by National Comprehensive Cancer Network (NCCN) criteria, 41 (75%) patients were classified as resectable (R), six (11%) as borderline resectable (BR) and eight (15%) as unresectable locally advanced (UR-LA) (11). The baseline characteristics of the patients are summarized in Table I. Figure 1 shows representative images for PC.
Patient characteristics (n=55).
Representative enhanced CT, and fluorodeoxyglucose-positron emission tomography (FDG-PET). (A) CT revealed a low-density tumor in the pancreatic body (black arrow). (B) Fluorodeoxyglucose uptake was detected in the pancreatic body (maximum standard uptake value: 8.7) (white arrow). CT: Computed tomography.
Of the 55 patients, six (11%) patients had occult metastasis including positive peritoneal cytology (n=6), and peritoneal dissemination (n=1). The rate of occult metastasis was 7% in R, 0% in BR, and 38% in UR-LA patients. Four patients underwent chemotherapy and the other two patients received best supportive care due to poor performance status. Two patients repeated SL; their CY+ status converted to CY negative after systemic chemotherapy. In one of them, CY+ status persisted in the second SL, thus, the chemotherapy regimen was changed. She was CY negative in the third SL, and then they underwent successful curative pancreatectomy (Table II).
Clinical and treatment outcomes of cases with occult metastasis.
Outcome of SL according to history of previous abdominal surgery. A total of 32 (58%) patients had previous abdominal surgeries before SL (Table III). The most common surgeries were appendectomy (47%), gastrectomy (16%), and cholecystectomy (13%). Although intra-abdominal adhesions were seen in 23 (72%) patients, peritoneal lavage could be performed in all patients. Due to severe adhesions, full inspection of peritoneal cavity could not be achieved in three (9%) patients who had previous open surgeries of gastrectomy, cholecystectomy and pancreatoduodenectomy.
Characteristics of patients who underwent previous abdominal surgery.
Perioperative outcome of SL. The surgical outcome is outlined in Table IV. The median operative time was 40 min (range=18-115), and the median volume of blood loss was 3 ml (range=0-100). Although the most common complications were surgical site infection (n=1), and delirium (n=1), there were no severe complications (Clavien-Dindo III or higher).
Perioperative outcomes of patients who underwent staging laparoscopy.
Predictive factors associated with occult metastasis. Table V shows risk factors for occult metastasis in patients with PC by univariate analysis. The resectability of UR-LA was the most significant risk factors for occult metastasis (p=0.0211).
Univariate analysis of risk factors for occult metastasis.
Discussion
The present study was a prospective observational cohort study investigating the yield of SL in patients with PC with no radiological distant metastasis. In this study, six (11%) patients had occult metastasis including positive peritoneal cytology (n=6), and peritoneal dissemination (n=1). The rate of patients with occult metastasis was smaller in this study (11%) than in previous studies (range=15-40%) (6-9). Multimodality imaging is critical in the diagnosis and staging of PC with triple-phase helical CT being the best-validated and most widely available modality. MRI or FDG-PET was not routinely performed in previous studies, although it has been reported that EOB-MRI and FDG-PET have superior diagnostic performance in detecting distant metastasis from PC (12, 13). NCCN guidelines suggest that MRI or FDG-PET can be considered a helpful adjunct modality in high-risk patients of metastatic disease, such as those with borderline resectable disease, markedly elevated CA19-9, large primary tumors, or large regional nodes (14). Since all patients in this study underwent CT, EOB-MRI, and FDG-PET, the presence of peritoneal metastases or liver metastases might be low.
A total of 32 (58%) patients had previous abdominal surgeries before undergoing SL. Following abdominal surgery, extensive adhesions often occur and may cause difficulties during SL. However, there are no studies describing the relationship between previous laparotomy and SL. Although full inspection of peritoneal cavity could not be achieved in three (9%) patients, peritoneal lavage could be performed in all patients. Peritoneal cytology (CY) has been used widely in the diagnosis and staging of various cancers, such as ovarian, and gastric cancer (15-17). Positive peritoneal cytology (CY+) in patients with PC is equivalent to metastatic disease and Stage IV according to the American Joint Committee on Cancer and the NCCN (18, 19). On the other hand, the CY status had not included to determine the tumor stage in Japan Pancreas Society (20, 21). Upfront surgery had previously been performed in patients with PC regardless of CY status, because the prognostic outcome of CY+ on PC was controversial due to the reports of single-center or limited number of cases (21-23). A recent large-scale retrospective multicenter study from the Japan Pancreas Society showed that CY+ was the most significant poor predictor after curative pancreatic resection (24). Neoadjuvant chemotherapy with gemcitabine (GEM) and S-1 therapy has been considered the standard treatment for resectable PC, supported by results from the Prep02/JSAP-05 trial (25, 26). Therefore, the standard treatment for PC is preoperative chemotherapy with or without radiation, surgery and postoperative adjuvant chemotherapy (26, 27). Based on these results, upfront surgery in patients with CY+ status is not recommended in the Japanese guidelines (28, 29). However, SL regardless of previous abdominal surgery with peritoneal cytology is essential to determine accurate staging because CY cannot be detected by preoperative image.
Neoadjuvant chemotherapy is introduced following SL, therefore, identifying postoperative complications and rapid induction of chemotherapy are important (9). In a previous meta-analysis, complication rates were minimal at 0.5% (15/3305), including hemorrhage requiring laparotomy (n=3), port site abscess/infection (n=3), pneumonia (n=2), pancreatitis (n=2), bile leak (n=2), port site hematoma (n=2), and port site recurrence (n=1) (30). There was one mortality 0.03% (1/3,305) due to myocardial infarction (30). In this study, SL was carried out within one hour under general anesthesia and the complication was seen in two patients with surgical site infection (n=1), and delirium (n=1). There were no mortalities. Among 52 (95%) patients who received preoperative chemotherapy, preoperative chemotherapy was initiated median 10 (range=4-31) days after SL. Based on these results, we believe that routine SL may be safe and acceptable.
In general, SL may be used not routinely, however, should be used selectively in patients who are at a high risk of occult metastasis. Although there are studies suggesting high risk factors, such as markedly elevated CA19-9, large primary tumors, male sex, preoperative resectability, no neoadjuvant chemotherapy, or pancreatic body/tail lesions, there is not enough evidence for predictive factors (31, 32).
This study confirmed that the resectability of UR-LA was the most significant risk factor for occult metastasis. However, occult metastasis was detected even in resectable PC. Therefore, SL should be performed routinely in patients with PC, without radiological distant metastasis because it helps determine an appropriate treatment strategy.
This study had several limitations. First, it was conducted in a single center. Second, the number of enrolled patients was small. Thus, there might be a potential for several biases. Therefore, prospective multicenter studies are required to further explore the efficacy of SL.
Conclusion
In conclusion, SL with peritoneal cytology regardless of previous abdominal surgery is safe and effective to determine accurate staging. Therefore, SL with peritoneal cytology should be considered for patients with PC without radiological distant metastasis, especially in those with UR-LA.
Acknowledgements
We would like to express our gratitude to Ms. Takako Iijima, and Ms. Shiho Yamada for their skillful laboratory work.
Footnotes
Authors’ Contributions
YS and HN designed the study. YS, YT, HM, MN, YK, MI and TI contributed to acquisition of data. YS and NS conducted data analysis and interpretation. YS drafted the manuscript. YS, ST and HN reviewed the statistics and contributed to critical revisions. All Authors have approved the final version of the article.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received July 22, 2023.
- Revision received August 30, 2023.
- Accepted August 31, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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