Abstract
Background/Aim: To assess the perioperative outcomes of cholecystectomy in cytoreductive procedures for epithelial ovarian cancer (EOC). Patients and Methods: Prospectively collected perioperative data of patients that underwent cytoreduction for advanced EOC, between 2014 and 2018, were analysed. Patients were divided in two groups on the basis of whether cholecystectomy was performed. Results: A total of 144 patients with stage IIIC/IV EOC were included. Cholecystectomy was performed in 22 (15.3%) patients. Those who underwent cholecystectomy more likely required diaphragmatic peritonectomy, splenectomy, lesser omentectomy, excision of disease from the porta hepatis and liver's capsule (p<0.001). There was no difference in the cytoreductive outcomes (complete or optimal) and the rate of grade 3-5 complications between the two groups (p=0.10 & p=0.06, respectively). No direct complications related to cholecystectomy were observed. Conclusion: A significant percentage of patients with advanced EOC require cholecystectomy. Gynecologic oncologists should embrace the opportunity to develop advanced surgical skills including cholecystectomy.
Approximately two thirds of patients diagnosed with advanced epithelial ovarian cancer (EOC) present at an advanced stage (1, 2). Primary cytoreductive surgery (CRS) followed by platinum-based chemotherapy, remains the gold standard for the management of advanced disease. The aim of cytoreductive surgery is removal of all gross visible disease in the abdomen and pelvis or, if this is not possible, an attempt should be made to resect disease to tumour nodules no greater than 1 cm (3, 4).
Bulky upper abdominal disease (tumour nodules of greater than 1 cm in diameter) can be encountered in up to 59% of patients with stage IIIC ovarian cancer (5). Hence, in order to achieve complete cytoreduction a more comprehensive and aggressive surgical approach is required in the upper abdomen (6-8). As a result, an ongoing expansion of gynecologic oncologists' surgical skills has been observed over the past decades, including complex abdominal procedures such as radical pelvic dissection, bowel resection, partial cystectomy, diaphragmatic peritonectomy or splenectomy. Available literature data suggest the specialty training of the physicians (gynecologic oncologists versus other specialties) performing the operation appears to influence the outcome of cytoreduction and overall survival of patients with metastatic ovarian cancer (9). However, the technical limitations of gynecological oncologists performing complex upper abdominal procedures during cytoreductive surgery for metastatic ovarian cancer often necessitates the involvement of other specialists, such as an upper gastrointestinal (GI) or hepatobiliary surgeon. Procedures such as cholecystectomy and resection of disease from the porta hepatis can be associated with significant perioperative morbidity and are not often part of the training curriculum in gynecological oncology.
Available data suggest that between 2.5-20% of patients undergoing cytoreductive surgery for metastatic ovarian cancer require cholecystectomy to achieve resection to tumour diameter no greater than 1 cm (10, 11). However, it is not clear from these studies if gynecological oncologists or general surgeons performed these cholecystectomies. The aim of this study was to assess the perioperative outcomes of cholecystectomy when performed by gynecological oncologists, as part of cytoreductive procedures for ovarian cancer.
Patients and Methods
This is a study of patients who underwent elective cytoreductive surgery for International Federation of Gynecology and Obstetrics (FIGO) stage IIIC and IV EOC, at a gynecological oncology centre in the United Kingdom between July 2014 and November 2018. All patients with suspected metastatic ovarian, fallopian tube or primary peritoneal cancer underwent initial evaluation with a computed tomography (CT) scan of the chest, abdomen and pelvis, and measurement of serum cancer antigen 125 (CA 125) and carcinoembryonic antigen (CEA) levels. Patients with good performance status and no gross extra-abdominal disease (except those with extra-abdominal disease limited to inguinal lymph nodes and/or cardiophrenic lymph nodes) underwent primary cytoreductive surgery. Patients with poor performance status or presence of gross extra-abdominal disease were offered neoadjuvant chemotherapy (NACT), the response to which was assessed after three cycles of chemotherapy using CT scan criteria and measurement of CA125 levels. If there was no disease progression and cytoreduction to residual tumour diameter no greater than 1 cm was feasible, then this group of patients underwent surgery. We excluded from the study patients with non-epithelial tumour histology and those with borderline tumours.
Patients' characteristics.
Cholecystectomy-surgical technique. A midline incision extending from the xiphoid process to pubic symphysis was employed in all patients, to enable a thorough assessment of the dissemination of disease in the peritoneal cavity.
Mobilization of the gallbladder began at its fundus, moving in a retrograde manner towards the cystic duct and artery. The gallbladder was dissected away from the liver bed; the dissection plane was typically avascular during this step. The peritoneum of the cystohepatic triangle (of Calot) was mobilized and divided. The layer of the hepatoduodenal ligament that covers the porta hepatis was mobilized and the common bile duct was identified. Attention was paid at all times towards any anatomic variations in the Calot's triangle (e.g. a short cystic duct), which are relatively common. The cystic artery was ligated and divided. The cystic duct was identified, ligated and divided, taking care to avoid injury to the common bile duct. A routine cholangiogram was not performed. All procedures were performed by a team of consultant gynecological oncologists.
Data collection and analysis. Demographic and clinic data were collected prospectively and included patient age at the time of initial surgery, body mass index (BMI) in kg/m2, the American Society of Anaesthesiologists (ASA) preoperative score, preoperative serum CA125 and albumin levels, volume of ascites, primary tumor origin, FIGO stage, histologic type and grade. We also collected data on the procedures performed, length of operation, estimated intraoperative blood loss and length of hospital stay. Perioperative complications were defined as adverse events related to the operation that occurred within 30 days of surgery and they were classified according to the Clavien-Dindo system (12). In this study, we reported only grade 3-5 complications, i.e. those who required surgical, endoscopic or radiologic intervention, intensive care unit admission or death of the patient. As per the criteria from the Gynecologic Oncology Group (GOG), ‘complete cytoreduction’ was defined as the presence of no gross visible residual disease at the end of the procedure, whilst ‘optimal cytoreduction’ was defined as residual tumour diameter no greater than 1 cm.
The data collection and analysis were performed according to our institutional clinical governance protocol and was adherent to Decalaration of Helsinki. Descriptive statistics were performed using Wizard Pro software, version 1.9.22. Normality was investigated by the Kolmogorov-Smirnov test. Chi-square and z-test were used to analyze the difference between binomial and continuous data, respectively.
Additional surgical procedures performed.
Results
Over a 53-month period, 144 patients underwent cytoreductive surgery for stage IIIC and IV ovarian, fallopian tube and primary peritoneal cancer. Cholecystectomy was performed in 22 (15.3%) patients. The subgroup of patients requiring cholecystectomy was significantly younger (63.9 versus 68.5 years, p-value=0.02). Significantly more patients in the cholecystectomy group underwent primary cytoreductive surgery compared to the rest of the cohort (91% versus 50%, p-value <0.001). There was no significant difference in other clinical and tumour characteristics between the two groups, as presented in Table I.
All patients underwent at least one additional surgical procedure in the upper abdomen at the time of surgery (Table II). Patients who underwent cholecystectomy were more likely to require diaphragmatic peritonectomy, splenectomy, lesser omentectomy, excision of disease from the porta hepatis and Glisson's capsule of the liver (p<0.001). Similarly, significantly more women in the cholecystectomy group underwent radical oophorectomy (en-block resection of the ovaries, fallopian tubes, uterus, cervix, rectosigmoid and pelvic peritoneum).
Complete cytoreduction in the cholecystectomy group was achieved in 12 (54.5%) patients, while 10 (45.5%) patients had residual tumour diameter between 1-10 mm in the mesentery and/or serosa of the small bowel. There was no difference in the cytoreductive outcomes between the two groups (p=0.10). The mean operating time was significantly longer in the group of patients who underwent cholecystectomy (487 min versus 262 min respectively, p<0.001). Significantly more patients in the cholecystectomy group experienced blood loss greater than 1000 ml. The length of hospital stay for both groups of patients was similar (p=0.24). The rate of grade 3-5 complications was not different between the patients who required cholecystectomy and the remainder of the cohort (22.7% versus 9% respectively, p=0.06) as shown in Table III. One patient who required re-suturing of the laparotomy scar was found to have a small biloma as a result of the extensive resection of disease from the liver capsule. There were no cases of common bile duct injury and none of the patients required postoperative interventions such as Endoscopic Retrograde Cholangiopancreatography (ERCP) for retained stones or bile leak. There was one case of death within 30 days following surgery in the group of patients who did not require cholecystectomy.
Discussion
Incorporation of extensive upper abdominal procedures, including cholecystectomy, is associated with increased complete cytoreductive rates and significantly improved survival in patients with advanced ovarian cancer (5, 13, 14). However, the presence of upper abdominal disease is the principal reason why gynecologic oncologists decide against primary cytoreduction or are unable to achieve at least optimal cytoreduction, with the portal triad being the main site of disease precluding desired outcome (15). Lack of familiarization with complex procedures in the upper abdomen has been shown to breed concerns about their efficacy (p=0.01), sub-optimising the provision of care to advanced EOC patients (15).
Perioperative outcomes.
In the current study, we report on the perioperative outcomes of cholecystectomy when performed by gynecologic oncologists as part of cytoreductive surgery for advanced EOC. Of a cohort of 144 patients who underwent cytoreductive surgery in our institution, cholecystectomy was required in 22 (15.3%) women. Chi et al. have found that 11% of patients who underwent primary surgery for advanced ovarian, tubal, and peritoneal carcinomas required cholecystectomy (16), while Panici and colleagues have reported 19.8% of patients with advanced ovarian cancer with upper abdominal spread required cholecystectomy and/or disease resection from the porta hepatis (10).
Cholecystectomy is a complex surgical procedure with potential significant morbidity. In a large series of 1629 patients who underwent cholecystectomy due to primary gallbladder disease, Wolf et al. have reported an overall complication rate of 34%. Amongst 136 patients treated by open surgery, major complication and mortality rates were 4.4% and 2.9%, respectively (17). Available data for patients who underwent aggressive cytoreductive surgery, including cholecystectomy, for advanced ovarian, tubal or peritoneal disease confirm a major morbidity rate varying from 18.6 to 22% and mortality rate ranging from 0.71 to 3.4% (16, 18, 19). Panici et al. have found that biliary surgery is an independent predictor of severe (grade 3 and 4) complications (p=0.049) (18). These studies did not report morbidity data separately for patients undergoing cholecystectomy or resection of disease from the porta hepatis.
In our cohort, we observed no significant difference in the rate of grade 3-5 complications in the group of patients undergoing cholecystectomy. The higher complication rate observed in the group of patients undergoing cholecystectomy (22.7% versus 9%), although not statistically significant, is likely to be related to more complex surgery performed in this group overall. Reports regarding open cholecystectomy due to primary gallbladder disease have traditionally demonstrated a complication rate ranging from 6% to 21% (20). Lower major complication (bile duct injury, bile leak, and bleeding requiring reoperation or transfusion) rates of 4.4% have been reported with contemporary surgical practice (17). In the current study, we found no direct complications related to the cholecystectomy.
Gynecological oncology surgeons performed the cholecystectomies in this cohort. Our team developed surgical skills in cytoreductive surgery in the upper abdomen with the support of colleagues from hepatobiliary and upper gastrointestinal tract surgery. Attending regular cadaveric dissection workshops and careful studying of the relevant surgical anatomy further enhanced these skills.
The main limitation of this study is the small sample size and in particular the number of patients who underwent cholecystectomy. In addition, although in our study we observed that more than 75% of cholecystectomy cases were performed in the last 22 months of the study, the long duration of the study period results to longer intervals between each surgical procedure. To overcome this issue and maintain the skills required, it is important to attend cadaveric dissection workshops or use anatomy demonstration facilities.
In conclusion, it is important to maintain a multidisciplinary approach for the management of patients with advanced ovarian cancer. However, gynecologic oncological surgeons should embrace the opportunity to develop advanced surgical skills including cholecystectomy through mentoring and support from colleagues. This initial report suggests no significant increase in the morbidity rates for cholecystectomy as part of the cytoreductive surgery for advanced ovarian cancer.
Footnotes
Authors' Contributions
All Authors have made a substantial contribution to the study and approved the final version of the manuscript.
Conflicts of Interest
The Authors declare no conflict of interest regarding this study.
- Received January 9, 2020.
- Revision received February 19, 2020.
- Accepted February 21, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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