Hepatobiliary Disease Resection in Patients with Advanced Epithelial Ovarian Cancer: Prognostic Role and Optimal Cytoreduction

Objective The purpose of this study was to evaluate the feasibility and safety in terms of prognostic significance and perioperative morbidity and mortality of cytoreduction in patients affected by advance ovarian cancer and hepato-biliary metastasis. Methods Patients with a least one hepatobiliary metastasis who have undergone surgical treatment with curative intent of were considered for the study. Perioperative complications were evaluated and graded with Accordion severity Classification. Five-year PFS and OS were estimated using the Kaplan–Meier curve. Results Sixty-seven (20.9%) patients had at least one metastasis to the liver, biliary tract, or porta hepatis. Forty-four (65.7%) and 23 (34.3%) patients underwent respectively high and intermediate complexity surgery according. Complete cytoreduction was achieved in 48 (71.6%) patients with hepato-biliary disease. In two patients (2.9%) severe complications related to hepatobiliary surgery were reported. The median PFS for the patients with hepato-biliary involvement (RT = 0 vs. RT > 0) was 19 months [95% confidence interval (CI) 16.2–21.8] and 8 months (95% CI 6.1–9.9). The median OS for the patients with hepato-biliary involvement (RT = 0 vs. RT > 0) 45 months (95% CI 21.2–68.8 months) and 23 months (95% CI 13.9–32.03). Conclusions Hepatobiliary involvement is often associated with high tumor load and could require high complex multivisceral surgery. In selected patients complete cytoreduction could offer survival benefits. Morbidity related to hepatobiliary procedures is acceptable. Careful evaluation of patients and multidisciplinary approach in referral centers is mandatory. Electronic supplementary material The online version of this article (10.1245/s10434-020-08989-3) contains supplementary material, which is available to authorized users.

associated with low chance of optimal cytoreduction. 7 -9 However, increase perioperative care and gynecology's surgical skills have achieved better results in terms of optimal cytoreduction also in presence of disease in challenging area. Initial experiences in liver resection, biliary surgery, and porta hepatis have been reported. 8,10 -12 The purpose of this study was to evaluate the feasibility and safety in term of prognostic impact and perioperative morbidity of cytoreduction in patients affected by advance ovarian cancer and at least one histologically proven hepatobiliary metastasis.

MATERIALS AND METHODS
The medical records of all patients elected to surgical intervention for Ovarian Cancer at the Maternal and Child and Urological Sciences Department of Umberto I Hospital, Sapienza, University of Rome, from January 2005 to December 2018, were retrospectively extracted from a prospective collected database. Inclusion criteria were: histologically confirmed ovarian cancer, informed consent signed, follow-up completed, and at least one histologically proven hepatobiliary metastasis. Exclusion criteria were as follows: patients who denied access to their medical information for research purposes, ovarian cancer not histologically confirmed, lost follow-up, and synchronous invasive cancers. All patients signed informed consent to the processing of personal data. The study received the ethical approval of our Department Review Board. Demographic data, operative and pathological reports, and clinical outcomes were extracted from the database. Missing data and data concerning preexisting medical conditions present at the time of primary surgery were extracted from the patient's medical records. The following preoperative information were collected for statistical analysis: age, body mass index (BMI), serum level of Ca125, hemoglobin (Hb), and albumin. Intraoperative information was recorded, including operative time, surgical procedures performed, and diameter of largest residual tumor nodule. Information obtained from the final pathology report included stage, tumor histology, and tumor grade. All patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) system. Surgical complications were graded according to Accordion severity Classification of postoperative complication expanded classification, divided in early (\ 30 days) and late ([ 30 and \ 60 days). 13 The complexity of the surgical procedures performed was evaluated using the Surgical Complexity Scoring System (SCS) from 1 to 3 (simple to complex, respectively). 14 Surgical outcomes in ovarian cancer are classified according to the size of the largest residual tumor present after surgery, which is one of the most important prognostic factors; resection of the tumor is considered as complete if no macroscopically visible tumor remains. 15 The primary outcome of this study was to evaluate the prognostic impact in terms of progression disease-free survival (PFS) and overall survival (OS) of primary optimal cytoreduction in patients affected by advance ovarian cancer and at least one hepatobiliary metastasis. The secondary endpoint was to evaluate perioperative morbidity.

Statistical Analysis
Standard statistical analysis was used to evaluate descriptive analysis, such as mean, frequencies, and percentages. Incidence of event was analyzed for statistical significance by using the Fisher exact test. Normality testing (D'Agostino and Pearson test) was performed to determine whether data were sampled from a Gaussian distribution. The t test and Mann-Whitney U test were used to compare continuous parametric and nonparametric values, respectively. Predicting variables were evaluated for their association with complication rate on the basis of logistic regression model. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated for each comparison. PFS was calculated in months from the date of surgery to the last follow-up or date of first recurrence. OS was calculated in months from the date of surgery to the last follow-up or date of death from disease. Five-year PFS, and OS were estimated using the Kaplan-Meier curve. Cox regression analysis was used to calculate both univariate and multivariate analysis for variables influencing PFS and OS. Associations were summarized by calculating hazard ratio (HR) and corresponding 95% CI. All calculated p values were two-sided. The p value \ 0.05 were considered statistically significant. Statistical analysis was performed with IBM Microsoft's SPSS Statistics version 25.0 for Mac (IBM Corp., Armonk, NY).

DISCUSSION
One of five patients affected by advanced stage ovarian cancer had hepatobiliary involvement in our series. These data are consistent with literature, despite only few authors investigated this aspect. 12,15 -17 In autoptic analysis half of the patients with ovarian cancer have liver metastases. 18 Computed tomography (CT) scan failed to identify HCLN or porta hepatitis involvement in almost all cases. 19 Instead, the positron emission tomography (PET) CT scan seems to have a superior diagnostic sensibility. 12 Therefore, real incidence of hepatobiliary involvement could be underestimated in published series. As a consequence, diaphragms after liver mobilization, epiploon retro cavity, or porta hepatis should be always explored during cytoreductive surgery to identify potentially nonvisible disease at preoperative instrumental examinations.
One of the major finding of the present study was the rate of 71.6% of patients affected by ovarian cancer with hepatobiliary involvement who had macroscopically complete resection of all visible tumor. Our data seem to be consistent with literature (Table 5) even if population of studies are heterogeneous. 6,12,15 -17,19 -29 As reported in a recently published multicentric prospective trial, 8.5% (55/ 647) and 20% (130/647) of selected ovarian cancer patients underwent partial hepatectomy and resection of porta hepatis, achieving a complete debulking. 15 This study suggested that an optimal surgery also could be achieved even though liver and porta hepatis are involved. Moreover, the reason of incomplete cytoreduction was in 42% (8/19) of cases was not correlated with residual disease in hepatobiliary area. This finding is of really importance since some authors have classically considered the presence of a hepatobiliary metastasis as a criterion of unresectability. In our opinion, nonresectability is even more related to the spread of disease than to the presence of a single hepatobiliary metastasis. Nevertheless, excluding patients only on account of presence of a hepatobiliary metastasis could deprive a considerable number of women the benefits of surgery, particularly those with an acceptable performance and nutritional status, in whom gross disease can reasonably be removed. Although, often, but not always, hepatobiliary involvement may be related to a  24 Because the majority of patients with hepatobiliary metastasis had a high tumor burden, they therefore required multiple complex procedures. Our results confirm these findings; indeed no patients in our series received low complexity surgery, whereas two of three patients underwent high complexity surgery. Anyway, not all women should be candidates to these highly complex surgical procedures, but only those who may reach survival benefit from optimal residual tumor. Treatment must be personalized taking into account not only tumor spread but also patient's characteristics. The challenge of the decisionmaking process for high-risk patients for surgery with curative intent versus palliative treatment lies in the balance between an expected improved survival, if complete debulking is achieved and the expected surgical morbidity and mortality. In our series 58% of patients with metastatic involvement of hepatobiliary region had at least one complication, but only in 10.4% of cases were severe. Because the study includes only patients undergone surgical treatment with curative intent and at least one histologically proven hepatobiliary metastasis, the worst patients have been considered more frequently inoperable or unresectable. This carefully perioperative assessment could explain the low severe postoperative morbidity experienced. Moreover, complications seem to be  significantly associated with high scores of Surgical Complexity Score, and in only two patients (2.9%), the severe complications reported were directly related to hepatobiliary surgery. Hepatobiloma is a potential complication in liver surgery 30 usually treated with percutaneous catheter drainage. In order to prevent this type of complications, some authors suggested the use of intraoperatory ultrasound to evaluate rapport between liver metastasis and bile ducts. 31 In liver surgery, it is important not only to avoid directly injure but also to avoid burning and necrotizing the intrahepatic bile vessels. In liver surgery, it is important not only to avoid directly injure but also to avoid burning and necrotizing the intrahepatic bile vessels. Current data are not available to allow accurate risk prediction of surgical mortality in ovarian cancer. Different algorithms have been proposed, but nowadays there is not unanimous consensus in literature. 32 A recent metanalysis based on 46 studies that involved 18,579 patients has evaluated predictors of 30-day mortality in patients undergoing primary cytoreduction for ovarian cancer demonstrating that combined effects of increased age and advanced clinical stage factors greatly increased the risk of perioperative mortality. 32,33 However, some authors have showed benefits of complete cytoreduction in terms of survival, regardless of age. 33,34 As reported by Langstraat et al., despite elderly patients had increase risk surgical morbidity and mortality after multivisceral surgery, they also could potentially have survival advantage from radical surgical approach similar to that of younger one. 35,36 However, patients' comorbidities seem to have a strongly effect on mortality and morbidity, and aging-associated state of increased vulnerability, in frail patients, influences complications rate and survival. 37 Our study suggests that the presence of metastatic involvement of hepatobiliary region represents a negative indicator of survival (hepatobiliary vs. no hepatobiliary involvement

CONCLUSIONS
Hepatobiliary involvement in patients with EOC often is associated with high tumor load and could be considered as independent risk factor for early recurrent disease. The surgical treatment of EOC is a complex issue and requires a multidisciplinary assessment. Tailored strategy and multivisceral surgical approach, in selected patients, could allow to achieve complete resection of disease. Demolitive surgery should be limited to cases in which optimal residual Patients underwent randomization only if macroscopically complete resection had been achieved tumor can be achieved, but selection is a challenge. All patients with EOC should be referred to specialized dedicated center in order to receive the best treatment. Multicentric prospective studies to confirm our results are warranted.
ACKNOWLEDGEMENTS Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement.
FUNDING The authors received no financial support for the research, authorship, and/or publication of this article.
DISCLOSURES The authors declare that they have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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