Epithelial ovarian cancer remains the leading cause of death from gynecologic malignancies in the United States. An estimated 22,240 new cases of ovarian cancer were diagnosed in 2013, with an estimated 14,030 deaths from this disease.1 More than 70% of newly diagnosed conditions of patients with ovarian cancer present as advanced-stage disease (FIGO stage III or IV).1 Current management of advanced-stage ovarian cancer is guided by the principle of complete macroscopic cytoreduction followed by platinum-based chemotherapy. An inverse relationship between survival and the size of residual disease after cytoreductive surgery for ovarian cancer has been understood since the 1970s.2 Approximately 70% to 80% of patients who undergo complete cytoreduction and platinum-based chemotherapy will have no evidence of disease at the completion of their treatment3; however, two thirds of these patients will experience recurrence.4 The benefit of secondary cytoreduction has been demonstrated for several decades; however, the implementation of aggressive upper abdominal surgery to achieve complete macroscopic cytoreduction has become an area of increasing interest.5–8
Although many elements of aggressive cytoreduction have developed over the years, few have explored the implementation of liver resection in the setting of recurrent ovarian cancer in patient selection for secondary cytoreduction. Until recently, large-volume upper abdominal disease involving the diaphragm, liver, and spleen were considered unresectable. Studies have demonstrated that up to 50% of patients who die of gynecologic cancers had concurrent hepatic metastases at autopsy.9 The role of hepatic resection for metastatic gynecologic cancers was described as early as 1963 by Brunschwig10 with subsequent series including larger cohorts of ovarian cancer patients.8,9,11 In early publications, only patients with single metastasis to the liver were selected for secondary cytoreduction; patients with extrahepatic or multiple liver metastases were excluded from these studies as the disease was deemed less likely to be completely cytoreduced. As advances have been made in liver resection techniques, however, the morbidity and mortality associated with liver resection have declined.12,13 These advances have made it possible to expand the pool of patients who can be considered as candidates for secondary cytoreductive surgeries involving liver metastasis.
Given the limited number of publications in the literature, we selected patients who had undergone liver resection for both single and multiple metastases to determine the feasibility and utility of liver resection at the time of secondary cytoreductive surgery.
MATERIALS AND METHODS
After obtaining approval from our institutional review board, we performed a retrospective review on all of the patients who had undergone hepatic resection for ovarian carcinomas involving the liver between September 1988 and February 2012. Extracted from patient medical records, data included demographic variables, the specific histologic diagnosis, grade, chemotherapeutic agents used, and the stage at initial presentation. The database included a patient selection from multiple gynecologic oncologists and surgical oncologists at our institution, representing a specialized multidisciplinary approach to the management of advanced ovarian malignancies. All of the patients had imaging studies confirming metastatic disease to the liver before the procedure. The general principles that were followed for offering secondary cytoreduction were based on the disease-free interval from the primary staging procedure and the number of disease sites identified on imaging studies. In general, secondary cytoreduction was not offered to patients with more than 5 sites of recurrence, to patients with a location of the disease that does not allow optimal resection, or to patients who had a disease-free interval of less than 6 months. Only patients with parenchymal metastasis were included in the study cohort. Patient with only liver capsule involvement were not included in this analysis. Data concerning surgical procedures performed, sites of metastatic disease, and the volume of the residual tumor were extracted from the operative report of the surgeon that performed the procedure. In addition, specifics concerning the liver resections were collected, including type of liver resections (eg, wedge resection, segmentectomy, multisegmentectomy, and lobectomy) and resection of any extrahepatic disease. Data concerning surgical time, estimated blood loss, complications, and postoperative hospital stay were also collected. Patients who had intraoperative liver biopsies alone were excluded.
Patients with no visible disease at the completion of the procedure, less than 1 cm residual disease, and greater than 1 cm residual disease were included in the study population.
Progression-free survival (PFS) was defined as the interval from the date of the primary surgery to the date of disease progression. Overall survival (OS) was defined as the interval from the date of the primary surgery to the date of death or last follow-up. Platinum sensitivity was defined as complete remission after primary platinum-based chemotherapy for at least 6 months.
The SPSS Statistical version 19 (SPSS Inc., Chicago, IL) was used for all analyses. Survival estimates were determined with the use of the Kaplan-Meier method, and a P value of less than 0.05 was deemed statistically significant.
A total of 76 patients were identified who had undergone liver resection as part of their cytoreductive surgery during the study period. Twenty-seven of the 76 patients’ surgeries were in the setting of secondary cytoreduction. The median age at the time of liver resection was 62 years (range, 32–74). Most patients presented at the time of the initial diagnosis with advanced disease; 1 patient presented with stage I, 1 with stage II, 7 with stage IV (3 with pleural effusion and 4 with metastasis to the liver), and the remaining 18 with stage III disease. The primary tumors were mostly grade 3 (82%, 22/27) and with papillary serous histologic diagnosis (89%, 24/27; Table 1). All patients received platinum-based combination chemotherapy at the time of the initial diagnosis. Four patients of our cohort that were identified as having stage IV disease had hepatic resection at the time of the primary surgery.
The median disease-free interval was 27 months (range, 3–87 months) from the time of primary surgery to their secondary cytoreduction. All but 1 patient had a disease-free interval of at least 6 months after primary platinum-based chemotherapy. All recurrences were confirmed by computed tomography scan. Most patients had multiple liver metastasis (56%, 15/27), whereas 12 patients (44%, 12/57) had single metastasis described on the operative and pathologic reports. The largest liver metastasis was 10 cm (range, 2–10 cm), with the median size being 4.5 cm. The location of metastasis was on the left side of the liver in 7 patients, on the right side in 15 patients, and bilateral in 5 patients. The types of liver resections performed were multisegmentectomy (3), lobectomy (4), segmentectomy (11), and wedge resection (9). Pathologic reports revealed recurrent disease in all cases. In 3 of the 27 liver specimens, the margins showed microscopic involvement. In addition to requiring liver resection, 9 patients also required diaphragmatic resection, 2 patients required large bowel resection, and 2 patients required splenectomy operation. Cytoreduction with no visible disease or less than 1 cm residual disease was achieved in 25 of the 27 patients (Table 2). Of the 27 patients undergoing secondary cytoreduction with liver resection, 4 had undergone liver resection as part of their primary cytoreductive surgery.
There were no intraoperative or perioperative deaths within 30 days of surgery. The median estimated blood loss (EBL) was 300 mL (range, 50–2500 mL), with only 3 patients experiencing an estimated blood loss of greater than 1.5 L. No patients required postoperative blood transfusions. The median length of surgery was 209 minutes (range, 96–352 minutes), with no surgery lasting greater than 6 hours. The median length of hospital stay was 6 days (range, 1–57 days). Complications were assessed using the Clavien-Dindo classification system.14 There were only 3 high-grade complications—2 patients required reoperation because of anastomotic leak, and 1 patient required an intensive care unit admission secondary to the development of postoperative sepsis. In summary, the overall complication rate was 11%.
The median OS for this group from the time of their primary diagnosis to the last follow-up or death was 56 months (range, 12–249 months). Twenty died of the disease with a median OS of 12 months from the time of the liver resection (2–190 months), and 7 patients were alive with the disease at the time of the last follow-up. Factors considered for statistical analysis were age at diagnosis, disease stage, volume of the disease at the completion of cytoreduction both at the time of initial surgery and secondary cytoreduction, number of liver metastasis, and disease-free interval. Based on a Kaplan-Meier survival analysis, the factors associated with the longest survival after the liver resection (2–190 months) were the interval from the primary surgery of less than 24 months (n = 13) versus more than 24 months (n = 14) (95% confidence interval, 50.4–69.5; P = 0.044) and secondary cytoreduction residual disease less than 1 cm (n = 25) versus residual disease greater than 1 cm (n = 2) (95% confidence interval, 50.4–69.5; P = 0.014; Fig. 1). There was no significant difference (P = 0.97) in survival when solitary liver mass resections were compared with multiple liver mass resections done at the time of secondary cytoreduction.
Although the benefits of aggressive and complete excision of recurrent disease at the time of secondary cytoreduction have been well described,3,6,7 safe performance of liver resection at the time of secondary debulking is an evolving area of interest. Improvement in operative techniques, anesthesia, patient selection, and postoperative care have allowed for wider implementation of hepatic resection for metastatic carcinoma with a substantial decrease in perioperative morbidity and mortality. In patients with isolated metastatic colon cancer, liver resection has become a well-accepted management strategy. Major hepatic surgery has been safely performed in these patients with perioperative morbidity of less than 5% and significant improvement in survival.13
The role of hepatic resection for metastatic gynecologic cancers was first described at a memorial hospital in 1963 by Brunschwig10 in a patient with metastatic uterine cancer. In 1997, the memorial group published a series of 12 patients with gynecologic cancers of which 7 had ovarian cancer. For the purpose of this initial study, only patients with a single metastasis to the liver were selected, whereas patients with extrahepatic or multiple liver metastases were excluded. There were no deaths reported in the study with a perioperative morbidity of 8%. The overall survival of this group was compared favorably with those previously reported in the literature, demonstrating an increased benefit without an increase in morbidity.9 In a follow-up study by Yoon et al,15 the same group of authors further explored the utility of resecting liver metastases at the time of secondary cytoreduction by analyzing data of 24 patients with recurrent ovarian and fallopian cancers that had undergone a liver resection procedure at the Memorial Sloan-Kettering Cancer Center.15 Again, they were able to demonstrate improved OS with minimal morbidity. The reported median OS was 62 months (range, 6–94 months). Though the cited complication rate was 21%, only 3 were high-grade complications, with no perioperative deaths reported.15
The other large series published by Merideth et al16 analyzed the data of 26 patients who had undergone hepatic resection at the time of secondary cytoreduction at the Mayo Clinic. Again, most patients had undergone resection of a single liver metastatic liver lesion. The median disease-related OS from the time of liver resection was 26.3 months. Again, no perioperative deaths occurred, and only 2 high-grade complications were noted.16
Important prognostic factors identified in both series included prolonged PFS and the ability to achieve cytoreduction to less than 1 cm at the time of liver resection. In the study, the Mayo Clinic patients who had undergone primary surgery more than 12 months before liver resection achieved improved outcomes. The number of liver lesions, the specific location of the lesion in relation to the porta hepatis, and the initial stage of the disease were not found to be of prognostic value in this series. Similarly, in the series by Yoon et al,15 no significant prognostic factors were identified on univariate analysis.
In our cohort, similarly to the series of Merideth et al,16 we found the length of the interval from the time of primary surgery to the liver resection to be an important prognostic factor. Based on the Kaplan-Meier survival analysis, the factor associated with the longest survival after liver resection (2–190 months) was the progression-free interval from the primary surgery to secondary cytoreduction procedure longer than 24 months. Among the patients in our series, the median PFS was 27 months from the time of primary surgery to the secondary cytoreduction procedure.
The utility of liver resection with regard to the number of liver lesions resected has been extensively explored in colon cancer patients. Numerous studies have shown that improved outcome can be achieved by resecting multiple liver metastases in patients with primary colon cancer.13,17,18 In a series of metastatic colon cancer patients, prognosis was not impacted by the number of liver metastases resected. Bolton et al18 divided patients into those that had fewer than 3 liver metastases and those that had 4 or more liver metastases at the time of liver resection. They demonstrated that the patients in the 2 groups experienced no difference in survival if complete resection of the disease in the liver was achieved.18
When an international panel of multidisciplinary experts recently convened to develop recommendations for the management of patients with liver metastases from colorectal cancer, 1 of the questions they addressed was whether there exists a maximum number of metastases at which point potentially curative surgery should not be attempted. The panel concluded that neither an abundance of metastases nor the age of the patient should serve as absolute contraindications to surgical intervention combined with chemotherapy.17
The question of single versus multisegmental liver resection in ovarian cancer has not been addressed, largely because of the paucity of patients that would be candidates for such an approach. Historically, liver resection in ovarian cancer patients was reserved for patients with single liver metastasis; however, in both our series and that reviewed by Merideth et al,16 the resection of multiple liver metastases did not negatively impact the OS. In our series, there was no significant difference (P = 0.97) in survival when solitary liver mass resections were compared with multiple liver mass resections done at the time of secondary cytoreduction. We believe that this was feasible and safe because of the use of a multiteam approach in performing these advanced surgical interventions.
In our institution, any patient whose preoperative imaging suggested the potential need for hepatectomy was independently evaluated by a member of the hepatobiliary surgery service with significant experience in liver resection. Techniques for safe resection included the selective use of portal triad clamping, an emphasis on maintaining low intravascular volumes during parenchymal transection, and meticulous attention to hemostasis and biliostasis. Furthermore, all cases were performed in concert with a dedicated anesthesiology team with extensive experience in complicated liver surgery, including liver transplantation and extensive hepatectomy. Postoperatively, patients were followed according to the liver resection postoperative protocol established at our institution by both surgical services to monitor for complications.
Some of the observed complications were due to a number of additional surgical procedures being performed at the time of the liver resection. These additional surgical interventions carry their own, at times, significant risks of complications. In our study group, there were 0 perioperative deaths, 2 bowel leaks, and 1 episode of sepsis requiring admission to the surgical intensive care unit, with an overall complication rate of 11%. The 2 bowel leaks, interestingly, occurred in 2 patients who had undergone cytoreduction to greater than 1 cm of residual disease. Thus, consideration should be given to the number and complexity of the added procedures performed at the time of liver resection.
Some of the weaknesses of our study are inherent to the retrospective study design and lack of a comparison group. Information was unavailable on how many patients during this same period developed liver metastasis and were not considered for hepatic resection. In addition, we lacked data regarding patients that had undergone ablative treatment or received only salvage chemotherapy during the study period.
Given the limited number of reviews in the literature, most of which have come out of 2 specialized high-volume institutions, there is a clear lack of data to guide the management of liver metastasis in ovarian cancer. We reviewed our patients and found the results to be comparable with those published in recent prior studies, demonstrating the applicability of these findings on a larger scale at institutions where a multidisciplinary approach can be implemented. Our surgical teams were composed of specialty trained surgeons from the gynecologic oncology, surgical oncology, and/or liver transplant teams. Through this multidisciplinary approach, we believe, we were able to perform these complicated surgical procedures safely and possibly extend the survival of patients who have limited therapeutic alternatives. Based on our series and that of others, aggressive secondary cytoreduction—including liver resection—seems to improve the OS; however, more data are needed.
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