Addressing hepatic metastases in ovarian cancer: Recent advances in treatment algorithms and the need for a multidisciplinary approach.

The lifetime risk for ovarian cancer incidence is 1.39% and the lifetime risk of death is 1.04%. Most ovarian cancer patients are diagnosed at advanced stages (III, IV) because there were no specific symptoms or existing screening tests. Liver metastases have been found in up to 50% of patients dying of advanced ovarian cancer. Recent studies indicate the need for a multidisciplinary approach from initial diagnosis to oncologic surgery and chemotherapy treatment, mandating the involvement of gynecologic oncologists, surgical oncologist, medical oncologists, hepatobiliary surgeons, and interventional radiologists.

2017 Update on Ovarian Cancer Peritoneal Carcinomatosis Multimodal-Treatment Considerations.

Ovarian cancer peritoneal carcinomatosis requires a multimodal-treatment approach. Current treatment considerations are analyzed in this update and include the management of recurrent malignant ascites and the understanding of its pathophysiology, the role of peritoneal washing cytology in detecting peritoneal metastases, capsular invasion and ovarian cancer histologic type, interpretation of pretreatment Ca-125 levels at different time points of ovarian cancer therapeutic management, characteristics of 10-year survivors of high-grade ovarian cancer, and the role of lymphadenectomy in ovarian cancer peritoneal carcinomatosis. This update also includes current considerations on the role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in ovarian cancer peritoneal carcinomatosis as well as relevant ongoing phase III randomized controlled trial protocols.

Is cholecystectomy and removal of the round ligament of the liver a necessary step in cytoreductive surgery and HIPEC, for peritoneal carcinomatosis?

AIM: To determine if cholecystectomy and liver's round ligament removal is a necessary step during cytoreductive surgery (CRS) and HIPEC METHODS: This was a retrospective observational study based on records from 180 patients treated in our center from 2005 to 2014. All patients have been offered CRS and HIPEC for peritoneal pseudomixoma (20 patients), peritoneal mesothelioma (7 patients), peritoneal carcinomatosis from ovarian cancer (66 patients), colorectal cancer (42 patients), gastric cancer (10 patients), mucinous adenocarcinoma of the appendix (28), and other abdominal malignancies (7 patients). We performed a cholecystectomy and we removed the round ligament of the liver in all patients, even if there wasn't a macroscopic tumor infiltration of the above anatomical structures. We reviewed the histological reports of all 180 patients. RESULTS: Patients with peritoneal carcinomatosis from mucinous adenocarcinoma of the appendix were treated more aggressively, due to the macroscopic appearance of the disease. Histologic report show no evidence of metastases at the round ligament of the liver in 21, 4% of the patients that were treated with CRS although it was estimated to be involved based on the macroscopic examination at the time of surgery. Tumor involvement of the gallbladder was overestimated, macroscopically, at the same patients in 25% of the cases. In patients with peritoneal carcinomatosis from ovarian cancer, macroscopic appearance of the gallbladder may be delusive. In 25% of the above patients there was a microscopic tumor involvement of the gallbladder, although there was not macroscopic evidence of the disease. CONCLUSION: More extended cytoreductive surgery is needed in case of peritoneal carcinimatosis from ovarian cancer. In case of PC from mucinous adenocarcinoma of the appendix, it's difficult to calculate the extent of the disease and avoid unnecessary surgical excisions. More data is needed to confirm the above. KEY WORDS: Cytoreductive surgery, Gallbladder, HIPEC, Peritoneal carcinomatosis, Round ligament of the liver.

The role of cytoreductive surgery and HIPEC in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common cause of death from gynecological cancer in the Western world. The current standard treatment of these patients consists of cytoreduction and systemic chemotherapy. One of the most distinct features of EOC is the tendency to disseminate into the peritoneal cavity and remain confined to the peritoneum and intra-abdominal viscera. This makes it an ideal target for loco-regional therapy. Improved long-term results can be achieved in highly selected patients using cytoreductive surgery (CRS), in combination with intra-operative hyperthermic intra-peritoneal chemotherapy (HIPEC). Optimal cytoreduction of advanced ovarian cancer is currently the most relevant prognostic factor. However, even when a complete resection is possible, the appearance of recurrences during follow-up is very common, due to the presence of microscopic residual disease, not visible to the surgeon. HIPEC has become a useful therapeutic strategy to obtain a higher degree of debulking by trying to eliminate the residual microscopic component responsible for recurrences. A summary of the current clinical evidence suggests that the most interesting settings first to explore in randomized trials are secondary CRS after upfront incomplete CRS for stage III ovarian cancer and salvage CRS for recurrent ovarian cancer, two time-points representing failure to initial standard therapy. There is much less indirect evidence for a potential benefit of HIPEC for less advanced stages (I - II) and for earlier time-points in the treatment of ovarian cancer (upfront, interval and consolidation). CRS and HIPEC offer a significant survival benefit in patients with recurrent EOC. This observation applies to both platinum-sensitive and platinum-resistant disease.

Digestive fistulas after cytoreductive surgery & HIPEC in peritoneal carcinomatosis.

PURPOSE: The development of digestice fistulas is a complication of gastrointestinal operations during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). In this article we present the incidence, management and outcome of enterocutaneous digestive fistulas after CRS and HIPEC. METHODS: Over the past 10 years (2005-2014), 184 patients with peritoneal carcinomatosis underwent CRS and HIPEC. HIPEC was administered in the operating room immediately after CRS, but in 48 (26%) patients this happened before the formation of intestinal anastomosis or repair of seromuscular tears, using the open (coliseum) technique; in the remaining 137 (74%) patients the anastomoses were performed before HIPEC. All patients were operated on by the same surgical team. RESULTS: Of the 185 patients 16 (8.6%) developed an enterocutaneous digestive fistula. Spontaneous fistula closure was observed in 14 (87.5%) patients. The median duration of spontaneous closure was 18 days (range 9-56). Reoperation was needed in 2 (12.5%) patients. There were 2 (12.5%) deaths. CONCLUSION: CRS and HIPEC is a well-known treatment modality for peritoneal carcinomatosis. The incidence of digestive fistulas is increased a little compared to that of conventional digestive surgery.

Mapping the location of peritoneal metastases using the peritoneal cancer index and the correlation with overall survival: a retrospective study.

PURPOSE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising treatment for patients with peritoneal carcinomatosis (PC). Our objective was to identify new prognostic factors within the Peritoneal Cancer Index (PCI) score in PC patients. METHODS: 140 patients (60 ovarian, 45 colon, 14 gastric, 10 pseudomyxoma peritonei, 5 mesothelioma, 6 sarcoma) with PC treated with CRS+HIPEC from 2007 to December 2013 were retrospectively included. Tumor extent and location were assessed by the PCI and residual disease was recorded using the Completeness of Cytoreduction (CC) score. All clinical data were computed in univariate and multivariate analysis using survival as primary endpoint. RESULTS: The PCI remains the most important factor concerning the long-term survival. Involved areas 4, 5 and 8 are more favorable in survival vs areas 9, 10 and 11, which predict a significantly worse outcome (p<0.002). Prognosis varies not only depending on how many peritoneal areas are involved but also on the location of the primary tumor. CONCLUSION: We demonstrated that the involvement of different areas in the PCI system has a significant impact on the final prognosis and survival.

Cytoreductive surgery and HIPEC for peritoneal carcinomatosis. A review on morbidity and mortality.

PURPOSE: To review morbidity and mortality of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis. METHODS: A literature search was conducted to identify studies from centers that perform CRS and HIPEC, and to collect and analyse data about morbidity and mortality. RESULTS: Twenty-five articles, published from 2006 to 2014 were reviewed. The studies included 24-1069 patients that had been treated with CRS and HIPEC for peritoneal carcinomatosis. The overall rate of severe perioperative morbidity ranged from 0 to 62% and the mortality rate varied from 0 to 10%. Major morbidity was correlated with age, peritoneal carcinomatosis index (PCI), comorbidities, number of digestive anastomoses and institution where the treatment was performed. CONCLUSION: Although the resultant morbidity is not negligible, with good patient selection this modality appears to be overall safe and effective in experienced hands. The results indicated that this treatment should be practised by institutions with expertise in the management of peritoneal carcinomatosis.

Clinical history of patients with peritoneal carcinomatosis exluded from cytoreductive surgery & HIPEC.

PURPOSE: The aim of this study was to explore the natural course of peritoneal carcinomatosis (PC) in patients who are not fit to undergo cytoreductive (CRS) surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Over an 8-year period (2006-2013) 320 patients were excluded from CRS and HIPEC at our center. Exclusion criteria were: (a) age >75 years; (b) ASA score ≥ 3; (c) extraperitoneal disease; (d) massive disease involvement of the small bowel; (e) disease involvement of the hepatic pedicle or the pancreas; (f) invasion of retroperitoneal space; (g) more than two stenoses of the small bowel. Another 130 patients underwent CRS and HIPEC. RESULTS: In the HIPEC group (N=130), the mean overall survival was 26.2±11.7 months, while from the non- HIPEC group (N=320), 200 patients underwent palliative surgery, with a mean overall survival of 11.7±8.3 months. Only 120 patients received palliative chemotherapy with a mean overall survival of 7.2±4.3 months. CONCLUSION: Our study suggests that, in patients unfit to undergo CRS & HIPEC, an exploratory laparotomy and palliative surgery should be performed, offering a survival benefit and improved quality of life.

The role of cytoreductive surgery in advanced ovarian cancer: the general surgeon's perspective.

Ovarian cancer is one of the most common and lethal cancers worldwide and is usually diagnosed at advanced stages. A radical and effective management of advanced ovarian cancer is needed. Cytoreductive surgery followed by intravenous chemotherapy is currently the gold standard for the management of this disease. However, the recurrence rates still remain high. The introduction of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) combined with complete cytoreductive surgery is a well-promising approach for advanced-stage disease, as well as for recurrent cases. This review aimed to present the surgical management of advanced ovarian cancer and the recent literature about the role and the therapeutic effectiveness of cytoreduction.

Management of peritoneal surface malignancy: a review of the recent literature.

Peritoneal carcinomatosis (PC) is a condition that has been associated with poor outcomes and up until recently was considered a terminal condition. However, recent data suggest that cytoreductive surgery (CRS) and the administration of hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective therapeutic approach. This paper is a review of the recent literature regarding this issue.

The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are gaining acceptance as treatment for selected patients with colorectal cancer with peritoneal carcinomatosis (CRCPC). Tremendous variations exist in the HIPEC delivery. METHODS: The American Society of Peritoneal Surface Malignancies (ASPSM) examined the overall survival in patients with CRCPC who underwent a complete cytoreduction and HIPEC with Oxaliplatin vs. Mitomycin C (MMC), stratifying them by the Peritoneal Surface Disease Severity Score (PSDSS). RESULTS: Median overall survival (OS) of 539 patients with complete cytoreduction was 32.6 months, 32.7 months for the MMC group and 31.4 months for the Oxaliplatin group (P = 0.925). However, when stratified by PSDSS, median OS rates in PSDSS I/II patients were 54.3 months in those receiving MMC vs. 28.2 months in those receiving oxaliplatin (P = 0.012), whereas in PSDSS III/IV patients, median OS rates were 19.4 months in those receiving MMC vs. 30.4 months in those receiving Oxaliplatin (P = 0.427). CONCLUSION: These data suggest that MMC might be a better agent for HIPEC delivery than Oxaliplatin in patients with CRCPC, favorable histologies and low burden of disease (PSDSS I/II) undergoing complete cytoreduction. Prospective studies are warranted, which stratify patients by their PSDSS and randomize them to HIPEC with MMC vs. Oxaliplatin.

Short bowel syndrome after cytoreductive surgery and HIPEC: nutritional considerations.

PURPOSE: The aim of this study was to present a group of patients with <150 cm of small intestine after cytoreductive surgery (CRS)+hyperthermic intraperitoneal chemotherapy (HIPEC) and the special problems arising from this condition. METHODS: From November 2005 to November 2013, 130 patients were treated for peritoneal carcinomatosis (PC) with CRS+HIPEC. Ten patients (7.7%) were left with a short bowel due to anatomical and surgical reasons. All these patients were subjected to ileostomy. Four patients (40%) were treated for ovarian carcinoma, 4 (40%) for colon and appendiceal carcinoma, 1 for peritoneal mesothelioma and 1 patient for primary peritoneal carcinoma. The completeness of cytoreduction (CC) score was CC-0 in 4 patients (40%), CC-1 in 3 (30%) and CC-2 in 3 (30%). RESULTS: The mean length of the remaining small bowel was 105 cm (range 80-150). Mean hospitalization was 42 days vs 24 days in other patients with CRS+HIPEC (p<0.002). The daily ileostomy output increased between the 3rd to 4th week as a result of oral feeding and decreased at the 4th week due to somatostatin analogue administration and possible intestinal adaptation. The mean ileostomy output at 6 months was 810±100 ml vs 1590±210 ml the first month after CRS+HIPEC (p<0.001). The overall morbidity and mortality rate was the same as in patients without extensive resection. The impact of small bowel syndrome (SBS) on overall survival was very important, as the mean overall survival in the SBS group was 28.6 months vs 41 months in other CRS+HIPEC patients (p<0.001). CONCLUSIONS: SBS is sometimes inevitable in order to perform optimal cytoreduction. Special management is required for these patients, including special nutritional efforts and home total parenteral nutrition (TPN). Extensive small bowel resection may constitute a contraindication in the management of peritoneal carcinomatosis.

The American Society of Peritoneal Surface Malignancies (ASPSM) Multiinstitution Evaluation of the Peritoneal Surface Disease Severity Score (PSDSS) in 1,013 Patients with Colorectal Cancer with Peritoneal Carcinomatosis.

BACKGROUND: Extensive clinical experience suggests that hyperthermic intraperitoneal chemotherapy (HIPEC) may play an important role in the management of colorectal cancer patients with peritoneal carcinomatosis (CRCPC). However, there remains no established nonsurgical process to rationally select patients for this management, either for inclusion/stratification in clinical trials or as a component of standard of care. The Peritoneal Surface Disease Severity Score (PSDSS) was introduced as a basis to improve patient selection. METHODS: The American Society of Peritoneal Surface Malignancies conducted a retrospective review of 1,013 CRCPC patients. The PSDSS was evaluated on 3 specific criteria obtained before surgery (symptoms, extent of peritoneal dissemination, and primary tumor histology). Overall survival was analyzed according to four tiers of disease severity, and a comparison was made between patients who underwent cytoreductive surgery + HIPEC and those who did not. RESULTS: The PSDSS was calculated on 884 patients (87 %). The median survival of 275 patients not undergoing CRS/HIPEC based on their PSDSS-I (n = 8), II (n = 80), III (n = 55), and IV (n = 132)-was 45, 19, 8, and 6 months, respectively. The median survival of 609 patients who underwent CRS/HIPEC based on their PSDSS-I (n = 75), II (n = 317), III (n = 82), and IV (n = 135)-was 86, 43, 29, and 28 months, respectively. CONCLUSIONS: These data support that the PSDSS, undertaken before surgery, is capable of defining CRCPC populations who have a statistically defined high or considerably lower likelihood of long-term survival after CRS/HIPEC. The PSDSS can be quite useful in the decision to enter CRCPC patients into, and their stratification within, clinical trials.

Management of diaphragmatic peritoneal carcinomatosis: surgical anatomy guidelines and results.

Surgical resections, such as peritoneal stripping (peritonectomy) or full-thickness resection of the diaphragm (FTDR), are performed for disseminated diaphragmatic lesions in patients with peritoneal carcinomatosis (PC). This article presents the anatomical steps of diaphragmatic surgery in order to avoid intraoperative and postoperative complications and to decrease the morbidity and mortality of cytoreductive surgery in patients with PC.

Diagnosis and management of peritoneal metastases from ovarian cancer.

The management and the outcome of peritoneal metastases or recurrence from epithelial ovarian cancer are presented. The biology and the diagnostic tools of EOC peritoneal metastasis with a comprehensive approach and the most recent literatures data are discussed. The definition and the role of surgery and chemotherapy are presented in order to focuse on the controversial points. Finally, the paper discusses the new data about the introduction of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced epithelial ovarian cancer.

The influence of tumor cell entrapment phenomenon on the natural history of Pseudomyxoma peritonei syndrome.

BACKGROUND/AIMS: Pseudomyxoma peritonei syndrome (PMP) may be associated with slow "benign" or malignant process. However, the natural history of this disease is slow progression to death. Its treatment is variable and controversial. In this current study we have compared the patients with Pseudomyxoma peritonei syndrome with recurrences due to the cell entrapment hypothesis. METHODOLOGY: Data were derived from a database of patients with PMP treated at our hospitals from 2004 to 2009. All patients had undergone various surgical operations prior to referral to our institutions for definitive treatment. All patients had recurrences in special sites due to entrapment of malignant cells. RESULTS: There are 6 patients, four men and two women. The initial clinical presentation of the disease was hernia in one, appendicitis in three and ovarian mass in one. The mean time from the initial operation to be definitive management was 23.5 months with an average of 1.83 operations per patient. After cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) the mean survival was 31 months with minimal recurrences and only 0.3 operations per patient. CONCLUSIONS: Our data suggest that the patients should be referred to a center with a peritoneal surface malignancy program after the PMP diagnosis as soon as possible. Incomplete debulking procedures and minimal invasive operations promote uncontrollable intraabdominal tumor growth due to tumor cell entrapment and the tendency of PMP to grow at wound sites.