The role of cytoreductive surgery and HIPEC for the treatment of primary and secondary peritoneal malignancies-experience from a tertiary care center in Germany.

PURPOSE: Peritoneal surface malignancies (PSM) are commonly known to have a dismal prognosis. Over the past decades, novel techniques such as cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been introduced for the treatment of PSM which could improve the overall survival and quality of life of patients with PSM. The decision to proceed with CRS and HIPEC is often challenging due the complexity of the disease, the extent of the procedure, associated side effects, and potential risks. Here, we present our experience with CRS and HIPEC to add to the ongoing discussion about eligibility criteria, technical approach, and expected outcomes and contribute to the evolution of this powerful and promising tool in the multidisciplinary treatment of patients with primary and secondary PSM. METHODS: A single-center retrospective chart review was conducted and included a total of 40 patients treated with CRS and HIPEC from April 2020 to September 2022 at the University Hospital Münster Department of Surgery. All patients had histologically confirmed primary or secondary peritoneal malignancies of various primary origins. RESULTS: Our study included 22 patients with peritoneal metastases from gastric cancer (55%), 8 with pseudomyxoma peritonei (20%), 4 with mesothelioma of the peritoneum (10%), and 6 patients with PSM originating from other primary tumor locations. Median PCI at time of cytoreduction was 4 (0-25). Completeness of cytoreduction score was 0 in 37 patients (92.5%), 1 in two patients (5%), and 2 in one patient (2.5%). Median overall survival across all patients was 3.69 years. CONCLUSION: Complete cytoreduction during CRS and HIPEC can be achieved for patients with low PCI, for patients with high PCI in low-grade malignancies, and even for patients with initially high PCI in high-grade malignancies following a significant reduction of cancer burden due to extensive preoperative treatment with PIPAC and systemic chemotherapy.

Neoadjuvant chemotherapy does not improve survival for patients with high volume colorectal peritoneal metastases undergoing cytoreductive surgery.

BACKGROUND: Colorectal peritoneal metastases (CRPM) affects 15% of patients at initial colorectal cancer diagnosis. Neoadjuvant chemotherapy (NAC) prior to cytoreductive surgery (CRS) has been demonstrated to be a safe and feasible option, however there is limited data describing its efficacy in advanced peritoneal disease. This study evaluated the effect of NAC on survival in patients with high volume CRPM undergoing CRS with or without HIPEC. METHODS: A retrospective review of all patients who underwent CRS with or without HIPEC for CRPM from 2004 to 2019 at our institution was performed. The cohort was divided based on peritoneal carcinomatosis index (PCI) at surgery: Low Volume (PCI ≤ 16) and High Volume (PCI > 16). RESULTS: A total of 326 patients underwent CRS with HIPEC for CRPM. There were 39 patients (12%) with High Volume disease, and 15 of these (38%) received NAC. Patients with High Volume disease had significantly longer operating time, lower likelihood of complete macroscopic cytoreduction (CC-0 score), longer intensive care unit length of stay and longer hospital stay compared to Low Volume disease. In High Volume disease, the NAC group had a significantly shorter median survival of 14.4 months compared to 23.8 months in the non-NAC group (p = 0.046). CONCLUSION: Patients with High Volume CRPM achieved good median survival following CRS with HIPEC, which challenges the current PCI threshold for offering CRS. The use of NAC in this cohort did not increase perioperative morbidity but was associated with significantly shorter median survival compared to upfront surgery.

Comparison of outcomes between surgical treatment of colorectal cancer metastatic to the liver and the peritoneum: Review of the literature.

BACKGROUND: Liver and peritoneum are two of the most common sites of colorectal metastases. METHODS: We searched for articles comparing outcomes of surgical management for metastatic colorectal cancer to the liver and peritoneum. CONCLUSION: Cytoreductive surgery/heated intraperitoneal chemotherapy has a similar safety profile and survival outcomes as hepatectomy for colorectal metastases after stratifying by resection status and should be incorporated earlier in the management algorithm for colorectal cancer patients with peritoneal metastases METHODS: We performed a wide search on PubMed, EMBASE, and Google Scholar for articles comparing outcomes of surgical management for metastatic colorectal cancer to the liver and peritoneum. We focused on studies comparing their perioperative clinical outcomes as well as their oncological outcomes. The following words were included in the search: comparison, outcomes, metastasectomy, colorectal cancer, liver, peritoneal surface disease, hepatectomy, and cytoreduction. RESULTS: One hundred and twenty studies were evaluated. Six of these studies met the criteria for this review.

Fragmentation of Care in Patients with Peritoneal Metastases Undergoing Cytoreductive Surgery.

BACKGROUND: The delivery of multimodal treatment at a high-volume center is known to optimize the outcomes of gastrointestinal malignancies. However, patients undergoing cytoreductive surgery (CRS) for peritoneal metastases often must 'fragment' their surgical and systemic therapeutic care between different institutions. We hypothesized that this adversely affects outcomes. PATIENTS AND METHODS: Adults undergoing CRS for colorectal or appendiceal adenocarcinoma at our institution between 2016 and 2022 were identified retrospectively and grouped by care network: 'coordinated care' patients received exclusively in-network systemic therapy, while 'fragmented care' patients received some systemic therapy from outside-network providers. Factors associated with fragmented care were also ascertained. Overall survival (OS) from CRS and systemic therapy-related serious adverse events (SAEs) were compared across the groups. RESULTS: Among 85 (80%) patients, 47 (55%) had colorectal primaries and 51 (60%) received fragmented care. Greater travel distance [OR 1.01 (CI 1.00-1.02), p = 0.02] and educational status [OR 1.04 (CI 1.01-1.07), p = 0.01] were associated with receiving fragmented care. OS was comparable between patients who received fragmented and coordinated care in the colorectal [32.5 months versus 40.8 months, HR 0.95 (CI 0.43-2.10), p = 0.89] and appendiceal [31.0 months versus 27.4 months, HR 1.17 (CI 0.37-3.74), p = 0.55] subgroups. The frequency of SAEs (7.8% versus 17.6%, p = 0.19) was also similar. CONCLUSIONS: There were no significant differences in survival or SAEs based on the networks of systemic therapy delivery. This suggests that patients undergoing CRS at a high-volume center may safely receive systemic therapy at outside-network facilities with comparable outcomes.

Prognostic Impact of Mesenteric Lymph Node Status on Digestive Resection Specimens During Cytoreductive Surgery for Ovarian Peritoneal Metastases.

BACKGROUND: The most common mode of ovarian cancer (OC) spread is intraperitoneal dissemination, with the peritoneum as the primary site of metastasis. Cytoreductive surgery (CRS) with chemotherapy is the primary treatment. When necessary, a digestive resection can be performed, but the role of mesenteric lymph nodes (MLNs) in advanced OC remains unclear, and its significance in treatment and follow-up evaluation remains to be determined. This study aimed to evaluate the prevalence of MLN involvement in patients who underwent digestive resection for OC peritoneal metastases (PM) and to investigate its potential prognostic value. METHODS: This retrospective, descriptive study included patients who underwent CRS with curative intent for OC with PM between 1 January 2007 and 31 December 2020. The study assessed MLN status and other clinicopathologic features to determine their prognostic value in relation to overall survival (OS) and progression-free survival (PFS). RESULTS: The study enrolled 159 women with advanced OC, 77 (48.4%) of whom had a digestive resection. For 61.1% of the patients who underwent digestive resection, MLNs were examined and found to be positive in 56.8%. No statistically significant associations were found between MLN status and OS (p = 0.497) or PFS ((p = 0.659). CONCLUSIONS: In anatomopathologic studies, MLNs are not systematically investigated but are frequently involved. In the current study, no statistically significant associations were found between MLN status and OS or PFS. Further prospective studies with a systematic and standardized approach should be performed to confirm these findings.

Analysis of the characteristics and outcomes of patients with pseudomyxoma peritonei of appendiceal origin treated with curative-intent surgery.

BACKGROUND: There are no previous studies on pseudomyxoma peritonei regarding the details of surgical procedures included in cytoreductive surgery and quantitative evaluation for peritoneal metastases by region in the abdominal cavity. This study aimed to describe the characteristics and procedural details involved in cytoreductive surgery, and survival outcomes of patients with pseudomyxoma peritonei originating from appendiceal mucinous neoplasm, and identify differences in the difficulty of cytoreductive surgery based on tumor location. METHODS: Patient characteristics and survival outcomes were studied through a retrospective review. The complete cytoreduction rate (i), the 5-year survival rate for patients with complete cytoreduction (ii), and an index as a complement (i × ii × 100) were described for patients who had tumors larger than 50 mm in one of the 13 regions of the abdominal cavity. RESULTS: A total of 989 patients were treated with curative-intent cytoreductive surgery. The median peritoneal cancer index was 18 (interquartile range, 6-29), with complete cytoreduction achieved in 702 patients (71%); the major complication rate was 17%. The median overall survival was 92.9 months, compared to 53.8 months for patients who underwent total gastrectomy and 30.4 months for those who underwent total colectomy. In the 13 abdominal regions, the index scores indicating cytoreduction difficulty were categorized into three risk groups: upper and mid-abdominal (>20), lateral abdominal (10-20), and small bowel (<10). CONCLUSIONS: Cytoreductive surgery offered favorable survival outcomes, even in cases involving total gastrectomy. The difficulty of achieving complete cytoreduction varied across abdominal regions and was classified into three levels.

Adoption of cytoreductive surgery in the management of peritoneal malignancies-Global trends.

Cytoreductive surgery (CRS) has now been accepted as an integral component in the management of gastrointestinal and gynecological cancers with peritoneal metastases. Since the adoption of CRS is influenced by access to advanced medical facilities, trained multidisciplinary teams, and funding, there is wide variability in incorporation of CRS into routine clinical practice between high- versus low- and middle-income countries. This review highlights the global trends in the adoption of CRS for peritoneal malignancies with a specific focus on the establishment of CRS programs and barriers to incorporate CRS into routine clinical care in low- and middle-income countries.

[Japanese practice of comprehensive treatment for peritoneal metastasis of gastric cancer].

Patients with peritoneal metastasis (PM) from gastric cancer (GC) have a poor prognosis. Surgery or systemic treatment alone hardly improves the prognosis and overall survival (OS). A newly developed comprehensive treatment involving a combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been used to treat patients with PM from GC. The Peritoneal Dissemination Center of Kishiwada Tokushukai Hospital in Japan has been committed to treating patients with PM from GC. Selected patients undergo laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC), preoperative intraperitoneal (IP) chemotherapy, and systemic chemotherapy that includes intravenous and oral chemotherapy prior to surgery. CRS plus HIPEC is then performed to achieve complete cytoreduction. Postoperative IP chemotherapy or systemic chemotherapy is also administered to nearly all patients. The results demonstrate that comprehensive treatment, including neoadjuvant chemotherapy and CRS plus HIPEC, can significantly improve the prognosis and OS of selected patients with PM from GC.

Perioperative and Oncological Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastasis of Rectal Origin.

BACKGROUND: The peritoneum is a common metastatic site of colorectal cancer (CRC) and associated with worse oncological outcomes. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been shown to improve outcomes in selected patients. Studies have demonstrated significant difference in survival of patients with primary colon and rectal tumors both in local and in metastatic setting; but only few assessed outcomes of CRS/HIPEC for rectal and colon tumors. We studied the perioperative and oncological outcomes of patients undergoing CRS/HIPEC for rectal cancer. METHODS: A retrospective analysis of a prospectively maintained database between 2009 and 2021 was performed. RESULTS: 199 patients underwent CRS/HIPEC for CRC. 172 patients had primary colon tumors and 27 had primary rectal tumors. Primary rectal location was associated with longer surgery (mean 4.32, hours vs 5.26 h, p = 0.0013), increased blood loss (mean 441cc vs 602cc, p = 0.021), more blood transfusions (mean 0.77 vs 1.37units, p = 0.026) and longer hospitalizations (mean 10 days vs 13 days, p = 0.02). Median disease-free survival (DFS) was shorter in rectal primary group; 7.03 months vs 10.9 months for colon primaries (p = 0.036). Overall survival was not statistically significant; 53.2 months for rectal and 60.8 months for colon primary tumors. Multivariate analysis indicated origin (colon vs rectum) and Peritoneal Cancer Index to be independently associated with DFS. CONCLUSIONS: Patients with rectal carcinoma undergoing CRS/HIPEC for peritoneal metastasis had worse peri-operative and oncological outcomes. Overall survival was excellent in both groups. This data may be used for risk stratification when considering CRS/HIPEC for patients with rectal primary.

Magnesium inhibits peritoneal calcification as a late-stage characteristic of encapsulating peritoneal sclerosis.

Peritoneal calcification is a prominent feature of the later stage of encapsulating peritoneal sclerosis (EPS) in patients undergoing long-term peritoneal dialysis (PD). However, the pathogenesis and preventive strategy for peritoneal calcification remain unclear. Peritoneum samples from EPS patients were examined histologically. Peritoneal calcification was induced in mice by feeding with an adenine-containing diet combined with intraperitoneal administration of lipopolysaccharide and a calcifying solution containing high calcium and phosphate. Excised mouse peritoneum, human mesothelial cells (MeT5A), and mouse embryonic fibroblasts (MEFs) were cultured in calcifying medium. Immunohistochemistry confirmed the appearance of osteoblastic differentiation-marker-positive cells in the visceral peritoneum from EPS patients. Intraperitoneal administration of magnesium suppressed peritoneal fibrosis and calcification in mice. Calcifying medium increased the calcification of cultured mouse peritoneum, which was prevented by magnesium. Calcification of the extracellular matrix was accelerated in Met5A cells and MEFs treated with calcification medium. Calcifying medium also upregulated osteoblastic differentiation markers in MeT5A cells and induced apoptosis in MEFs. Conversely, magnesium supplementation mitigated extracellular matrix calcification and phenotypic transdifferentiation and apoptosis caused by calcifying conditions in cultured MeT5A cells and MEFs. Phosphate loading contributes to the progression of EPS through peritoneal calcification and fibrosis, which can be prevented by magnesium supplementation.

Iron increases the profibrotic properties of the senescent peritoneal mesothelial cells.

BACKGROUND: Treatment of anemia in peritoneal dialysis patients often requires intravenous iron supplementation. Iron diffuses into the peritoneal cavity and is injurious to the peritoneum. We studied how intermittent exposure to iron changes the properties of the senescent peritoneal mesothelial cells (MC). METHODS: Replicative senescence was induced in MC in control medium (Con) or in control medium with intermittent exposure to iron isomaltoside 15 µg/dL (Con-IIS). After 10 passages properties of MC from both groups were compared to MC not exposed to replicative senescence. RESULTS: In senescent MC population doubling time was elongated, intracellular generation of free radicals and staining for ß-galactosidase was stronger than in MC not exposed to replicative senescence. All these effects were stronger in MC intermittently exposed to IIS. In these cells intracellular iron content was also higher. Also expression of genes p21 and p53 was stronger in MC intermittently treated with IIS. In senescent cells higher release and expression of IL6 and TGFß1 was observed and that effect was stronger in MC treated with iron. Senescent MC had reduced fibrinolytic activity, what may predispose to the peritoneal fibrosis. Synthesis of collagen was higher in senescent cells, more in MC treated with iron. CONCLUSION: MC aging results in change of their genotype and phenotype which lead to their profibrotic effect. Exposure to iron enhances these changes.

Prognostic indicators for colorectal peritoneal metastases are different for patients with complete versus incomplete cytoreductive surgery.

BACKGROUND: In the management of peritoneal metastases in patients with colorectal cancer, the completeness of cytoreduction has consistently been the most prominent prognostic indicator. Other clinical and histologic features have been described that may also have an impact on survival. METHODS: The colorectal peritoneal metastases patients treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy were divided into two groups. One group had complete CRS and the second group had an incomplete CRS. The prognostic variables in these two groups of patients were statistically analyzed for their impact on survival. RESULTS: In the complete CRS group of 124 patients lymph node positivity, poorly differentiated histopathology, asymptomatic status following treatment with systemic chemotherapy, incomplete response to systemic chemotherapy, and moderate to high peritoneal cancer index showed a significantly reduced survival. All five of these prognostic variables ceased to show statistical significance in the group of 82 patients with incomplete cytoreduction. CONCLUSION: The cause for significance of five prognostic indicators identified in patients with complete cytoreduction versus loss of significance of these indicators in patients with incomplete cytoreduction has not been determined. An absence of residual disease in complete CRS patients and a widely variable extent of residual disease in incomplete CRS patients may be important. Prognostic indicators in patients with colorectal peritoneal metastases find their greatest usefulness in patients who have had a complete cytoreduction.