Synchronous Peritoneal Metastases Research Articles

Abstract 2759: Transcriptional intra-tumoral heterogeneity of putative therapeutic targets in colorectal cancer peritoneal metastases

Abstract Background: The poor prognosis of peritoneal metastasis (PM) in colorectal cancer (CRC) is typically attributed to, and characterized by, resistance to systemic chemotherapy and immunotherapy. The evolutionarily conserved plasma-peritoneal barrier as well as reduced tumor tissue vascularity contributes to poorer responses to systemically administered antineoplastic therapy. Beyond these, we sought to understand transcriptomic variations of important therapeutic targets implicated in peritoneal organotropism and by extension, resistance to systemic regimens in CRC PM. Methodology: FFPE tissue samples from CRC patients were collected during oncological surgical resection of the synchronous PM (cytoreductive surgery [CRS] with or without hyperthermic intra-peritoneal chemotherapy [HIPEC]), or exploratory laparotomy for palliative surgery, with the majority of patients receiving systemic therapy prior to surgery. Samples were sequenced with whole transcriptomic sequencing. Paired and unpaired T-tests between PT and PM samples were undertaken with log2(fragments per kilobase of exon per million mapped [FPKM]) gene expression values. Results: Fifty-six (22 primary tumor [PT], 34 peritoneal metastases [PM]) samples from 35 patients, comprising 21 paired PT-PM samples, were included in this analysis. TEAD1 (unpaired T-test, p=0.087; paired T-test, p=0.041), FGFR1 (unpaired T-test, p=0.003; paired T-test, p<0.001), PIK3CA (unpaired T-test, p=0.034; paired T-test, p=0.003), SMAD4 (unpaired T-test, p=0.095; paired T-test, p=0.010), and HAVCR2 (unpaired T-test, p=0.009; paired T-test, p=0.007) were found to be upregulated in the PM. Conversely, MET was found to be downregulated in PM samples (unpaired T-test, p=0.004; paired T-test, p=0.002). There were no significant differences in gene expression profiles of BRAF, RHOA, CD274, CTLA4, PDCD1 and TIGIT between PT-PM (all p>0.05). Conclusion: Through CRC PT-PM comparisons, we identify potential therapeutic targets implicated in transcoelomic metastasis and provide rationale for development of immunotherapeutic biology and drug discovery for CRC PM. These findings underscore an exigent need to develop intra-peritoneal therapeutic strategies to overcome resistance to systemic regimens. Citation Format: Joseph J. Zhao, Johnny CA Ong, Daryl Kai Ann Chia, Melissa Ching Ching Teo, Qiu Xuan Tan, Gillian Ng, Joey Wee-Shan Tan, Haoran Ma, Xuewen Ong, Su Ting Tay, Patrick Tan, Raghav Sundar. Transcriptional intra-tumoral heterogeneity of putative therapeutic targets in colorectal cancer peritoneal metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2759.

Pilot Study: Prophylatic Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Colorectal Cancers at High Risk of Developing Peritoneal Metastases in a Tertiary Asian Centre

Introduction: The second most common site of Colorectal Cancer (CRC) recurrence is the peritoneum. The primary aim of this study was to assess feasibility of prophylactic Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Asian patients, and to determine the associated morbidity and time to start of adjuvant chemotherapy. Materials and methods: Patients at high-risk of developing Peritoneal Metastases (PM) include the following: T4 on imaging, krukenburg tumours, perforated tumours, limited synchronous PM, and peritoneal fluid cytology positive for malignant cells. Recruited patients were divided into two groups; newly diagnosed CRC patients with any of the high-risk features (Group 1), and patients who had recent surgery (less than 8 weeks from recruitment) with histological confirmation of high-risk features (Group 2). Results: 12 patients were recruited, of which there were 10 Group 1 patients and 2 Group 2 patients. Of the 10 patients in Group 1, 7 had T4 disease and another 3 had limited PM suspected on staging scans. All patients completed the Cytoreductive Surgery (CRS) and HIPEC procedure with no mortalities. 2 patients experienced major morbidity. Median time to adjuvant chemotherapy was 46 days (IQR 42.75-52.85). Median Length of Stay (LOS) was 13.5 days (IQR 8-15) comparable to our control group (N=214), which included all patients undergoing CRS and HIPEC with a median LOS of 14 days (IQR 11-19, p=0.11). Conclusion: Prophylactic HIPEC is feasible in a highly selected group of patients with newly diagnosed locally advanced CRC and those with limited synchronous PM, with appropriate time to receiving adjuvant chemotherapy.

Peritoneal metastases in patients with neuroendocrine neoplasms: a challenging site of metastases with clinical and prognostic implications.

Peritoneal metastases (PM) of neuroendocrine neoplasm (NEN) origin are identified with increasing frequency and exert a significant effect on quality of life and clinical status of the patients. The aim of this study was to identify the characteristics and the prognostic significance of PM in patients with NENs. A retrospective analysis of the data of patients from two tertiary referral centers was performed. We defined a control group of age- and gender-matched NEN patients with comparable stage IV disease but no PM. We analysed 70 patients (41 females) with PM. Small intestine was the most common primary NEN site (87.1%). PM prevalence was 10.3%. Forty-four patients presented with synchronous PM, whereas 26 developed metachronous PM. The majority of patients had other concomitant metastases (50 hepatic, 6 lung and 12 bone metastases). Twelve patients developed intestinal obstruction. After PM diagnosis, 76% of patients received treatment with somatostatin analogues while six patients (8.6%) were treated with peptide receptor radionuclide therapy (PRRT). The median progression-free survival (PFS) in the PRRT-treated group was 15months (95% CI 2-28). Median overall survival (OS) in the PM group was 142months [95% CI 71-213] while it was not reached in the control group. Peritoneal metastases show low prevalence among NEN patients and are most likely to develop in patients with small intestinal NENs and advanced metastatic disease. The presence of PM does seem to be associated with a negative prognostic impact on OS of NEN patients and their identification and prompt treatment is of major importance.

Recurrence and Survival Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Synchronous and Metachronous Peritoneal Metastases of Colorectal Origin

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has improved the 5-year survival for colorectal cancer (CRC) patients with peritoneal metastases (PM). Little is known about recurrence patterns and recurrence rates between synchronous (S) and metachronous (M) PM following CRS+HIPEC. We aimed to describe the recurrence patterns, overall survival (OS) and disease-free survival (DFS) in S-PM and M-PM patients after complete CRS+HIPEC. From June 2006 to December 2020, a prospective cohort study included 310 CRC patients, where 181 patients had S-PM (58.4%) and 129 patients had M-PM (41.6%). After a median 10.3-month follow-up, 247/310 (79.7%) patients experienced recurrence, and recurrence sites included isolated peritoneal (32.4%), multifocal (peritoneal and liver and/or lung(s)) (22.7%), isolated liver (17.8%), isolated lung (10.5%) and other (16.6%) sites. Recurrence patterns did not differ between S-PM and M-PM. M-PM patients had an impaired DFS compared to S-PM patients (9.4 months (95% CI: 7.3–12.1) vs. 12.5 months (95% CI: 11.2–13.9), p = 0.01). The median OS was similar for S-PM and M-PM (38.4 months (95% CI: 31.2–46.8) vs. 40.8 months (95% CI: 28.8–46.8), p = 0.86). Despite frequent recurrence at extraperitoneal locations, long-term survival was achievable after CRS+HIPEC in CRC patients with PM. The recurrence patterns and OS did not differ between groups, yet M-PM patients had a shorter DFS.

OGC P19 Peritoneal metastases from gastric cancer in a nationwide cohort: incidence, treatment and survival

Abstract Background The aims of this study were to investigate incidence, risk factors and treatment of synchronous or metachronous peritoneal metastases (PM) from gastric cancer and to estimate survival of these patients using population-based data. Methods Patients diagnosed with gastric cancer in 2015-2016 were selected from the Netherlands Cancer Registry. The incidence of synchronous and metachronous PM were calculated. Multivariable regression analyses were performed to identify factors associated with the occurrence of PM. Treatment and survival were compared between patients with synchronous and metachronous PM. Results Of 2147 patients with gastric cancer, 656 (31%) were diagnosed with PM. Of these, 498 (23%) had synchronous PM. The cumulative incidence of metachronous PM in patients who underwent potentially curative treatment (n=675) was 22.8% at 3 years. A factor associated with synchronous and metachronous PM was diffuse type histology. Patients diagnosed with synchronous PM more often received systemic treatment than patients with metachronous PM (35% vs. 18% respectively, p<0.001). Median overall survival was comparable between synchronous and metachronous PM (3.2 vs. 2.3 months respectively, p=0.731). Conclusions Approximately one third of all patients with gastric cancer are diagnosed with PM, either at primary diagnosis or during 3-year follow-up after potentially curative treatment. Patients with metachronous PM less often received systemic treatment than those with synchronous PM but survival was comparable between both groups. Future trials are warranted to detect gastric cancer at an earlier stage and to examine strategies that lower the risk of peritoneal dissemination. Also, specific treatment options for patients with gastric PM should be further investigated.

Prognostic value of hyperthermic intraperitoneal chemotherapy in gastric cancer with synchronous peritoneal metastases: a real-world retrospective study.

Peritoneal metastasis in gastric cancer (GC) is a late-stage condition with a poor prognosis. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a popular treatment for peritoneal metastases. Here, we aim to investigate the real-world application and efficacy of HIPEC alone for GC patients with synchronous peritoneal metastases. We conducted a retrospective analysis on GC patients with synchronous peritoneal metastasis at the Sixth Affiliated Hospital of Sun Yat-sen University between January 2011 and December 2022. Survival analyses and Cox regression models were performed based on overall survival (OS) and cancer-specific survival (CSS), and subgroup analysis was used to determine the prognostic value of HIPEC across different treatment. We enrolled 250 patients, of whom 120 (48%) received HIPEC while 130 (52%) did not. HIPEC showed no survival benefit for GC patients (P = 0.220 for OS and P = 0.370 for CSS). However, subgroup analysis found that HIPEC can only improve OS and CSS when combined with primary tumor resection (P = 0.034 for OS and P = 0.036 for CSS). Moreover, survival analyses also demonstrated that HIPEC independently improved OS (HR for OS = 0.58, 95% CI 0.37-0.92, P = 0.020) and CSS (HR for CSS = 0.58, 95% CI 0.37-0.93, P = 0.024) for patients who underwent primary site resection, but not for those who did not. HIPEC can improve survival in GC patients with synchronous peritoneal metastases who have primary tumor resection, but not in those without primary tumor resection.

Neo-adjuvant PIPAC and Systemic Chemotherapy in Management of Synchronous Peritoneal Metastasis From Gastric Cancer

Introduction: Polycystic Ovarian Disorder (PCOD) is a prevalent endocrine illness in women of reproductive age. It has hormonal abnormalities, irregular menstrual cycles and tiny ovarian cysts. Lifestyle and food affect PCOD development and maintenance, coupled with Peritoneal metastasis from gastric cancer remains a major problem. The aim of our study is a retrospective analysis in two different groups with used PIPAC as neo-adjuvant management of synchronous peritoneal metastasis. Group A: 42 patients received as neo-adjuvant treatment 2 cycles of PIPAC (Doxorubicin 3 mgr/m2, cisplatin 10 mgr/m2) and 6 cycles of neo-adjuvant systemic chemotherapy with FLOT and we performed CRS+HIPEC (with cisplatin 80 mgr/m2, mitomycin 35 mgr/m2) for 90 min and 6 cycles of adjuvant systemic chemotherapy with FLOT. Group B: 26 patients received 4 cycles of neo-adjuvant systemic chemotherapy with FLOT, we performed CRS+HIPEC as Group A and 4 cycles of systemic chemotherapy with FLOT. For patients of Group A, the Median survival time is 46months.Group B patients had a median OS of 36 months. For patients of Group A, the Median Disease Time (DFS) was 37 months. Group B patients had a median DFS of 30 months. For each degree increase in the PCI pre score and for the same treatment group, the PCI posr score increases by 0.573 degrees. Group 2, for the same PCIpre score, have a 163% higher PCI posr score. On patients with singet ring cell adenocarcinoma there is a statistical significance difference in OS for PIPAC group. Patients of group A had a median OS of 26 months. For patients of group B, the median OS was 14 months. Morbidity and mortality in both groups are 53,4% and 4,7% for Group A and 44,5% and 5,5% for Group B respectively. The neo-adjuvant PIPAC with systemic chemotherapy might be a promising approach for patients with peritoneal metastasis from gastric cancer. PIPAC is a safe and well tolerated procedure.

Peritoneal metastases from gastric cancer in a nationwide cohort: Incidence, treatment and survival.

The aims of this study were to investigate incidence, risk factors and treatment of synchronous or metachronous peritoneal metastases (PM) from gastric cancer and to estimate survival of these patients using population-based data. Patients diagnosed with gastric cancer in 2015 to 2016 were selected from the Netherlands Cancer Registry. The incidence of synchronous and metachronous PM were calculated. Multivariable regression analyses were performed to identify factors associated with the occurrence of PM. Treatment and survival were compared between patients with synchronous and metachronous PM. Of 2206 patients with gastric cancer, 741 (34%) were diagnosed with PM. Of these, 498 (23%) had synchronous PM. The cumulative incidence of metachronous PM in patients who underwent potentially curative treatment (n = 675) was 22.8% at 3 years. A factor associated with synchronous and metachronous PM was diffuse type histology. Patients diagnosed with synchronous PM more often received systemic treatment than patients with metachronous PM (35% vs 18%, respectively, P < .001). Median overall survival was comparable between synchronous and metachronous PM (3.2 vs 2.3 months, respectively, P = .731). Approximately one third of all patients with gastric cancer are diagnosed with PM, either at primary diagnosis or during 3-year follow-up after potentially curative treatment. Patients with metachronous PM less often received systemic treatment than those with synchronous PM but survival was comparable between both groups. Future trials are warranted to detect gastric cancer at an earlier stage and to examine strategies that lower the risk of peritoneal dissemination. Also, specific treatment options for patients with gastric PM should be further investigated.

Clinical Impact of Radical Resection of Synchronous and Metachronous Peritoneal Metastases from Colorectal Cancer.

According to some case series, patients with colorectal cancer (CRC) who underwent radical resection of synchronous peritoneal metastases (PM) with the primary tumor had better survival than patients who underwent non-surgical treatment. However, little evidence exists regarding the significance of radical resection for metachronous PM. This study aimed to evaluate the clinical significance of surgical intervention for isolated PM from CRC, with a particular focus on time to PM. A total of 74 consecutive patients with isolated PM from CRC, including 40 and 34 patients with synchronous and metachronous PM, respectively, treated between 2007 and 2018 were retrospectively analyzed. The primary outcome measure was overall survival (OS) from diagnosis, and the OS was compared between radical resection and palliative chemotherapy. Five-year OS was 39.7% for all patients. Patients with radical resection had significantly better 5-year OS compared with those with palliative chemotherapy (62.8% vs. 11.0%; p<0.0001). According to time to PM, patients with radical resection had significantly better 5-year OS compared with those with palliative chemotherapy for both synchronous PM (47.6% vs. 0%; p=0.019) and metachronous PM (77.2% vs. 15.2%; p<0.0001). Multivariable analysis stratified by time to PM revealed that surgical intervention is a significant favorable prognostic factor only in patients with metachronous PM (hazard ratio 0.117, 95% confidence interval 0.020-0.678; p=0.017). Patients with radical resection of PM had good survival compared with those with chemotherapy alone, especially for metachronous PM. Surgical intervention should be considered for isolated metachronous PM when radical resection is feasible.

Treatment and prognosis of colorectal cancer with synchronous peritoneal metastases: 11-year single institute experience

BackgroundTreatment of colorectal cancer (CRC) with synchronous peritoneal metastases (SPM) is controversial, and its prognosis remains poor. Here, we analysed the association between treatment strategies and the outcomes of patients...

Gastric Cancer (GC) with Peritoneal Metastases (PMs): An Overview of Italian PSM Oncoteam Evidence and Study Purposes.

Gastric cancer (GC) continues to be one of the leading types of malignancies worldwide, despite an ongoing decrease in incidence. It is the fifth most frequent type of cancer in the world and the fourth leading cause of cancer death. Peritoneal metastases (PMs) occur in 20-30% of cases during the natural history of the disease. Systemic chemotherapy (SC) is undoubtedly the standard of care for patients with GC and PMs. However, with the development of highly effective regimens (SC combined with intraperitoneal chemotherapy), significant tumor shrinkage has been observed in many patients with synchronous GC and PMs, allowing some to undergo curative resection "conversion surgery" with long-term survival. In recent years, there has been growing interest in intraperitoneal chemotherapy for PMs, because the reduced drug clearance associated with the peritoneal/plasma barrier allows for direct and prolonged drug exposure with less systemic toxicity. These procedures, along with other methods used for peritoneal surface malignancies (PSMs), can be used in GCs with PMs as neoadjuvant chemotherapy or adjuvant treatments after radical surgery or as palliative treatments delivered either laparoscopically or-more recently-as pressurized intraperitoneal aerosol chemotherapy. The great heterogeneity of patients with stage IV gastric cancer did not allow us to carry out a systemic review; therefore, we limited ourselves to providing readers with an overview to clarify the indications and outcomes of integrated treatments for GCs with PMs by analyzing reports from the international clinical literature and the specific experiences of our oncoteam.

Comparison of genetic variation between primary colorectal cancer and metastatic peritoneal cancer.

Among cancer metastases by primary colorectal cancer (CRC), peritoneal metastasis is the second most common metastatic lesion after liver metastasis. In treating metastatic CRC, it is very important to differentiate targeted-therapy and chemotherapy according to the characteristics of each lesion because the genetic variation of the primary and metastatic lesions are different. However, there are few studies of genetic characteristics on peritoneal metastasis caused by primary CRC, so molecular-level studies are continuously required. We propose an appropriate peritoneal metastasis treatment policy by identifying the genetic characteristics between primary CRC and synchronous peritoneal metastatic lesions. Primary CRC and synchronous peritoneal metastasis samples were analyzed in pairs from six patients using Comprehensive Cancer Panel (409 cancer-related genes, Thermo Fisher Scientific, USA) and next-generation sequencing (NGS). The mutations were commonly found on the KMT2C and THBS1 genes in both primary CRC and peritoneal metastasis. The PDE4DIP gene was mutated in all cases except for on a sample of peritoneal metastasis. As a result of analysis using the mutation database, we confirmed that the gene mutations of primary CRC and the peritoneal metastasis derived from it showed the same tendency, although we did not accompany the gene expression level or epigenetic study. It is thought that the treatment policy through molecular genetic testing of primary CRC can also be applied to peritoneal metastasis treatment. Our study is expected to be the basis for further peritoneal metastasis research.

Bidirectional Approach with PIPAC and Systemic Chemotherapy for Patients with Synchronous Gastric Cancer Peritoneal Metastases (GCPM)

BackgroundThis study evaluated the efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with systemic chemotherapy as a bidirectional approach for gastric cancer (GC) patients with synchronous peritoneal metastases (SPM).MethodsA retrospective analysis of a prospective PIPAC database was queried for patients who underwent a bidirectional approach between October 2019 and April 2022 at two high-volume GC surgery units in Italy (Verona and Siena). Surgical and oncological outcomes were analyzed.ResultsBetween October 2019 and April 2022, 74 PIPAC procedures in 42 consecutive patients with Eastern Cooperative Oncology Group performance status ≤2 were performed—32 patients treated in Verona and 10 in Siena. Twenty-seven patients (64%) were female and median age at first PIPAC was 60.5 years (I–III quartiles: 49–68 years). Median Peritoneal Cancer Index (PCI) was 16 (I–III quartiles: 8–26) and 25 patients (59%) had at least two PIPAC procedures. Major complications according to the Common Terminology Criteria for Adverse Events (CTCAE; 3 and 4) occurred in three (4%) procedures, and, according to the Clavien–Dindo classification (>3a), one (1%) severe complication occurred. There were no reoperations or deaths within 30 days. Median overall survival (mOS) from diagnosis was 19.6 months (range 14–24), and mOS from first PIPAC was 10.5 months (range 7–13). Excluding cases with very heavy metastatic peritoneal burden, with PCI from 2 to 26, treated with more than one PIPAC, mOS from diagnosis was 22 months (range 14–39). Eleven patients (26%) underwent curative-intent surgery after a bidirectional approach. R0 was achieved in nine (82%) patients and complete pathological response was obtained in three (27%) cases.ConclusionsPatient selection is associated with bidirectional approach efficacy and feasibility for SPM GC treatment, which may allow potentially curative surgical radicalization in highly selected cases.

15-month safety and efficacy data after intraperitoneal treatment with 224Radium-labelled microparticles after CRS-HIPEC for peritoneal metastasis from colorectal cancer.

3518 Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis. Improved survival can be achieved by extensive cytoreductive surgery (CRS), frequently used together with hyperthermic intraperitoneal chemotherapy (HIPEC), with median time to recurrence around 12 months. Radspherin is a novel treatment principle based on the delivery of short range and cytotoxic alpha particles emitted during the decay of 224Ra. Alpha particles have high linear energy transfer and a radiation range less than 100 µm (3-10 cell diameters), generating highly localized and effective radiation with non-repairable double-strand DNA breaks in affected cells. Our hypothesis is that Radspherin produces an alpha-particle radiation field exclusively to the surfaces and liquid volumes of the peritoneum, delivering lethal doses to remaining micrometastasis in the peritoneal linings and eradicate free-floating tumor cells after surgical resection, thus assumingly prolonging time to recurrence and potentially overall survival. Methods: A phase 1/2a study (EudraCT 2018-002803-33) is ongoing to evaluate safety, tolerability and signal of efficacy of Radspherin injected intraperitoneally two days after CRS-HIPEC. After completion of dose escalation (1-2-4-7 MBq), an activity-dose of 7 MBq was recommended. Assessment of safety and efficacy (diagnostic imaging) was performed every three months. Safety data and progression-free survival (PFS) at 15 months are presented. Results: Twenty-three patients (pts) were enrolled across cohorts (safety population), of these 12 pts received the recommended dose of 7MBq, 9 pts single dose and 3 pts split dose (3,5 MBq x2). Twelve pts had synchronous PM and 11 metachronous PM. Median age was 64 years (28-78), 70 % were female and median peritoneal cancer index was 7 (3-19). To date, 271 adverse events (AE) were reported, whereof only 7 (all grade 1-2) were deemed related to Radspherin. Fourteen serious adverse events (SAEs) in 8 pts have been reported, none considered related to Radspherin. At 15 months, 9 out of 23 pts (39 %) had recurred, whereof 4 pts recurred in the peritoneum. In the expansion cohort (7MBq), 3 out of 12 pts (25 %) had recurred and none of these pts had peritoneal recurrences. Median PFS was not reached in the two populations. Conclusions: Radspherin was well tolerated with no related SAEs reported. At 15 months median PFS has not been reached and none of the patients at recommended dose had peritoneal recurrences. The results are encouraging and warrant further exploration of Radspherin as a novel treatment principle in clinical trials. Clinical trial information: NCT03732781 .

A prediction model to refine the timing of an early second-look laparoscopic exploration in patients with colon cancer at high risk of early peritoneal metastasis recurrence.

In patients at high risk of peritoneal metastasis (PM) recurrence following surgical treatment of colon cancer (CC), second-look laparoscopic exploration (SLLE) is mandatory; however, the best timing is unknown. We created a tool to refine the timing of early SLLE in patients at high risk of PM recurrence. This international cohort study included patients who underwent CC surgery between 2009 and 2020. All patients had PM recurrence. Factors associated with PM-free survival (PMFS) were assessed using Cox regression. The primary endpoint was early PM recurrence defined as a PMFS of <6 months. A model (logistic regression) was fitted and corrected using bootstrap. In total, 235 patients were included. The median PMFS was 13 (IQR, 8-22) months, and 15.7% of the patients experienced an early PM recurrence. Synchronous limited PM and/or ovarian metastasis (hazard ratio [HR]: 2.50; 95% confidence interval [CI]: [1.66-3.78]; p < 0.001) were associated with a very high-risk status requiring SLLE. T4 (HR: 1.47; 95% CI: [1.03-2.11]; p = 0.036), transverse tumor localization (HR: 0.35; 95% CI: [0.17-0.69]; p = 0.002), emergency surgery (HR: 2.06; 95% CI: [1.36-3.13]; p < 0.001), mucinous subtype (HR: 0.50; 95% CI [0.30, 0.82]; p = 0.006), microsatellite instability (HR: 2.29; 95% CI [1.06, 4.93]; p = 0.036), KRAS mutation (HR: 1.78; 95% CI: [1.24-2.55]; p = 0.002), and complete protocol of adjuvant chemotherapy (HR: 0.93; 95% CI: [0.89-0.96]; p < 0.001) were also prognostic factors for PMFS. Thus, a model was fitted (area under the curve: 0.87; 95% CI: [0.82-0.92]) for prediction, and a cutoff of 150 points was identified to classify patients at high risk of early PM recurrence. Using a nomogram, eight prognostic factors were identified to select patients at high risk for early PM recurrence objectively. Patients reaching 150 points could benefit from an early SLLE.

Prolonged hyperthermic intraperitoneal chemotherapy duration with 90 minutes cisplatin might increase overall survival in gastric cancer patients with peritoneal metastases.

Advanced gastric cancer with synchronous peritoneal metastases (GC-PM) is associated with a poor prognosis. Although cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is a promising approach, only a limited number of Western studies exist. To investigate the clinicopathological outcomes of patients who underwent CRS-HIPEC for GC-PM. A retrospective analysis of patients with GC-PM was conducted. All patients were seen at the Department of General and Visceral Surgery, Hospital Barmherzige Brüder, Regensburg, Germany between January 2011 and July 2021 and underwent CRS-HIPEC. Preoperative laboratory results, the use of neoadjuvant trastuzumab, and the details of CRS-HIPEC, including peritoneal carcinomatosis index, completeness of cytoreduction, and surgical procedures were recorded. Disease-specific (DSS), and overall survival (OS) of patients were calculated. A total of 73 patients were included in the study. Patients treated with neoadjuvant trastuzumab (n = 5) showed longer DSS (P = 0.0482). Higher white blood cell counts (DSS: P = 0.0433) and carcinoembryonic antigen levels (OS and DSS: P < 0.01), and lower hemoglobin (OS and DSS: P < 0.05) and serum total protein (OS: P = 0.0368) levels were associated with shorter survival. Longer HIPEC duration was associated with more advantageous median survival times [60-min (n = 59): 12.86 mo; 90-min (n = 14): 27.30 mo], but without statistical difference. To obtain additional data from this observation, further separation of the study population was performed. First, propensity score-matched patient pairs (n = 14 in each group) were created. Statistically different DSS was found between patient pairs (hazard ratio = 0.2843; 95% confidence interval: 0.1119-0.7222; P = 0.0082). Second, those patients who were treated with trastuzumab and/or had human epidermal growth factor receptor 2 positivity (median survival: 12.68 mo vs 24.02 mo), or had to undergo the procedure before 2016 (median survival: 12.68 mo vs 27.30 mo; P = 0.0493) were removed from the original study population. Based on our experience, CRS-HIPEC is a safe and secure method to improve the survival of advanced GC-PM patients. Prolonged HIPEC duration may serve as a good therapy for these patients.

Abstract 989: Ascites in colorectal peritoneal carcinomatosis supersedes mutational status and other clinical variables as negative prognostic factor for CRS-HIPEC via EMT pathway

Abstract Peritoneal metastasis in colorectal cancer, also known as colorectal peritoneal carcinomatosis (CPC), signifies poor prognosis for patients and is associated with worse prognosis compared to other sites of metastasis. Treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in selected patients has been shown to improve survival. In this study, we aimed to identify potential prognostic factors to predict survival in CRS-HIPEC patients and explore the molecular mechanism implicated in CPC. Patient demographic and clinicopathological characteristics, including MSI status, RAS/RAF, TP53, and APC mutational status were collected from 70 CPC patients who underwent CRS-HIPEC procedure at National Cancer Centre Singapore. Synchronous peritoneal metastasis (median OS = 43.6 months, p=0.008) and the presence of ascites (median OS = 29.53 months, p=0.013) were linked to poorer overall survival. In comparison, no significant difference in OS was observed when stratifying for tumor mutational status. Multivariate analysis demonstrated that the presence of ascites was the most significant clinical prognostic factor in CPC (HR 3.097; 95% CI 1.18-8.12). To interrogate the role of ascites in the biology of CPC, we performed transcriptomic profiling of CPC and peritoneal mesothelial cell lines, and identified Epithelial-Mesenchymal Transition (EMT) pathway as a common signaling pathway enriched upon treatment with CPC ascites. Proteomics analysis of CPC ascites revealed that EMT-related proteins were highly abundant. Combining both analyses, we identified 5 putative prognostic targets (TNC, POSTN, LUM, THBS1 and MXRA5) that drive ascites-induced EMT process in CPC. Taken together, these findings suggest that careful consideration should be given to performing CRS-HIPEC in CPC patients with clinically observable ascites, as CRS-HIPEC alone is insufficient to improve survival and novel therapeutic strategies are required as an adjunct. The combination of transcriptomics and proteomics analysis of CPC ascites provides insights into the dynamic interactions between tumor cells and their microenvironment, which can be harnessed for identification of prognostic surrogate markers and future development of targeted therapy in CPC. In this study, we identified putative targetable targets driving ascites-induced EMT activation independent of the inherent molecular aberration in the CPC tumor. Citation Format: Josephine Hendrikson, Ying Liu, Qiu Xuan Tan, Joey Wee-Shan Tan, Gillian Ng, Clara Yieh Lin Chong, Chin Jin Seo, Jolene Si Min Wong, Claramae Shulyn Chia, Chin-Ann Johnny Ong. Ascites in colorectal peritoneal carcinomatosis supersedes mutational status and other clinical variables as negative prognostic factor for CRS-HIPEC via EMT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 989.

Delaying Surgery After Neoadjuvant Chemotherapy Affects Survival in Patients with Colorectal Peritoneal Metastases: A BIG-RENAPE Network Multicentric Study.

Multimodal treatment for patients with peritoneal metastases (PM) from colorectal cancer (CRC), including perioperative chemotherapy (CT) plus complete resection, is associated with prolonged survival. The oncologic impact of therapeutic delays is unknown. The aim of this study was to assess the survival impact of delaying surgery and CT. Medical records from the national BIG RENAPE network database of patients with complete cytoreductive (CC0-1) surgery of synchronous PM from CRC who received at least one neoadjuvant CT cycle plus one adjuvant CT cycle were retrospectively reviewed. The optimal interval between the end of neoadjuvant CT to surgery, surgery to adjuvant CT, and total interval without systemic CT were estimated using Contal and O'Quigley's method plus restricted cubic spline methods. From 2007 to 2019, 227 patients were identified. After a median follow-up of 45.7 months, the median overall survival (OS) and progression-free survival (PFS) was 47.6 and 10.9months, respectively. The best cut-off period was 42 days in the preoperative interval, no cut-off period was optimal in the postoperative interval, and the best cut-off period in the total interval without CT was 102 days. In multivariate analysis, age, biologic agent use, high peritoneal cancer index, primary T4 or N2 staging, and delay to surgery of more than 42 days (median OS 63 vs. 32.9months; p=0.032) were significantly associated with worse OS. Preoperative delay of surgery was also significantly associated with PFS, but only in univariate analysis. In selected patients undergoing complete resection plus perioperative CT, a period of more than 6 weeks from completion of neoadjuvant CT to cytoreductive surgery was independently associated with worse OS.

Insights into synchronous peritoneal metastases from hepatobiliary origin: Incidence, risk factors, treatment, and survival from a nationwide database

Introduction– This population-based study aimed to investigate incidence, risk factors, treatment, and survival of synchronous peritoneal metastases (PM) of hepatobiliary origin. Methods– All Dutch patients diagnosed with hepatobiliary cancer between 2009 and 2018 were selected. Factors associated with PM were identified with logistic regression analyses. Treatments for patients with PM were categorized into local therapy, systemic therapy, and best supportive care (BSC). Overall survival (OS) was investigated using log-rank test. Results– In total, 12 649 patients were diagnosed with hepatobiliary cancer of whom 8% (n = 1066) were diagnosed with synchronous PM (12% [n = 882/6519] in biliary tract cancer [BTC] vs. 4% [n = 184/5248] in hepatocellular carcinoma [HCC]). Factors that were positively associated with PM were the female sex (OR 1.18, 95% CI 1.03–1.35), BTC (OR 2.93, 95% CI 2.46–3.50), diagnosis in more recent years (2013–2015: OR 1.42, 95% CI 1.20–1.68; 2016–2018: OR 1.48, 95% CI 1.26–1.75), T3/T4 stage (OR 1.84, 95% CI 1.55–2.18), N1/N2 stage (OR 1.31, 95% CI 1.12–1.53) and other synchronous systemic metastases (OR 1.85, 95% CI 1.62–2.12). Of all PM patients, 723 (68%) received BSC only. Median OS was 2.7 months (IQR 0.9–8.2) in PM patients. Conclusion– Synchronous PM were found in 8% of all hepatobiliary cancer patients and occurred more often in BTC than in HCC. Most patients with PM received BSC only. Given the high incidence and dismal prognosis of PM patients, extended research in hepatobiliary PM is needed to achieve better outcome in these patients.

Real world analysis of peritoneal metastasis from renal cell carcinoma: Meet-Uro 27 study.

638 Background: Peritoneal metastases (PM) have been reported in approximately 1% of patients (pts) with metastatic Renal Cell Carcinoma (mRCC). Outcome data are limited due to the rarity of this metastatic site. Therefore, the aim of our study is to describe RCC pts with PM treated as per clinical practice. Methods: Baseline characteristics and outcome data of pts with PM from RCC were retrospectively collected from 12 Italian oncological referral centers adhering to the Meet-Uro group, from January 2016 to September 2022. Results: We collect 91 RCC pts with PM. 87/91 pts received systemic treatment, 4/87 only best supportive care. First line treatment included TKI and ImmuneOncology(IO)-TKI with different Objective Response Rate(ORR) (41% vs 53.8%, respectively) and Disease Control Rate (DCR) (57.1% and 80.7%, respectively) as well as median PFS (9.9 mo (95%CI 4.5-15.4) for TKI and not reached (NR) for IO-TKI (69.7% pts were free from progression at a median follow up of 13.8 months). Primary refractory (PR) pts were 35.7% for TKI and 7.7% for IO-TKI. According to IMDC score, mPFS was consistent among risk categories, 36.8 mo (95%CI 9.6-63.9) for good risk pts, 13.8 mo (95%CI 8.8-18.8) for intermediate pts and 2.9 mo (95%CI 2.2-3.7) for poor risk pts. Synchronous PM was associated to shorter mPFS 11.0 (95%CI 3.1-19.0) compared to patients with metacronous involvement as well as ORR (31.3%) and DCR (43.1%) whereas PR was higher (34.7%). Only 43/87 pts (45.7%) received a second line treatment that was TKI ( ORR 30.7%; DCR 61.5%; or IO (ORR 20.6%; DCR 41.3%). mOS was 21.8 mo (12.0-31.5) for TKI and NR for pts treated with IO-TKI (80.8 alive at 1 yrs). According to IMDC score, mOS was NR for good risk pts, 24.6 (95%CI 15.8-33.3) and 3.4 (95%CI 2.4-4.3) for intermediate and poor risk, respectively. Conclusions: We report one of the largest case series regarding PM from RCC. Poor risk patients according to IMDC score, sarcomatoid feature and liver metastasis were more represented in our population, compared to historical control, suggesting a more aggressive behavior of PM mRCC. Outcome data suggest that TKI-IO as first line treatment, compared to TKI monotherapy, and TKI as second line, compared to IO, are more active treatment for these pts with dismal prognosis. Nevertheless, synchronous PM has been reported in 57% of pts with poorer outcome and lower response rate. [Table: see text]