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PURPOSE: Despite advances in systemic therapy, outcomes of patients with gastric cancer (GC) peritoneal carcinomatosis (PC) remain poor, in part because of poor penetrance of systemic therapy into peritoneal metastasis due to the plasma-peritoneal barrier and anarchic intra-tumoral circulation. Hence, regional treatment approach with administration of chemotherapy directly into the peritoneal cavity (intraperitoneal, IP) under various conditions, combined with or without cytoreductive surgery (CRS) has remained an area of significant research interest. The purpose of this review is to provide high-level evidence for regional treatment approaches in the management of GCPC with limited peritoneal disease. METHODS: A review of the current literature and ongoing clinical trials for regional IP therapies for GCPC was performed. Studies included in this review comprise of phase III randomized controlled trials, non-randomized phase II studies, high-impact retrospective studies, and active ongoing clinical trials for each available IP modality. RESULTS: The three common IP approaches are heated intraperitoneal chemotherapy (HIPEC), normothermic intraperitoneal chemotherapy (NIPEC) and more recently introduced, pressurized intraperitoneal aerosolized chemotherapy (PIPAC). These IP approaches have been combined with systemic therapy and/or CRS with varying degrees of promising results, demonstrating evidence of improvements in survival rates and peritoneal disease control. Patient selection, optimization of systemic therapy, and completeness of cytoreduction have emerged as major factors influencing the design of contemporary and ongoing trials. CONCLUSION: IP chemotherapy has a clear role in the management of patients with GCPC, and when combined with CRS in appropriately selected patients has the potential to significantly improve survival. Ongoing and upcoming IP therapy clinical trials hold great promise to shape the treatment paradigm for GCPC.

The iPocc trial, a randomized, global phase 3 study that compared intraperitoneal (IP) and intravenous (IV) carboplatin with dose-dense paclitaxel chemotherapy in epithelial ovarian cancer (EOC) patients, demonstrated improved progression-free survival in patients who received IP chemotherapy. The present study aimed to investigate the role of preexisting tumor immunity in the clinical outcomes of patients receiving IP chemotherapy. This study involved analyzing patient data from the iPocc trial, selectively of those whose tumor specimens were preserved at the time of primary surgery. A total of 116 cases ((IP; n = 59), (IV; n = 57)) were subjected to microarray analysis. Single-sample gene set enrichment analyses were performed to evaluate the tumor immune microenvironment. Patients with enhanced tumor infiltration of T cells, natural killer (NK) cells, and cytotoxic lymphocytes in the IP group had a longer overall survival (OS) than those in the IV group, but not in the group with low infiltration. IP therapy improved the OS of patients with high expression of immune-related genes such as CD8A and FOXP3. In patients' subdivided into "immune Hot" and "immune Cold" groups based on hierarchical clustering analysis using four parameters representing "Innate immunity," "T cells," "IFNG response" and "Inhibitory molecules," IP therapy significantly improved prognosis in the "immune Hot" group, but not in the "immune Cold" group compared to that of IV therapy. IP chemotherapy enhances the survival rates of patients with EOC with an immune-Hot phenotype in the tumor microenvironment prior to treatment. (Japan Registry of Clinical Trials number, jRCTs031180141.) • High infiltration of T cells, cytotoxic lymphocytes, and NK cells was related with better outcomes in IP vs. IV chemotherapy. • Patients with high expression of immune-related genes, such as CD8A, FOXP3, and ARG1, showed improved survival with IP therapy. • The "immune Hot" group, defined by innate immunity and IFN-γ response, had significantly better outcomes with IP therapy. • Multifaceted immune factors involved in the cancer immune cycle can help predict treatment outcomes in EOC. [ABSTRACT FROM AUTHOR]

Background: Ascites is common in advanced gastrointestinal cancers with peritoneal metastases (PM) and negatively impacts patient survival. No study to date has specifically evaluated the relationship between ascites, PM and survival outcomes in metastatic colorectal cancer (mCRC) and metastatic gastric cancer (mGC). Objectives: This study aims to investigate and elucidate the relationship between malignant ascites, PM and survival outcomes in both mCRC and mGC patients. Design: This is a retrospective analysis of prospectively collected clinical trial data of mCRC and mGC patients with PM. Methods: We performed two pooled analyses, firstly of two Italian randomized trials enrolling patients with mCRC eligible for systemic therapy (TRIBE2; VALENTINO), and secondly of gastric cancer and peritoneal metastasis (GCPM) patients who underwent bi-directional therapeutic treatment comprising systemic and peritoneal-directed therapies. Results: Of 900 mCRC patients, 39 (4.3%) had PM with malignant ascites. Compared to the group without PM, median progression-free and overall survival were significantly inferior in the ascites group (hazard ratio (HR) for progression-free survival (PFS) 1.68, 95% confidence interval (CI): 1.21–2.35, p = 0.007; HR for overall survival (OS) 2.14, 95% CI: 1.57–3.01, p < 0.001), but not in the group of PM without ascites (HR for PFS 1.10, 95% CI: 0.91 – 1.34; HR for OS 1.04, 95% CI: 0.84 – 1.30). Of 170 patients with GCPM, those with ascites had higher median Peritoneal Cancer Index scores (23 vs 9, p < 0.001). Median OS was significantly inferior among those with ascites compared to those without (13.0 vs 21.0 months, HR 1.71, 95% CI: 1.16–2.52, p = 0.007). Conclusion: Ascites identifies a subgroup of patients with PM and poor outcomes, for whom tailored research are needed. [ABSTRACT FROM AUTHOR]

This manuscript reports the results of an international consensus on technologies of hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) performed with the following goals: To provide recommendations for the technological parameters to perform HIPEC. To identify the role of heat and its application forms in treating peritoneal metastases. To provide recommendations regarding the correct dosimetry of intraperitoneal chemotherapy drugs and their carrier solutions. To identify for each intraperitoneal chemotherapy regimen the best dosimetry and fractionation. To identify areas of future research pertaining to HIPEC technology and regimens. This consensus was performed by the Delphi technique and comprised two rounds of voting. In total, 96 of 102 eligible panelists replied to both Delphi rounds (94.1%) with a consensus of 39/51 questions on HIPEC technical aspects. Among the recommendations that met with the strongest consensus were those concerning the dose of HIPEC drug established in mg/m2, a target temperature of at least 42°C, and the use of at least three temperature probes to pursue hyperthermia. Ninety minutes as the ideal HIPEC duration seemed to make consensus. These results should be considered when designing new clinical trials in patients with peritoneal surface malignancies. [ABSTRACT FROM AUTHOR]

Peritoneal metastatic carcinoma refers to the spread of malignant tumors from the primary site to the peritoneum. It is commonly observed in the advanced stages of various cancer types, including gastric cancer, colorectal cancer, ovarian cancer and pseudomyxoma peritonei (PMP). Peritoneal metastatic carcinoma seriously impair human health due to their high recurrence and mortality rates, and palliative treatment based on chemotherapy is usually provided after radical surgery or in the advanced stage of peritoneal metastases. The difficulties in the treatment of peritoneal metastatic carcinoma are the lack of targeted drugs and the difficulty of drugs to cross the blood-peritoneal barrier, resulting in poor systemic effects. Intraperitoneal chemotherapy, as an important therapeutic means, has a broad application prospect in the treatment of peritoneal metastatic carcinoma. In recent years, innovations in intraperitoneal chemotherapy techniques such as hyperthermic intraperitoneal chemotherapy (HIPEC), pressurized intraperitoneal aerosol chemotherapy (PIPAC) and the development of novel drugs have significantly improved patients' quality of life. The development of novel drugs has significantly improved patient survival. However, the diversity and complexity of these diseases have led to clinical variability and uncertainty in the efficacy of intraperitoneal chemotherapy in terms of treatment strategies such as mode of administration, drug type and dose. Although evidence-based guidelines and recommended treatment strategies have been developed, there is a need to further support these regimens through additional clinical trials and higher levels of evidence-based medicine. This review summarized the development history and recent advances in intraperitoneal chemotherapy, compared and analyzed the treatments such as surgery combined with traditional IPC, HIPEC and PIPAC, and summarized the research progress of recently conducted intraperitoneal chemotherapy techniques; moreover, in terms of the clinical application of intraperitoneal chemotherapy techniques, this paper elaborated on its use in diseases such as gastric cancer, colorectal cancer, gynecological oncology, PMP, cholangiocarcinoma and pancreatic cancer. For the limitations of intraperitoneal chemotherapy technology, it is proposed that the innovative development of nanomedicine is expected to provide a safer and more effective option for the treatment of peritoneal metastatic carcinoma. In conclusion, this review summarized the latest progress, shortcomings and future development of intraperitoneal chemotherapy, with the aim of providing a feasible direction for more effective clinical treatment of peritoneal metastatic carcinoma.

Peritoneal metastatic carcinoma refers to the spread of malignant tumors from the primary site to the peritoneum. It is commonly observed in the advanced stages of various cancer types, including gastric cancer, colorectal cancer, ovarian cancer and pseudomyxoma peritonei (PMP). Peritoneal metastatic carcinoma seriously impair human health due to their high recurrence and mortality rates, and palliative treatment based on chemotherapy is usually provided after radical surgery or in the advanced stage of peritoneal metastases. The difficulties in the treatment of peritoneal metastatic carcinoma are the lack of targeted drugs and the difficulty of drugs to cross the blood-peritoneal barrier, resulting in poor systemic effects. Intraperitoneal chemotherapy, as an important therapeutic means, has a broad application prospect in the treatment of peritoneal metastatic carcinoma. In recent years, innovations in intraperitoneal chemotherapy techniques such as hyperthermic intraperitoneal chemotherapy (HIPEC), pressurized intraperitoneal aerosol chemotherapy (PIPAC) and the development of novel drugs have significantly improved patients' quality of life. The development of novel drugs has significantly improved patient survival. However, the diversity and complexity of these diseases have led to clinical variability and uncertainty in the efficacy of intraperitoneal chemotherapy in terms of treatment strategies such as mode of administration, drug type and dose. Although evidence-based guidelines and recommended treatment strategies have been developed, there is a need to further support these regimens through additional clinical trials and higher levels of evidence-based medicine. This review summarized the development history and recent advances in intraperitoneal chemotherapy, compared and analyzed the treatments such as surgery combined with traditional IPC, HIPEC and PIPAC, and summarized the research progress of recently conducted intraperitoneal chemotherapy techniques; moreover, in terms of the clinical application of intraperitoneal chemotherapy techniques, this paper elaborated on its use in diseases such as gastric cancer, colorectal cancer, gynecological oncology, PMP, cholangiocarcinoma and pancreatic cancer. For the limitations of intraperitoneal chemotherapy technology, it is proposed that the innovative development of nanomedicine is expected to provide a safer and more effective option for the treatment of peritoneal metastatic carcinoma. In conclusion, this review summarized the latest progress, shortcomings and future development of intraperitoneal chemotherapy, with the aim of providing a feasible direction for more effective clinical treatment of peritoneal metastatic carcinoma. [ABSTRACT FROM AUTHOR]

Several abdominal-located cancers develop metastasis within the peritoneum, what is called peritoneal carcinomatosis (PC), constituting a clinical challenge in their therapeutical management, often leading to poor prognoses. Current multidisciplinary strategies, including cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC), demonstrate efficacy but have limitations. In response, alternative strategies are explored in the drug delivery field for intraperitoneal chemotherapy. Controlled drug delivery offers a promising avenue, maintaining localized drug concentrations for optimal PC management. Drug delivery systems (DDS), including hydrogels, implants, nanoparticles, and hybrid systems, show potential for sustained and region-specific drug release. The present review aims to offer an overview of the advances and current designs of DDS for PC chemotherapy administration, focusing on their composition, main characteristics, and principal experimental outcomes, highlighting the importance of biomaterial rationale design and in vitro/vivo models for their testing. Moreover, since clinical data for human subjects are scarce, we offer a critical discussion of the gap between bench and bedside in DDS translation, emphasizing the need for further research. [Display omitted] • Emphasis on the chemical and structural properties of drug delivery systems (DDS) for intraperitoneal chemotherapy (IPEC). • Analysis of key findings and clinical potential from testing DDS formulations on in vitro and in vivo cancer models. • Overview of the patent landscape and clinical trials, identifying development constraints to bridge the translational gap. [ABSTRACT FROM AUTHOR]

Simple Summary: Intraperitoneal (IP) administration of Paclitaxel (PTX) is a logical approach for treating peritoneal metastases (PMs), as it allows direct drug infiltration into PMs, providing prolonged exposure at high concentrations with minimal systemic side effects. However, the optimal timing for combining intravenous (IV) and IP administration remains uncertain. This study demonstrated that IP administration of PTX resulted in higher concentrations of PTX in peritoneal tumors, as well as increased levels of intravenously administered Carboplatin (CBDCA) when given four days after PTX administration. These findings suggest that IP PTX may enhance the efficacy of subsequent systemic chemotherapy. Therefore, staggered and repeated systemic chemotherapy following IP PTX appears to be a highly effective strategy for managing PMs. Despite advances in systemic chemotherapy, patients with gastric cancer (GC) and peritoneal metastases (PMs) continue to have poor prognoses. Intraperitoneal (IP) administration of Paclitaxel (PTX) combined with systemic chemotherapy shows promise in treating PMs from GC. However, methods of drug administration need to be optimized to maximize efficacy. In this study, we utilized a mouse model with PMs derived from a human GC cell line, administering PTX either IP or intravenously (IV), and Carboplatin (CBDCA) IV 0, 1, and 4 days after PTX administration. The PMs were resected 30 min later, and concentrations of PTX and CBDCA in resected tumors were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results indicated that PTX concentrations were higher with IP administration than with IV administration, with significant differences observed on days 0 and 1. CBDCA concentrations 4 days post-IP PTX administration were higher than with simultaneous IV PTX administration. These findings suggest that IP PTX administration enhances CBDCA concentration in peritoneal tumors. Therefore, sequential IV administration of anti-cancer drugs appears more effective than simultaneous administration with IP PTX, a strategy that may improve prognoses for patients with PMs. [ABSTRACT FROM AUTHOR]

BackgroundStudies from Asia indicate that normothermic intraperitoneal chemotherapy (NIPEC) may confer survival benefit in patients with gastric peritoneal carcinomatosis (PC). However, data regarding this approach is lacking in western population. The current STOPGAP trial is intended to assess 1-year progression-free survival benefit of sequential systemic chemotherapy and paclitaxel NIPEC in patients with gastric/ gastroesophageal junction (GEJ) adenocarcinoma PC.MethodsThis is a prospective, single center, single arm, phase II investigator-initiated clinical trial. Patients with histologically proven gastric/GEJ (Siewert 3) adenocarcinoma with positive peritoneal cytology or PC will be eligible to participate after three months of standard of care systemic chemotherapy and with no evidence of visceral metastasis on restaging scans. The primary treatment is iterative paclitaxel NIPEC with systemic paclitaxel and 5-fluorouracil, which will be administered on days1 and 8 and repeated every three weeks for 4 cycles. Patients will undergo diagnostic laparoscopy both before and after NIPEC to assess peritoneal cancer index (PCI). Patients with PCI less than or equal to 10 in whom complete cytoreduction (CRS) is feasible may opt to undergo CRS with heated intraperitoneal chemotherapy (HIPEC). The primary endpoint is 1-year progression free survival and secondary endpoints are overall survival and patient reported quality of life outcomes measured by EuroQol- 5 dimensions-5 level (EuroQol-5D-5L) questionnaire.DiscussionIf the sequential approach of systemic chemotherapy followed by paclitaxel NIPEC proves beneficial, then this approach could be used in larger, muti-institutional randomized clinical trial of gastric PC.Trial registrationThe trial was registered on 21/02/2021, under clinical trials.gov; Identifier: NCT04762953.

Background: Platinum‐based chemotherapy is the backbone of the medical management of ovarian cancer. The dose, route and timing of treatment are ongoing areas of debate. Intraperitoneal (IP) chemotherapy is an alternative delivery method treatment to the conventional intravenous (IV) route for patients with epithelial ovarian cancer, with efficacy supported by Level 1 evidence. Aims: To compare the outcomes and feasibility of IP to IV delivery of platinum‐based chemotherapy in patients with advanced epithelial ovarian cancer. Materials and Methods: In a single institution, patients receiving adjuvant chemotherapy (IP and IV) for Stages III and IV epithelial ovarian cancer over the period January 2006–December 2018 were identified through a prospectively maintained database. All patients with an IP port inserted were included. A control group of patients treated with IV chemotherapy was created using criteria identified during the study and in the randomised trials that tested IP chemotherapy. Assessments were made for relapse‐free survival (RFS) and overall survival (OS) for each cohort. Results: A total of 639 patients received adjuvant chemotherapy (73 IP and 566 IV) during the study period. Both the IP group and matched IV control group (65 patients) had a median RFS of 26 months. The median OS in the IP group was 63.9 months, and in the IV group was 57.2 months. At ten years, a significantly higher proportion of patients were alive in the IP group cohort (16% vs 3%, relative risk 5.5, 95% CI 1.29–24, P = 0.012). IP chemotherapy was well tolerated by our cohort. In the IP group, 73% had four or more IP cycles and 99% received six or more cycles of chemotherapy. Conclusions: Our cohort had a high rate of completion of IP chemotherapy with excellent rates of completion of six cycles of any treatment. The RFS and OS in the IP chemotherapy group were comparable to each other and reflected those in the published literature. A significantly higher proportion of patients in the IP cohort were alive at ten years than in the IV cohort. [ABSTRACT FROM AUTHOR]

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors. The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT's multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia. [ABSTRACT FROM AUTHOR]

Objective To systematically evaluate the effect of intraperitoneal chemotherapy (IP) combined with intravenous chemotherapy (IV) on the prognosis of patients with ovarian cancer. Methods PubMed, EMBASE, Cochrane Library and CNKI were searched from inception to January 1, 2023. Randomized controlled trials about IP and IV in the treatment of ovarian cancer were collected. The study group was treated with IP combined with IV, and the control group was treated with IV alone. The progression-free survival (PFS), overall survival (OS) and the incidence of adverse reactions were analyzed. Results A total of seven studies involving 4 057 patients were included. The results of meta-analysis showed that the PFS of the study group was significantly longer than that of the control group, and the difference was statistically significant (HR=0. 86, 95%CI:0. 77-0. 95, P=0. 004) . The results of subgroup analysis showed that there was no significant difference in PFS between the two groups (HR=0. 85, 95%CI:0. 68-1. 05, P=0. 12) . The OS of the study group was longer than that of the control group, and the difference was statistically significant (HR=0. 89, 95%CI:0. 79-1. 00, P=0. 04) . The incidence of adverse reactions (≥grade 3) in the study group was lower than that in the control group, and the difference was statistically significant (HR=1. 22, 95%CI:1. 09-1. 37, P=0. 000 8) . The results of subgroup analysis showed that there were significant differences in the incidence of gastrointestinal adverse reactions, infection and thrombosis between the two groups (P＜0. 05) . However, there was no significant difference in the incidence of hematological toxicity and neurotoxicity (P＞0. 05) . Conclusion IP combined with IV can prolong the survival time of patients with ovarian cancer and delay the recurrence time, but it is necessary to be alert to the occurrence of severe adverse reactions. [ABSTRACT FROM AUTHOR]

Peritoneal metastasis is a common finding in patients with advanced gastric cancer. Beyond systemic chemotherapy, additive local treatments such as cytoreductive surgery and intraperitoneal chemotherapy are considered an inherent part of different multimodal treatment concepts for selected patients with peritoneal metastatic gastric cancer. This review article discusses the role of cytoreductive surgery (CRS) and intraperitoneal chemotherapy, including HIPEC, NIPS, and PIPAC, as additive therapeutic options with curative and palliative intent.

Peritoneal metastasis is a common finding in patients with advanced gastric cancer. Beyond systemic chemotherapy, additive local treatments such as cytoreductive surgery and intraperitoneal chemotherapy are considered an inherent part of different multimodal treatment concepts for selected patients with peritoneal metastatic gastric cancer. This review article discusses the role of cytoreductive surgery (CRS) and intraperitoneal chemotherapy, including HIPEC, NIPS, and PIPAC, as additive therapeutic options with curative and palliative intent. [ABSTRACT FROM AUTHOR]

Opinion statement: In our clinical practice, we have shifted away from the use of adjuvant normothermic intraperitoneal (IP) chemotherapy, particularly following the publication of GOG 252. Our decision is rooted in the accumulating evidence indicating a lack of demonstrable superiority, alongside the recognized toxicities and logistical challenges associated with its administration. This strategic departure is also influenced by the rising utilization of maintenance therapies such as bevacizumab and PARP inhibitors, which present viable alternatives for improving patient outcomes. Our utilization of hyperthermic IP chemotherapy (HIPEC) is currently reserved for a specific cohort of patients, mirroring the patient population studied in the OVHIPEC-1 trial. Specifically, our HIPEC protocol applies to patients presenting with newly diagnosed stage IIIC high-grade epithelial ovarian cancer who are deemed ineligible for primary debulking surgery. Patients must exhibit at least stable disease with neoadjuvant platinum-based chemotherapy, maintain a favorable performance status (ECOG score 0–1), possess good nutritional reserves (with no evidence of protein-calorie malnutrition and an albumin level exceeding 3.5), and not have chronic kidney disease. When HIPEC is planned, it is administered at the time of interval debulking surgery, contingent upon the attainment of optimal surgical outcomes (< 1 cm of residual disease). Our HIPEC protocol adheres to the original OVHIPEC-1 trial guidelines, employing cisplatin at a dosage of 100 mg/m2. We administer at least two antiemetics, antihistamines, and sodium thiosulfate to mitigate known side effects. Postoperatively, patients are admitted to the general surgical floor, reserving the intensive care unit for those in critical condition. We follow Enhanced Recovery After Surgery principles, incorporating early ambulation and feeding into our postoperative care strategy. We have encountered encouraging results with this approach, with most patients having largely uncomplicated postoperative courses and resuming adjuvant chemotherapy within 3 to 4 weeks of surgery. [ABSTRACT FROM AUTHOR]

Since the latest practice guidelines for ovarian cancer were developed by the Korean Society of Gynecologic Oncology (KSGO) in 2021, many studies have examined the efficacy and safety of various treatments for epithelial ovarian cancer (EOC). Therefore, the need to develop recommendations for EOC treatments has been raised. This study searched the literature using 4 key items and the Population, Intervention, Comparison, and Outcome: the efficacy and safety of poly-ADP ribose polymerase inhibitors in newly diagnosed advanced EOC; the efficacy and safety of intraperitoneal plus intravenous chemotherapy in optimally debulked advanced EOC; the efficacy and safety of secondary cytoreductive surgery in platinumsensitive recurrent ovarian cancer; and the efficacy and safety of the addition of bevacizumab to platinum-based chemotherapy in first platinum-sensitive recurrent EOC patients who received prior bevacizumab. The evidence for these recommendations, according to each key question, was evaluated using a systematic review and meta-analysis. The committee of ovarian cancer of the KSGO developed updated guidelines for treatments of EOC. [ABSTRACT FROM AUTHOR]

With a 5-year overall survival of less than 5%, colorectal peritoneal metastasis (CPM) patients are often managed with palliative chemotherapy (CTx). In the past few decades, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been introduced as a possible curative treatment for highly selective CPM patients. We share our experience of CRS and HIPEC given the unique characteristics of the medical system and the benefit of CRS and HIPEC in palliative setting. From April 2017 to October 2021, CPM patients who underwent CRS and HIPEC were analyzed. Patients were allocated into perioperative and palliative CTx arm based on the duration between initial diagnosis of CPM to undergoing CRS and HIPEC of 6 months. Data including perioperative parameters, postoperative outcomes, and survival were analyzed with a median follow-up of 28.5 months. Twenty-six CPM patients underwent CRS and HIPEC. Mean time from diagnosis of CPM to CRS and HIPEC was 5.5 months with 14 patients in the perioperative arm and 12 patients in the palliative arm. Perioperative group showed a longer RFS of 13.5 months compared to 8 months in the palliative group. Median overall survival of palliative group was 41.50 months, and 18 patients among all groups are alive at the time of this report. CRS and HIPEC could be a treatment option for a carefully selected CPM patients performed by experienced surgeons. Overall survival of 41.50 months in palliative group compared to 16.8 months from conventional systemic CTx supports CRS and HIPEC even in palliative patients. [ABSTRACT FROM AUTHOR]

Background: Peritoneal metastasis (PM) is the most common site of dissemination of gastric cancer (GC) and is associated with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for GC with PM remains controversial due to modest survival and significant morbidity. Methods: We conducted a retrospective analysis of patients with GC and PM treated with CRS and HIPEC with cisplatin and paclitaxel for 90 min from June 2019 to December 2022. Results: Twenty-two patients were included and received a median of 7 (interquartile range [IQR] 4–8) cycles of neoadjuvant systemic therapy. Seventeen patients (77%) underwent a single neoadjuvant laparoscopic HIPEC, and six (27%) patients received chemoradiation. The median Peritoneal Carcinomatosis Index at the time of CRS was 1 (IQR 0–4), and 21 patients (95%) underwent complete cytoreduction (CC-0). An R0 resection was achieved in 20 (91%) patients, and the median length of stay was 5.5 (IQR 4–7.5) days. There were six (27%) 90-day major complications (Clavien–Dindo grade ≥ 3), one (4%) Common Terminology Classification for Adverse Events (CTCAE) grade 4 cytopenia, and one (4%) acute kidney injury. The rate of anastomotic leak (all grades) was 14%, the 30-day readmission rate was 18%, and the 90-day mortality rate was 0%. At a median follow-up of 24 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. The 1-, 2-, and 3-year PFS rates were 65%, 56%, and 40%, respectively, and the 1-, 2-, and 3-year OS rates were 96%, 78%, and 55%, respectively. Conclusions: CRS and HIPEC with paclitaxel and cisplatin is well tolerated and is associated with favorable oncologic and perioperative outcomes. [ABSTRACT FROM AUTHOR]

Patients with colorectal cancer (CRC) and diffuse peritoneal metastasis (PM) are not eligible for surgical intervention. Thus, palliative treatment remains the standard of care in clinical practice. Systemic chemotherapy fails to cause drug accumulation at the lesion sites, while intraperitoneal chemotherapy (IPC) is limited by high clearance rates and associated complications. Given the poor prognosis, a customized OxP/R848@PLEL hydrogel delivery system has been devised to improve the clinical benefit of advanced CRC with diffuse PM. This system is distinguished by its simplicity, security, and efficiency. Specifically, the PLEL hydrogel exhibits excellent injectability and thermosensitivity, enabling the formation of drug depots within the abdominal cavity, rendering it an optimal carrier for IPC. Oxaliplatin (OxP), a first‐line drug for advanced CRC, is cytotoxic and enhances the immunogenicity of tumors by inducing immunogenic cell death. Furthermore, OxP and resiquimod (R848) synergistically enhance the maturation of dendritic cells, promote the expansion of cytotoxic T lymphocytes, and induce the formation of central memory T cells. Moreover, R848 domesticates macrophages to an anti‐tumor phenotype. OxP/R848@PLEL effectively eradicates peritoneal metastases, completely inhibits ascites production, and significantly prolongs mice lifespan. As such, it provides a promising approach to managing diffuse PM in patients with CRC without surgical indications. [ABSTRACT FROM AUTHOR]

Background: We reviewed outcomes following cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with appendiceal or colorectal neoplasms and evaluated key prognostic indicators for treatment. Methods: All patients who underwent cytoreductive surgery/HIPEC for appendiceal and colorectal neoplasms were identified from an IRB-approved database. Patient demographics, operative reports, and postoperative outcomes were reviewed. Results: 110 patients [median age 54.5 (18-79) years, 55% male] were included. Primary tumor location was colorectal (58; 52.7%) and appendiceal (52; 47.3%). 28.2%, .9%, and 12.7% had right, left, and sigmoid tumors, respectively; 11.8% had rectal tumors. 12/13 rectal cancer patients underwent preoperative radiotherapy. Mean Peritoneal Cancer Index was 9.6 ± 7.7; complete cytoreduction was achieved in 90.9%. 53.6% developed postoperative complications. Reoperation, perioperative mortality, and 30-day readmission rates were 1.8%, .09%, and 13.6%, respectively. Recurrence at a median of 11.1 months was 48.2%; overall survival at 1 and 2 years was 84% and 56.8%, respectively; disease-free survival was 60.8% and 33.7%, respectively, at a median follow-up of 16.8 (0-86.8) months. Univariate analysis of preoperative chemotherapy, primary malignancy location, primary tumor perforated or obstructive, postoperative bleeding complication, and pathology of adenocarcinoma, mucinous adenocarcinoma and negative lymph nodes were identified as possible predictive factors of survival. Multivariate logistic regression analysis showed that preoperative chemotherapy (P < .001), perforated tumor (P = .003), and postoperative intra-abdominal bleeding (P < .001) were independent prognostic indicators for survival. Conclusions: Cytoreductive surgery/HIPEC for colorectal and appendiceal neoplasms has lowmortality and high completeness of cytoreduction score. Preoperative chemotherapy, primary tumor perforation, and postoperative bleeding are adverse risk factors for survival. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is the gynaecological malignancy with the highest mortality and diagnosis often occurs in its advanced stages. Standard treatment in these cases is based on complete cytoreductive surgery with adjuvant intravenous chemotherapy. Other types of treatment are being evaluated to improve the prognosis of these patients, including intraperitoneal chemotherapy and antiangiogenic therapy. These may improve survival or time to relapse in addition to intravenous chemotherapy. Objective: The aim of this meta-analysis is to determine whether treatment with intravenous chemotherapy remains the gold standard, or whether the addition of intraperitoneal chemotherapy has a benefit in overall survival (OS) and disease-free interval (DFS). Materials and methods: A literature search was carried out in Pubmed and Cochrane, selecting clinical studies and systematic reviews published in the last 10 years. Statistical analysis was performed using the hazard ratio measure in the RevMan tool. Results: Intraperitoneal chemotherapy shows a benefit in OS and DFS compared with standard intravenous chemotherapy. The significant differences in OS (HR: 0.81 CI 95% 0.74–0.88) and in DFS (HR: 0.81 CI 95% 0.75–0.87) are statistically significant (p < 0.00001). There were no clinical differences in toxicity and side-effects. Conclusion: Intraperitoneal chemotherapy is an option that improves OS and DFS without significant toxicity regarding the use of intravenous chemotherapy alone. However, prospective studies are needed to determine the optimal dose and treatment regimen that will maintain the benefits while minimising side effects and toxicity and the profile of patients who will benefit most from this treatment. [ABSTRACT FROM AUTHOR]

Cytoreductive surgery (CRS), combined with hyperthermic intraperitoneal chemotherapy, has significantly improved survival outcomes in patients with peritoneal carcinomatosis from colorectal cancer (CRC). Regorafenib is an oral agent administered in patients with refractory metastatic CRC. Our aim was to investigate the outcomes of intraperitoneal administration of regorafenib for intraperitoneal chemotherapy (IPEC) or/and CRS in a rat model of colorectal peritoneal metastases regarding immunology and peritoneal cytology. A total of 24 rats were included. Twenty-eight days after carcinogenesis induction, rats were randomized into following groups: group A: control group; group B: CRS only; group C: IPEC only; and group D: CRS + IPEC. On day 56 after carcinogenesis, euthanasia and laparotomy were performed. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) as well as peritoneal cytology were investigated. Groups B and D had statistically significant lower mean levels of IL-6 and TNF-α compared to groups A and C, but there was no significant difference between them. Both B and D groups presented a statistically significant difference regarding the rate of negative peritoneal cytology, when compared to the control group, but not to group C. In conclusion, regorafenib-based IPEC, combined with CRS, may constitute a promising tool against peritoneal carcinomatosis by altering the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Intraperitoneal sporadic tumor is a common and complicated syndrome in cancers, causing a high rate of death, and people find that intraperitoneal chemotherapy (IPC) can treat intraperitoneal sporadic tumors better than intravenous chemotherapy and surgery. However, the effectiveness and side effects of IPC are controversial, and the operation process of IPC is complicated. Herein, the injectable paclitaxel‐loaded (PTX‐loaded) electrospun short fibers are constructed through a series process of electrospinning, homogenizing, crosslinking, and subsequent polydopamine coating and folate acid (FA) modification. The evenly dispersed short fibers exhibited effective tumor cell killing and good injectable ability, which is convenient to use and greatly improved the complex operation procedure. Mussel‐like protein poly‐dopamine coating and FA modification endowed short fibers with the ability of targeted adhesion to tumors, and therefore the short fibers further acted as a kind of micro membrane that could release drugs to tumors at close range, maintaining local high drug concentration and prevent paclitaxel killing normal tissues. Thus, the target‐adhesive injectable electrospun short fibers are expected to be the potential candidate for cancer treatment, especially the intraperitoneal sporadic tumors, which are hard to treat by surgery or intravenous chemotherapy. [ABSTRACT FROM AUTHOR]

The peritoneum is a common site of metastases for gastrointestinal tumors that predicts a poor outcome. In addition to decreased survival, peritoneal metastases (PMs) can significantly impact quality of life from the resulting ascites and bowel obstructions. The peritoneum has been a target for regional therapies due to the unique properties of the blood–peritoneum barrier. Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) have become accepted treatments for limited-volume peritoneal disease in appendiceal, ovarian, and colorectal malignancies, but there are limitations. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) improves drug distribution and tissue penetration, allowing for a minimally invasive application for patients who are not CRS/HIPEC candidates based on high disease burden. PIPAC is an emerging treatment that may convert the patient to resectable disease, and may increase survival without major morbidity, as indicated by many small studies. In this review, we discuss the rationale and benefits of PIPAC, as well as sentinel papers describing its application for gastric, colorectal, appendiceal, and pancreatobiliary PMs. While no PIPAC device has yet met FDA approval, we discuss next steps needed to incorporate PIPAC into neoadjuvant/adjuvant treatment paradigms, as well as palliative settings. Data on active clinical trials using PIPAC are provided. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced gastric cancer (GCa) is associated with poor prognosis due to the challenge of peritoneal disease, the most common site of metastasis at initial diagnosis, staging laparoscopy, and recurrence. Unfortunately, current standards of care for peritoneal metastasis (PM) in GCa are palliative therapies, despite hyperthermic intraperitoneal chemotherapy (HIPEC) being a proven standard of care for other peritoneal malignancies. Fortunately, results from studies investigating the impact of HIPEC in patients suffering from GCa with PM are encouraging. Additionally, several ongoing trials may offer further data and some centers have incorporated HIPEC into their treatment of patients with metastatic GCa. HIPEC can potentially confer improved survival outcomes in select patients with GCa and PM, who historically have dismal outcomes, and further well-designed clinical trials are warranted. This manuscript provides a comprehensive review of the current evidence supporting the use of HIPEC and cytoreductive surgery (CRS) in patients suffering from GCa with PM. Gastric cancer (GCa) is an aggressive malignancy, representing the third leading cause of cancer mortality worldwide. The poor prognosis of GCa can be associated with the prevalence of peritoneal metastasis (PM). Current international and national GCa treatment guidelines only recommend palliative treatment options for patients with PM. Since the 1980s there have been multiple single arm trials, randomized controlled trials, and metanalysis investigating the use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with advanced GCa, with or without PM. Results from these studies have been encouraging, with some large-volume centers even incorporating HIPEC into their treatment algorithms for patients with advanced GCa. Additionally, there are several ongoing trials that, when completed, will increase our understanding of the efficacy of CRS & HIPEC in patients with GCa metastatic to the peritoneum. Herein we review the current evidence, ongoing trials, consensus guidelines, and future considerations regarding the use of CRS & HIPEC in patients suffering from GCa with PM. [ABSTRACT FROM AUTHOR]

Simple Summary: Intraperitoneal (IP) chemotherapy is a treatment for cancers in the abdomen, delivering anti-cancer drugs directly into the peritoneal cavity. While this method has shown promising outcomes, limited drug penetration into tumors remains a challenge due to their unique pathophysiology. Our study aims to investigate drug delivery during IP chemotherapy using a mathematical model. We incorporated a real tumor image into our model to understand how tumor vessels and their distribution affect drug delivery. Our model allowed us to analyze the spatiotemporal distribution of drug concentration in the tumor. We also quantitatively evaluated treatment efficacy by examining drug availability in the tumor, drug penetration depth, and the fraction of killed cells during the treatment. Our findings revealed that each tumor's specific vascular network can impact drug delivery during IP chemotherapy. Our model provides valuable insights into the challenges of IP chemotherapy and holds promise for applications in personalized medicine. Intraperitoneal (IP) chemotherapy is a promising treatment approach for patients diagnosed with peritoneal carcinomatosis, allowing the direct delivery of therapeutic agents to the tumor site within the abdominal cavity. Nevertheless, limited drug penetration into the tumor remains a primary drawback of this method. The process of delivering drugs to the tumor entails numerous complications, primarily stemming from the specific pathophysiology of the tumor. Investigating drug delivery during IP chemotherapy and studying the parameters affecting it are challenging due to the limitations of experimental studies. In contrast, mathematical modeling, with its capabilities such as enabling single-parameter studies, and cost and time efficiency, emerges as a potent tool for this purpose. In this study, we developed a numerical model to investigate IP chemotherapy by incorporating an actual image of a tumor with heterogeneous vasculature. The tumor's geometry is reconstructed using image processing techniques. The model also incorporates drug binding and uptake by cancer cells. After 60 min of IP treatment with Doxorubicin, the area under the curve (AUC) of the average free drug concentration versus time curve, serving as an indicator of drug availability to the tumor, reached 295.18 mol·m−3·s−1. Additionally, the half-width parameter W1/2, which reflects drug penetration into the tumor, ranged from 0.11 to 0.14 mm. Furthermore, the treatment resulted in a fraction of killed cells reaching 20.4% by the end of the procedure. Analyzing the spatial distribution of interstitial fluid velocity, pressure, and drug concentration in the tumor revealed that the heterogeneous distribution of tumor vasculature influences the drug delivery process. Our findings underscore the significance of considering the specific vascular network of a tumor when modeling intraperitoneal chemotherapy. The proposed methodology holds promise for application in patient-specific studies. [ABSTRACT FROM AUTHOR]

For decades, intraperitoneal chemotherapy (IPC) was used as a liquid solution for the treatment of peritoneal metastasis. Due to its advantageous physical properties, foam-based intraperitoneal chemotherapy (FBIC) was recently proposed as a treatment for peritoneal metastasis. For the first time, this study intends to examine the feasibility, expansion, drug distribution, and penetration of FBIC in vivo. Three swine received contrast-enhanced FBIC doxorubicin delivered using a bicarbonate carrier system. During the procedure, intraoperative blood analyses and periumbilical diameter, as well as foam distribution, penetration, and expansion of the FBIC were analyzed. The swine received an abdominal CT scan to evaluate the contrast distribution. Furthermore, a hematoxylin-eosin (HE) staining of peritoneal samples was performed, and fluorescence microscopy was conducted. FBIC was performed without complications. The periumbilical diameter peaked after 5 min and then decreased. Blood analyses showed changes in blood parameters, with a reduction in the pH levels of serum calcium and potassium. CT scan detected contrast-enhanced FBIC throughout the abdominal cavity. Fluorescence microscopy confirmed that all areas were exposed to doxorubicin and no pathologies were detected in the HE histology. Our preliminary results are quite encouraging and indicate that FBIC is a feasible approach. However, in order to discuss possible clinical applications, further studies are required to investigate the pharmacologic, pharmacodynamic, and physical properties of FBIC. [ABSTRACT FROM AUTHOR]

International guidelines exclude from surgery patients with peritoneal carcinosis of colorectal origin and a peritoneal cancer index (PCI) ≥ 16. This study aims to analyze the outcomes of patients with colorectal peritoneal carcinosis and PCI greater or equal to 16 treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) (CRS + HIPEC). We retrospectively performed a multicenter observational study involving three Italian institutions, namely the IRCCS Policlinico San Matteo in Pavia, the M. Bufalini Hospital in Cesena, and the ASST Papa Giovanni XXIII Hospital in Bergamo. The study included all patients undergoing CRS + HIPEC for peritoneal carcinosis from colorectal origin from November 2011 to June 2022. The study included 71 patients: 56 with PCI < 16 and 15 with PCI ≥ 16. Patients with higher PCI had longer operative times and a statistically significant higher rate of not complete cytoreduction, with a Completeness of Cytoreduction score (CC) 1 (microscopical disease) of 30.8% (p = 0.004). The 2-year OS was 81% for PCI < 16 and 37% for PCI ≥ 16 (p < 0.001). The 2-years DFS was 29% for PCI < 16 and 0% for PCI ≥ 16 (p < 0.001). The 2-year peritoneal DFS for patients with PCI < 16 was 48%, and for patients with PCI ≥ 16 was 57% (p = 0.783). CRS and HIPEC provide reasonable local disease control for patients with carcinosis of colorectal origin and PCI ≥ 16. Such results form the basis for new studies to reassess the exclusion of these patients, as set out in the current guidelines, from CRS and HIPEC. This therapy, combined with new therapeutical strategies, i.e., pressurized intraperitoneal aerosol chemotherapy (PIPAC), could offer reasonable local control of the disease, preventing local complications. As a result, it increases the patient's chances of receiving chemotherapy to improve the systemic control of the disease. [ABSTRACT FROM AUTHOR]

Abstract Patients with colorectal cancer (CRC) and diffuse peritoneal metastasis (PM) are not eligible for surgical intervention. Thus, palliative treatment remains the standard of care in clinical practice. Systemic chemotherapy fails to cause drug accumulation at the lesion sites, while intraperitoneal chemotherapy (IPC) is limited by high clearance rates and associated complications. Given the poor prognosis, a customized OxP/R848@PLEL hydrogel delivery system has been devised to improve the clinical benefit of advanced CRC with diffuse PM. This system is distinguished by its simplicity, security, and efficiency. Specifically, the PLEL hydrogel exhibits excellent injectability and thermosensitivity, enabling the formation of drug depots within the abdominal cavity, rendering it an optimal carrier for IPC. Oxaliplatin (OxP), a first‐line drug for advanced CRC, is cytotoxic and enhances the immunogenicity of tumors by inducing immunogenic cell death. Furthermore, OxP and resiquimod (R848) synergistically enhance the maturation of dendritic cells, promote the expansion of cytotoxic T lymphocytes, and induce the formation of central memory T cells. Moreover, R848 domesticates macrophages to an anti‐tumor phenotype. OxP/R848@PLEL effectively eradicates peritoneal metastases, completely inhibits ascites production, and significantly prolongs mice lifespan. As such, it provides a promising approach to managing diffuse PM in patients with CRC without surgical indications.

Simple Summary: Cancer that spreads to the lining of the abdomen, the peritoneum, is currently treated with heated chemotherapy and surgery. However, the effects of the high temperature on the cancer cells and the immune cells are still unclear. In this review, we summarize the available data to show that high temperatures may have both positive and negative effects, and that further study is necessary to distinguish these effects. Hyperthermia combined with intraperitoneal (IP) drug delivery is increasingly used in the treatment of peritoneal metastases (PM). Hyperthermia enhances tumor perfusion and increases drug penetration after IP delivery. The peritoneum is increasingly recognized as an immune-privileged organ with its own distinct immune microenvironment. Here, we review the immune landscape of the healthy peritoneal cavity and immune contexture of peritoneal metastases. Next, we review the potential benefits and unwanted tumor-promoting effects of hyperthermia and the associated heat shock response on the tumor immune microenvironment. We highlight the potential modulating effect of hyperthermia on the biomechanical properties of tumor tissue and the consequences for immune cell infiltration. Data from translational and clinical studies are reviewed. We conclude that (mild) hyperthermia and HIPEC have the potential to enhance antitumor immunity, but detailed further studies are required to distinguish beneficial from tumor-promoting effects. [ABSTRACT FROM AUTHOR]

Cytoreductive surgery (CRS) has emerged as a survival-extending treatment of peritoneal metastasis (PM); recent advances include using intraperitoneal chemotherapy (IPC) at normothermic or hyperthermic temperatures, or under pressure (CRS + IPC). Clinical CRS + IPC research has established its highly variable efficacy and suggested tumor size, tumor locations and presence of ascites as potential determinants. On the other hand, there is limited knowledge on the effects of pharmaceutical properties on treatment outcomes. The present study investigated the inter-subject variability of paclitaxel binding to proteins in patient ascites because some PM patients show accumulation of ascites and because activity and transport of highly protein-bound drugs such as paclitaxel are affected by protein binding. Ascites samples were collected from 26 patients and investigated for their protein contents using LC/MS/MS proteomics analysis and for the concentrations of total proteins and two major paclitaxel-binding proteins (human serum albumin or HSA and α-1-acid glycoprotein or AAG). The association constants of paclitaxel to HSA and AAG and the extent of protein binding of paclitaxel in patient ascites were studied using equilibrium dialysis. Proteomic analysis of four randomly selected samples revealed 288 proteins, >90% of which are also present in human plasma. Between 72% - 94% of paclitaxel was bound to proteins in patient ascites. The concentrations of HSA and AAG in ascites showed substantial inter-subject variations, ranging from 14.7 – 46.3 mg/mL and 0.13–2.56 mg/mL, respectively. The respective paclitaxel association constants to commercially available HSA and AAG were ∼ 3.5 and ∼ 120 mM. Calculation using these constants and the HSA and AAG concentrations in individual patient ascites indicated that these two proteins accounted for >85% of the total protein-binding of paclitaxel in ascites. The extensive drug binding to ascites proteins, by reducing the pharmacologically active free fraction, may lead to the diminished CRS efficacy in PM patients with ascites. Clinical advances in CRS + IPC have outpaced current knowledge of pharmaceutical properties in this setting. IPC, as a locally acting therapy, is subjected to processes different from those governing systemic treatments. This study, to our knowledge, is the first to illustrate the implications of drug properties in the CRS + IPC efficacy against PM. While drugs are now an integral part of PM patient management, there is limited pharmaceutical research in this treatment setting (e.g., effects of hyperthermia or pressure on drug transport or release from delivery systems, pharmacokinetics, pharmacodynamics). Hence, CRS + IPC of PM represents an area where additional pharmaceutical research can assist further development and optimization. [Display omitted] • Peritoneal metastasis is managed by surgery+intraperitoneal chemotherapy (CRS + IPC). • IPC efficacy against peritoneal metastasis appears lowered by presence of ascites. • Extensive protein binding of paclitaxel reduces % active free drug in patient ascites. • Albumin and α-1-acid glycoprotein account for >85% paclitaxel binding in ascites. • Current study is an example on using pharmaceutical research to optimize CRS + IPC. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment with intraperitoneal hyperthermic chemotherapy (HIPEC) has been criticized in ovarian cancer due to the lack of prospective and randomized clinical trials demonstrating its efficacy in improving outcomes. However, the publication of the Dutch clinical trial five years ago has not changed the usual clinical practice within the Spanish peritoneal oncologic surgery group. In this paper we analyze and reflect on the future of this technique in patients with peritoneal dissemination of ovarian cancer. Ovarian cancer is the leading cause of death due to gynecological tumors in the female population. Despite optimal first-line treatment, including cytoreduction and platinum-based systemic chemotherapy, recurrences are frequent. The use of hyperthermic intraperitoneal chemotherapy (HIPEC) has been criticized, especially because of the lack of randomized controlled trials (RCTs) with convincing results to support the use of HIPEC in patients with ovarian cancer with peritoneal dissemination. In 2018, the clinical trial published by Van Driel et al. reported improved outcomes in favor of HIPEC treatment with cisplatin. In this study, we conducted a national survey within the Spanish group of peritoneal surgical oncology (Grupo Español de Cirugía Oncológica Peritoneal, GECOP) to explore the impact of the results of this RCT on clinical practice. A total of 33 groups completed the survey. Routine clinical practice was not changed in 28 of the 33 groups (85%) based on the results of the Van Driel trial. Despite the results of this RCT, most groups considered that more RCTs are needed and that, in the future, HIPEC may become the standard of care. In conclusion, the results from RCTs evaluating HIPEC treatment in patients with ovarian cancer has not been transferred to clinical practice. [ABSTRACT FROM AUTHOR]

The relevance of the problem of increasing the effectiveness of standard treatment of ovarian cancer is determined by the following characteristics of the disease: high one‑year mortality, high recurrence rate and unsatisfactory results of their treatment. Peritoneal carcinomatosis in ovarian cancer occurs in 65–70 % of cases. The standard modern approach to the treatment of ovarian cancer is a combination of surgical treatment and systemic intravenous chemotherapy. At the same time, more than 70 % of ovarian cancer cases are first diagnosed at stages III–IV. However, despite the successes in the field of surgery and drug treatment, the five‑year survival rate is no more than 24 % at the III and 4.6 % at the IV stage of the disease. One of the frontiers of ovarian cancer resistance to therapy is peritoneal carcinomatosis. Its resistance to therapy is due to the low bioavailability of cytostatics in metastases on the peritoneum to almost zero. In order to increase bioavailability, various forms of intra‑abdominal chemotherapy are used. The technique of pressurized intraperitoneal aerosol chemotherapy (PIPAC) has a number of advantages over other methods of intra‑abdominal antitumor treatment. These advantages include the uniform distribution of cytostatics over the peritoneum, the absence of penetration of cytostatics beyond the peritoneum, which allows PIPAC to be combined with systemic chemotherapy, low trauma and good tolerability of the procedure. PIPAC was implemented into clinical practice in 2011, and since then has been widely used in a number of foreign and domestic clinics. The conducted studies confirm the safety of the technique and its effectiveness against peritoneal carcinomatosis. The data of multicenter studies and the analysis of available literature data, as well as the successful own experience of PIPAC use create prerequisites for investigating the effectiveness of intra‑abdominal aerosol chemotherapy under pressure in relation to peritoneal carcinomatosis in ovarian cancer.

Abstract Background Studies from Asia indicate that normothermic intraperitoneal chemotherapy (NIPEC) may confer survival benefit in patients with gastric peritoneal carcinomatosis (PC). However, data regarding this approach is lacking in western population. The current STOPGAP trial is intended to assess 1-year progression-free survival benefit of sequential systemic chemotherapy and paclitaxel NIPEC in patients with gastric/ gastroesophageal junction (GEJ) adenocarcinoma PC. Methods This is a prospective, single center, single arm, phase II investigator-initiated clinical trial. Patients with histologically proven gastric/GEJ (Siewert 3) adenocarcinoma with positive peritoneal cytology or PC will be eligible to participate after three months of standard of care systemic chemotherapy and with no evidence of visceral metastasis on restaging scans. The primary treatment is iterative paclitaxel NIPEC with systemic paclitaxel and 5-fluorouracil, which will be administered on days1 and 8 and repeated every three weeks for 4 cycles. Patients will undergo diagnostic laparoscopy both before and after NIPEC to assess peritoneal cancer index (PCI). Patients with PCI less than or equal to 10 in whom complete cytoreduction (CRS) is feasible may opt to undergo CRS with heated intraperitoneal chemotherapy (HIPEC). The primary endpoint is 1-year progression free survival and secondary endpoints are overall survival and patient reported quality of life outcomes measured by EuroQol- 5 dimensions-5 level (EuroQol-5D-5L) questionnaire. Discussion If the sequential approach of systemic chemotherapy followed by paclitaxel NIPEC proves beneficial, then this approach could be used in larger, muti-institutional randomized clinical trial of gastric PC. Trial Registration The trial was registered on 21/02/2021, under clinical trials.gov; Identifier: NCT04762953.

Abstract Sanjay M. Desai Objectives Epithelial ovarian cancer (EOC) is a heterogeneous, essentially peritoneal disease. Standard treatment consists of staging, cytoreductive surgery (CRS), and adjuvant chemotherapy. In this study, we intended to assess the effectiveness of single-dose intraperitoneal (IP) chemotherapy in optimally debulked advanced EOC patients. Materials and Methods A prospective randomized study of 87 patients with advanced EOC was done from January 2017 to May 2021 in a tertiary care center. Patients who underwent primary and interval cytoreduction received a single dose of IP chemotherapy for 24 hours after being divided into four groups: group A, IP cisplatin; group B, IP paclitaxel; group C, IP paclitaxel and cisplatin; and group D, saline. Pre- and postperitoneal IP cytology was assessed along with possible complications. Statistical Analysis Logistic regression analysis was used to assess for intergroup significance in cytology and complications. Kaplan–Meir analysis was done to assess disease-free survival (DFS). Results Of 87 patients, 17.2% of patients had FIGO stage IIIA, 47.2% had IIIB, and 35.6% had IIIC. Also, 22 (25.3%) patients were in group A (cisplatin), 22 (25.3%) patients in group B (paclitaxel), 23 (26.4%) in group C (cisplatin and paclitaxel), and 20 (23%) in group D (saline). Cytology samples taken during staging laparotomy were positive, and 48 hours post-IP chemotherapy, 2 (9%) of 22 samples in cisplatin group and 14 (70%) of 20 samples in saline group were positive; all of the post-IP samples in groups B and C were negative. No major morbidity was noted. In our study, DFS in saline group was 15 months, while in IP chemotherapy group it was 28 months and was statistically significant based log-rank test. However, there was no significant difference in DFS between different IP chemotherapy groups. Conclusion Complete or optimal CRS in advanced EOC does have a possibility of microscopic peritoneal residue. Adjuvant locoregional strategies should be considered to prolong DFS. Single-dose normothermic IP chemotherapy can be offered to the patients with minimal morbidity, and its prognostic benefits are comparable to hyperthermic IP chemotherapy. Future clinical trials are required to validate these protocols.

Background and objectives The management of patients with extensive appendiceal mucinous neoplasms and mesothelioma is controversial. Our aims were to analyze overall survival (OS), disease-free survival (DFS) and independent prognostic factors associated with high peritoneal cancer index (PCI) status in patients who underwent cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC).Methods A prospectively-maintained database for patients with appendiceal neoplasms and mesothelioma undergoing CRS/PIC from year 1996 to 2018 was retrospectively analyzed. Patients who achieved complete cytoreduction were stratified into limited (PCI < 30) and extensive (PCI ≥ 30) disease groups.Results 260 female and 235 male patients were identified. The 5-year survival for low-grade appendiceal mucinous neoplasms (LAMN) was significantly higher in the low PCI group (96.2% vs. 63.5%, p 8 units) were independent positive and negative prognostic factors, respectively, associated with OS. Meanwhile, use of EPIC conferred benefit in DFS while increased blood transfusion (>8 units) and elevated preoperative CA125 were predictive of a poor DFS.Conclusion Long-term survivals following CRS/PIC are achievable with acceptable mortality and higher morbidity rates in extensive appendiceal mucinous neoplasms and mesothelioma. High PCI status does not preclude treatment with CRS/PIC.

Ovarian cancer is the seventh most common cancer worldwide in women and the most lethal gynecologic malignancy due to the lack of accurate screening tools for early detection and late symptom onset. The absence of early-onset symptoms often delays diagnosis until the disease has progressed to advanced stages, frequently when there is peritoneal involvement. Although ovarian cancer is a heterogeneous malignancy with different histopathologic types, treatment for advanced tumors is usually based on chemotherapy and cytoreduction surgery. CAR T cells have shown promise for the treatment of hematological malignancies, though their role in treating solid tumors remains unclear. Outcomes are less favorable owing to the low capacity of CAR T cells to migrate to the tumor site, the influence of the protective tumor microenvironment, and the heterogeneity of surface antigens on tumor cells. Despite these results, CAR T cells have been proposed as a treatment approach for peritoneal carcinomatosis from colorectal and gastric origin. Local intraperitoneal administration of CAR T cells has been found to be superior to systemic administration, as this route is associated with increased tumor reduction, a more durable effect, protection against local relapse and distant metastases, and fewer systemic adverse effects. In this article we review the application of CAR T cells for the treatment of ovarian cancer and peritoneal carcinomatosis from ovarian cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) patients with extensive peritoneal metastases who are not candidates for CRS-HIPEC have poor prognoses. We evaluated the role of systemic and intra-peritoneal (IP) chemotherapy in these patients. CRC patients with confirmed peritoneal metastasis were enrolled. After implantation of IP chemoport patients received weekly IP paclitaxel in incremental doses of 20 mg/m2 with systemic chemotherapy. The primary end-points were the feasibility, safety, and tolerance (perioperative complications), and the secondary end-point was the clinico-radiological response. Patients included in the study were registered between January 2018 and November 2021. IP chemoport was implanted in 18 patients of which 14 patients underwent successful instillation of IP chemotherapy. Four patients did not receive IP chemotherapy in view of port-site infection for which IP ports were removed. The median age was 39 years (range: 19–61 years). The site of the primary tumor was equal in the colon and rectum. Fifty percent of patients had signet ring-cell adenocarcinoma, and 21% had poorly differentiated adenocarcinoma. The median serum of CEA level was 12.27 ng/mL (1.63–116.16 ng/mL). The median PCI score was 25 (18–35). The median number of IP chemotherapy cycles (weekly) was 3.5 (1–12 cycles). In 14.3% of patients, IP chemoport had to be removed due to block and infection. Three, five, and four patients had clinico-radiologically disease progression, stable disease, and partial response, respectively. One patient underwent subsequent successful CRS-HIPEC. There were no grade 3–5 (CTCAE 3.0) complications. Incremental doses of IP paclitaxel with systemic chemotherapy is safe and feasible in selected colorectal adenocarcinoma patients with peritoneal metastases without any serious adverse events. [ABSTRACT FROM AUTHOR]

To maximize the results of treatments for peritoneal metastases for rare abdominal or pelvic tumors, selection of patients with a possibility for long-term success is necessary. Because these malignancies are rare, data from which these selection factors can be extracted do not exist. In order to facilitate knowledgeable patient selection for treatment, the well established clinical and histopathologic features of the common malignancies treated for peritoneal metastases were reviewed. The potential application of selection factors for common diagnoses was explored in an attempt to provide selection factors for rare tumors. The histopathologic grade, the lymph node status, the Ki-67 proliferation index, prior surgical score (PSS), preoperative radiologic imaging, preoperative laparoscopic assessment, response to neoadjuvant chemotherapy, peritoneal cancer index (PCI), and completeness of cytoreduction score were all included in this search for relevant selection factors for a rare disease. To facilitate the use of selection factors from common peritoneal metastases diagnoses, these diseases were divided into four groups. Placement of the rare cause of peritoneal metastases into one of these four groups will allow knowledgeable selection for treatment. Rare diseases with a natural history resembling low-grade appendiceal neoplasms are in group 1, diseases resembling lymph node negative colorectal cancer are in group 2, diseases resembling lymph node positive colorectal peritoneal metastases in group 3, and diseases resembling gastric cancer in group 4. [ABSTRACT FROM AUTHOR]

A newly introduced combination of intraperitoneal dehydration and hyperthermia has recently been shown to be feasible and cytotoxic for colon cancer cells in vivo. For the first time, our study now aims to evaluate dehydration under hyperthermic conditions combined with chemotherapy for potential use in the clinical setting. In this study, in vitro colon cancer cells (HT-29) were subjected to single or several cycles of partial dehydration under hyperthermic conditions (45 °C), followed by chemotherapy (triple exposure) with oxaliplatin or doxorubicin in various configurations. The viability, cytotoxicity, and proliferation of cells after the proposed protocols were assessed. Intracellular doxorubicin uptake was measured via flow cytometry. After one cycle of triple exposure, the viability of HT-29 cells was significantly reduced versus the untreated control (65.11 ± 5%, p < 0.0001) and versus only chemotherapy (61.2 ± 7%, p < 0.0001). An increased chemotherapeutic inflow into the cells after triple exposure was detected (53.4 ± 11%) when compared to cells treated with chemotherapy alone (34.23 ± 10%) (p < 0.001). Partial dehydration in a hyperthermic condition combined with chemotherapy increases the overall cytotoxicity of colon cancer cells significantly compared to chemotherapy alone. This could possibly be related to enhanced intracellular uptake of chemotherapeutic agents after partial dehydration. Further studies are required for the further evaluation of this new concept. [ABSTRACT FROM AUTHOR]

Simple Summary: Peritoneal metastases have a poor prognosis, and one potential treatment option is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). The specific role of HIPEC is still poorly defined. In this cross-sectional study, we systematically analyzed all HIPEC trials registered on ClinicalTrials.gov to identify current research areas and to provide a perspective on expected outcomes. Only 11% (n = 26) of HIPEC trials registered on ClinicalTrials.gov (n = 234) have been published. The registered trials are very heterogeneous regarding methodological approaches and study designs. Currently, research is being conducted on 20 different drugs. The most studied cancers in HIPEC trials are peritoneal metastatic colorectal tumors, gastric cancer, and ovarian cancer. Introduction: Over the past two decades, cytoreductive surgery and HIPEC has improved outcomes for selected patients with peritoneal metastasis from various origins. This is a cross-sectional study with descriptive analyses of HIPEC trials registered on ClinicalTrials.gov. This study aimed to characterize clinical trials on HIPEC registered on ClinicalTrials.gov with the primary objective of identifying a trial focus and to examine whether trial results were published. Methods: The search included trials registered from 1 January 2001 to 14 March 2022. We examined the associations of exposure variables and other trial features with two primary outcomes: therapeutic focus and results reporting. Results: In total, 234 clinical trials were identified; 26 (11%) were already published, and 15 (6%) trials have reported their results but have not been published as full papers. Among ongoing nonpublished trials, 81 (39%) were randomized, 30 (14%) were blinded, n = 39 (20%) were later phase trials (i.e., phases 3 and 4), n = 152 (73%) were from a single institution, and 91 (44%) had parallel groups. Most of the trials were recruiting at the time of this analysis (75, 36%), and 39 (20%) were completed but had yet to publish results. In total, 68% of the trials focused on treatment strategies, and 53% investigated the oncological outcome. The most studied neoplasms for HIPEC trials were peritoneally metastasized colorectal cancer (32%), gastric cancer (29%), and ovarian cancer (26%). Twenty different drugs were analyzed in these clinical trials. Conclusions: Many study results are awaited from ongoing HIPEC trials. Most HIPEC trials focused on gastric, colorectal, or ovarian cancer. Many clinical trials were identified involving multiple entities and chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

The four-tied peritoneal regression grading score (PRGS) is increasingly used to evaluate the response of peritoneal metastases (PM) to chemotherapy. The minimal number of peritoneal biopsies needed for PRGS determination remains unclear.

Objectives: Compound Kushen injection (CKI) combined with intraperitoneal chemotherapy (IPC) is widely used in the treatment of malignant ascites (MA). However, evidence about its efficacy and safety remains limited. This review aimed to evaluate the efficacy and safety of CKI combined with IPC for the treatment of MA. Methods: Protocol of this review was registered in PROSPERO (CRD42022304259). Randomized controlled trials (RCTs) on the efficacy and safety of IPC with CKI for the treatment of patients with MA were searched through 12 electronic databases and 2 clinical trials registration platforms from inception until 20 January 2023. The Cochrane risk-of-bias tool was used to assess the quality of the included trials through the risk of bias assessment. We included RCTs that compared IPC single used or CKI combined with IPC for patients with MA schedule to start IPC. The primary outcome was identified as an objective response rate (ORR), while the secondary outcomes were identified as the quality of life (QoL), survival time, immune functions, and adverse drug reactions (ADRs). The Revman5.4 and Stata17 software were used to calculate the risk ratio (RR) at 95% confidence intervals (CI) for binary outcomes and the mean difference (MD) at 95% CI for continuous outcomes. The certainty of the evidence was assessed according to the GRADE criteria. Results: A total of 17 RCTs were assessed, which included 1200 patients. The risk of bias assessment of the Cochrane risk-of-bias tool revealed that one study was rated high risk and the remaining as unclear or low risk. Meta-analysis revealed that CKI combined with IPC had an advantage in increasing ORR (RR = 1.31, 95% CI 1.20 to 1.43, p < 0.00001) and QoL (RR = 1.50, 95% CI 1.23 to 1.83, p < 0.0001) when compared with IPC alone. Moreover, the combined treatment group showed a lower incidence of myelosuppression (RR = 0.51, 95%CI 0.40-0.64, p < 0.00001), liver dysfunction (RR = 0.33, 95%CI 0.16 to 0.70, p = 0.004), renal dysfunction (RR = 0.39, 95%CI 0.17 to 0.89, p = 0.02), and fever (RR = 0.51, 95%CI 0.35 to 0.75, p = 0.0007) compared to those of the control group. The quality of evidence assessment through GRADE criteria showed that ORR, myelosuppression, and fever were rated moderate, renal dysfunction and liver dysfunction were rated low, and QoL and abdominal pain were rated very low. Conclusion: The efficacy and safety of CKI combined with IPC were superior to that with IPC alone for the treatment of MA, which indicates the potentiality of the treatment. However, more high-quality RCTs are required to validate this conclusion. [ABSTRACT FROM AUTHOR]

Objective: We aimed to compare the survival outcomes and adverse events of hyperthermic intraperitoneal chemotherapy (HIPEC), intraperitoneal chemotherapy (IP)and intravenous chemotherapy (IP)for primary advanced ovarian cancer. Methods: PubMed, CENTRAL (Cochrane Central Registry of Controlled Trials), Embase, Web of Science and Scopus were searched using multiple terms for primary advanced ovarian cancer, including randomized controlled trials and comparative studies in both Chinese and English (up to date 15 August 2022). Outcomes include overall survival, progression-free survival and adverse events. The data were pooled and reported as hazard ratio (HRs) with 95% confidence intervals. The Newcastle–Ottawa Scales were used to assess the risk of bias in the included comparative study. The Cochrane Collaboration's Risk of Bias Tool was used for randomized controlled trials. Results: In total, 32 studies, including 6347 patients and 8 different platinum-based chemotherapy regimens, were included in this network meta-analysis. Our analysis results showed that HIPEC2 (carboplatin with area under the curve 10) exhibited a statistically significant OS benefit compared to IV, weekly dose-dense chemotherapy and HIPEC1 (cisplatin with 75/100 mg/m2). Intraperitoneal plus intravenous chemotherapy was associated with a statistically significantly better likelihood of overall survival compared to IV. For progression-free survival, our statistical results only suggest a better progression-free survival in ovarian cancer patients treated with HIPEC1 compared with weekly dose-dense chemotherapy. No evidence of difference was observed between the other comparison groups. Compared with the non-HIPEC group, HIPEC may had a higher incidence of electrolyte disturbances (≥grade 3). Conclusion: Our statistical analysis suggests that the groups receiving HIPEC2 had a better OS than the groups receiving IV, weekly dose-dense chemotherapy and HIPEC1. For PFS, our analysis only showed HIPEC1 is better than IV. Moreover, HIPEC may lead to a higher incidence of electrolyte disturbances (≥grade 3). HIPEC therapy for advanced ovarian cancer is currently controversial. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to examine the 7-year follow-up results of cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for peritoneal metastasis (PM) of colorectal cancer. Methods: We performed 54 cases of CRS and IPC in 53 patients with PM of colorectal cancer from December 2011 to December 2013. We prospectively collected data and analyzed peritoneal carcinomatosis grade, completeness of cytoreduction, and long-term follow-up (median, 10 [range, 2–92] months) results. Results: The mean peritoneal cancer index was 15 (1 ~ 35), and complete cytoreduction was possible in 35 (64.8%) patients. Excluding the four patients who died, 11 (22.4%) out of the 49 patients were alive at the time of the last follow-up, and the overall median survival period was 10.3 months. The overall 2- and 5-year survival rates were 31% and 17%, respectively. Patients with complete cytoreduction had a median survival period of 22.6 months, which was significantly longer than that for patients without complete cytoreduction (3.5 months) (P < 0.001). The 5-year survival rate for patients with complete cytoreduction was 24%, and four patients were still alive without disease. Conclusions: CRS and IPC show a 5-year survival rate of 17% in patients with PM of colorectal cancer. A possibility of long-term survival is observed in a selected group. Multidisciplinary team evaluation for careful patient selection and CRS training program to achieve complete cytoreduction are significantly important factors in improving survival rate. [ABSTRACT FROM AUTHOR]