Heated Intraperitoneal Chemotherapy Research Articles

Abstract 1756: Characterizing the mutational spectrum of metastatic mucinous adenocarcinoma of the appendix

Abstract Background: Appendiceal cancer (AC) is an orphan malignancy with only 1-2 cases per 100,000 people in the US. The genomic composition of metastatic, mucinous AC is yet to be resolved at the whole exome level and few groups have assessed the clinical actionability of target genes. Here we performed whole-exome sequencing (WES) on AC specimens to 1) elucidate the mutational spectrum of AC, 2) identify recurrent mutations at frequencies unique to AC or in common with colorectal cancer (CRC), and 3) uncover recurrent AC mutations that are associated with patient survival outcomes. Methodology: Twenty-four FFPE samples, one from each of 24 AC patients treated at our institution with cytoreductive surgery (CRS) followed by heated intraperitoneal chemotherapy (HIPEC), were collected from our tumor bank with IRB approval. DNA from tumor and corresponding normal tissue (PBMCs) was extracted, assessed for integrity and quantity, then analyzed by WES using the Illumina NextSeq 6000 platform. The resulting data were processed using both GATK and DRAGEN pipelines. The frequencies of recurrent mutations in AC were compared with those of CRC from cBioPortal and statistically compared by Fisher’s Exact Test. Logrank test was performed to estimate survival associations based off mutation status. Mutational signatures derived from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were cross-compared to our cohort to identify previously unknown mutational processes in AC. Results: The most frequent mutations were found in MUC6 (63%), KRAS (58%), HLA-B (54%), PABPC1 (50%), and MUC5AC (50%). Distinct from a 534-patient CRC cohort, AC had lower rates of alteration in APC (4% vs 73% CRC, p<0.001) and TP53 (21% vs. 62%, p<0.001), with higher rates of alteration in HLA-B (54% vs 3%, p<0.001), GNAS (38% vs 5%, p<0.001), and ABCA1 (29% vs 7%, p=0.001). Notably, ABCA1 mutation frequency was higher in mucinous CRC (n=56) when compared to non-mucinous CRC (n=478, 20% vs 7%; p<0.001), suggesting that ABCA1 may be uniquely altered in bowel cancers of mucinous phenotype. Alterations in Rho-A were a statistically significant predictor of poor survival in both AC (p<0.001) and CRC (p=0.05). PCAWG analysis showed that the predominant mutational signature in AC most resembles SBS5, suggesting that the mutational etiology of AC may be linked to age and/or smoking status. Discussion: Here we present the largest whole-exome sequencing analysis of AC analyzed to date and identify previously undescribed recurrently mutated genes unique to AC as compared to CRC. We demonstrate novel associations between altered genes and patient survival, which opens discussion regarding the clinical utility of molecular markers in AC for assisting treatment decision making. Citation Format: Daniel J. Gironda, Ming Leung, Guangxu Jin, Liang Liu, Konstantinos I. Votanopoulos, Edward A. Levine, Lance D. Miller. Characterizing the mutational spectrum of metastatic mucinous adenocarcinoma of the appendix [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 1756.

Regional Therapy Approaches for Gastric Cancer with Limited Peritoneal Disease.

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. 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. 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. 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.

PIPAC for Gastrointestinal Malignancies.

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.

Increased Incidence of Liver Metastases in Colorectal Versus Appendiceal Adenocarcinoma Peritonectomy Patients Despite Equivocal Survival.

Colorectal adenocarcinoma (CRAdenoCa) and appendiceal adenocarcinoma (AAdenoCa) are diseases of the same histopathological type that metastasise to the liver and peritoneum. In selected subgroups, peritonectomy and heated intraperitoneal chemotherapy (HIPEC) may be indicated as part of the multimodal treatment plan. However, literature comparing the survival outcomes and preoperative tumour activity and burden of CRAdenoCa and AAdenoCa peritonectomy patients without synchronous liver metastases (sLM) is scarce. Little is also known about the comparative incidence of sLM and metachronous LM (mLM) between CRAdenoCa and AAdenoCa peritonectomy patients. This study aimed to clarify the above. A retrospective cohort study of 684 CRAdenoCa and AAdenoCa primary peritonectomy patients between 2001-2021 was conducted at St George Hospital in Sydney, Australia. Median overall survival (years) was equivocal between CRAdenoCa and AAdenoCa peritonectomy patients (1.7 vs. 1.9, p=0.35). Peritoneal cancer index and preoperative carcinoembryonic antigen (CEA) were significantly elevated (25 vs. 9, p<0.0001 and 7.9 vs. 5, p=0.0080) in AAdenoCa versus CRAdenoCa peritonectomy patients without sLM. The incidence of sLM and mLM was increased in CRAdenoCa peritonectomy patients (24% vs. 3.1%, p<0.0001 and 26% vs. 10%, p=0.0001). This study demonstrates similar survival outcomes between CRAdenoCa and AAdenoCa peritonectomy patients. Despite elevated preoperative tumour burden and biological activity in AAdenoCa patients, CRAdenoCa patients had higher rates of sLM and mLM. Further studies are warranted to validate and identify cellular and molecular targets that increase CRAdenoCa's ability to metastasise to the liver.

Oral administration of bromelain and acetylcysteine in pseudomyxoma peritonei (PMP) caused by low-grade appendiceal mucinous neoplasm (LAMN): a case report

BackgroundPseudomyxoma Peritonei (PMP) is a severe neoplastic clinical syndrome characterised by secretion of mucin from tumors often originating in the appendix. The standard treatment includes cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC). A new perspective in PMP treatment aims at the mucins themselves as a therapeutic target.Case presentationHere we report the first case of PMP with peritoneal dissemination of mucinous implants caused by low-grade appendiceal mucinous neoplasm (LAMN) in a 58-year-old white male exclusively treated by appendectomy and oral administration of bromelain and acetylcysteine in the context of a medical self-experimentation (by co-author T.R.). Observation so far covers a period of 48 months including regular magnetic resonance imaging (MRI) with stable findings.ConclusionsOral administration of bromelain and acetylcysteine can be used in the treatment of PMP caused by LAMN without relevant clinical side effects.

Prognostic and predictive significance of pre- and post-operative plasma tumor markers in patients with appendiceal adenocarcinoma undergoing cytoreductive surgery: Insights from a single-center study.

3539 Background: Appendiceal adenocarcinomas (AA) are both rare and heterogeneous diseases. Cytoreductive (CRS) surgery followed by heated intraperitoneal chemotherapy (HIPEC) remains the best treatment for AA patients with peritoneal metastasis. This study seeks to investigate the clinical utility of pre- and post-operative plasma tumor markers (TM, CEA, CA19-9, CA-125) by association with survival outcomes. Methods: Under an approved IRB protocol the Palantir Foundry software system was used to query MD Anderson internal database to identify patients with AA who underwent CRS between 2016 to 2022. Elevation of TM was defined as above the laboratory upper limit of normal (CEA &gt; 3 ng/mL, CA 19-9 &gt; 37 U/mL, and CA-125 &gt; 37 U/mL). Relationship between normal and elevated serum TM and progression-free survival (PFS) and overall survival (OS) was evaluated using univariate and multivariate Cox-proportional hazards regression analysis, considering multiple clinicopathologic variables. Results: 296 patients were identified; preoperative CEA, CA19-9 and CA125 was elevated in 60%, 29% and 28% of patients, respectively. Preoperative elevation of any TM was associated with higher PCI score (22 vs. 15, p&lt; 0.0001). Moreover, elevated preoperative TM was associated with incompleteness of cytoreduction (OR = 6.5, p&lt; 0.0001). Compared to preoperative measurements, all TM levels dropped after surgery (Mean score 31 vs 11 for CEA, 136 vs 32 for CA19-9 and 36 vs 17 for CA125). Preoperative elevation of any TM (HR = 1.5, p= 0.0288) and post-op elevation of any TM were with poor PFS on univariate analysis, however only post-op elevated TM levels (HR = 2.3, p= 0.0001) were associated with poor PFS on multivariate analysis. Interestingly, elevated TM was not associated with OS. Post-op TM levels were analyzed to evaluate the positive and negative predictive value in prediction of relapse in 6 months from surgery, PPV was 45% and NPV was 84%. Conclusions: Preoperative elevation of TM can identify patients at higher risk for incomplete cytoreduction and relapse after surgery. Postoperative elevation of TM is a risk factor for relapse. [Table: see text]

Open versus Closed technique for administration of heated intraperitoneal chemotherapy (HIPEC): Morbidity and Mortality outcomes from a high-volume centre

Background and aimsCytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is an established treatment in selected patients with peritoneal metastases, delivered in the UK in specialist centres. HIPEC can be administered via the open coliseum technique as first described by Sugarbaker (O-HIPEC) or using a closed technique (C-HIPEC). Data comparing the safety and outcomes of these different approaches is limited. This study aims to compare morbidity and mortality rates of O-HIPEC and C-HIPEC following CRS for peritoneal metastases from colorectal cancer and appendiceal tumours. MethodsConsecutive patients undergoing CRS with open (05/2019–04/2020) and closed (05/2020–04/2021) HIPEC were identified from a prospectively maintained database. Baseline data including primary pathology, HIPEC agent and major operative procedures were analysed using Chi-squared and Fishers exact tests to ensure comparability of groups. Primary outcomes were 30- and 60-day postoperative mortality and morbidity (Common Terminology Criteria for Adverse Events, CTCAE). Secondary outcomes were length of critical care and overall hospital stay. In addition, morbidity and mortality were compared between HIPEC agents (mitomycin and oxaliplatin/5-fluorouracil). Results99 patients (39.3%) and 153 patients (60.7%) underwent O-HIPEC, C-HIPEC respectively. Groups were well matched for baseline demographics, pathology, and HIPEC agent. In the O-HIPEC and C-HIPEC groups respectively, the incidence of 60-day complications (CTCAE 1–4) was 40.4% vs 39.3% (chi squared 0.94) and severe complications (CTCAE 3–4) 14% vs 13% (Fisher's exact p = 1) There was no perioperative mortality but one death in each group within the follow up period. There was no difference in morbidity or mortality between those receiving mitomycin or oxaliplatin. ConclusionClosed administration of HIPEC is safe with no difference in post-operative morbidity or mortality compared to open HIPEC administration. Differences in longer term oncological outcomes including overall survival and disease-free survival between open and closed HIPEC techniques are yet to be determined.

Ex vivo assessment of chemotherapy sensitivity of colorectal cancer peritoneal metastases.

Patients with peritoneal metastasis from colorectal cancer (PMCRC) may have a chance of cure when treated with cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC)1–5. Choice of chemotherapy for HIPEC has been based on knowledge of its systemic effects, pharmacokinetics, technical feasibility, hyperthermic efficacy enhancement, and tolerance6–8. Selection of cancer drugs for treatment based on phenotypical assessment of patient cancer cell drug sensitivity ex vivo is one approach to personalized cancer treatment. One technique for this is the fluorometric microculture cytotoxicity assay (FMCA) that has been used in drug development and for the development of personalized cancer medicine9–16. This study investigated whether ex vivo assessment of drug sensitivity by the FMCA provides predictive information in terms of peritoneal recurrence-free survival (PRFS) and overall survival (OS) in patients treated with CRS and HIPEC for isolated PMCRC. The patient cohort for this study was from a prospectively maintained institutional database at the Uppsala University Hospital, a tertiary care unit for PMCRC in Uppsala, Sweden. Patients with PMCRC treated with CRS and HIPEC have been registered since 2003. Ex vivo drug sensitivity testing using the FMCA started in April 2007. Thus, consecutive patients treated with CRS and HIPEC for PMCRC from April 2007 to October 2018 were considered for providing data for this report. Patients underwent HIPEC with either single-drug oxaliplatin, mitomycin C, or irinotecan, or a combination of oxaliplatin and irinotecan. HIPEC was performed in an open manner according to the coliseum method. Single-drug oxaliplatin was dosed at 350–460 mg/m2, and oxaliplatin and irinotecan combined at 360 mg/m2 for both drugs. These treatments lasted for 30 min. Mitomycin C was dosed at 35 mg/m2 divided into three injections with 50 per cent given at time 0, 25 per cent at 30 min, and 25 per cent at 60 min from the start of HIPEC for a total of 90 min. Follow-up data on PRFS and OS were collected for the final analysis. The Uppsala University ethical committee approved the study (Dnr 2007/237 for tumour sampling and ex vivo assessment of drug activity, and Dnr 2013/203 for clinical data collection).

Phase II clinical trial of sequential treatment with systemic chemotherapy and intraperitoneal paclitaxel for gastric and gastroesophageal junction peritoneal carcinomatosis - STOPGAP trial

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.

Immunological effects of heated intraperitoneal chemotherapy can be augmented by thymosin α1

BackgroundPeritoneal metastases of colorectal carcinoma origin (PM-CRC) are treated by cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC). However, the majority of patients recur, calling for novel treatments. We explored the immunogenic changes induced by HIPEC and the possibility to use thymosin α1 (Tα1) as an immune-stimulatory agent. MethodsWe used an experimental murine model of PM-CRC combined with mitomycin (MMC)-based HIPEC. We determined immune cell infiltration into tumor metastases after HIPEC administration by means of immunohistochemistry, and determined immunogenic cell death signals in tumor cells by real-time polymerase chain reaction. ResultsMice with PM-CRC treated by HIPEC had increased overall survival (OS) compared to sham-treated mice (median OS 22.8 vs 18.9 days, respectively; P < 0.001). HIPEC induced increased infiltration of CD4+, CD8+, CD68 + and CD20 + cells into omental and visceral metastases at a magnitude of 40–100 %. We searched for potential immune signals induced by HIPEC by determining its effects on known immunogenic cell death proteins (heat-shock protein [HSP]-70, HSP-90 and calreticulin). HIPEC significantly increased HSP-90 mRNA expression (2.37 ± 1.5 vs 1-fold change, P < 0.05). The OS of Tα1 treated mice significantly improved compared to HIPEC-treated mice (16.3 ± 0.8 vs 14.1 ± 0.6 days, respectively, P = 0.02) and vs sham (11.8 ± 0.8 days, P = 0.007). ConclusionsHIPEC induced immunogenic changes that led to increased immune cell infiltration. These changes were further augmented by Tα1 treatment. Future studies aimed at optimizing Tα1 treatment should focus upon the immune response it evokes.

Cytoreductive surgery and HIPEC in colorectal cancer peritoneal metastases (CRPM): Real-world outcomes in systemic anticancer treatment–naïve patients.

39 Background: The role of heated intraperitoneal chemotherapy (HIPEC) in colorectal cancer peritoneal metastases (CRPM) is confounded by cytoreductive surgery (CRS) or receipt of peri-operative systemic anticancer therapy (SACT). Following Prodige-7, the role of Oxaliplatin HIPEC in addition to CRS has been debated. We evaluated a patient series undergoing CRS with Oxaliplatin (368mg/m2 for 30 mins) or Mitomycin C (MMC) (35mg/m2 for 90 mins) HIPEC stratified by extent of CRS and SACT. Methods: Data collected retrospectively from a prospective database of CRPM patients undergoing CRS +/- HIPEC at a single UK Peritoneal Tumour Centre included sex, primary tumour detail: site, TNM stage, SACT: adjuvant, peri-operative, operation details: peritoneal cancer index (PCI), cytoreductive score (CC), HIPEC agent, molecular profile: RAS, BRAFV600E, PIK3CA, microsatellite status, date of last follow-up or recurrence/death to 1st July 2022. Univariable and multivariable (MVA) analysis were performed for overall survival (OS) and recurrence free survival (RFS). Outcomes were compared among three patient groups: 1. all comers (all patients who underwent CRS +/- HIPEC), 2. CC0-1 (those who achieved CC0-1) and 3. SACT naïve (CC0-1 and no SACT pre-CRS, adjuvant SACT post primary resection allowed if completed &gt; 6 months). Results: From April 2005 to April 2021, 409 patients received HIPEC: 271 (66%) MMC, 138 (34%) Oxaliplatin; 395 patients (97%) had CRPM (all comers); 336 (85%) achieved CC0-1; 187 (47%) were SACT naïve. Median OS for all comer, CC0-1 and SACT naïve groups were 39, 44 and 47 months respectively. MMC vs Oxaliplatin HIPEC median OS was 44 (95% CI 38-49) vs 50 (95% 40-60) months, p=0.3 in CC0-1. Median OS in SACT naïve was 46 (95% CI 34-58) vs 60 (95% CI 38-82) months, p=0.3. Oxaliplatin HIPEC showed a trend to benefit PCI &lt;15 and SACT naïve (table). OS MVA in CC0-1 and SACT naïve showed Oxaliplatin HIPEC was comparable to MMC HR: 0.85, 95% CI (0.60-1.19) p=0.3, HR: 0.83, 95% CI (0.51-1.35) p=0.5, respectively. Oxaliplatin HIPEC had a significant benefit on local RFS in CC0-1 (MMC vs Oxaliplatin RFS 9 vs 12 months p=0.01; distant RFS 10 vs 12 months p=0.5, local and distant RFS 6 vs 8 months p=0.3). Local RFS MVA showed a HR: 0.64, 95% CI (0.41-0.99), p=0.04 for Oxaliplatin HIPEC when corrected by PCI, N stage and grade. Conclusions: The study shows a trend to better OS with Oxaliplatin HIPEC in selected patients with low volume CRPM not requiring SACT. CRS with Oxaliplatin HIPEC is beneficial in local RFS, suggesting there is a role for local control in CRPM with Oxaliplatin HIPEC. This needs to be further explored in clinical trials. [Table: see text]

Neoadjuvant Chemotherapy (NACT) in Malignant Peritoneal Mesothelioma (MPeM) treated with Cytoreduction (CRS) and Heated Intraperitoneal Chemotherapy (HIPEC)

Neoadjuvant Chemotherapy (NACT) in Malignant Peritoneal Mesothelioma (MPeM) treated with Cytoreduction (CRS) and Heated Intraperitoneal Chemotherapy (HIPEC)

Comparing Survival Outcomes and Impact of EPIC in Patients Undergoing CRS/HIPEC for Mucinous Appendiceal Neoplasm.

This study sought to investigate the difference in survival outcomes in patients with complete cytoreduction (CC)-0 or CC-1 mucinous appendiceal cancer undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC). It also investigated what effect early postoperative intraperitoneal chemotherapy (EPIC) may have on survival based on CC score and histology. This was a retrospective single centre study of patients that underwent CRS/HIPEC +/- EPIC for mucinous appendiceal neoplasms from June 2003 to February 2022. A total of 545 patients were identified. Although there was a survival difference between CC-0 and CC-1 on univariate analyses, this was not statistically significant on multivariate analysis. Histology, peritoneal cancer index, and EPIC status were demonstrated to be independent factors that affected overall survival (OS) on multivariate analysis. Patients with CC-1 that received EPIC had significantly improved OS (mean OS 14 years) when compared to patients that did not receive EPIC (mean OS 6 years). In CC-1, OS was significantly improved in patients that received EPIC in both low-grade (p<0.001) and high-grade (p=0.012) disease. OS for patients that received EPIC at 1, 5, and 10 years was 95%, 80%, and 59%, respectively. OS for patients that did not receive EPIC at 1, 5, and 10 years was 84%, 49%, and 30%, respectively. There was no difference in OS between CC-0 and CC-1. The implementation of EPIC in patients with CC-1 significantly improved OS in both low-grade and high-grade disease and thus we recommend its addition in CC-1 disease to achieve optimal survival outcome.

PD-1 Blockade Combined with Heated Intraperitoneal Chemotherapy Improves Outcome in Experimental Peritoneal Metastases from Colonic Origin in a Murine Model.

Heated intraperitoneal chemotherapy (HIPEC) was shown to induce immunogenicity of peritoneal metastases from colorectal cancer (PM-CRC) by induction of immunogenic cell death. We aimed to explore whether the addition of a checkpoint inhibitor would augment the effect of HIPEC in an experimental murine model of PM-CRC. PM-CRC was established in C57BL mice by intraperitoneal inoculation of MC38 colon cancer cells. HIPEC was administered using the closed technique with mitomycin C (MMC). Clinical and immunological parameters were compared between animals treated with HIPEC alone and those treated with HIPEC+anti-programmed death receptor-1 (aPD-1). MMC-based HIPEC increased the overall survival of animals compared with sham-treated animals (22.8; 95% confidence interval [CI] 21.14-24.53 vs. 18.9 days; 95% CI 17.6-20.3, p<0.001). The extent of peritoneal disease as measured by the modified peritoneal carcinomatosis index was also reduced by HIPEC. This clinical benefit was accompanied by increased infiltration of CD8+, CD68+, and CD20+ cells into tumor metastases in HIPEC-treated animals compared with sham-treated animals. We identified heat shock protein (HSP)90 as a potential immunogenic cell death protein whose expression is increased under HIPEC conditions (fold change: 2.37±1.5 vs. 1 without HIPEC, p<0.05). Combined HIPEC+PD-1 treatment ameliorated survival compared with HIPEC alone and sham treatment (24.66; 95% CI 20.13-29.2 vs. 19; 95% CI 15.85-22.14 and 14.33 days; 95% CI 9.6-19.04, respectively; p=0.008). This clinical effect was accompanied by increased CD8+ tumor infiltration. HIPEC induced the expression of immunogenic cell death signals that can support an anti-tumor immune response. This response can be further exploited by a checkpoint inhibitor.

Long-term outcomes of elderly patients with peritoneal metastases of colorectal origin after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

IntroductionCytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) were reportedly safe for the elderly. However, long-term survival data in this subgroup of patients are scarce. Our aim was to evaluate the peri-operative and long-term outcomes of CRS + HIPEC in colorectal peritoneal metastases (CRC-PM) in patients ≥70 years of age. Material and methodsWe retrospectively analyzed our combined institutional databases for patients who underwent CRS + HIPEC for CRC-PM. Clinical and pathological characteristics, as well as overall survival (OS) and progression-free survival (PFS) were compared between the groups. Tumor extent was measured by the peritoneal carcinomatosis index (PCI) and completeness of cytoreduction by the CCR score. Major morbidity was defined according to Clavien-Dindo classification. ResultsThe dataset of 159 patients included 33 elderly and 126 non-elderly patients. Clinical characteristics between the groups differed only in medical comorbidities (Charlson comorbidity index 10 vs. 7, P < 0.001) and delivery of post-HIPEC adjuvant treatment (12.5% vs. 43.8%, P = 0.004). Overall PCI and CCR0 rates were similar between the groups, as were length of stay and major morbidity and mortality rates. Long-term outcomes in the elderly group were lower than those of the non-elderly (median OS: 21.8 vs. 40.5 months, P < 0.001; median PFS: 6 vs. 8 months, P = 0.02, respectively). ConclusionsCRS + HIPEC in selected elderly patients can be safe in terms of postoperative morbidity and mortality. However, despite the same surgical extents and radicality, their long-term outcomes are inferior, possibly due to under-usage of systemic chemotherapy.

Oncologic outcomes of secondary cytoreductive surgery in the era of poly (ADP-ribose) polymerase inhibitors maintenance (549)

Objectives: We sought to examine the oncologic outcomes of secondary cytoreductive surgery (SCS) pre/post FDA approval of Poly (ADP-ribose) polymerase inhibitors (PARPi) maintenance therapy for recurrent ovarian cancer (OC). Methods: Patients (pts) who underwent SCS for their first recurrent platinum-sensitive OC from January 1, 2013, to January 1, 2020, were identified. Pts with prior chemotherapy for recurrent disease or procedures performed for bowel obstruction or palliative intent were excluded. Data were dichotomized for pre/post-January 2017 (PreP)/ (PostP), the year of FDA approval for PARPi maintenance in recurrent OC. The histologic subtype, BRCA status, surgical approach, SCS residual disease (RD): >1 cm, 0.6-1 cm, <0.5cm, complete gross resection (CGR), rate of PARPi maintenance, and subsequent disease status were abstracted. The use of bevacizumab maintenance and heated intraperitoneal chemotherapy (HIPEC) in second-line management was also identified. PFS2 was defined as progression-free survival (PFS) from the date of SCS. Standard statistical tests were utilized. Results: In total, 245 pts were identified, including 131 (53%) PreP and 114 (47%) PostP. High-grade serous histology was present in 109/131 (83%) PreP and 103/114 (90%) PostP (p=0.13). Among the pts tested, BRCA1/2 mutations were identified in 32/120 (27%) PreP, 32/113 (28%) PostP (p=0.88). Disease-free interval following primary therapy was 6-12 months in 21/131 (16%) PreP and 20/114 (17.5%) PostP; 12-30 months in 73/131 (56%) PreP and 67/114 (59%) PostP; >30 months in 37/131 (28%) PreP and 27/114 (24%) PostP (p=0.79). SCS was performed via laparotomy in 106/131 (81%) PreP and 87/114 (76%) PostP, by laparoscopy /robotic in 22/131 (17%) PreP and 23/114 (20%) PostP and by other surgical approaches in 3/131 (2%) PreP and 4/114 (4%) PostP (p=0.73). CGR was achieved in 112/131(85%) PreP and 98/114 PostP (86%) (p>0.99). Of the 35 pts who had residual disease, 17/35 (48.5%) had 1-5 mm RD, 1/35 (3%) had 6-10mm RD, and 17/35 (48.5%) were suboptimal (>1cm). Upon completing SCS and chemotherapy, PARPi maintenance was used in 5/131 (4%) PreP and 31/114 (27%) PostP (p<0.001). Bevacizumab was used in 2/131 (1.5%) PreP and 14/114 (12%) PostP (p<0.001). HIPEC was used in 22/131 PreP (17%) and 19/114 (17%) PostP (p>0.99). Median PFS2 was 19 months (95%CI, 17-23) in PreP and 20.1 months (95%CI, 17-26) in PostP. In PostP, 84.5% CGR pts achieved 1-year PFS2 (95% CI: 75.5-90.4) and 31.3% achieved 3-year PFS2 (95% CI: 21.6-41.4) compared to patients with residual disease, 56.2% (95% CI: 29.5-76.2) and 12.5% (95% CI: 2.1-32.8) of whom achieved 1-year PFS2 and 3-year PFS2, respectively (p=0.001). Conclusions: In this analysis, the use of PARPi maintenance therapy for the first recurrent platinum-sensitive ovarian cancer markedly increased following its FDA approval in 2017. Optimal secondary cytoreductive surgery maintained a benefit to oncologic outcomes in this setting. In concert with expanding systemic therapy options, surgical resection remains a valuable component in the evolving management of recurrent ovarian cancer. Objectives: We sought to examine the oncologic outcomes of secondary cytoreductive surgery (SCS) pre/post FDA approval of Poly (ADP-ribose) polymerase inhibitors (PARPi) maintenance therapy for recurrent ovarian cancer (OC). Methods: Patients (pts) who underwent SCS for their first recurrent platinum-sensitive OC from January 1, 2013, to January 1, 2020, were identified. Pts with prior chemotherapy for recurrent disease or procedures performed for bowel obstruction or palliative intent were excluded. Data were dichotomized for pre/post-January 2017 (PreP)/ (PostP), the year of FDA approval for PARPi maintenance in recurrent OC. The histologic subtype, BRCA status, surgical approach, SCS residual disease (RD): >1 cm, 0.6-1 cm, <0.5cm, complete gross resection (CGR), rate of PARPi maintenance, and subsequent disease status were abstracted. The use of bevacizumab maintenance and heated intraperitoneal chemotherapy (HIPEC) in second-line management was also identified. PFS2 was defined as progression-free survival (PFS) from the date of SCS. Standard statistical tests were utilized. Results: In total, 245 pts were identified, including 131 (53%) PreP and 114 (47%) PostP. High-grade serous histology was present in 109/131 (83%) PreP and 103/114 (90%) PostP (p=0.13). Among the pts tested, BRCA1/2 mutations were identified in 32/120 (27%) PreP, 32/113 (28%) PostP (p=0.88). Disease-free interval following primary therapy was 6-12 months in 21/131 (16%) PreP and 20/114 (17.5%) PostP; 12-30 months in 73/131 (56%) PreP and 67/114 (59%) PostP; >30 months in 37/131 (28%) PreP and 27/114 (24%) PostP (p=0.79). SCS was performed via laparotomy in 106/131 (81%) PreP and 87/114 (76%) PostP, by laparoscopy /robotic in 22/131 (17%) PreP and 23/114 (20%) PostP and by other surgical approaches in 3/131 (2%) PreP and 4/114 (4%) PostP (p=0.73). CGR was achieved in 112/131(85%) PreP and 98/114 PostP (86%) (p>0.99). Of the 35 pts who had residual disease, 17/35 (48.5%) had 1-5 mm RD, 1/35 (3%) had 6-10mm RD, and 17/35 (48.5%) were suboptimal (>1cm). Upon completing SCS and chemotherapy, PARPi maintenance was used in 5/131 (4%) PreP and 31/114 (27%) PostP (p<0.001). Bevacizumab was used in 2/131 (1.5%) PreP and 14/114 (12%) PostP (p<0.001). HIPEC was used in 22/131 PreP (17%) and 19/114 (17%) PostP (p>0.99). Median PFS2 was 19 months (95%CI, 17-23) in PreP and 20.1 months (95%CI, 17-26) in PostP. In PostP, 84.5% CGR pts achieved 1-year PFS2 (95% CI: 75.5-90.4) and 31.3% achieved 3-year PFS2 (95% CI: 21.6-41.4) compared to patients with residual disease, 56.2% (95% CI: 29.5-76.2) and 12.5% (95% CI: 2.1-32.8) of whom achieved 1-year PFS2 and 3-year PFS2, respectively (p=0.001). Conclusions: In this analysis, the use of PARPi maintenance therapy for the first recurrent platinum-sensitive ovarian cancer markedly increased following its FDA approval in 2017. Optimal secondary cytoreductive surgery maintained a benefit to oncologic outcomes in this setting. In concert with expanding systemic therapy options, surgical resection remains a valuable component in the evolving management of recurrent ovarian cancer.

Outcomes of Stable Lung Colorectal Metastases on Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

BackgroundCytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) have demonstrated benefit in patients with colorectal peritoneal metastases (CRPM). Traditionally, extraperitoneal disease is considered a contraindication to CRS/HIPEC. Stable lung metastases in patients with colorectal cancer often have an indolent course, while the presence of untreated peritoneal metastases poorly affects short-term survival. We sought to evaluate the outcomes of patients undergoing CRS/HIPEC for peritoneal disease with known stable lung metastases. MethodsWe retrospectively reviewed our prospectively maintained CRS/HIPEC database. In 2017, we adopted a policy of considering patients with stable lung metastases for CRS/HIPEC as part of multidisciplinary treatment. We compared the oncologic outcome and safety of CRS/HIPEC with peritoneal only (PM) against patients with peritoneal and lung metastases (PLM). ResultsOur database includes 570 patients with CRS/HIPEC of which 174 with CRPM that underwent CRS/HIPEC, 18 with preoperatively diagnosed peritoneal and lung metastases. The demographics of the PM and PLM group were similar with the exception of operative time that was longer in the PLM group. Median PCI of the cohort was 7, similar in both groups (p = 0.89). Three-year overall survival (OS) of PLM patients was 68%, compared to 71% in PM (p = 0.277). Three-year progression-free survival (PFS) rate was 20% in PLM and 23% in PM (p = 0.688). ConclusionsPresence of stable lung metastases from colorectal cancer in patients with CRPM does not appear to affect the outcomes of CRS/HIPEC. Patients with stable lung disease should be considered for CRS/HIPEC after multidisciplinary discussion.

Cytoreductive Surgery and HIPEC for Malignant Peritoneal Mesothelioma: Outcomes and Survival From an Australian Centre

The aim of the study was to determine outcomes and overall survival (OS) in patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) for malignant peritoneal mesothelioma (MPM). This was a retrospective cohort study from a prospectively maintained database of patients that underwent CRS/HIPEC for MPM from April 1999 to December 2021. A total of 81 patients were identified with MPM. Median OS was 53 months with a 1-, 3- and 5-year OS of 76%, 55% and 49% respectively. Multivariate analysis identified lymph node status, PCI and CC score as statistically significant prognostic factors that impact survival. Median OS for PCI 0-20 was 103 months vs. 33 months for PCI 21-39 (p=0.005). Median OS for CC0, CC1 and CC2 were 104, 30 and 2.7 months respectively (p<0.001). Hazard ratio for node-positive disease over node-negative was 2.14 (95% CI=1.07-4.31, p<0.033). Grade III/IV complication rate was 43.2% and mortality 4.9%. CRS/HIPEC remains the gold standard for treating patients with MPM with excellent patient OS. Lymph node status, PCI and CC score were independent prognostic factors that affect OS.

The effect of metastasis location on outcome after cytoreductive surgery and heated intraperitoneal chemotherapy.

ObjectivesThis study aims to evaluate how metastases in the seven topographical regions of the simplified peritoneal cancer index (sPCI) affect the survival of patients treated with cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC) from colorectal (CRC) or appendiceal cancers.MethodsData was collected retrospectively from patient records. Abdominal regions affected by PC were identified using the histological verification of surgically removed tumours found in the electronic pathology report. Verified tumours were grouped according to the sPCI topography.ResultsOne hundred and eighty-three patients treated with CRS and HIPEC were included. Metastases in the small bowel had a negative impact on survival with a hazard ratio of 1.89 (p=0.005). A significantly impaired survival was also detected for patients affected by metastases in the ileocolic region (p=0.01) and in the omentum and spleen (p=0.04).ConclusionsWhen selecting patients for CRS and HIPEC a more cautious approach may be applied by considering the regions affected.

Hyperthermic Intraperitoneal Chemotherapy and Cytoreductive Surgery in Ovarian Cancer: An Umbrella Review of Meta-Analyses.

BackgroundThe utility of heated intraperitoneal chemotherapy (HIPEC) in the management of epithelial ovarian cancer (EOC) has been assessed in several randomised clinical trials and meta-analyses, and it is still a subject of controversy. Therefore, we performed an umbrella review of existing meta-analyses to summarise the outcomes of HIPEC and cytoreductive surgery (CRS) association in ovarian cancer.MethodsWe examined the MEDLINE, Cochrane Library, Scopus, Prospero, Web of Science and Science Direct from inception to May 30, 2020, for meta-analyses of randomised controlled trials and observational studies. Analyses of overall survival, disease free survival and progression survival were performed separately for primary and recurrent ovarian cancers.ResultsWe identified 6 meta-analyses investigating the association of HIPEC with CRS in the management of ovarian cancer. Three year overall survival was significantly improved by the association of CRS and HIPEC for primary (HR: 0.66, 95%CI:0.56-0.78) and recurrent ovarian cancers (HR:0.50, 95%CI:0.38-0.64). This benefit was also demonstrated on disease-free survival for primary (HR: 0.54, 95%CI:0.48-0.61) and recurrent ovarian cancer (HR: 0.60, 95%CI:0.46-0.78). The pooled hazard ratios confirmed the advantage of HIPEC and CRS association with respect to CRS alone on progression free survival for primary and recurrent ovarian cancer respectively with HR: 0.50, 95%CI: 0.43-0.58 and HR: 0.59, 95%CI: 0.41-0.85.ConclusionWhile waiting for the results of the current prospective studies, the present umbrella study suggests that HIPEC performed at the end of CRS may be a complementary effective asset for ovarian cancer patient management.