Colorectal Peritoneal Carcinomatosis Research Articles

First clinical study reporting safety and outcomes of high dose oxaliplatin use in PIPAC for colorectal peritoneal carcinomatosis.

e15606 Background: PIPAC in inoperable colorectal peritoneal carcinomatosis has showed better oncological outcomes at existing doses of 92mg/m2. However the maximum dose that can be used and its clinical outcomes is not defined yet. Methods: PIPAC was done at dose 120 mg /m2 oxaliplatin which was established from a phase 2 study. The patient demographics, perioperative findings, adverse events, and outcomes were prospectively recorded. Response rate was graded as Peritoneal Regression Grading Score (PRGS). QoL of the patients was studied according to the EORTC QLQ - C30 score. Results: 42 PIPAC administrations were performed in 15 patients. The median hospital stay was 1.5 day (1-3 day). CTCAE grade 3 was observed in 5 patients, for abdominal pain and nausea, grade 3 fatigue in 4 patients. Transient increase in C- reactive protein was seen in 8 patients, haematological, renal and hepatic functions were not impaired in any patients except for mild transient elevation in AST and ALT levels in 7 patients. 12 patients completed 3 cycles of PIPAC. Of the 15 patients, 3 had complete response (PRGS 1) and 8 had major (PRGS 2), 3 had minor response (PRGS 3). There was improvement in functional scale, symptom scale and overall global health status for all patients. Conclusions: PIPAC can be performed safely at dose of oxaliplatin 120mg/m2. There is better objective & pathological response with this dose with no major complications or side effects to the patients. There is also improvement in quality of life. This dose should be new standard of care for further studies.

In Situ Formed, Peritoneum‐Adhesive Immunogels Synergizing Low‐Dose Fractionated Radiotherapy Against Colorectal Peritoneal Carcinomatosis

Immune checkpoint blockade (ICB) therapy holds great potentials for the treatment of colorectal peritoneal carcinomatosis (CRPC). However, its efficacy is often suboptimal due to the low immunogenic tumor phenotype, immunosuppressive tumor microenvironment (TME), and low antibody bioavailability at the peritoneal site. Herein, an in situ formed, anti‐cluster of differentiation 47 (aCD47) and anti–programmed cell death 1 ligand 1 (aPDL1) co‐loaded hydrogel (aCD47/aPDL1@PB–TA gel) with excellent peritoneum‐adhesive property and reactive oxygen species (ROS)‐responsive degradation is developed, bridging low‐dose fractionated radiotherapy (LDFRT) and ICB therapy for CRPC. The aCD47/aPDL1@PB‐TA gel is formed instantly upon mixing of the intraperitoneally injected, antibody‐containing solutions of phenylboronic acids‐containing polymer (PB) and tannic acid (TA), which can adhere to the peritoneum over 4 d. LDFRT promotes an immunogenic tumor phenotype by upregulating CD47 and PDL1, and reverses the immunosuppressive TME by fostering M1‐type macrophage polarization, dendritic cell maturation, and T cell infiltration. Moreover, LDFRT generates ROS to degrade the hydrogel and release the antibodies, consequently activating innate and adaptive immune responses. LDFRT and ICB therapy then cooperate to eliminate peritoneally metastasized CT26 colon tumor nodules in mice. Herein, a promising strategy is provided for LDFRT‐reinforced immunotherapy of CRPC, especially for patients with low immunogenic tumor.

Incomplete Cytoreductive Surgery for Appendiceal and Colorectal Peritoneal Carcinomatosis: Characteristics and Outcomes of an Overlooked Group

Aguirre, Nicole; Goffredo, Paolo MD; Mohamed, Mostafa; Cercek, Andrea MD; Pappou, Emmanouil MD, PhD, FACS, FASCRS; Paty, Philip B MD, FACS; Smith, Jesse Joshua MD, PhD FACS; Weiser, Martin R MD, FACS; Garcia-Aguilar, Julio E MD, FACS; Nash, Garrett M MD, FACS Author Information

Vaccinia virus and peptide-receptor radiotherapy synergize to improve treatment of peritoneal carcinomatosis

Tumor-specific overexpression of receptors enables a variety of targeted cancer therapies, exemplified by peptide-receptor radiotherapy (PRRT) for somatostatin receptor (SSTR)-positive neuroendocrine tumors. While effective, PRRT is restricted to tumors with SSTR overexpression. To overcome this limitation, we propose using oncolytic vaccinia virus (vvDD)-mediated receptor gene transfer to permit molecular imaging and PRRT in tumors without endogenous SSTR overexpression, a strategy termed radiovirotherapy. We hypothesized that vvDD-SSTR combined with a radiolabeled somatostatin analog could be deployed as radiovirotherapy in a colorectal cancer peritoneal carcinomatosis model, producing tumor-specific radiopeptide accumulation. Following vvDD-SSTR and 177Lu-DOTATOC treatment, viral replication and cytotoxicity, as well as biodistribution, tumor uptake, and survival, were evaluated. Radiovirotherapy did not alter virus replication or biodistribution, but synergistically improved vvDD-SSTR-induced cell killing in a receptor-dependent manner and significantly increased the tumor-specific accumulation and tumor-to-blood ratio of 177Lu-DOTATOC, making tumors imageable by microSPECT/CT and causing no significant toxicity. 177Lu-DOTATOC significantly improved survival over virus alone when combined with vvDD-SSTR but not control virus. We have therefore demonstrated that vvDD-SSTR can convert receptor-negative tumors into receptor-positive tumors and facilitate molecular imaging and PRRT using radiolabeled somatostatin analogs. Radiovirotherapy represents a promising treatment strategy with potential applications in a wide range of cancers.

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

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

Incomplete cytoreductive surgery for appendiceal and colorectal peritoneal carcinomatosis: Characteristics and outcomes of an overlooked group.

Complete cytoreductive surgery (CRS) may prolong survival for selected patients with peritoneal carcinomatosis from colorectal cancer (CRC). However, there is a paucity of data on outcomes following incomplete procedures. Patients with incomplete CRS for well-differentiated (WD) and moderate/poorly-differentiated (M/PD) appendiceal cancer, right and left CRC were identified at a single tertiary center (2008-2021). Of 109 patients, 10% were WD and 51% M/PD appendiceal cancers, and 16% right and 23% left CRC. There were no differences in gender, BMI (mean = 27), ASA score, previous abdominal surgery (72%), and extent of CRS. The PC Index differed between appendiceal and colorectal cancers (mean = 27 vs. 17, p < 0.01). Overall, the perioperative outcomes were similar among the groups, with 15% experiencing complications. Postoperatively, 61% received chemotherapy, and 51% required ≥1 subsequent procedure. The 1 and 3-year survival for the WD, M/PD, right and left CRC subgroups were 100%, 67%, 44%, 51%, and 88%, 17%, 12%, and 23%, respectively (p = 0.02). Incomplete CRS was associated with significant morbidity and number of subsequent palliative procedures. Prognosis correlated with histologic subtype; WD appendiceal cancer patients having superior outcomes, while those with right sided CRC the worst survival. These data may help guiding expectations in the setting of incomplete procedures.

Clinical characteristics and survival trends of patients with metastatic colorectal cancer (mCRC) and peritoneal carcinomatosis who receive metastases surgery in a Spanish cohort.

159 Background: Peritoneal metastases in patients with mCRC are commonly associated with poor outcomes. Some of these patients are candidates to undergo metastases surgery, which may result in better prognosis; however, clinical and molecular characteristics of these patients remain uncertain. Methods: We conducted a retrospective analysis of 166 patients with mCRC and peritoneal metastases in a tumor registry from 2015 to 2021, analyzing the clinical and molecular characteristics, as well as progression-free survival (PFS) and overall survival (OS) of patients who received peritoneal surgery versus those who did not. Results: From the whole population, 65 patients (39%) underwent peritoneal metastases surgery, and several characteristics were more frequent in this subgroup: ECOG 0 (n = 26, OR 2.75, p = 0,0069), age &amp;lt;65 years (n = 43, OR 2.29, p = 0,0162), absence of hepatic metastases (n = 56, OR 3.31, p = 0,0037), single metastatic location (n = 43, OR 3.48, p = 0,0002), normal CEA levels at diagnosis (n = 33, OR 2.02, p = 0,0455) and BRAF mutation (n = 12, OR 3.32, p = 0,0345). Moreover, these patients received more lines of systemic treatment (2.8 vs 2, p = 0,006) and more metastases surgeries (1.7 vs 0.9, p = 0,000). Significant differences in tumor mutational status regardless of BRAF (KRAS, NRAS, MSI, PI3K and HER2), sex and primary tumor location between groups were not found. PFS was longer in patients receiving metastases surgery (median, 13.68 vs 7.76 months; HR for progression 0.64; 95 % confidence interval (CI) 0.46 to 0.89; p = 0,009), as well as overall survival (median NR vs 29.53; HR for death 0.39; 95 % CI, 0.25 to 0.60; p = 0,000). Conclusions: In our cohort, patients with mCRC and peritoneal carcinomatosis who underwent metastases surgery had more frequently less than 65 years, ECOG 0, absence of liver metastases, single metastatic location, normal CEA levels at diagnosis and BRAF mutation. Moreover, this subgroup showed better outcomes with a statistically significant increase in PFS and OS.

Effect of the MiR-99b and MiR-135b on peritoneal carcinomatosis and liver metastasis in colorectal cancer

AimThis study aimed to evaluate the expression levels of miR-99b and miR-135b in peritoneal carcinoma and liver metastases associated with Colorectal Cancer (CRC), assess their association with the intracellular signaling pathway proteins Kirsten Rat Sarcoma Virus (KRAS) and Akt, and investigate their effects on survival. Materials and methodsChanges in the KRAS gene and Akt proteins, expression levels of miR-99b and miR-135b, and factors affecting survival were compared between colorectal cancer-associated peritoneal carcinomatosis and liver metastasis. ResultsThe expression levels of miR-99b and miR-135b and the immunohistochemical grade classification score of Akt were higher in colorectal cancer, peritoneal carcinomatosis, and liver metastasis than in normal tissues (p < 0.05). MiR-99b expression was highest in CRC, whereas miR-135b expression was highest in peritoneal carcinomatosis (p < 0.05). The expression level of miR-99b decreased and that of miR-135b increased in peritoneal and liver metastases compared with that in the tumor tissue. MiR-99b, Akt, and recurrence were risk factors that affected the overall survival rate in the model of clinical predictions (p = 0.045, p = 0.006, and p = 0.012, respectively). ConclusionWhile the expression of miR-99b was highest in the primary tumor, its decrease in liver metastasis and peritoneal carcinomatosis suggests that miR-99b has a protective effect against liver metastasis and peritoneal carcinomatosis. However, the detection of miR-135b expression was highest in peritoneal carcinomatosis and liver metastasis compared with that in the colorectal cancer tissues suggesting that it facilitates peritoneal carcinomatosis and liver metastasis. Furthermore, miR-99b, KRAS mutations, and Akt are risk factors for the overall survival of colorectal cancer.

Hyperthermic Intraperitoneal Chemotherapy Following Cytoreductive Surgery for Colorectal Peritoneal Carcinomatosis Patients: A Review.

Colorectal peritoneal carcinomatosis (CPC) is an advanced malignancy and is typically associated with a poor prognosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) following complete cytoreductive surgery (CRS) is a novel, advanced loco-regional treatment for colorectal cancer that is currently being used to treat peritoneal carcinomatosis (PC). The present review aims to describe the evidence-based literature on the efficacy and safety of this treatment approach in patients with PC originating from colorectal cancer and to summarize its complications. All published literature regarding the efficacy of HIPEC for the treatment of CPC was reviewed; 16 studies were included in this paper. The overall survival rate for the HIPEC group ranged from 63% to 93%. The overall median survival for the HIPEC and non-HIPEC groups ranged from 13 to 60.1 months and 12.6 to 41.2 months, respectively. The overall median survival of patients in the HIPEC group was comparatively better than those in the non-HIPEC group. There was insufficient evidence to suggest whether this treatment regimen was associated with a high or low morbidity rate in comparison to other groups. However, the mortality rate associated with this treatment regimen was low. In conclusion, the present data provide insufficient evidence regarding the beneficial effects of using HIPEC following CRS treatment. Therefore, further studies are required to determine the benefits of HIPEC for CPC patients.

Utilizing Patient-Derived Organoids in the Management of Colorectal Cancer with Peritoneal Metastases: A Review of Current Literature.

Treatment of colorectal cancer-derived peritoneal carcinomatosis (CRC-PC) is challenging due to cellular heterogeneity that exhibits variable degrees of resistance to systemic as well as intraperitoneal chemotherapy. Therefore, it is not a surprise that the majority of patients undergoing cytoreductive surgery with HIPEC will experience recurrence. Patient-derived tumor organoids (PTOs) may be potentially capable of informing clinical treatment decisions at the level of the individual patient. In this study, we review the current landscape of CRC-PC PTO literature. PubMed was queried for peer-reviewed publications studying CRC-PC organoids. Original articles which harnessed organoids as a research platform to study CRC-PC were included for review. Xenograft organoid studies were excluded. A total of 5 articles met inclusion criteria published between 2017 and 2022 and underwent complete analysis. Study topics included optimization of current therapies, identification of novel drug applications, and identification of disease mechanisms. Current therapies studied included systemic chemotherapy, targeted inhibitors, and HIPEC regimens. Patient-derived tumor organoids are a valuable personalized research tool that can complement real-time clinical settings. Additional research is needed to optimize methodologies of organoid incorporation in patients with colorectal cancer with peritoneal carcinomatosis.

Conductive Gas Plasma Treatment Augments Tumor Toxicity of Ringer's Lactate Solutions in a Model of Peritoneal Carcinomatosis.

Reactive species generated by medical gas plasma technology can be enriched in liquids for use in oncology targeting disseminated malignancies, such as metastatic colorectal cancer. Notwithstanding, reactive species quantities depend on the treatment mode, and we recently showed gas plasma exposure in conductive modes to be superior for cancer tissue treatment. However, evidence is lacking that such a conductive mode also equips gas plasma-treated liquids to confer augmented intraperitoneal anticancer activity. To this end, employing atmospheric pressure argon plasma jet kINPen-treated Ringer’s lactate (oxRilac) in a CT26-model of colorectal peritoneal carcinomatosis, we tested repeated intraabdominal injection of such remotely or conductively oxidized liquid for antitumor control and immunomodulation. Enhanced reactive species formation in conductive mode correlated with reduced tumor burden in vivo, emphasizing the advantage of conduction over the free mode for plasma-conditioned liquids. Interestingly, the infiltration of lymphocytes into the tumors was equally enhanced by both treatments. However, significantly lower levels of interleukin (IL)4 and IL13 and increased levels of IL2 argue for a shift in intratumoral T-helper cell subpopulations correlating with disease control. In conclusion, our data argue for using conductively over remotely prepared plasma-treated liquids for anticancer treatment.

Oncological Outcomes After Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in the Treatment of Peritoneal Carcinomatosis.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique for the treatment of initially unresectable peritoneal carcinomatosis (PC). Our objective was to assess its oncological outcomes. Between July 2016 and September 2020, data from 100 PIPAC procedures with oxaliplatin or doxorubicin-cisplatin in 49 patients with PC (all etiologies) were analyzed. We studied the evolution of the peritoneal cancer index (PCI), the need for radical surgery (R0), and overall survival (OS). The patients' median age was 65 (59; 71) years, and 55.1% were women. Median PIPAC procedures per patient were 2 (1-3), and 28 (57.1%) underwent more than one PIPAC procedure. Median PCI at the first PIPAC was 19 (15-22). PCI decreased for 37%, remained stable for 29.6%, and increased for 33.4% patients. Four (8.3%) underwent radical R0 surgery after PIPAC. After a median follow-up of 16.1months (1.5-90.1), the median overall survival from PC diagnosis was 29.1months (14.8-34.3), with a median gastric and colorectal PC survival of 11.3 (7.2-34.3) and 29.1months (16.1-31) respectively. Overall survival after the first PIPAC session was 11.6months (6-17.3), with median survival after gastric and colorectal PCs being 6 (2.9-15.5) and 13.3months (5-17.6), respectively. Stratification of patients according to the number of lines of systemic chemotherapy, PIPAC procedures, and the chronology of PC onset did not result in a significant difference in survival. The OS was in line with the literature. PIPAC could delay oncological progression and improve survival. These encouraging results justify the ongoing and future evaluations of PIPAC by prospective randomized trials.

Delineating the intra-patient heterogeneity of molecular alterations in treatment-naïve colorectal cancer with peritoneal carcinomatosis

AbstractIn a non-negligible number of patients with metastatic colorectal cancer (mCRC), the peritoneum is the predominant site of dissemination. Cure can be achieved by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but this procedure is associated with long-term morbidity and high relapse rates. Thus, there is a pressing need for improved therapeutic strategies and complementary biomarkers. The present study explored the molecular heterogeneity in mCRC with peritoneal carcinomatosis (PC), and the potential clinical implications thereof. Multi-region immunohistochemical profiling and deep targeted DNA-sequencing was performed on chemotherapy-naïve tumours from seven patients with synchronous colorectal PC who underwent CRS and HIPEC. In total, 88 samples (5-19 per patient) were analysed, representing primary tumour, lymph node metastases, tumour deposits, PC and liver metastases. Expression of special AT-rich sequence-binding protein 2 (SATB2), a marker of colorectal lineage, was lacking in the majority of cases, and a conspicuous intra-patient heterogeneity was denoted for expression of the proposed prognostic and predictive biomarker RNA-binding motif protein 3 (RBM3). Loss of mismatch repair proteins MLH1 and PSM2, observed in one case, was concordant with microsatellite instability and the highest tumour mutational burden. When present in a patient, mutations in key CRC driver genes, i.e., KRAS, APC and TP53, were homogenously distributed across all samples, while less common mutations were more heterogenous. On the same note, copy number variations showed intra-patient as well inter-patient heterogeneity. In two out of seven cases, hierarchical clustering revealed that samples from the PC and lymph node metastases were more similar to each other than to the primary tumour. In summary, these findings should encourage additional studies addressing the potential distinctiveness of mCRC with PC, which might pave the way for improved personalized treatment of these patients.

Application of Imaging Indicators Based on 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Colorectal Peritoneal Carcinomatosis.

ObjectiveThe imaging features of peritoneal carcinomatosis (PC) with different locations and pathological types of colorectal cancer (CRC) on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) were analyzed and discussed.MethodsThe PET/CT data of 132 patients with colorectal peritoneal carcinomatosis (CRPC) who met the inclusion and exclusion criteria between May 30, 2016, and December 31, 2019, were collected and analyzed. Observations included the location and pathological type of CRC, the peritoneal cancer index (PCI), standardized uptake maximum value (SUVmax), and retention index (RI) of the CRPC. Statistical analysis was performed using SPSS 20.0 software, and P < 0.05 was considered statistically significant.Results(1) The range of the PCI in the 132 patients studied was 2–30, with a mean value of 7.40 ± 8.14. The maximum long diameter of the CRPC lesions ranged from 0.6 to 12.1 cm, with an average of 3.23 ± 1.94 cm. The SUVmax ranged from 1.2 to 31.0, with a mean value of 9.65 ± 6.01. The SUVmax and size correlation coefficient for maximal CRPC lesions was r = 0.47 (P < 0.001). The RI range of the 72 patients who underwent time-lapse scanning was -10.0–112.2%, with RI quartiles of 13.5–48.9%; RI was ≥5% in 65 cases and <5% in seven cases. (2) The patients were grouped by the location of their CRC: the right-sided colon cancer (RCC, n = 37), left-sided colon cancer (LCC, n = 44), and rectal cancer groups (RC, n = 51). There were significant differences in the CRC pathological types (P = 0.009) and PCI scores (P = 0.02) between the RCC and RC groups and the RI between the RCC group and the other two groups (P < 0.001). (3) There were 88 patients organized into three groups by the pathology of their CRC: the moderately well-differentiated adenocarcinoma (group A, n = 57), poorly differentiated adenocarcinoma (group B, n = 16), and mucinous adenocarcinoma groups (group C, n = 15 cases, including one case of signet-ring cell carcinoma). There were significant differences in the CRC position (P = 0.003) and SUVmax (P = 0.03) between groups A and C.ConclusionThe PCI, SUVmax, and RI of peritoneal metastatic carcinoma caused by CRC in different locations and pathological types vary. Mucinous adenocarcinoma and poorly differentiated adenocarcinoma are relatively common in the right colon, and the PCI of peritoneal metastatic carcinoma is fairly high, but the SUVmax and RI are somewhat low.

Update for Advance CAR-T Therapy in Solid Tumors, Clinical Application in Peritoneal Carcinomatosis From Colorectal Cancer and Future Prospects

Latest advances in the field of cancer immunotherapy have developed the (Chimeric Antigen Receptor) CAR-T cell therapy. This therapy was first used in hematological malignancies which obtained promising results; therefore, the use of CAR-T cells has become a popular approach for treating non-solid tumors. CAR-T cells consist of T-lymphocytes that are engineered to express an artificial receptor against any surface antigen of our choice giving us the capacity of offering precise and personalized treatment. This leaded to the development of CAR-T cells for treating solid tumors with the hope of obtaining the same result; however, their use in solid tumor and their efficacy have not achieved the expected results. The reason of these results is because solid tumors have some peculiarities that are not present in hematological malignancies. In this review we explain how CAR-T cells are made, their mechanism of action, adverse effect and how solid tumors can evade their action, and also we summarize their use in colorectal cancer and peritoneal carcinomatosis.

Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis.

Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal peritoneal carcinomatosis. Nude mice were implanted intraperitoneally with luciferase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 ± 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intravenous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S-2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single- versus three-cycle therapy were evaluated in mice 26-27 days post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approximately 2-fold to 84.5 days in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS > 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic "cure") at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42-52.5 days (P < 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached.

Laparoscopic total pelvic peritonectomy for colorectal cancer pelvic carcinomatosis: a retrospective case series and photographic/videographic step-by-step guide.

Cytoreductive surgery (CRS) for colorectal cancer peritoneal carcinomatosis has been shown to prolong survival with acceptable morbidity rates. Total pelvic peritonectomy (TPP), or complete removal of all pelvic peritoneum, constitutes an important and technically challenging component of CRS. Here we report our experience and describe our technique of laparoscopic total pelvic peritonectomy (LTPP), using a photographic/videographic step-by-step guide. All patients who underwent LTPP for pelvic carcinomatosis from a colorectal origin were included in the study. Only patients with peritoneal cancer index (PCI) score of ≤ 10 were selected for CRS with LTPP. Patients who had extra-abdominopelvic cavity metastases were excluded. The final decision to proceed with CRS was made following laparoscopic assessment. From January 2017 to December 2020, 15 consecutive patients underwent LTPP for colorectal cancer pelvic carcinomatosis. Median patient age and PCI score was 53years (range 33-78) and 8 (range 3-10), respectively. Complete cytoreduction was achieved in all patients. Thirteen patients (87%) underwent concomitant hyperthermic intraperitoneal chemotherapy (HIPEC). The median operative duration was 748min (interquartile range [IQR] 681-850). Median intra-operative blood loss and length of hospital stay was 100ml (IQR 50-300) and 10days (IQR 8-12), respectively. Five patients (33%) experienced 30-day post-operative morbidity, with one (6.7%) experiencing a higher grade (Clavien-Dindo IIIa) complication. Median follow-up duration was 13months (IQR 3-19), during which four (27%) had systemic recurrence and one (6.7%) died after 15months following peritoneal and systemic recurrences. LTPP is a feasible option for low-volume pelvic carcinomatosis from colorectal cancer, offering the benefits of a minimally invasive approach. Strict patient selection is essential, and the procedure should be converted if the PCI score cannot be assessed or complete cytoreduction cannot be achieved. Proficiency at laparoscopic pelvic surgery is mandatory for performing LTPP.

Abstract 1391: Self-assembling and disassembling bispecific antibody platform for pretargeted radioimmunotherapy against GPA33 in a xenograft model of colorectal peritoneal carcinomatosis

Abstract Objectives: There is increasing interest in the potential role of radioimmunotherapy in the treatment of peritoneal carcinomatosis (PC), locoregional metastasis throughout the peritoneal cavity. We recently described a SADA platform when applied to GD2-specific PRIT using beta and alpha emitting radioisotopes achieved exceptional therapeutic indices (TI) achieving tumor cures without myelo-, renal-, neuro-, or hepatic toxicities (1). We applied SADA technology to a tumor associated antigen GPA33 expressed by colorectal cancer in a PC model, and compared that to a 3 step PRIT which requires a clearing agent (CA), previously reported to produce durable responses including histologic cures of GPA33-expressing SW1222 subcutaneous (2) and intraperitoneal (ip) colorectal xenograft models (3). Methods: SADA BsAb built from a humanized anti-GPA33 single chain Fv (scFv) and a humanized anti-DOTA scFv were expressed using the Expi293 Expression System and purified by affinity chromatography (1). Biochemical purity of &amp;gt;90% was confirmed via size exclusion HPLC and antigen binding confirmed by surface plasmon resonance and by flow cytometry on GPA33(+) cell lines. 8 wk old female athymic nude mice were inoculated ip with 5E6 cells of stably luciferase/GFP-transfected SW1222 in 200 µL media. PC tumor progression was monitored by in vivo BLI. GPA33-SADA and control GD2-SADA were injected intravenously (iv) on day 26, followed 48 hr later with 1 mCi (37 MBq,200 pmol) [177Lu]Lu-DOTA-Bn ip. In the 3 step PRIT group, mice were treated with 250µg (1.19nmol) GPA33-BsAb (n=4) followed 24 hr later by 20 µg (2.21 nmol) of CA iv, before the injection of 1 mCi (37 MBq,200 pmol) [177Lu]Lu-DOTA-Bn ip 4 hr later. In an additional control group, no SADA was given before 1 mCi (37 MBq,200 pmol) [177Lu]Lu-DOTA-Bn ip. Biodistribution was performed 24 hr after injection of ip 177Lu radiohapten. Results: Radioactivity absorbed in harvested ip SW1222 xenograft tumors treated with SADA-GPA33 (4.92 + 1.59 [mean + SD] percentage injected dose per gram [%ID/g]) was greater than that of harvested tumors treated with the traditional 3 step PRIT to GPA33 (2.68 + 0.179 %ID/g, p=0.043) or with negative control SADA-GD2 (0.513 + 0.293 %ID/g, p&amp;lt;0.001). In mice treated with SADA-GPA33, the ratio of tumor-to-organ radioactivity uptake was 19.6 + 5.08 for all organs, 4.12 + 0.734 for kidneys, 30.5 + 6.14 for liver, and 122.8 + 22.6 for blood. Conclusions: SADA-PRIT targeting GPA33 has favorable TI for colorectal PC. When compared to 3 step PRIT, SADA showed more selectivity and TI. {{References}}: 1. Santich BH, Cheal SM, Ahmed M, et al. Clin Cancer Res. 2020; 2. Cheal SM, Xu H, Guo HF, et al. Eur J Nucl Med Mol Imaging. 2016;43(5):925-937.3. Chandler C, Cheal SM, Nash G, et al. Journal of Nuclear Medicine. 2020;61. Citation Format: Sebastian Chung, Mao Wang, Darren Veach, Sarah Cheal, Daniela Burnes Vargas, Shin Hyuk Seo, Blesida Punzalan, Brian Santich, Hong-fen Guo, Hong Xu, Garrett Nash, Andrea Cercek, Christopher Chandler, Steven Larson, Nai-Kong Cheung. Self-assembling and disassembling bispecific antibody platform for pretargeted radioimmunotherapy against GPA33 in a xenograft model of colorectal peritoneal carcinomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1391.

RESULTS OF HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY AND CYTOREDUCTIVE SURGERY FOR PERITONEAL CARCINOMATOSIS OF COLORECTAL ORIGIN

Abstract INTRODUCTION Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is supported by clinical practice and published series as a fundamental treatment for increasing survival of selected patients with colorectal peritoneal carcinomatosis. The results were evaluated since having implemented a peritoneal oncological surgery program five years ago. MATERIAL AND METHODS Descriptive analysis was conducted to patients who had been diagnosed with peritoneal carcinomatosis from May 2014 to December 2020. 36 out of 100 patients who had undergone surgery were included in the CRS and HIPEC assessment and 6 patients without HIPEC, were excluded. RESULTS The mean preoperative PCI was 7.81±6.61 accomplishing complete cytoreduction CC 0-CC-1 in the 36 cases. An average of 1.86±1.22 peritonectomies were performed. Among procedures, complete pelviperitonectomy (11 patients) and liver metastasis resection (6 patients) should be noticed. Complications were presented in 16 patients (8 patients over Clavien Dindo&amp;gt;III) and 6 required reinterventions due to hematoma (2) or anastomotic leak (2) mostly. The 4-year overall survival is 76.2% and the disease-free interval is 34 months within an average follow-up of 23 months. CONCLUSIONS The overall survival and disease-free interval rates are above the standards. Currently, peritoneal carcinomatosis might be considered a curative disease. The multidisciplinary assessment allows selecting patients who will benefit from surgery.

Postoperative Inflammatory Marker Surveillance in Colorectal Peritoneal Carcinomatosis

BackgroundThe prognostic significance of inflammatory markers in solid cancers is well-established, albeit with considerable heterogeneity. This study sought to investigate the postoperative inflammatory marker trend in peritoneal carcinomatosis (PC), with a focus on colorectal PC (CPC), and to propose optimal surveillance periods and cutoffs.MethodsData were collected from a prospectively maintained database of PC patients treated at the authors’ institution from April 2001 to March 2019. The platelet–lymphocyte ratio (PLR), the neutrophil–lymphocyte ratio (NLR), and the lymphocyte–monocyte ratio (LMR) were collected preoperatively and on postoperative days 0, 1 to 3, 4 to 7, 8 to 21, 22 to 56, and 57 to 90 as averages. Optimal surveillance periods and cutoffs for each marker were determined by maximally selected rank statistics. The Kaplan–Meier method and Cox proportional hazard regression models were used to investigate the association of inflammatory markers with 1-year overall survival (OS) and recurrence-free survival (RFS) using clinicopathologic parameters.ResultsThe postoperative inflammatory marker trend and levels did not differ between the patients with and those without hyperthermic intraperitoneal chemotherapy (HIPEC). Low postoperative LMR (days 4–7), high postoperative NLR (days 8–21), and high postoperative PLR (days 22–56) were optimal for prognosticating poor 1-year OS, whereas high postoperative PLR and NLR (days 57–90) and low postoperative LMR (days 8–21) were associated with poor 1-year RFS. A composite score of these three markers was prognostic for OS in CPC.ConclusionsThe reported cutoffs should be validated in a larger population of CPC patients. Future studies should account for the inflammatory response profile when selecting appropriate surveillance periods.