Top Peritoneal Surface Malignancy Articles from 2022 to Inform your Cancer Practice.

Over the last few decades, the role of cytoreductive surgery (CRS) with or without regional-based peritoneal therapies such as hyperthermic intraperitoneal chemotherapy (HIPEC) has evolved in the management of patients with peritoneal surface malignances (PSMs). Despite the benefit of CRS in improving oncologic outcomes, significant challenges remain in the treatment of patients with advanced PSMs, and the role of HIPEC continues to be questioned. Additionally, while there has been improvement in perioperative outcomes, long-term survival remains poor. As a result, there is much need to improve our understanding of the processes that drive tumor biology, thereby improving patient selection for various treatment approaches. Additionally, newer therapies are needed for patients who remain poor surgical candidates and who progress on systemic therapy. This article highlights recently published studies that we consider impactful in the care of patients with PSMs.

Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer.

INTRODUCTION: Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line. PATIENTS AND METHODS: PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37 °C and 42 °C with and without bromelain pretreatment. RESULTS: From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12/16, 75%) and high-grade AC (4/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, p = 0.0009) or NAC alone (47% versus 12.8%, p = 0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p < 0.001) and > 66% in 48 h (p < 0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p = 0.0001) and 35.5% (p = 0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p = 0.009) and Bcl-xL (p = 0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p < 0.03) and II (p < 0.031) were increased; while ATG7 (p < 0.01), ATG 12 (p < 0.04), and Becline 1(p < 0.03), expression decreased in bromelain-treated PTOs. CONCLUSIONS: Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.

Detection of Residual Peritoneal Metastases Following Cytoreductive Surgery Using Pegsitacianine, a pH-Sensitive Imaging Agent: Final Results from a Phase II Study.

BACKGROUND: For patients with peritoneal carcinomatosis, extent of disease and completeness of cytoreductive surgery (CRS) are major prognostic factors for long-term survival. Assessment of these factors could be improved using imaging agents. Pegsitacianine is a pH-sensitive polymeric micelle conjugated to the fluorophore indocyanine green. The micelle disassembles in acidic microenvironments, such as tumors, resulting in localized fluorescence unmasking. We assessed the utility of pegsitacianine in detecting residual disease following CRS. PATIENTS AND METHODS: NCT04950166 was a phase II, non-randomized, open-label, multicenter US study. Patients eligible for CRS were administered an intravenous dose of pegsitacianine at 1 mg/kg 24-72 h before surgery. Following CRS, the peritoneal cavity was reexamined under near-infrared (NIR) illumination to evaluate for fluorescent tissue. Fluorescent tissue identified was excised and evaluated by histopathology. The primary outcome was the rate of clinically significant events (CSE), defined as detection of histologically confirmed residual disease excised with pegsitacianine or a revision in the assessment of completeness of CRS. Secondary outcomes included acceptable safety and pegsitacianine performance. RESULTS: A total of 53 patients were screened, 50 enrolled, and 40 were evaluable for CSE across six primary tumor types. Residual disease was detected with pegsitacianine in 20 of 40 (50%) patients. Pegsitacianine showed high sensitivity and was well tolerated with no serious adverse events (SAEs). Transient treatment-related, non-anaphylactic infusion reactions occurred in 28% of patients. CONCLUSIONS: Pegsitacianine was well tolerated and facilitated the recognition of occult residual disease following CRS. The high rate of residual disease detected suggests that the use of pegsitacianine augmented surgeon assessment and performance during CRS.

Phase 1 randomized trial of inpatient high-intensity interval training after major surgery.

BACKGROUND: High-intensity interval training (HIT) can provide physiologic benefits and may improve postoperative recovery but has not been evaluated in inpatients. This study aimed to evaluate the safety and tolerability of HIT after major surgery. METHODS: We performed a phase I randomized study comparing HIT with low-intensity continuous ambulation (40 m) during the initial inpatient stay after major surgery at a large academic center. Clinicopathologic and pre- and post-exercise physiologic data were captured. Perceived exertion was measured throughout the intervention. RESULTS: Twenty-two subjects were enrolled and randomized with 90% (20 subjects, 10 per arm) completing all aspects of the study. One patient declined participation in the exercise intervention. The HIT and continuous ambulation groups were relatively similar in terms of median age (65.5 vs 63.5), female sex (20% vs 40%), White race (90% vs 90%), having a cancer diagnosis (100% vs 80%), undergoing gastrointestinal surgery (60% vs 80%), median Karnofsky score (60 vs 60), and ability to independently ambulate preoperatively (100% vs 90%). All subjects completed the exercise without protocol deviation, cohort crossover, or safety events. Compared with the continuous ambulation group, the HIT group had higher end median perceived exertion (5.0 [IQR, 5.5] vs 3.0 [IQR, 1.8]), shorter overall time to complete assigned exercise (56.6 seconds vs 91.8 seconds), and a trend toward higher median gait speed over 40 m (0.71 m/s vs 0.44 m/s, P = .126). CONCLUSION: HIT in the hospitalized postoperative patient is safe and may be implemented to help promote positive physiologic outcomes and recovery.

Distance Traveled and Disparities in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: The impact of distance traveled on cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) outcomes needs further investigation. METHODS: This retrospective study reviewed a prospectively managed single-center CRS/HIPEC 1992-2022 database. Zip codes were used to calculate distance traveled and to obtain data on income and education via census data. Patients were separated into three groups based on distance traveled in miles (local: ≤50 miles, regional: 51-99 miles, distant: ≥100 miles). Descriptive statistics, Kaplan-Meier method, and Cox regression were performed. RESULTS: The 1614 patients in the study traveled a median distance of 109.5 miles (interquartile range [IQR], 53.36-202.29 miles), with 23% traveling locally, 23.9% traveling regionally, and 53% traveling distantly. Those traveling distantly or regionally tended to be more white (distant: 87.8%, regional: 87.2%, local: 83.2%), affluent (distant: $61,944, regional: $65,014, local: $54,390), educated (% without high school diploma: distant: 10.6%, regional: 11.5%, local: 13.0%), less often uninsured (distant: 2.3%, regional: 4.6%, local: 5.2%) or with Medicaid (distant: 3.3%, regional: 1.3%, local: 9.7%). They more often had higher Peritoneal Carcinomatosis Index (PCI) scores (distant: 15.4, regional: 15.8, local: 12.7) and R2 resections (distant: 50.3%, regional: 52.2%, local: 40.5%). Median survival did not differ between the groups, and distance traveled was not a predictor of survival. CONCLUSION: More than 50% of the patients traveled farther than 100 miles for treatment. Although regionalization of CRS/HIPEC may be appropriate given the lack of survival difference based on distance traveled, those who traveled further had fewer health care disparities but higher PCI scores and more R2 resections, which raises concerns about access to care for the underserved, time to treatment, and surgical quality.

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

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

Quality-of-Life Outcomes for Patients Taking Opioids and Psychotropic Medications Before Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: The impact of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) on quality of life (QoL) for patients taking opioids and psychotropic medications preoperatively is unclear. METHODS: This study retrospectively reviewed a CRS-HIPEC single-center prospectively maintained database for 2012-2016. Demographics and clinical data on opioids/psychotropic medication use were collected via chart review. The study collected QoL outcomes at baseline, then 3, 6, and 12 months postoperatively via the Center for Epidemiologic Studies Depression Scale (CES-D), Brief Pain Inventory, Functional Assessment of Cancer Therapy, and 36-Item Short-Form Health Survey. Differences in QoL between the groups were calculated using repeated measures analysis of variance regression. Descriptive statistics and Kaplan-Meier analyses were performed. RESULTS: Of 388 patients, 44.8% were taking opioids/psychotropic medications preoperatively. At baseline, those taking opioids/psychotropic medications preoperatively versus those not taking these medications had significantly worse QoL. By 1 year postoperatively, the QoL measures did not differ significantly except for emotional functioning (e.g., no medications vs. opioids/psychotropic medications: CES-D, 5.6 vs. 10.1). Median survival did not differ significantly (opioids/psychotropic medications vs. no medications: 52.3 vs. 60.6 months; p = 0.66). At 1 year after surgery, a greater percentage of patients were taking opioids, psychotropic medications, or both than at baseline (63.2% vs. 44.8%; p < 0.001). CONCLUSION: Despite worse baseline QoL, patients who took opioids/psychotropic medications had QoL scores 1 year postoperatively similar to the scores of those who did not except in the emotional domains. These data point to the potential utility of a timed psychosocial intervention to enhance emotional adaptation and further support the role of CRS-HIPEC in improving QoL.

Comparison of survival for metastatic pancreatic cancer patients treated with CPI-613 versus resected borderline-resectable pancreatic cancer patients.

INTRODUCTION: Treatment of advanced pancreatic adenocarcinoma remains suboptimal. Therapeutic agents with a novel mechanism of action are desperately needed; one such novel agent is CPI-613 targets. We here analyze the outcomes of 20 metastatic pancreatic cancer patients treated with CPI-613 and FOLFIRINOX in our institution and evaluate their outcomes to borderline-resectable patients treated with curative surgery. METHODS: A post hoc analysis was performed of the phase I CPI-613 trial data (NCT03504423) comparing survival outcomes to borderline-resectable cases treated with curative resection at the same institution. Survival was measured by overall survival (OS) for all study cases and disease-free survival (DFS) for resected cases with progression-free survival for CPI-613 cases. RESULTS: There were 20 patients in the CPI-613 cohort and 60 patients in the surgical cohort. Median follow-up times were 441 and 517 days for CPI-613 and resected cases, respectively. There was no difference in survival times between CPI-613 and resected cases with a mean OS of 1.8 versus 1.9 year (p = 0.779) and mean PFS/DFS of 1.4 versus 1.7 years (p = 0.512). There was also no difference in 3-year survival rates for OS (hazard ratio [HR] = 1.063, 95% confidence interval [CI] 0.302-3.744, p = 0.925) or DFS/PFS (HR = 1.462, 95% CI 0.285-7.505, p = 0.648). CONCLUSION: The first study to evaluate the survival between metastatic patients treated with CPI-613 versus borderline-resectable cases undergoing curative resection. Analysis revealed no significant differences in survival outcomes between the cohorts. Study results are suggestive that there may be potential utility with the addition of CPI-613 to potentially resectable pancreatic adenocarcinoma, although additional research with more comparable study groups are required.

Risk factors and outcomes for cholangitis after hepatic resection.

INTRODUCTION: There is a paucity in the literature in regard to the incidence, risk factors, and outcomes for post-operative cholangitis following hepatic resection. METHODS: Retrospective review of the ACS NSQIP main and targeted hepatectomy registries for 2012-2016. RESULTS: A total of 11,243 cases met the selection criteria. The incidence of post-operative cholangitis was 0.64% (151 cases). Multivariate analysis identified several risk factors associated with the development of post-operative cholangitis, stratified out by pre-operative and operative factors. The most significant risk factors were biliary anastomosis and pre-operative biliary stenting with odds ratios (OR) of 32.39 (95% CI 22.91-45.79, P value < 0.0001) and 18.32 (95% CI 10.51-31.94, P value < 0.0001) respectively. Cholangitis was significantly associated with post-operative bile leaks, liver failure, renal failure, organ space infections, sepsis/septic shock, need for reoperation, longer length of stay, increased readmission rates, and death. CONCLUSION: Largest analysis of post-operative cholangitis following hepatic resection. While a rare occurrence, it is associated with significantly increased risk for severe morbidity and mortality. The most significant risk factors were biliary anastomosis and stenting.

Conditional Survival After Hepatectomy for Colorectal Liver Metastasis: Results from the Colorectal Liver Operative Metastasis International Collaborative (COLOMIC).

INTRODUCTION: Complete resection of colorectal liver metastasis (CLM) improves long-term survival in colorectal cancer. However, there is limited recent data on conditional survival (CS) as postoperative survival milestones are achieved post-hepatectomy. METHODS: A retrospective analysis was performed on the penta-institutional Colorectal Liver Operative Metastasis International Collaborative (COLOMIC), with 906 consecutive CLM hepatectomy cases. CS was calculated using Bayes' theorem and Kaplan-Meier analysis. Additional CS analyses were performed on additional clinicopathologic risk factors, including colon cancer laterality, KRAS mutation status, and extrahepatic disease. RESULTS: The 5-year CS was 40.6%, 45.3%, 52.8%, and 65.3% at 0, 1, 2, and 3 years postoperatively, with significant improvements each year (p < 0.005). CS was not significantly different between right-sided and left-sided colorectal cancers by 3 years postoperatively. Patients with KRAS mutations had worse CS at all timepoints (p < 0.001). Extrahepatic disease was a poor prognostic factor for OS and CS (p < 0.001). However, CS for patients with KRAS mutations or extrahepatic disease improved significantly as 2-year, postoperative survival was achieved (p < 0.05). CONCLUSIONS: Five-year CS after hepatectomy for CLM improved with each passing year of survival postoperatively. Although extrahepatic disease and KRAS mutations are poor prognostic factors for OS, these populations still had improved CS after 2 years postoperatively.

Survival Outcomes of Optimally Treated Colorectal Metastases: The Importance of R0 Status in Surgical Treatment of Hepatic and Peritoneal Surface Disease.

BACKGROUND: Although colorectal hepatic metastases (HM) and peritoneal surface disease (PSD) are distinct biologic diseases, they may have similar long-term survival when optimally treated with surgery. METHODS: This study retrospectively reviewed prospectively managed databases. Patients undergoing R0 or R1 resections were analyzed with descriptive statistics, the Kaplan-Meier method, and Cox regression. Survival was compared over time for the following periods: 1993-2006, 2007-2012, and 2013-2020. RESULTS: The study enrolled 783 HM patients undergoing liver resection and 204 PSD patients undergoing cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). Compared with PSD patients, HM patients more often had R0 resections (90.3% vs. 32.4%), less often had pre-procedure chemotherapy (52.4% vs. 92.1%), and less often were functionally independent (79.7% vs. 95.6%). The 5-year overall survival for HM was 40.9%, with a median survival period of 45.8 months versus 25.8% and 33.4 months, respectively, for PSD (p < 0.05). When stratified by resection status, R0 HM and R0 PSD did not differ significantly in median survival (49.0 vs. 45.4 months; p = 0.83). The median survival after R1 resection also was similar between HM and PSD (32.6 vs. 26.9 months; p = 0.59). Survival between the two groups again was similar over time when stratified by resection status. The predictors of survival for HM patients were R0 resection, number of lesions, intraoperative transfusion, age, and adjuvant chemotherapy. For the PSD patients, the predictors were peritoneal cancer index (PCI) score, estimated blood loss (EBL), and female gender. CONCLUSION: The study showed that R0 resections are associated with improved outcomes and that median survival is similar between HM and PSD patients when it is achieved. Surveillance and treatment strategies that facilitate R0 resections are needed to improve results, particularly for PSD.

Long-Term Survival in Patients Treated with Cytoreduction and Heated Intraperitoneal Chemotherapy for Peritoneal Mesothelioma at a Single High-Volume Center.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare diagnosis with a dismal prognosis if untreated. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is shown to significantly improve survival. Our institution is uniquely positioned to report long-term outcomes in MPM with CRS-HIPEC, due to our robust peritoneal surface disease program existing over the past three decades. METHODS: Our prospectively maintained, single-institution database of CRS-HIPEC cases was reviewed, identifying 111 consecutive patients with MPM over 28 years (1993-2021). Prognostic, operative, and pathologic factors were reviewed. Overall survival (OS) and conditional survival (CS) analyses were performed. RESULTS: The average age was 55.1 years; 58.6% of patients were male; 17 of 111 patients (15.3%) had a second CRS-HIPEC. At first CRS-HIPEC, the average PCI score was 18.7, and the perfusate drugs were platinum-based (72.1%) and mitomycin C (27.9%). The resection status at first CRS-HIPEC was R2a (46.4%), followed by R0-1 (29.1%), and R2b-c (24.5%). Median OS was 3.3 years for the entire cohort, with 75th and 25th percentiles at 10.7 months and 10.6 years. Median CS was improved if patients survived to the 1-year postoperative mark (4.9 years, p < 0.01) and trended toward further improvement with each passing year. If 3-year postoperative survival was achieved, the median CS improved to 6.1 years. CONCLUSIONS: This represents one of the largest and lengthiest, single-center, longitudinal, case series of peritoneal mesothelioma treated with CRS-HIPEC. The OS suggests efficacy for CRS-HIPEC for MPM. Long-term survival improves significantly after patients achieve the 1-year, postoperative mark.

Machine Learning Models for Predicting the Outcomes of Surgical Treatment of Colorectal Liver Metastases.

BACKGROUND: Surgical intervention remains the cornerstone of a multidisciplinary approach in the treatment of colorectal liver metastases (CLM). Nevertheless, patient outcomes vary greatly. While predictive tools can assist decision-making and patient counseling, decades of efforts have yet to result in generating a universally adopted tool in clinical practice. STUDY DESIGN: An international collaborative database of CLM patients who underwent surgical therapy between 2000 and 2018 was used to select 1,004 operations for this study. Two different machine learning methods were applied to construct 2 predictive models for recurrence and death, using 128 clinicopathologic variables: gradient-boosted trees (GBTs) and logistic regression with bootstrapping (LRB) in a leave-one-out cross-validation. RESULTS: Median survival after resection was 47.2 months, and disease-free survival was 19.0 months, with a median follow-up of 32.0 months in the cohort. Both models had good predictive power, with GBT demonstrating a superior performance in predicting overall survival (area under the receiver operating curve [AUC] 0.773, 95% CI 0.743 to 0.801 vs LRB: AUC 0.648, 95% CI 0.614 to 0.682) and recurrence (AUC 0.635, 95% CI 0.599 to 0.669 vs LRB: AUC 0.570, 95% CI 0.535 to 0.601). Similarly, better performances were observed predicting 3- and 5-year survival, as well as 3- and 5-year recurrence, with GBT methods generating higher AUCs. CONCLUSIONS: Machine learning provides powerful tools to create predictive models of survival and recurrence after surgery for CLM. The effectiveness of both machine learning models varies, but on most occasions, GBT outperforms LRB. Prospective validation of these models lays the groundwork to adopt them in clinical practice.