Fragmentation of Care in Patients with Peritoneal Metastases Undergoing Cytoreductive Surgery.

BACKGROUND: The delivery of multimodal treatment at a high-volume center is known to optimize the outcomes of gastrointestinal malignancies. However, patients undergoing cytoreductive surgery (CRS) for peritoneal metastases often must 'fragment' their surgical and systemic therapeutic care between different institutions. We hypothesized that this adversely affects outcomes. PATIENTS AND METHODS: Adults undergoing CRS for colorectal or appendiceal adenocarcinoma at our institution between 2016 and 2022 were identified retrospectively and grouped by care network: 'coordinated care' patients received exclusively in-network systemic therapy, while 'fragmented care' patients received some systemic therapy from outside-network providers. Factors associated with fragmented care were also ascertained. Overall survival (OS) from CRS and systemic therapy-related serious adverse events (SAEs) were compared across the groups. RESULTS: Among 85 (80%) patients, 47 (55%) had colorectal primaries and 51 (60%) received fragmented care. Greater travel distance [OR 1.01 (CI 1.00-1.02), p = 0.02] and educational status [OR 1.04 (CI 1.01-1.07), p = 0.01] were associated with receiving fragmented care. OS was comparable between patients who received fragmented and coordinated care in the colorectal [32.5 months versus 40.8 months, HR 0.95 (CI 0.43-2.10), p = 0.89] and appendiceal [31.0 months versus 27.4 months, HR 1.17 (CI 0.37-3.74), p = 0.55] subgroups. The frequency of SAEs (7.8% versus 17.6%, p = 0.19) was also similar. CONCLUSIONS: There were no significant differences in survival or SAEs based on the networks of systemic therapy delivery. This suggests that patients undergoing CRS at a high-volume center may safely receive systemic therapy at outside-network facilities with comparable outcomes.

Early Integrated Palliative Care Within a Surgical Oncology Clinic.

Importance: Advance directive (AD) designation is an important component of advance care planning (ACP) that helps align care with patient goals. However, it is underutilized in high-risk surgical patients with cancer, and multiple barriers contribute to the low AD designation rates in this population. Objective: To assess the association of early palliative care integration with changes in AD designation among patients with cancer who underwent surgery. Design, Setting, and Participants: This cohort study was a retrospective analysis of a prospectively maintained registry of adult patients who underwent elective surgery for advanced abdominal and soft tissue malignant tumors at a surgical oncology clinic in a comprehensive cancer center with expertise in regional therapeutics between June 2016 and May 2022, with a median (IQR) postoperative follow-up duration of 27 (15-43) months. Data analysis was conducted from December 2022 to April 2023. Exposure: Integration of ACP recommendations and early palliative care consultations into the surgical workflow in 2020 using electronic health records (EHR), preoperative checklists, and resident education. Main Outcomes and Measures: The primary outcomes were AD designation and documentation. Multivariable logistic regression was performed to assess factors associated with AD designation and documentation. Results: Among the 326 patients (median [IQR] age 59 [51-67] years; 189 female patients [58.0%]; 243 non-Hispanic White patients [77.9%]) who underwent surgery, 254 patients (77.9%) designated ADs. The designation rate increased from 72.0% (131 of 182 patients) before workflow integration to 85.4% (123 of 144 patients) after workflow integration in 2020 (P = .004). The AD documentation rate did not increase significantly after workflow integration in 2020 (48.9% [89 of 182] ADs documented vs 56.3% [81 of 144] ADs documented; P = .19). AD designation was associated with palliative care consultation (odds ratio [OR], 41.48; 95% CI, 9.59-179.43; P < .001), palliative-intent treatment (OR, 5.12; 95% CI, 1.32-19.89; P = .02), highest age quartile (OR, 3.79; 95% CI, 1.32-10.89; P = .01), and workflow integration (OR, 2.05; 95% CI, 1.01-4.18; P = .048). Patients who self-identified as a race or ethnicity other than non-Hispanic White were less likely to have designated ADs (OR, 0.36; 95% CI, 0.17-0.76; P = .008). AD documentation was associated with palliative care consulation (OR, 4.17; 95% CI, 2.57- 6.77; P < .001) and the highest age quartile (OR, 2.41; 95% CI, 1.21-4.79; P = .01). Conclusions and Relevance: An integrated ACP initiative was associated with increased AD designation rates among patients with advanced cancer who underwent surgery. These findings demonstrate the feasibility and importance of modifying clinical pathways, integrating EHR-based interventions, and cohabiting palliative care physicians in the surgical workflow for patients with advanced care.

Adoption of cytoreductive surgery in the management of peritoneal malignancies-Global trends.

Cytoreductive surgery (CRS) has now been accepted as an integral component in the management of gastrointestinal and gynecological cancers with peritoneal metastases. Since the adoption of CRS is influenced by access to advanced medical facilities, trained multidisciplinary teams, and funding, there is wide variability in incorporation of CRS into routine clinical practice between high- versus low- and middle-income countries. This review highlights the global trends in the adoption of CRS for peritoneal malignancies with a specific focus on the establishment of CRS programs and barriers to incorporate CRS into routine clinical care in low- and middle-income countries.

Palliative Care and Characterization of Symptoms in Patients Undergoing Cytoreductive Surgery/Hyperthermic Intraperitoneal Chemotherapy.

INTRODUCTION: Palliative care for advanced cancer patients has been associated with improvements in symptom management and quality of life (QoL). Patients with peritoneal metastases undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) often report symptoms adversely affecting QoL. We characterized and compared symptoms elucidated by palliative care versus surgical providers in this setting. METHODS: CRS/HIPEC patients who saw both surgical oncology and palliative care providers from 2016 to 2020 at a tertiary care center were identified from a retrospective database. Documentation of QoL-associated symptoms in surgical oncology and palliative care visits was recorded and analyzed. RESULTS: A total of 118 patients were included in this study. The most common primary histologies were appendiceal (36.4%) and colorectal (28.8%). Symptoms most frequently reported by palliative care were pain (60.2%) and fatigue (54.2%). The median number of symptoms documented was three (2, 5) in palliative care notes and two (0, 3) in surgical oncology notes (P < 0.001). Palliative care providers documented most symptoms statistically more frequently than surgical oncology providers. CONCLUSIONS: Patients who underwent CRS/HIPEC experienced various QoL-associated symptoms. Palliative care providers elicited more symptoms than surgical oncology providers. Additional studies are needed to explore the impact on outcomes of perioperative palliative care in this challenging patient population.

Role of Tumor-informed Personalized Circulating Tumor DNA Assay in Informing Recurrence in Patients With Peritoneal Metastases From Colorectal and High-grade Appendix Cancer Undergoing Curative-intent Surgery.

OBJECTIVE: To investigate the role of a personalized, tumor-informed circulating tumor DNA (ctDNA) assay in informing recurrence in patients with peritoneal metastases (PM) from colorectal (CRC) and high-grade appendix (HGA) cancer after curative cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). BACKGROUND: Over 50% of patients with CRC/HGA-PM recur after optimal CRS-HIPEC. The limited sensitivity of axial imaging and diagnostic biomarkers is a significant cause of delay in the detection of recurrence and initiation of further therapies. Plasma ctDNA has a promising role in monitoring response to treatment and/or recurrence after primary cancer resection. METHODS: Patients with CRC/HGA-PM who underwent curative CRS-HIPEC and serial postresection ctDNA assessments were included. Patients with rising postoperative ctDNA levels were compared with those with stable, undetectable ctDNA levels. Primary outcomes were the percentage of patients with recurrence and disease-free survival (DFS). Secondary outcomes were overall survival, ctDNA sensitivity, lead time, and performance of ctDNA compared with carcinoembryonic antigen. RESULTS: One hundred thirty serial postresection ctDNA assessments [median 4, interquartile range (IQR), 3 to 5] were performed in 33 patients (n = 13 CRC, n = 20 HGA) who underwent completeness of cytoreduction-0/1 CRS with a median follow-up of 13 months. Of the 19 patients with rising ctDNA levels, 90% recurred versus 21% in the stable ctDNA group (n = 14, < 0.001). Median DFS in the rising ctDNA cohort was 11 months (IQR, 6 to 12) and not reached in the stable ( P = 0.01). A rising ctDNA level was the most significant factor associated with DFS (hazard ratio: 3.67, 95% CI: 1.06-12.66, P = 0.03). The sensitivity and specificity of rising ctDNA levels in predicting recurrence were 85% and 84.6%, respectively. The median ctDNA lead time was 3 months (IQR, 1 to 4). Carcinoembryonic antigen was less sensitive (50%) than ctDNA. CONCLUSIONS: This study supports the clinical validity of serial ctDNA assessment as a strong prognostic biomarker in informing recurrence in patients with CRC/HGA-PM undergoing curative resection. It also holds promises for informing future clinical trial designs and further research.

PI3K Pathway Alterations in Peritoneal Metastases are Associated with Earlier Recurrence in Patients with Colorectal Cancer Undergoing Optimal Cytoreductive Surgery.

BACKGROUND: Colorectal cancer with peritoneal metastasis (CRC-PM) represents a biologically heterogeneous disease; yet little is known regarding the impact of tumor biology on survival outcomes following optimal cytoreductive surgery (CRS). We analyzed the frequency of alterations in cancer signaling pathways in patients with CRC-PM and their impact on recurrence-free survival (RFS) following optimal CRS. METHODS: Thirty-five consecutive CRC-PM patients who underwent optimal CRS/HIPEC and next generation sequencing of peritoneal metastases were included in the study. Alterations in eight cancer-related signaling pathways were analyzed: Wnt/APC, p53, RTK-RAS, PI3K, TGF-B, Notch, Myc, and cell cycle. The association of pathway alterations with RFS and OS following optimal cytoreduction was estimated using Cox proportional hazard modeling. RESULTS: The most frequently altered pathways were Wnt/APC (63%), p53 (63%), RTK-RAS (60%), and PI3K (23%). Among optimally cytoreduced patients with CRC-PM, PI3K pathway alterations were an independent predictor of worse RFS (hazard ratio 3.2, 95% confidence interval CI 1.3-8.3, p = 0.01) with a clinically meaningful impact on median months to recurrence (5 vs. 13 months, p = 0.02). Alterations in p53, Wnt, and RTK-RAS pathways were not significantly associated with a difference in RFS following CRS. Alterations in the four pathways were not associated with differences in OS following CRS (median OS was 50 (interquartile range 23-80) months). CONCLUSIONS: In patients with CRC-PM, PI3K pathway alterations are associated with earlier recurrence following optimal CRS, which may represent a distinct molecular subtype. This novel finding can tailor clinical trials by using PIK3CA-directed interventions to reduce risk of recurrence after optimal CRS.

Mutational profiles and prognostic impact in colorectal and high-grade appendiceal adenocarcinoma with peritoneal metastases.

BACKGROUND: Next-generation sequencing (NGS) personalizes cancer treatments. In this study, we analyze outcomes based on NGS testing for colorectal cancer (CRC) and high-grade appendiceal adenocarcinoma (HGA) with peritoneal metastases. METHODS: Retrospective review of genomic analyses and outcomes in patients with CRC or HGA with peritoneal metastases at a high-volume center from 2012 to 2019. RESULTS: Ninety-two patients (57 CRC, 35 HGA) were identified. Overall survival was longer for CRC (52.8 vs. 30.5 months, p = 0.03), though rates of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) were similar. Multiple genes were more frequently mutated in CRC, including KRAS (51% vs. 29%, p = 0.04), TP53 (47% vs. 20%, p < 0.01), and APC (46% vs. 6%, p < 0.01). For CRC, multivariate regression showed an increased hazard ratio (HR) with increasing peritoneal cancer index (1.06 [1.01-1.11], p = 0.02) and a decreased HR following CRS/HIPEC (0.30 [0.11-0.80], p = 0.02). PIK3CA mutation associated with significantly increased HR (3.62 [1.06-12.41], p = 0.04), though only in non-CRS/HIPEC patients. Multivariate analysis in the HGA group showed a benefit following CRS/HIPEC (0.18 [0.06-0.61], p = 0.01) and for mucinous disease (0.38 [0.15-0.96], p = 0.04), while there was an increased HR with TP53 mutation (6.89 [2.12-22.44], p < 0.01). CONCLUSION: CRC and HGA with peritoneal spread have distinct mutational profiles. PIK3CA and TP53 mutations are associated with survival for CRC or HGA with peritoneal metastases, respectively.

The role of cytoreductive surgery and intraperitoneal chemotherapy in gastric cancer.

Gastric cancer (GC) with peritoneal carcinomatosis (PC) progresses rapidly and has historically dismal survival rates. Given the aggressive tumor biology and poor survival outcomes of patients with GC/PC, additional treatments beyond systemic chemotherapy are needed. Cytoreductive surgery and intraperitoneal chemotherapy have been effective management options for peritoneal surface malignancies, with increasing data to support their use in GC/PC. This review highlights the evolution of the surgical treatment of GC/PC, and discusses critical studies supporting the role of cytoreductive surgery, appropriate patient selection, and various methods in the delivery of intraperitoneal chemotherapy for patients with GC/PC.

Celecoxib and Myrtol: A Novel Therapy for Recurrent Appendiceal Mucinous Neoplasms With Extensive Peritoneal Dissemination.

BACKGROUND: Unresectable appendiceal mucinous neoplasms (AMNs) with extensive peritoneal dissemination cause significant morbidity and have limited treatment options. We evaluated a novel combination of Celecoxib and Myrtol in treating such AMNs. METHODS: Patients with recurrent AMNs with extensive peritoneal disease treated with a daily regimen of 200 mg Celecoxib and 1200 mg Myrtol Standardized were included. Progression-free survival (PFS) and overall survival (OS) were calculated, and carcinoembryonic antigen (CEA) trends were compared pretreatment and post-treatment in terms of percentage change. RESULTS: Thirteen patients with extensive, recurrent disease (median peritoneal carcinomatosis index of 36) were included between 2017 and 2020. The median age was 63 years (interquartile range: 55 to 67) and 7 (54%) were male. A total of 85% had undergone prior cytoreductive surgery while 15% underwent cytoreductive surgery >2 times. 54% had received multiple cycles of systemic chemotherapy before starting Celecoxib-Myrtol. After a median follow-up of 8 months, median PFS and OS were 16 months (interquartile range: 5 to 17) and 27 months, respectively. Nine (69.2%) showed improvement in CEA values 3 months after treatment compared with 3-month pretreatment CEA trends. None had adverse events attributable to Celecoxib-Myrtol. CONCLUSIONS: Our feasibility study suggests that a regimen of Celecoxib-Myrtol is well tolerated and may prolong PFS and OS in patients with recurrent AMNs with peritoneal spread.

Differences in Sociodemographic Disparities Between Patients Undergoing Surgery for Advanced Colorectal or Ovarian Cancer.

BACKGROUND: Cytoreductive surgery (CRS) for ovarian cancer with peritoneal metastases (OPM) is an established treatment, yet access-related racial and socioeconomic disparities are well documented. CRS for colorectal cancer with peritoneal metastases (CRPM) is garnering more widespread acceptance, and it is unknown what disparities exist with regards to access. METHODS: This retrospective cross-sectional multicenter study analyzed medical records from the National Cancer Database from 2010 to 2015. Patients diagnosed with CRPM or ORP only and either no or confirmed resection were included. Patient- and facility-level characteristics were analyzed using uni- and multivariable logistic regressions to identify associations with receipt of CRS. RESULTS: A total of 6634 patients diagnosed with CRPM and 14,474 diagnosed with OPM were included in this study. Among patients with CRPM, 18.1% underwent CRS. On multivariable analysis, female gender (odds ratio [95% CI] 2.04 [1.77-2.35]; P < 0.001) and treatment at an academic or research facility (OR 1.55 [1.17-2.05]; P = 0.002) were associated with CRS. Among patients with OPM, 87.1% underwent CRS. On multivariable analysis, treatment at facilities with higher-income patient populations was positively associated with CRS, while age (OR 0.97 [0.96-0.98]; P < .0001), use of nonprivate insurance (OR 0.69 [0.56-0.85]; P = 0.001), and listed as Black (OR 0.62 [0.45-0.86]; P = 0.004) were negatively associated with CRS. CONCLUSION: There were more systemic barriers to CRS for patients with OPM than for patients with CRPM. As CRS becomes more widely practiced for CRPM, it is likely that more socioeconomic and demographic barriers will be elucidated.

Novel Application of Iterative Hyperthermic Intraperitoneal Chemotherapy for Unresectable Peritoneal Metastases from High-Grade Appendiceal Ex-Goblet Adenocarcinoma.

BACKGROUND: Peritoneal metastases (PMs) from appendiceal ex-goblet adenocarcinoma (AEGA) are associated with a poor prognosis. While cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to prolong survival, the majority of patients are ineligible for complete cytoreduction. We describe a novel approach to the management of such patients with iterative HIPEC (IHIPEC). METHODS: Patients with signet ring/poorly differentiated AEGA with high Peritoneal Cancer Index (PCI) and extensive bowel involvement underwent IHIPEC with mitomycin C at 6-week intervals for a total of three cycles. Survival outcomes for these patients were compared with patients with high-grade appendiceal tumors matched for tumor burden who were treated with other conventional approaches, i.e. systemic chemotherapy only (SCO) or complete CRS + HIPEC. RESULTS: Between 2016 and 2019, seven AEGA patients with high PCI (median 32.5 [range 21-36]) underwent 18 IHIPEC cycles (median cycles per patient 3 [2-3]) in combination with systemic chemotherapy (median 2 lines [1-3], 12 cycles [10-28]). IHIPEC was delivered laparoscopically in 14/18 cases. Postoperatively, the median length of stay was 1 day (1-8 days), no procedure-related complications were reported, and five (28%) 90-day readmissions for bowel obstruction were documented. Median overall survival after IHIPEC was better compared with a matched group of patients (n = 16) receiving SCO (24.6 vs. 7.9 months; p = 0.005), and similar to those (n = 7) who underwent CRS + HIPEC (24.6 vs. 16.5 months; p = 0.62). CONCLUSIONS: IHIPEC in combination with systemic chemotherapy is tolerable, safe, and may be associated with encouraging survival outcomes compared with SCO in selected patients with high-grade, high-burden AEGA PM.

The impact of HIPEC vs. EPIC for the treatment of mucinous appendiceal carcinoma: a study from the US HIPEC collaborative.

INTRODUCTION: Mucinous appendiceal carcinoma is a rare malignancy that commonly spreads to the peritoneum leading to peritoneal metastases. Complete cytoreduction with perioperative intraperitoneal chemotherapy (PIC) is the mainstay of treatment, administered as either hyperthermic intra peritoneal chemotherapy (HIPEC) or early post-operative intraperitoneal chemotherapy (EPIC). Our goal was to assess the perioperative and long term survival outcomes associated with these two PIC methods. MATERIALS AND METHODS: Patients with mucinous appendiceal carcinoma were identified in the US HIPEC Collaborative database from 12 academic institutions. Patient demographics, clinical characteristics, and survival outcomes were compared among patients who underwent HIPEC vs. EPIC with inverse probability weighting (IPW) used for adjustment. RESULTS: Among 921 patients with mucinous appendiceal carcinoma, 9% underwent EPIC while 91% underwent HIPEC. There was no difference in Grade III-V complications between the two groups (18.5% for HIPEC vs. 15.0% for EPIC, p=.43) though patients who underwent HIPEC had higher rates of readmissions (21.2% vs. 8.8%, p<.01). Additionally, PIC method was not an independent predictor for overall survival (OS) or recurrence-free survival (RFS) after adjustment on multivariable analysis. CONCLUSIONS: Among patients with mucinous appendiceal carcinoma, both EPIC and HIPEC appear to be associated with similar perioperative and long-term outcomes.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Technical considerations and the learning curve.

Over the past decade, there has been a considerable increase in the utilization of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of patients with peritoneal metastases. This is due to improved safety and favorable oncologic outcomes, including curative potential. CRS/HIPEC has a steep learning curve and requires familiarity with peritonectomy procedures. This review will outline the technical aspects and learning curve of CRS/HIPEC.