The contemporary management of peritoneal metastasis: A journey from the cold past of treatment futility to a warm present and a bright future.

Peritoneal metastasis (PM) is often regarded as a less frequent pattern of spread; however, collectively across all spectra of primary tumors, the consequences of PM impact a large population of patients annually. Unlike other modes of metastasis, symptoms at presentation or during the treatment course are common, representing an additional challenge in the management of PM. Early efforts with chemotherapy and incomplete surgical interventions transiently improved symptoms, but durable symptom control and survival extension were rare, which established a perspective of treatment futility for PM through most of the 20th century. Notably, the continued development of better systemic therapy combinations, optimization of cytoreductive surgery (CRS), and rigorous investigation of combining regional therapy-specifically hyperthermic intraperitoneal chemotherapy-with CRS, have resulted in more effective multimodal treatment options for patients with PM. In this article, the authors provide a comprehensive review of the data establishing the contemporary approach for tumors with a high frequency of PM, including appendix, colorectal, mesothelioma, and gastric cancers. The authors also explore the emerging role of adding hyperthermic intraperitoneal chemotherapy to the well established paradigm of CRS and systemic therapy for advanced ovarian cancer, as well as the recent clinical trials identifying the efficacy of poly(adenosine diphosphate ribose) polymerase maintenance therapy. Finally, recent data are included that explore the role of precision medicine technology in PM management that, in the future, may help further improve patient selection, identify the best systemic therapy regimens, detect actionable mutations, and identify new targets for drug development.

Cytoreductive Surgery with HIPEC is a Safe and Effective Palliative Option in Chemorefractory Symptomatic Peritoneal Metastasis.

INTRODUCTION: The safety and efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in peritoneal metastasis in palliative settings remain poorly investigated and understood. Chemotherapy-refractory patients often present with symptomatic disease. This study investigated the safety and survival outcomes of optimal CRS/HIPEC performed primarily for palliation. METHODS: Palliative CRS/HIPEC was defined as asymptomatic patients who did not respond to three or more lines of chemotherapy, progression on current chemotherapy, and/or any symptomatic disease progression, including ascites, bowel obstruction, and pain. Data collected included demographics, histology, length of stay (LOS), perioperative complications, perioperative mortality, adjuvant chemotherapy use, peritoneal recurrence, overall recurrence, and overall survival. RESULTS: The median number of lines of chemotherapy received prior to CRS/HIPEC was 3.2, and 81% of patients were symptomatic. There were no postoperative deaths and the major complication rate was 22%. Ostomy creation and abdominal wall reconstruction were performed in 24% and 21% of patients, respectively. The median LOS was 11 days and successful palliation was achieved in 97% of patients. Overall survival was 13.5 months and factors associated with prolonged survival included optimal CRS (R1/R2a; p < 0.01) and the use of adjuvant chemotherapy (p < 0.001). Synchronous liver metastasis in the colon cancer subset did not negatively impact survival. CONCLUSION: CRS/HIPEC was performed safely in the palliative setting in patients with symptomatic progressive disease receiving multiple lines of chemotherapy. Median survival exceeded 1 year and factors associated with longer survival were optimal CRS and adjuvant chemotherapy. Liver metastasis did not preclude survival benefit in colon cancer patients. CRS/HIPEC can be considered for palliation but should be performed at high-volume centers.

Morbidity and Mortality Rates Following Cytoreductive Surgery Combined With Hyperthermic Intraperitoneal Chemotherapy Compared With Other High-Risk Surgical Oncology Procedures.

Importance: Currently, rates of referral of patients with peritoneal metastasis in the United States who qualify for cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) are low, in part because of the misperception of high morbidity and mortality rates. However, patients requiring major gastrointestinal surgical procedures with similar complication rates are routinely referred. Objective: To evaluate the relative safety of CRS/HIPEC. Design, Setting, and Participants: Retrospective cohort study of 34 114 patients who underwent CRS/HIPEC, right lobe hepatectomy, trisegmental hepatectomy, pancreaticoduodenectomy, and esophagectomy between January 1, 2005, and December 31, 2015, included in the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) database. Data analysis was performed in 2018. Main Outcomes and Measures: Data from the NSQIP database were used to compare perioperative and 30-day postoperative morbidity and mortality rates of CRS/HIPEC (1822 patients) with other, well-accepted, high-risk surgical oncology procedures: right lobe hepatectomy (5109 patients), trisegmental hepatectomy (2449 patients), pancreaticoduodenectomy (Whipple) (16 793 patients), and esophagectomy (7941 patients). Results: For 34 114 patients, median (interquartile range [IQR]) age was 63 (55-71) years and 42% were female. Patients undergoing CRS/HIPEC tended to be younger, with a median age of 57 years, and esophagectomy had the highest median (IQR) American Society of Anesthesiologists classification (3 [3-3]). When compared with CRS/HIPEC, higher complication rates were reported in the following categories: (1) superficial incisional infection in Whipple and esophagectomy (5.4% [95% CI, 4.4%-6.4%] vs 9.7% [95% CI, 9.3%-10.1%] and 7.2% [95% CI, 6.6%-7.8%], respectively; P < .001); (2) deep incisional infection in Whipple (1.7% [95% CI, 1.1%-2.3%] vs 2.7% [95% CI, 2.5%-2.9%]; P < .01); (3) organ space infection in right lobe hepatectomy (7.2% [95% CI, 6.0%-8.4%] vs 9.0% [95% CI, 8.2%-9.8%]; P = .02), trisegmental hepatectomy (12.4% [95% CI, 11.1%-13.7%]; P < .001), and Whipple (12.9% [95% CI, 12.4%-13.4%]; P < .001); and (4) return to the operating room for esophagectomy (6.8% [95% CI, 5.6%-8.0%] vs 14.4% [95% CI, 13.6%-15.2%]; P < .001). Median (IQR) length of hospital stay was lower in CRS/HIPEC (8 [5-11] days) than Whipple (10 [7-15] days) and esophagectomy (10 [8-16] days) (P < .001). Overall 30-day mortality was lower in CRS/HIPEC (1.1%; 95% CI, 0.6%-1.6%) compared with Whipple (2.5%; 95% CI, 2.3%-2.7%), right lobe hepatectomy (2.9%; 95% CI, 2.4%-3.4%), esophagectomy (3.0%; 95% CI, 2.6%-3.4%), and trisegmental hepatectomy (3.9%; 95% CI, 3.1%-4.7%) (P < .001). Conclusions and Relevance: Comparative analysis revealed CRS/HIPEC to be safe, often safer across the spectrum of NSQIP safety metrics when compared with similar-risk oncologic procedures. Patient selection was important in achieving observed outcomes. High complication rates are a misperception from early CRS/HIPEC experience and should no longer deter referral of patients to experienced centers or impede clinical trial development in the United States.

Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy in the Management of Colorectal Peritoneal Metastasis.

Historically, patients with peritoneal carcinomatosis secondary to colorectal cancer have a poor overall prognosis. Recent data support the use of cytoreductive surgery and heated intraperitoneal chemotherapy (CRS + HIPEC) to specifically address the peritoneal disease. Retrospective studies on CRS + HIPEC have been promising, showing significant improvements in OS compared with systemic chemotherapy alone. However, CRS + HIPEC carries morbidity similar to other advance oncology procedures such as liver resection and pancreatoduonectomy. It is hoped that ongoing clinical trials will clarify its role in the treatment of patients with peritoneal metastatic colorectal cancer.

The Efficacy of Dextran-40 as a Venous Thromboembolism Prophylaxis Strategy in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

The incidence of venous thromboembolism (VTE) in peritoneal malignancies can approach 30 to 50 per cent without prophylaxis. Prophylaxis in cytoreductive surgeries (CRS) presents a challenge to preoperative heparin-based therapy because of an increased risk of coagulopathy and potential for bleeding. Herein, we report the large series of CRS and hyperthermic intraperitoneal chemotherapy receiving dextran-40 prophylaxis. Retrospective chart review of peritoneal malignancies patients undergoing CRS at University of Nebraska Medical Center identified 69 individuals who received dextran-40 between 2010 and 2013. The incidences of VTEs, perioperative bleeding, complications, morbidity, and mortality were determined in-hospital and at 90 days. Of the 69 patients treated, the 30-day VTE rate was 8.7 per cent, and no pulmonary embolisms, bleeding, anaphylactoid reaction, or mortality were observed with dextran usage. The specific VTE events included three upper extremity and three lower extremity VTEs. No additional VTE events were identified between 30 and 90 days. In conclusion, dextran-40 prophylaxis was not associated with any perioperative bleeding events, and the observed incidence of VTE was comparable to reported heparin-based prophylaxis in CRS/hyperthermic intraperitoneal chemotherapy patients. This data supports further exploration of dextran-40 as a VTE prophylactic agent in complex surgical oncology cases.

The American Society of Peritoneal Surface Malignancies Multi-Institution evaluation of 1,051 advanced ovarian cancer patients undergoing cytoreductive surgery and HIPEC: An introduction of the peritoneal surface disease severity score.

BACKGROUND: Standard treatment for ovarian epithelial cancer (OEC) consists of cytoreductive surgery (CRS) and a platinum-taxane chemotherapy combination. There is increasing interest in evaluating hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with stage IIIC/IV disease. The peritoneal surface disease severity score (PSDSS) was introduced as a basis to improve patient selection for this therapy in OEC. METHODS: The charts of 1,051 patients with advanced OEC who underwent CRS/HIPEC were retrospectively evaluated using the following preoperatively obtained criteria: symptoms, peritoneal dissemination, and tumor histology. Overall survival was analyzed according to PSDSS as well as the timings and agents used during CRS/HIPEC. RESULTS: Median survival for all 1,051 patients was 73.4 months. PSDSS information was available for 553 patients. Survival correlated negatively with PSDSS (P < 0.001). Furthermore, combining PSDSS scores into I/II and III/IV described two distinct patient populations with vastly different outcomes, 100 versus 55 months, respectively (P < 0.001). Multivariate analysis failed to describe any differences between timings of HIPEC or chemotherapy agents used. CONCLUSION: PSDSS was capable of identifying a better surviving patient population in advanced-stage OEC. While randomized trials to evaluate the benefit of HIPEC are needed, the PSDSS may be a useful tool for selecting and stratifying OEC patients in clinical trials. J. Surg. Oncol. 2016;114:779-784. © 2016 2016 Wiley Periodicals, Inc.

Early identification of DPAM in at-risk low-grade appendiceal mucinous neoplasm patients: a new approach to surveillance for peritoneal metastasis.

BACKGROUND: Disseminated peritoneal adenomucinosis (DPAM) patients often have a history of appendectomy with identification of an incidental mucinous neoplasm (low-grade appendiceal mucinous neoplasm (LAMN)). The rate of developing DPAM is not well established. METHODS: Twenty-two patients with incidental LAMN were identified and monitored with cancer markers and CT every 4-6 months. Laparoscopy with peritoneal washing was performed in patients either in the event of radiographic disease or after 12 months in absence of radiographic disease. The rate of detecting peritoneal metastasis was determined for CT scan and laparoscopy. RESULTS: Peritoneal metastasis was detected in 5 (23 %) patients. Occult disease was detected in four patients at laparoscopy without a detectable disease on CT scan. One patient developed radiographic progression at 6 months confirmed with laparoscopy. Four patients were treated with cytoreductive surgery (CRS)/HIPEC and one with CRS only. The 17 patients with negative laparoscopy remain disease free with a median follow-up of 50 months. CONCLUSIONS: The rate of peritoneal metastasis in incidental LAMN patients was 23 %. Laparoscopy was the primary screening tool identifying occult metastasis. The median PCI of 7 was low, and all the patients underwent R0/R1 resections. This study revealed 1 in every 4.4 patients with LAMN may develop PMP. Longer follow-up and further patient surveillance is warranted.