Feasibility and effectiveness of opioid-free anesthesia in cytoreductive surgery with or without heated intraperitoneal chemotherapy.

BACKGROUND: Opioid-free anesthesia (OFA) provides analgesia minimizing opioids. OFA has not been evaluated in cytoreductive surgery (CRS) with or without heated intraperitoneal chemotherapy. We aim to evaluate OFA feasibility and effectiveness in CRS. METHODS: Retrospective cohort study of adult patients (84) undergoing CRS in a tertiary center from May 2020 until June 2021. Predefined protocols for either opioid-based anesthesia (OBA) or OFA were followed. RESULTS: OFA protocol patients (41) had better mean pain scores (1 ± 0.8 vs. 2 ± 1; p = 0.00) despite the avoidance of intravenous and epidural fentanyl intraoperatively (220 ± 104 and 194 ± 73 µg, respectively, in OBA vs. 0; p = 0.00). Postoperative epidural levobupivacaine was also lower in the OFA group (575 ± 192 vs. 706 ± 346 mg; p = 0.034) despite the lack of epidural fentanyl without difference in duration (4.3 ± 1.2 vs. 4 ± 1.2 days; p = 0.22). Morphine consumption was very low (4.1 ± 10 vs. 1.7 ± 5 mg; p = 0.16). Intraoperative hypertensive events and postoperative nausea and vomiting (PONV) were higher for OBA (43) (30.2% vs. 7.3%; p = 0.01% and 69.8% vs. 34.1%; p = 0.001, respectively). Postoperative epidural fentanyl was independently associated with PONV (p = 0.004). There was no difference in total complications or length of stay. CONCLUSION: OFA is feasible, safe, and offers optimal pain control while minimizing the use of opioids in CRS.

The Landmark Series: Surgical Treatment of Colorectal Cancer Peritoneal Metastases.

BACKGROUND: Peritoneal metastases (PM) are a form of metastatic spread affecting approximately 5-15% of colon cancer patients. The attitude towards management of peritoneal metastases has evolved from therapeutic nihilism towards a more comprehensive and multidisciplinary approach, in large part due to the development of cytoreductive surgery (CRS), usually coupled with heated intraperitoneal chemotherapy (HIPEC), along with the constant improvement of systemic chemotherapy of colorectal cancer. Several landmark studies, including 5 randomized controlled trials have marked the development and refinement of surgical approaches to treating colorectal cancer peritoneal metastases. METHODS: This review article focuses on these landmark studies and their influence in 4 key areas: the evidence supporting surgical resection of peritoneal metastases, the identification and standardization of important prognostic variables influencing patient selection, the role of surgery and intraperitoneal chemotherapy in prevention of colorectal PM and the role of intraperitoneal chemotherapy as an adjuvant to surgical resection. RESULTS: These landmark studies indicate that surgical resection of colorectal PM should be considered as a therapeutic option in appropriately selected patients and when adequate surgical expertise is available. Standardized prognostic variables including the Peritoneal Cancer Index and the Completeness of Cytoreduction Score should be used for evaluating both indications and outcomes. CONCLUSIONS: Current evidence does not support the use of second look surgery with oxaliplatin HIPEC or prophylactic oxaliplatin HIPEC in patients with high risk colon cancer nor the use of oxaliplatin HIPEC with CRS of colorectal PM.

A Near-Zero Anastomotic Leak Rate in Cytoreductive Surgery with Heated Intraperitoneal Chemotherapy is Achievable.

Gastrointestinal complications are the main source of severe morbidity after cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC), mainly in the form of anastomotic leak. Reducing the rate of anastomotic leaks is of paramount importance and should be approached both through risk factor understanding and reduction, as well as optimization of surgical team performance. We performed a study that describes the details of a technical protocol for the creation of anastomoses after colorectal resections in CRS and HIPEC and the anastomotic outcomes associated with its systematic application in a high-volume peritoneal surface malignancy center. An extremely low, near-zero anastomotic leak rate (0.85% in colorectal anastomoses, 1% in ileo-colic anastomoses, and 0% in ileo-rectal anastomoses) was observed among 1172 patients. Extremely low, near-zero rates of anastomotic leak after colorectal resections in CRS and HIPEC could be achievable in high-volume peritoneal malignancy centers. The described techniques could be adopted and validated in other high-volume peritoneal malignancy centers.

Safe Anastomoses without Ostomies in Cytoreductive Surgery with Heated Intraperitoneal Chemotherapy: Technical Considerations and Modifications.

BACKGROUND: Gastrointestinal complications, predominantly anastomotic leak (AL), are the most frequent source of severe morbidity after cytoreductive surgery (CRS). OBJECTIVE: The aim of this study was to present the technical standards for colorectal anastomoses developed and systematically applied to all patients undergoing CRS in a high-volume tertiary center, and the associated AL rates. METHODS: This was a descriptive study reporting the technical characteristics of a standardized protocol for three types of colorectal anastomoses (colorectal, ileorectal, and ileocolic) in CRS with heated intraperitoneal chemotherapy (HIPEC), and a retrospective analysis of prospectively collected data on anastomotic outcomes. All patients (1172) undergoing CRS with HIPEC from September 2006 to September 2020 were included. The anastomotic complications were classified according to the International Study Group of Rectal Cancer Surgery (ISGRCS) classification. RESULTS: Overall, 1172 patients underwent 1300 procedures and 1359 gastrointestinal anastomoses. An ileocolic anastomosis was performed in 408 patients, colorectal anastomosis in 469 patients, and ileorectal anastomosis in 16 patients, none with diverting ileostomy; 345 other gastrointestinal reconstructions and 82 urinary reconstructions were performed in these patients. The AL rate was 1% (4/408) for the ileocolic anastomosis, 0.85% (4/469) for the colorectal anastomosis, and 0% (0/16) for the ileorectal anastomosis. One patient died postoperatively due to AL. CONCLUSIONS: Systematic application of standardized techniques adapted to ensure optimal tissue healing (stapled anastomoses avoiding overlap, accurate staple deployment, and hand-sewn reinforcement) are associated with a very high level of anastomotic safety in a large cohort of patients undergoing CRS and HIPEC.

Decision-Making Analysis for Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer: A Survey by the Executive Committee of the Peritoneal Surface Oncology Group International (PSOGI).

OBJECTIVES: To assess the individual treatment strategies among international experts in peritoneal carcinosis, specifically their decision-making in the process of patient selection for hyperthermic intraperitoneal chemotherapy (HIPEC) in women suffering from ovarian cancer, to identify relevant decision-making criteria, and to quantify the level of consensus for or against HIPEC. METHODS: The members of the executive committee of the Peritoneal Surface Oncology Group International (PSOGI) were asked to describe the clinical conditions under which they would recommend HIPEC in patients with ovarian cancer and to describe any disease or patient characteristics relevant to their decision. All answers were then merged and converted into decision trees. The decision trees were then analyzed by applying the objective consensus methodology. RESULTS: Nine experts in surgical oncology provided information on their multidisciplinary treatment strategy including HIPEC for patients with advanced ovarian cancer. Three of the total of 12 experts did not perform HIPEC. Five criteria relevant to the decision on whether HIPEC is performed were applied. In patients with resectable disease, a peritoneal cancer index (PCI) <21, and epithelial ovarian cancer without distant metastasis, consent was received by 75% to perform HIPEC for women suffering from recurrent disease. Furthermore, in the primary disease setting, consent was received by 67% to perform HIPEC according to the same criteria. DISCUSSION AND CONCLUSION: Among surgical oncology experts in peritoneal surface malignancy and HIPEC, HIPEC plays an important role in primary and recurrent ovarian cancer, and the PCI is the most important criterion in this decision.

Five-year survival in patients with nodular and superficial spreading melanomas in the US population.

BACKGROUND: Although superficial spreading melanomas (SSM) are diagnosed as thinner lesions, nodular melanomas (NM) have a more rapid growth rate and are biologically more aggressive compared with other histologic subtypes. OBJECTIVE: To determine the difference in 5-year relative survival in patients with NM and SSM at the same Breslow depth and TNM stage. METHODS: A population-based cross-sectional analysis compared the 5-year relative survival of patients with NM and SSM using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)∗Stat software (version 8.2.1-8.3.5). Chi-square tests compared the proportions, and Kaplan-Meier method with Z-score compared 5-year relative survival. RESULTS: For patients receiving a diagnosis between 2004 and 2009, 5-year relative survival was lower in NM compared with SSM (53.7% vs 87.3%; Z score, -41.35; P < .001). Similarly, for patients receiving a diagnosis between 2010 and 2015, 5-year relative survival was lower in NM compared with SSM (61.5% vs 89.7%; Z score, -2.7078; P < .01). Subgroup analyses showed inferior survival in NM in T1b, and survival differences remained significant after excluding patients with nodal or distant metastases. CONCLUSIONS: Five-year relative survival is worse in NM compared with SSM especially in T1b, T2a, and T2b melanomas. Melanoma subtype should be taken into consideration when making treatment recommendations.

Predictors and Outcomes of Surgery in Peritoneal Mesothelioma: an Analysis of 2000 Patients from the National Cancer Database.

INTRODUCTION: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignancy associated with poor outcomes. Recent reports have shown longer survival with radical surgery, usually combined with intraperitoneal chemotherapy. However, surgical interventions in these patients have not been extensively studied at a population level. The objective of this retrospective cohort study is to assess the prevalence of surgical and nonsurgical interventions for DMPM patients, the influence of surgery on survival outcomes, and the associations between demographic and clinical factors with treatments and outcomes. METHODS: This study included adult patients diagnosed with DMPM from 2003 to 2014 and registered in the National Cancer Database (NCDB). The primary outcome was overall survival. Histologically confirmed mesothelioma was defined using International Classification of Diseases (ICD)-3 codes 9050/3, 9051/3, 90523, and 9053/3 and peritoneum as primary affected organ using ICD codes C17-19, C22-24, C26, C42, C48, and C76. Relationships between demographic and clinical variables, surgical treatments, and survival outcomes were evaluated using logistic and Cox modeling and log-rank tests. RESULTS: A total of 2062 patients were identified, of whom 1055 (51%) did not receive any surgery while 701 (34%) received radical surgery. Patients receiving radical surgery had overall survival of 38.4 months compared with 7.1 months for patients without surgery (p < 0.001) and 41.8 months in patients who received both radical surgery and systemic chemotherapy. CONCLUSIONS: Patients selected for and treated with radical surgery had significantly better overall survival compared with those receiving nonsurgical treatment. Patients newly diagnosed with DMPM should be evaluated for the possibility of receiving radical surgery.

Genomic profiling of breast cancer in African-American women using MammaPrint.

Breast cancer in African-American females (AAF) has a less favorable outcome than that in Caucasians. More information is needed regarding its biology. We evaluated gene expression in tumors from AAF presenting with early stage or locally advanced breast cancer using MammaPrint(®), BluePrint (®) (molecular subtype) and TargetPrint (®) [estrogen receptor (ER), progesterone receptor, and Human Epidermal Growth Factor Receptor 2 (HER2) mRNA levels]. Genomic information was correlated with clinical and pathologic characteristics and Oncotype DX(®) Recurrence Score(®) (RS). One hundred Patients were enrolled, 1 not evaluable by BluePrint. The median age was 60 years (range 22-98), and eighty-four (84 %) patients had stage I or II disease. High Risk MammaPrint was present in 66 % of patients and in 52 % of patients with stage I disease. High Risk MammaPrint was associated with young age (p = 0.02), high grade (p < 0.0001), HER2 expression (p = 0.016), and triple-negative phenotype (p < 0.001). Sixty-four tumors (65 %) were Luminal type (47 % of these were classified as High Risk), 26 (26 %) were Basal type, and 9 (9 %) HER2 type. Twenty-two cancers were triple negative (TN) by IHC and 19 (90 %) Basal type. Among the 15 tumors HER2 positive by IHC/FISH, 8 (53 %) were HER2 type by BluePrint. Eleven tumors with ER expression of 1-9 % were ER negative by TargetPrint and none of these was Luminal type. None of the seven tumors HER2 positive by IHC/FISH but negative by TargetPrint was HER type. RS results were available in 29 patients: two had High Risk both by RS and MammaPrint; eight had intermediate RS, with four High Risk by MammaPrint; 19 had a low RS, with eight High Risk by MammaPrint. AAF with stage I to III breast cancer often present with High Risk disease. Molecular heterogeneity is present within TN, HER2-positive, and ER-positive breast cancer. RS and MammaPrint offer different prognostic information.

Cytoreductive Surgery and HIPEC as a Treatment Option for Laparoscopic Resection of Uterine Leiomyosarcoma with Morcellation: Early Results.

BACKGROUND: A new and frequently utilized treatment option for symptomatic uterine leiomyoma is laparoscopic resection with morcellation so the specimen can be extracted through a small abdominal incision or through the vagina. Some of these tumors (approximately 0.2 %) have malignant foci of uterine leiomyosarcoma (ULMS) that is widely disseminated in the process of resection. These patients are in need of effective additional treatments. METHODS: Patients with ULMS were treated with a standardized cytoreductive surgery (CRS), hyperthermic perioperative chemotherapy (HIPEC), and early postoperative intraperitoneal chemotherapy (EPIC) specifically designed for sarcomatosis. Distribution of disease by Peritoneal Cancer Index was recorded by preoperative computed tomography or magnetic resonance imaging and at the time of CRS. Completeness of cytoreduction score was determined after completion of CRS. Morbidity and mortality, as well as interval to start systemic chemotherapy, were prospectively recorded. RESULTS: Six patients with disseminated ULMS after morcellation or slicing underwent CRS and HIPEC plus EPIC. All six patients had complete visible clearing of sarcoma prior to perioperative chemotherapy. Early intervention after morcellation was associated with a lesser extent of disease. No serious morbidity or mortality was observed in early referral patients, and patients eligible for systemic chemotherapy were treated with perioperative chemotherapy within 6 weeks of the CRS. CONCLUSIONS: The future use of laparoscopic resection of ULMS with morcellation is currently under debate. However, patients after laparoscopic resection and morcellation have CRS and HIPEC plus EPIC as a treatment option. Results regarding short-term benefit are suggested by these early data, especially with early referral.

Iterative cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent or progressive diffuse malignant peritoneal mesothelioma: clinicopathologic characteristics and survival outcome.

BACKGROUND: Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive disease for which cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been used with remarkable survival benefits. Our aim was to analyze the clinicopathologic characteristics and prognosis of recurrent DMPM managed with iterative CRS and HIPEC. METHODS: A retrospective analysis of a prospectively maintained database for all patients treated for DMPM from 1989 to 2012. RESULTS: Of 205 consecutive CRS and HIPEC procedures, 44 (21.5 %) patients underwent an iterative procedure-22 (50.0 %) males versus 22 (50.0 %) females. Mean age at recurrence was 51.5 years. There was no 30-day mortality following an iterative procedure, and the grade III-V morbidity was 2.3 %. The median overall survival of patients undergoing an iterative CRS and HIPEC was 54 months versus 77 months following an initial CRS and HIPEC (p = 0.96). Patients undergoing an iterative surgery had a 3- and 5-year survival of 61 and 46 %, respectively, versus 60 and 52 % following an initial CRS and HIPEC. Amongst the iterative group, the achieved complete cytoreduction (CC) score was 15.9, 18.2, 22.7, and 43.2 % for CC0, CC1, CC2 and CC3, respectively, versus 3.1, 43.5, 28.6 and 24.8 %, respectively, following initial CRS (p = 0.000). Significant predictors of an improved survival in multivariate analysis were an epithelioid subtype, female sex, complete or near CC (CC0 or CC1), HIPEC regimen utilized, absence of postoperative complication, and age at diagnosis. CONCLUSION: Iterative CRS and HIPEC can be performed safely and appear to have benefits with this group of patients showing an improved median survival.

Intravenous lidocaine infusion compared to thoracic epidural analgesia in cytoreductive surgery with or without heated intraperitoneal chemotherapy. A retrospective case-cohort study.

BACKGROUND: Intravenous (IV) lidocaine is a proven analgesic therapy but has not been evaluated in extensive procedures such as cytoreductive surgery (CRS). Our aim was to assess the effectiveness and safety of IV lidocaine in this setting. METHODS: This is a retrospective hybrid case-cohort study investigating analgesic effectiveness and complications of perioperative IV lidocaine at 1.5 mg/kg/h for 48 h compared to thoracic epidural anaesthesia (TEA) among patients undergoing CRS in a high-volume centre. RESULTS: Sixty patients were included, 20 received IV lidocaine and 40 underwent TEA. Pain scores were low (median ≤2) and similar in both groups (p = 0.88). At 72 h, the lidocaine group had a lower median pain score (p = 0.03). Overall opioid consumption in the first 48 h was lower in the lidocaine compared to the TEA group (median 0 (IQR 0-9.5) mg vs. 45.4 (0-62.4) MME respectively, p = 0.001). Opioid consumption was also lower in the lidocaine compared to the TEA group during the whole 5-day period (median 1 (IQR 1-13.5) mg vs. 112 (36.6-137.85) MME respectively, p = 0.000). The incidence of PONV was significantly lower in the lidocaine group (27.5% vs 5%, p = 0.047) with no difference in other complications or length of in-hospital stay. CONCLUSION: Intravenous lidocaine infusion may be a safe and effective analgesic approach in CRS and is associated with a significant reduction of opioid use and PONV compared to opioid-containing TEA.

Wound infiltration or transversus abdominis plane block after laparoscopic radical prostatectomy: a randomized clinical trial.

BACKGROUND: Regional anesthesia techniques are commonly used for postoperative pain management during laparoscopic surgery. Our aim was to compare the analgesic efficacy of pre-incisional subcutaneous wound infiltration (WI) with that of the transversus abdominis plane (TAP) block as part of a multimodal analgesic approach in laparoscopic radical prostatectomy. METHODS: In this prospective, double-blinded, randomized controlled clinical trial, 60 patients were assigned to either TAP or WI group. The main outcome was acute postoperative pain control assessed using the mean numeric rating scale (NRS) at the 24 hours postoperatively. The secondary outcomes were opioid requirements, procedure-related complications, overall complications, and length of stay. RESULTS: In this study, 60 patients were randomized: 30 to TAP group and 28 to WI (two were excluded due to conversion to open surgery). We found no significant difference in the median (1Q, 3Q) NRS scores during the 24 h postoperatively neither at rest (TAP, 0 (0, 1) vs. WI, 0 (0, 1), P = 0.812), nor during movement (TAP, 1 (0, 2) vs. WI, 1 (0, 2), P = 0.708). There were no statistical differences in the postoperative intravenous morphine requirements in the TAP vs. WI groups during the same period (1.7 ± 3.1 vs. 1.8 ± 4.1 mg; P = 0.910). Only one patient in the TAP group presented with postoperative nausea and vomiting. CONCLUSIONS: Both pre-incisional subcutaneous WI and TAP blockade were associated with very low pain scores as part of a non-opioid multimodal analgesic regimen in laparoscopic radical prostatectomy. This study did not demonstrate the benefits of WI over TAP.

The role of intraperitoneal chemotherapy in the treatment of patients with advanced gastric cancer.

AIM: To review the published literature analyzing the role of intraperitoneal chemotherapy in gastric cancer. MATERIAL OF STUDY: Peritoneal dissemination is a well recognized and important component of disease progression in gastric cancer. Considering that involvement of the peritoneal surface can be anticipated in a large number of patients who present with an advanced gastric cancer, research efforts have been focusing not only on treatment of established peritoneal disease but also on prevention of peritoneal dissemination during surgery for primary gastric cancer. RESULTS: The pharmacologic rationale for intraperitoneal chemotherapy has been well studied. The role and results of HIPEC combined with cytoreductive surgery for patients with established carcinomatosis from gastric cancer has been reported by several groups and appears to be a promising modality for a selected group of patients with limited disease. DISCUSSION: A possible approach to patients with carcinomatosis from gastric cancer includes the use of neoadjuvant bidirectional chemotherapy (intraperitoneal and intravenous or NIPS) with subsequent cytoreduction and HIPEC for patients with a positive response to NIPS. Even more importantly, in several randomized studies and one meta-analysis, the use of intraperitoneal chemotherapy was beneficial in patients undergoing surgery for a primary, advanced gastric cancer. CONCLUSION: It appears that a significant amount of data has accumulated regarding the KEY optimal use of cytoreductive surgery and intraperitoneal chemotherapy in gastric cancer. An algorithm for the management of gastric cancer patients incorporating these treatment modalities can be implemented.

Retrospective Review of Outcomes in Non-Invasive Mucinous Appendiceal Neoplasms with and without Peritoneal Spread: A Cohort Study.

Patients treated surgically for local non-invasive mucinous appendiceal neoplasm (NI-MAN) may recur with the development of peritoneal dissemination (PD). The risk of recurrence and predictive factors are not well studied. Patients with NI-MAN, with or without peritoneal dissemination at presentation, were included. Patients with limited disease underwent surgical resection only. Patients with peritoneal dissemination underwent cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC). Patients without PD (nPD) were compared to those who presented with PD. Thirty-nine patients were included, 25 in nPD and 14 in PD. LAMN was diagnosed in 96% and 93% of patients in nPD and PD, respectively. Acellular mucin on the peritoneal surface was seen in 16% of nPD patients vs. 50% of PD patients (p = 0.019). Two (8%) patients in the nPD group who had LAMN without wall rupture recurred, at 57 and 68 months, with a PCI of 9 and 22. The recurrence rate in the PD group was 36%. All recurred patients underwent CRS+HIPEC. A peritoneal recurrence is possible in NI-MANs confined to the appendix even with an intact wall at initial diagnosis. The peritoneal disease may occur with significant delay, which is longer than a conventional follow-up.

Pressurized Intraperitoneal Aerosol Chemotherapy: The Road from Promise to Proof.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an innovative drug delivery technique invented to be used for the treatment of peritoneal metastasis. Its application gained popularity over the past years. Several prospective clinical trials are being conducted to determine efficacy and safety. At this moment, there remain many challenges to overcome before PIPAC can be widely adopted in clinical practice.See related article by Kim et al., p. 1875.

Minimally invasive surgery for T4 colon cancer is associated with better outcomes compared to open surgery in the National Cancer Database.

Minimally invasive surgery (MIS) is favored for T1-T3 colon cancer resection due to improved short and long-term outcomes. Recommendations regarding T4 cancers remain controversial due to a paucity of clinical trials or large datasets assessing outcomes. We aim to compare outcomes for pT4 colon cancer patients treated with MIS or open surgery (OS) in the National Cancer Database (NCDB). We analyzed adults having MIS or OS for stage II or III pT4 colon cancers between 2010 and 2014 using propensity-score matching, Cox and logistic regression modeling. Of 21 998 T4 patients, 7532 (34.2%) underwent MIS, 14 466 (65.8%) OS and 22.3% were MIS converted to OS. After propensity score matching, 5624 patients in each cohort were included. MIS was associated with improved postoperative mortality (3.4 vs. 7.2%, p > .001), surgical margins, optimal lymph node harvest, adjuvant chemotherapy use and 5-year survival (46% vs. 41%, P < .001). MIS was associated with improved short and long term outcomes for T4 colon cancers compared to OS on multivariate analysis. Based on these findings, well selected pT4 colon cancers can be considered appropriate for MIS however, prospective clinical trials are needed to better define the role of MIS in T4b colon cancer.