Gastric cancer with peritoneal metastases: a single center outline and comparison of different surgical and intraperitoneal treatments.

INTRODUCTION: Gastric cancer with peritoneal metastasis (GCPM) has an unfavourable prognosis. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are promising treatment options that have been shown to improve survival. The aim of this study was to assess the impact of different treatments such as systemic chemotherapy, systemic chemotherapy + PIPAC, and CRS + HIPEC in patients with GCPM. MATERIAL AND METHODS: This single-centre retrospective study included 82 patients with GCPM treated between January 2016 and June 2021. After first-line chemotherapy, depending on disease response and burden, the patients were divided into three treatment groups: chemotherapy alone, chemotherapy + PIPAC, and CRS + HIPEC. The primary outcome was overall survival (OS) from diagnosis, which was compared among the treatment groups. RESULTS: Thirty-seven (45.1%) patients were administered systemic chemotherapy alone, 25 (30.4%) received chemotherapy + PIPAC, and 20 (24.4%) underwent CRS + HIPEC. The CRS + HIPEC group had better OS (median 24 months) than the PIPAC group (15 months, p = 0.01) and chemotherapy group (5 months, p = 0.0001). Following CRS + HIPEC, the postoperative grade 3-4 complication rate was 25%, and no postoperative in-hospital deaths occurred. The median disease-free survival (DFS) was 12 months. Multivariate analysis identified peritoneal carcinomatosis index (PCI) > 7 as an independent predictor of worse DFS. No independent predictors of OS were identified. CONCLUSION: Among patients with GCPM, we identified a highly selected population with oligometastatic disease. In this group, CRS + HIPEC provided a significant survival advantage with an acceptable major complication rate compared with other available therapies (systemic chemotherapy alone or in combination with PIPAC).

Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery in colorectal carcinoma at high risk of peritoneal carcinomatosis: short-term and long-term outcomes from the CHECK study - protocol for a randomised, multicentre, phase 3 trial.

INTRODUCTION: Up to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts' involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking. METHODS AND ANALYSIS: This is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method. ETHICS AND DISSEMINATION: This trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification.The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings. TRIAL REGISTRATION NUMBER: NCT03914820.

The prognostic value of skeletal muscle index on clinical and survival outcomes after cytoreduction and HIPEC for peritoneal metastases from colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: Cytoreductive surgery (CRS) and hypertermic intraperitoneal chemotherapy (HIPEC) represent the most effective strategy to manage peritoneal metastases (PM). This systematic review and meta-analysis aimed to assess the impact of body composition on clinical outcomes in patients with PM. METHODS: A systematic literature search was performed using Medline, Web of Science and EMBASE databases from inception to the 20st August 2020. Data were independently extracted by 3 authors. Newcastle-Ottawa Scale was used to assess quality and risk of bias of studies. Pooled analyses were performed using Mantel-Haenszel method to estimate overall effect size with mean differences or odd ratios (ORs) and 95% confidence interval (CI). The primary outcome was postoperative complication (POC) rate, while secondary outcomes were severe POC and postoperative mortality. RESULTS: A total of 4 studies were included in the systematic review and meta-analysis, including 582 patients. A significant association between low skeletal muscle mass and POC was found (OR 1.45, 95% CI 1.04 to 2.03; p = 0.03), while no differences were found in terms operative time, estimated blood loss, length of hospital stay, and postoperative mortality (p > 0.05). CONCLUSIONS: Low skeletal muscle mass at diagnosis is a valid prognostic factor for POC development in colorectal and PM patients undergoing CRS. Prospective and larger studies are needed to better investigate the role of CT scan derived body composition and to understand how to implement this tool in clinical practice.

Clinical and Molecular Features in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinosis from Colorectal Cancer.

PURPOSE: Careful patient selection plays a crucial role in avoiding overtreatment and further increases survival rates in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer (CRC) with peritoneal metastases (PM). METHODS: The clinical and molecular factors influencing survival in patients who had undergone CRS with HIPEC between January 2015 and December 2018 were analyzed. RESULTS: Sixty-six patients underwent CRS with HIPEC during the study period. The median overall survival (OS) was 36 months, with a 3-year OS of 43%. Multivariate analysis revealed increased PCI (HR: 1.21; 95% CI: 1.02-1.41; p = 0.020), right-sided primary tumor (HR: 3.01; 95% CI: 1.27-7.13; p = 0.017), and BRAF V600E mutation (HR: 4.55; 95% CI: 1.21-17.21; p = 0.025) as independent predictors for worse OS. CONCLUSION: In addition to confirming the prognostic role of PCI, our study extends the role of BRAF mutation and right primary tumor location as markers for worse prognosis.

Cytoreductive surgery and mitomycin C hyperthermic intraperitoneal chemotherapy with CO2 recirculation (HIPEC-CO2) for colorectal cancer peritoneal metastases: analysis of short-term outcomes.

Peritoneal dissemination from colorectal cancer (CRC) has long been associated with unfavorable prognosis. However, in the last decades, the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was able to obtain up to 30% 5-year survival rate in selected centers. Despite the wide diffusion of CRS and HIPEC, until now, there are no clear recommendations on the drug of choice for HIPEC nor its technique, and safety and efficacy data of HIPEC regimens and techniques are lacking. We performed a retrospective analysis of a prospectively maintained database of 26 CRS and mitomycin C HIPEC with CO2 recirculation (HIPEC-CO2) for CRC peritoneal metastasis (PM) performed at our center. The main endpoints were morbidity, mortality, the temperature of perfusate during HIPEC and metabolic changes throughout the procedure. Morbidity was assessed by analysis of postoperative adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Continuous variables of Arterial Blood Gas (ABG) analysis at three time-points were compared by the Student t test. There were no postoperative deaths. The overall grade 3-4 CTCAE complications rate at 30 days was 38.4%, with ten severe adverse events occurring to six (23.0%) patients. The temperature within HIPEC perfusion maintained between 41 and 42 °C in all cases and we experienced no HIPEC-related intraoperative complications. We observed a significant difference between all baseline and pre-HIPEC ABG parameters evaluated but no statistically significant differences between pre- and post-HIPEC ABG outcomes. This study shows that mitomycin C HIPEC-CO2 is feasible and has a safety profile comparable to that of other HIPEC techniques reported in the literature. Further research is needed to validate prospectively the safety and efficacy of this technique.

Hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancies using new hybrid CO2 system: preliminary experience in referral center.

The most frequent peritoneal surface malignancies originate principally by gastric cancer, colorectal cancer and ovarian cancer. Apart from the origin, peritoneal carcinosis (PC) is considered a negative prognostic factor. The hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal malignancies is considered an attractive method to deliver chemotherapy with enhanced effect directly at the tumor site. The use of such loco-regional approach has proved to improve prognosis of peritoneal carcinomatosis from different origins. Recently, new devices are suitable for loco-regional intraperitoneal chemotherapy as Peritoneal Recirculation System (PRS-1.0 Combat) with CO2 technology. This is a retrospective study with the aim to assess the perioperative outcomes using PRS. Seventeen patients were enrolled affected by colorectal or ovarian cancer. Complete cytoreduction (RT = 0) was achieved for all cases. Median operative time was 420 min (range: 335-665) and median drugs dose used for HIPEC was 137 mg/m2 (115-756). Median EBL was 200 ml (range 50-1000). Median post-operative hospital stay was 9 days (range: 4-24). Treatment-related early complications were recorded in 8 (47.0%) cases and were G1-G2 Major complications occurred in two (11.7%) cases. Considering our aim to test the PRS in different cases and in different pathologies, the results confirmed that the technique is feasible with good perioperative outcomes.

A novel HIPEC technique using hybrid CO2 recirculation system: intra-abdominal diffusion test in a porcine model.

The role of loco-regional treatment of peritoneal carcinomatosis using intraperitoneal chemotherapy is still investigated. Actually, new technologies are suitable for these procedures, especially a new hybrid system using CO2 called Peritoneal Recirculation System (PRS-1.0 Combat). A HIPEC procedure in a porcine model using the PRS system was conducted. The objective of experimentation was to assess the distribution of liquid inside the abdomen, by using methylene blue instead of chemotherapy. Moreover, we positioned six different thermal probes in different abdominal regions inside the abdomen to measure the temperature during procedure. During the procedure, all thermal probes recorded an average temperature of 41.5°. At the end of infusion, the abdomen was emptied and then opened; the tracer distribution was recorded. No technical problems were recorded during the procedure. Good distribution of tracer was recorded. More studies are needed to investigate better this new technology.

Krukenberg Tumors of Gastric Origin: The Rationale of Surgical Resection and Perioperative Treatments in a Multicenter Western Experience.

BACKGROUND: In case of Krukenberg tumor (KT) of gastric origin it is controversial and debated whether radical surgery in case of synchronous KT or metastasectomy in case of metachronous ones is associated with additional benefits. Role of perioperative treatments is unclear. METHODS: Among 2515 female patients who were diagnosed with gastric cancer between January 1990 and December 2012 from 9 Italian centers, 63 presented simultaneously or developed KT as recurrence. RESULTS: Thirty patients presented with synchronous KT, while 33 developed metachronous ovarian metastases during follow-up. The differences between the two groups were analyzed and compared. The median age of 63 patients was 48.0 years (range 31-71). Resection was possible in 53 patients (20 synchronous and 33 metachronous). Twelve patients in the synchronous group and 15 patients of the metachronous group underwent hyperthermic intraperitoneal chemotherapy after resection of KT. All of them underwent adjuvant chemotherapy after KT resection. The median survival for all population was 23 months (95 % confidence interval, 7-39 months). The median survival time in the metachronous group was 36 months, which was significantly longer than that in the synchronous group, 17 months, p < 0.0001. CONCLUSIONS: KT remains a clinical challenge for gastric cancer therapy. The extent of disease and feasibility of removal of the metastatic lesion must be carefully evaluated prior to surgery to define the patients group who could benefit most from a resection associated with perioperative treatments.

Improved outcomes for rectal cancer in the era of preoperative chemoradiation and tailored mesorectal excision: a series of 338 consecutive cases.

Neoadjuvant chemoradiation (CRT), tailored mesorectal excision, and intraoperative radiotherapy (IORT) have become the leading measures for rectal cancer treatment. The objective of this study was to evaluate early and long-term results of a multimodal treatment model for rectal cancer followed by curative surgery. Prospectively collected hospital records of 338 patients surgically treated for rectal cancer between January 1998 and December 2008 were retrospectively reviewed. Patients with high rectum level cancers and those with middle and low rectum cancers with clinical stage T1 to T2 underwent surgery, whereas those with T3 to T4 and N+ disease at the middle and low rectum received neoadjuvant CRT in 96.2 per cent of cases. Short-course neoadjuvant radiotherapy was not considered for neoadjuvant treatment. Postoperative major complications and mortality rates were 12.7 and 2.3 per cent, respectively. Overall 5-year disease-specific and disease-free survival were 80 and 73.1 per cent, respectively, whereas local recurrence rate was 6.1 per cent. At multivariate analysis, nodal status and circumferential margin status were independently associated with poor survival; local recurrence rates were independently affected by nodal and marginal status and tumor stage. The extent of mesorectal excision should be tailored depending on tumor location and the use of neoadjuvant chemotherapy, combined with IORT in advanced middle and low rectal cancer, leading to remarkable tumor downstaging with excellent prognosis in responding patients.

Intraoperative radiation therapy in resected pancreatic carcinoma: long-term analysis.

PURPOSE: The combination of external radiotherapy (RT) plus intraoperative radiotherapy (IORT) in patients with pancreatic cancer is still debated. This study presents long-term results (minimum follow-up, 102 months) for 26 patients undergoing integrated adjuvant RT (external RT+IORT). METHODS AND MATERIALS: From 1990 to 1995, a total of 17 patients with pancreatic cancer underwent IORT (10 Gy) and postoperative external RT (50.4 Gy). Preoperative "flash" RT was included for the last 9 patients. The liver and pancreatic head received 5 Gy (two 2.5-Gy fractions) the day before surgery. In the subsequent period (1996-1998), 9 patients underwent preoperative concomitant chemoradiation (39.6 Gy) with 5-fluorouracil, IORT (10 Gy), and adjuvant chemotherapy. RESULTS: Preoperative chemoradiation was completed in all patients, whereas postoperative therapy was completed in 13 of 17 patients. All 26 patients underwent pancreatectomy (25 R0 and one R1 resections). One patient died of postoperative complications (3.8%) not related to IORT. The 9 patients undergoing concomitant chemoradiation were candidates for adjuvant chemotherapy; however, only 4 of 9 underwent adjuvant chemotherapy. At last follow-up, 4 patients (15.4%) were alive and disease free. Disease recurrence was documented in 20 patients (76.9%). Sixteen patients (61.5%) showed distant metastasis, and 5 patients (19.2%) showed local recurrence. The incidence of local recurrence in R0 patients was 4 of 25 (16.0%). The overall 5-year survival rate was 15.4%. There was significant correlation with overall survival of tumor diameter (p=0.019). CONCLUSIONS: The incidence of local recurrence in this long follow-up series (19.2%) was definitely less than that reported in other studies of adjuvant RT (approximately 50%), suggesting a positive impact on local control of integrated adjuvant RT (IORT+external RT).

Combined-modality therapy in locally advanced primary rectal cancer.

PURPOSE: Patients with unresectable, locally advanced rectal cancer are reported to have a dismal prognosis. The aim of this study was to analyze the effect of combined-modality therapy on clinical outcome. METHODS: From March 1990 to December 1997, 43 patients (28 males; median age, 62 years; median follow-up, 74 months) with locally advanced (T4 and/or N3) nonmetastatic rectal cancer received external-beam radiation (23.6 plus 23.6 Gy (split course), 8 patients; 45 Gy, 35 patients) plus 5-fluorouracil (96-hour continuous infusion, Days 1-4, at 1,000 mg/m(2)/day) and mitomycin C (10 mg/m, intravenous bolus, Day 1). Concomitant chemotherapy was repeated at the beginning of the second course (split-course group) or in the last week of radiotherapy (continuous-course group). After 6 to 8 weeks, patients were evaluated for surgical resection and intraoperative radiation therapy (10 to 15 Gy). Thereafter, adjuvant chemotherapy (5-fluorouracil plus leucovorin, 6-9 courses) was prescribed. RESULTS: During chemoradiation, 5 patients (11.6 percent) developed Grade 3 to 4 hematologic toxicity. After chemoradiation, 29 patients (67.4 percent) had an objective clinical response (complete response, 2.3 percent; partial response, 65.1 percent). Thirty-eight patients underwent radical surgery (anterior resection, 24 patients; abdominoperineal resection, 14 patients; intraoperative radiation therapy boost on the tumor bed, 19 patients), and 2 patients had partial tumor resection. No perioperative deaths occurred in the patient group. Five-year survival and local control rates were 59.9 and 69.1 percent, respectively. Distant metastasis occurred in 44.2 percent of patients. Statistically significant relationships between intraoperative radiation therapy and local control (P = 0.0104), radical surgery and survival (P = 0.0120), and adjuvant chemotherapy and disease-free survival (P = 0.0112) were observed. CONCLUSIONS: Our data suggest that combined-modality therapy was relatively well tolerated and resulted in good local control and survival. With regard to the impact of surgical resection on survival, additional studies aimed at improving the local response rate are necessary, whereas the positive impact of intraoperative radiotherapy on local control appears to justify the inclusion of this therapeutic modality in prospective multi-institutional trials.