Treatment of Peritoneal Surface Malignancies by Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Spain: Results of the National Registry of the Spanish Group of Peritoneal Oncologic Surgery (REGECOP).

INTRODUCTION: Treatment of Peritoneal Surface Malignancies (PSM) with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has achieved results never seen before in these patients, which classically have a poor prognosis. The possibility of conducting clinical trials in these diseases is complicated, since some of them are rare, so the analysis of large databases provides very valuable scientific information. The aim of this study is to analyze the global results of the National Registry of the Spanish Group of Peritoneal Oncologic Surgery (REGECOP), whose objective is to register all patients scheduled for HIPEC nationwide. METHODS: This is a retrospective analysis of the data recorded in the REGECOP from 36 Spanish hospitals from 2001 to 2021. There were 4159 surgical interventions in 3980 patients. RESULTS: 66% are women and 34% are men with a median age of 59 years (range 17-86). 41.5% of the patients were treated for Peritoneal Metastases (PM) of colorectal cancer (CRC); 32.4% were women with ovarian cancer (OC) with PM; 12.8% were treated for pseudomyxoma peritonei (PMP); 6.2% had PM from gastric cancer (GC); 4.9% had PM of non-conventional origin; and, finally, 2.1% of cases were patients diagnosed with peritoneal mesothelioma. The median Peritoneal Cancer Index (PCI) was 9 (0-39), and complete cytoreduction was achieved in 81.7% of the procedures. Severe morbidity (Dindo-Clavien grade III-IV) was observed in 17.7% of surgeries, with 2.1% mortality. Median hospital stay was 11 days (0-259). Median overall survival (OS) was 41 months for CRC patients, 55 months for women with OC, was not reached in PMP patients, was 14 months for GC patients, and 66 months in mesothelioma patients. CONCLUSIONS: large databases provide extremely useful data. CRS with HIPEC in referral centers is a safe treatment with encouraging oncologic results in PSM.

Efficacy and Safety of Intraoperative Hyperthermic Intraperitoneal Chemotherapy for Locally Advanced Colon Cancer: A Phase 3 Randomized Clinical Trial.

Importance: Peritoneal metastasis in patients with locally advanced colon cancer (T4 stage) is estimated to recur at a rate of approximately 25% at 3 years from surgical resection and is associated with poor prognosis. There is controversy regarding the clinical benefit of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. Objective: To assess the efficacy and safety of intraoperative HIPEC in patients with locally advanced colon cancer. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted in 17 Spanish centers from November 15, 2015, to March 9, 2021. Enrolled patients were aged 18 to 75 years with locally advanced primary colon cancer diagnosed preoperatively (cT4N02M0). Interventions: Patients were randomly assigned 1:1 to receive cytoreduction plus HIPEC with mitomycin C (30 mg/m2 over 60 minutes; investigational group) or cytoreduction alone (comparator group), both followed by systemic adjuvant chemotherapy. Randomization of the intention-to-treat population was done via a web-based system, with stratification by treatment center and sex. Main Outcomes and Measures: The primary outcome was 3-year locoregional control (LC) rate, defined as the proportion of patients without peritoneal disease recurrence analyzed by intention to treat. Secondary end points were disease-free survival, overall survival, morbidity, and rate of toxic effects. Results: A total of 184 patients were recruited and randomized (investigational group, n = 89; comparator group, n = 95). The mean (SD) age was 61.5 (9.2) years, and 111 (60.3%) were male. Median duration of follow-up was 36 months (IQR, 27-36 months). Demographic and clinical characteristics were similar between groups. The 3-year LC rate was higher in the investigational group (97.6%) than in the comparator group (87.6%) (log-rank P = .03; hazard ratio [HR], 0.21; 95% CI, 0.05-0.95). No differences were observed in disease-free survival (investigational, 81.2%; comparator, 78.0%; log-rank P = .22; HR, 0.71; 95% CI, 0.41-1.22) or overall survival (investigational, 91.7%; comparator, 92.9%; log-rank P = .68; HR, 0.79; 95% CI, 0.26-2.37). The definitive subgroup with pT4 disease showed a pronounced benefit in 3-year LC rate after investigational treatment (investigational: 98.3%; comparator: 82.1%; log-rank P = .003; HR, 0.09; 95% CI, 0.01-0.70). No differences in morbidity or toxic effects between groups were observed. Conclusions and Relevance: In this randomized clinical trial, the addition of HIPEC to complete surgical resection for locally advanced colon cancer improved the 3-year LC rate compared with surgery alone. This approach should be considered for patients with locally advanced colorectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02614534.

Peritoneal Mesothelioma in a High Volume Peritoneal Surface Malignancies Unit.

Diffuse malignant peritoneal mesothelioma (PM) is a rare neoplasm, traditionally associated with a poor prognosis. There are other varieties of PM that are even less frequent and of uncertain malignancy. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has achieved prolonged survival in selected patients. The aim of this study is to analyze the patients with PM assessed in our center. Clinicopathological characteristics, diagnostic procedures and survival results from patients with PM appraised at our unit, according to the applied treatment, were analyzed. Seventeen patients were assessed between 2007 and 2019. Three cases had multicystic PM that were treated with complete CRS + HIPEC; all patients are alive and free of disease after a long follow-up. Three other cases had biphasic PM; a curative treatment could be performed in none of them, and their survival was minimal (<6 moths). Lastly, 11 cases with epithelioid PM were treated. Two cases were considered unresectable at laparoscopy (PCI 39); one of them had a long survival (67 months) with three iterative laparoscopic palliatives HIPECs for refractory ascites. The other nine cases were treated with curative CRS + HIPEC, with a median PCI of 14 (range 4-25), and a median overall survival (OS) of 58 months, with a 5-year OS of 47.4%. In conclusion, CRS + HIPEC, when possible, appears to be the optimal treatment for patients with PM. Knowledge of this therapeutic option is crucial, both to offer it to patients and to avoid delays in their referral to appropriate centers for treatment.

Gastric Cancer with Peritoneal Metastases: Current Status and Prospects for Treatment.

Gastric cancer (GC) has a poor prognostic and only one in four patients will have survived by 5 years after diagnosis. These poor results are due to the fact that most patients are diagnosed in advanced stages; peritoneal metastases (PM) are especially frequent and are difficult to treat. Currently, PM are considered a terminal stage of GC with a poor survival rate and are treated with palliative systemic chemotherapy. Since the beginning of the century, the treatment of PM from different origins has evolved; cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have become the treatment of choice for many malignant diseases that affect the peritoneum. CRS and HIPEC have also been used for patients with GC and PM, achieving survival results that have never been achieved when using systemic chemotherapy alone. The use of HIPEC can even prevent the development of peritoneal recurrences in patients with locally advanced GC as adjuvant therapy, can reduce the volume of peritoneal disease as neoadjuvant therapy, and can control symptoms in a palliative setting. The aim of this review is to collate the current scientific evidence regarding the treatment of PM of GC origin with surgery and intraperitoneal chemotherapy.

Predicting Adherence to Walking from Anxiety, Depression, Disease Impact, Catastrophizing, and Cognitive Fusion in Patients with Fibromyalgia: Does Pain Severity Matter?

AIM: This study analyzed whether the contribution of several factors associated with walking adherence in fibromyalgia (FM) patients varies across pain severity levels. METHODS: Participants were 228 women with FM (mean age 57 years; SD = 8.49). RESULTS: Bivariate analyses replicated the expected association between predictors (FM impact, anxiety, depression, catastrophizing, and cognitive fusion) and poorer adherence to walking. Multivariate analyses showed a negative contribution of FM impact, catastrophizing, and depression on walking adherence after controlling for pain levels (all p < 0.01). A moderation effect of pain severity in the relationship between predictors and adherence to walking was only found for cognitive fusion (B = -0.01, t = -2.02, p = 0.040). Specifically, cognitive fusion only contributed to poor walking adherence at moderate and severe pain levels, but not when pain was mild. The contribution of the remaining predictors was not moderated by pain levels, which means that they contributed to walking adherence irrespective of the pain severity of the patient. Pain severity did not contribute to walking adherence when controlling for the predictors. CONCLUSION: Clinical implications are discussed from the perspective of personalized interventions and preferable target interventions when attempting to increase adherence to walking in this population.

GECOP-MMC: phase IV randomized clinical trial to evaluate the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) with mytomicin-C after complete surgical cytoreduction in patients with colon cancer peritoneal metastases.

BACKGROUND: The French PRODIGE 7 trial, published on January 2021, has raised doubts about the specific survival benefit provided by HIPEC with oxaliplatin 460 mg/m2 (30 minutes) for the treatment of peritoneal metastases from colorectal cancer. However, several methodological flaws have been identified in PRODIGE 7, specially the HIPEC protocol or the choice of overall survival as the main endpoint, so its results have not been assumed as definitive, emphasizing the need for further research on HIPEC. It seems that the HIPEC protocol with high-dose mytomicin-C (35 mg/m2) is the preferred regime to evaluate in future clinical studies. METHODS: GECOP-MMC is a prospective, open-label, randomized, multicenter phase IV clinical trial that aims to evaluate the effectiveness of HIPEC with high-dose mytomicin-C in preventing the development of peritoneal recurrence in patients with limited peritoneal metastasis from colon cancer (not rectal), after complete surgical cytoreduction. This study will be performed in 31 Spanish HIPEC centres, starting in March 2022. Additional international recruiting centres are under consideration. Two hundred sixteen patients with PCI ≤ 20, in which complete cytoreduction (CCS 0) has been obtained, will be randomized intraoperatively to arm 1 (with HIPEC) or arm 2 (without HIPEC). We will stratified randomization by surgical PCI (1-10; 11-15; 16-20). Patients in both arms will be treated with personalized systemic chemotherapy. Primary endpoint is peritoneal recurrence-free survival at 3 years. An ancillary study will evaluate the correlation between surgical and pathological PCI, comparing their respective prognostic values. DISCUSSION: HIPEC with high-dose mytomicin-C, in patients with limited (PCI ≤ 20) and completely resected (CCS 0) peritoneal metastases, is assumed to reduce the expected risk of peritoneal recurrence from 50 to 30% at 3 years. TRIAL REGISTRATION: EudraCT number: 2019-004679-37; Clinicaltrials.gov: NCT05250648 (registration date 02/22/2022, ).

Review of management and treatment of peritoneal metastases from gastric cancer origin.

Gastric cancer (GC) is the third cause of cancer-related deaths in the world, with less than 25% survivors at 5 years. These results are largely related to the high incidence of peritoneal metastases (PM) in these patients. Nowadays, the standard treatment for GC with PM is palliative systemic chemotherapy (SCT) with a survival of 6 months. From the 2000s, the combination of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been gaining popularity for different neoplastic diseases that involve the peritoneal surface. The use of CRS and HIPEC has been studied for GC with PM, with promising results in selected patients, obtaining survival rates never seen before. Moreover, HIPEC and other intraperitoneal chemotherapy techniques have been used to prevent peritoneal recurrences in patients diagnosed on locally advanced GC without macroscopic PM (adjuvant or prophylactic HIPEC). Even, intraperitoneal chemotherapy [laparoscopic HIPEC and neoadjuvant intraperitoneal and systemic chemotherapy (NIPS)] has been used as neoadjuvant treatment to reduce peritoneal disease burden in order to improve the rate of patients in whom complete cytoreduction can be achieved. Finally, patients with high volume peritoneal disease can be treated by palliative intraperitoneal chemotherapy to control the symptoms resulting from malignant ascites, using laparoscopic HIPEC or pressurized intraperitoneal aerosol chemotherapy (PIPAC). This review aims to update the management of PM from GC origin in these different clinical scenarios, based on the literature and the experience of the authors.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Gastric Cancer with Peritoneal Carcinomatosis: Multicenter Study of Spanish Group of Peritoneal Oncologic Surgery (GECOP).

BACKGROUND: Gastric cancer (GC) with peritoneal carcinomatosis (PC) is traditionally considered a terminal stage of the disease. The use of a multimodal treatment, including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), can benefit these patients. Our goal was to evaluate the morbidity and survival outcomes of these patients. METHODS: This is a retrospective, multicenter study from a prospective national database of patients diagnosed with PC secondary to GC treated with CRS and HIPEC from June 2006 to October 2017. RESULTS: Eighty-eight patients from seven specialized Spanish institutions were treated with CRS and HIPEC, with median age of 53 years; 51% were women. Median Peritoneal Cancer Index (PCI) was 6, and complete cytoreduction was achieved in 80 patients (90.9%). HIPEC was administered in 85 cases with 4 different regimens (Cisplatin + Doxorubicin, Mitomycin-C + Cisplatin, Mitomycin-C and Oxaliplatin). Twenty-seven cases (31%) had severe morbidity (grade III-IV) and 3 patients died in the postoperative period (3.4%). Median follow-up was 32 months. Median overall survival (OS) was 21.2 months, with 1-year OS of 79.9% and 3-year OS of 30.9%. Median disease-free survival (DFS) was 11.6 months, with 1-year DFS of 46.1% and 3-year DFS of 21.7%. After multivariate analysis, the extent of peritoneal disease (PCI ≥ 7) was identified as the only independent factor that influenced OS (hazard ratio [HR] 2.37, 95% confidence interval [CI] 1.26-4.46, p = 0.007). CONCLUSIONS: The multimodal treatment, including CRS and HIPEC, for GC with PC can improve the survival results in selected patients (PCI < 7) and in referral centers.

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with gastric cancer and peritoneal carcinomatosis.

BACKGROUND: Gastric Cancer (GC) with Peritoneal Carcinomatosis (PC) has long been regarded as a terminal disease. Over the past two decades, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has changed the traditional concept of peritoneal metastases from being a systemic disease, to being considered a locoregional dissemination. PATIENTS AND METHODS: A prospective study was performed at a high-volume Carcinomatosis Center to evaluate survival, morbi-mortality and prognostic factors for survival in a cohort of patients with GC and PC treated with CRS + HIPEC between June 2006 and December 2016. RESULTS: Thirty-five patients were included in the study. Median follow-up was 54 months. Postoperative major complications (>grade IIIa) occurred in 25.7% of patients, including 2 deaths (mortality 5.7%). The median overall survival (OS) was 16 months and the 1-, 3- and 5-year OS rates were 70.8%, 21.3% and 21.3% %, respectively. The median OS for patients with PCI ≤6 was 19 months, in contrast to 12 months for the 19 patients with PCI >6. Three patients were included with only a positive cytology and their median OS was not reached. Perineural invasion was the only factor that had a negative influence in prognosis (HR 18.8) in multivariate analysis. CONCLUSION: Although GC with PC still has a poor prognosis, survival has improved in selected patients with CRS + HIPEC and perioperative systemic chemotherapy. Patients with isolated positive cytology or peritoneal carcinomatosis with PCI less than 6 had encouraging survival rates.

Systematic Second-look Surgery Plus HIPEC in Patients Without Evidence of Recurrence, at High Risk of Carcinomatosis After Colorectal Cancer Resection. / Cirugía de second look más HIPEC en pacientes sin evidencia de recidiva con alto riesgo de desarrollar carcinomatosis tras resección de cáncer colorrectal.

INTRODUCTION: To analyze the impact of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) performed 1 year after resection of the primary tumor, in asymptomatic patients at high risk of developing peritoneal carcinomatosis (PC). METHODS: Between 2012-2016, 33 patients without any sign of peritoneal recurrence on imaging studies were prospectively included in the study and underwent second-look surgery aimed at treating limited PC earlier and were prospectively recorded. They were selected based on 5 primary tumor-associated criteria: resected minimal synchronous macroscopic PC (n = 10), synchronous ovarian metastases (n = 2), positive peritoneal cytology (n = 2), pT4 primary tumors (n = 15) and perforation (n = 4). RESULTS: PC was found and treated by cytoreduction plus HIPEC in 10 of the 33 (30.3%) patients, although it was detected in only 2/15 patients of the pT4 subgroup (13.3%). The patients without PC underwent complete abdominal exploration plus HIPEC. Median follow-up was 14.5 months. One patient died postoperatively at day 55. Severe morbidity rate (Clavien-Dindo III-V) was low (15.2%). The 3-year overall survival rate was 93% and the 3-year disease-free survival rate was 33%. Peritoneal recurrences occurred in 4 patients (12.1%), 2 of whom had macroscopic PC discovered at the second-look (20%), while the other 2 patients had no macroscopic PC (8.7%) (P = .04). CONCLUSIONS: The second look + HIPEC strategy in our series of patients at high risk of developing PC, allows its early detection and its treatment in 30.3% of cases, with a very low rate of peritoneal recurrence. It is important to continue evaluating the results to increase the accuracy of the inclusion criteria, especially the pT4 criterion that in this series has a low predictive power for the occurrence of PC.

Cirugía de second look más HIPEC en pacientes sin evidencia de recidiva con alto riesgo de desarrollar carcinomatosis tras resección de cáncer colorrectal / Systematic Second-look Surgery Plus HIPEC in Patients Without Evidence of Recurrence, at High Risk of Carcinomatosis After Colorectal Cancer Resection

Introducción: Analizar el impacto de la cirugía de second look (CSL) combinada con quimioterapia intraperitoneal hipertérmica (HIPEC) realizada un año después de la cirugía del tumor primario en pacientes asintomáticos con alto riesgo de desarrollar carcinomatosis peritoneal (CP) tras resección de cáncer colorrectal. Métodos: Entre febrero 2012 y febrero 2016, 33 pacientes con alto riesgo de recidiva peritoneal, sin signos de recurrencia en pruebas de imagen fueron prospectivamente incluidos en el estudio y sometidos a CSL con el objetivo de tratar posibles recidivas peritoneales precozmente. Los pacientes fueron seleccionados por 5 criterios: pT4 (n = 15), citología peritoneal positiva por cáncer (n = 2), tumor perforado (n = 4), enfermedad peritoneal sincrónica resecada (n = 10), metástasis ováricas sincrónicas resecadas (n = 2). Resultados: Se detectó carcinomatosis peritoneal (CP) en 10 de los 33 pacientes (30,3%) (CP+), en los cuales se realizó citorreducción completa más HIPEC. En el subgrupo de los pacientes pT4 (n = 15) se detectó CP solo en 2 casos (13,3%). El resto de los pacientes (CP-) fueron sometidos a HIPEC profiláctica. La mediana de seguimiento después de CSL ha sido de 14,5 meses. La tasa de morbilidad postoperatoria grave (Clavien-Dindo III-V) fue del 15,2% (5/33) y la mortalidad del 3,0% (1 paciente al 55.° día postoperatorio). La supervivencia global a 3 años fue del 93% y la supervivencia libre de enfermedad del 33%. Tras CSL + HIPEC, 4/33 pacientes (12,1%) recidivaron en el peritoneo, 2 CP + (20%) y 2 CP - (8,7%) (p = 0,04). Conclusiones: La realización de CSL + HIPEC en nuestra serie de pacientes con alto riesgo de desarrollar CP permite su detección temprana y su tratamiento en el 30,3% de los casos, con una tasa muy baja de recurrencia peritoneal posterior. Es importante continuar evaluando los resultados para aumentar la precisión de los criterios de inclusión, especialmente del criterio pT4, que en esta serie tiene un bajo poder predictivo para la aparición de CP (AU)

Introduction: To analyze the impact of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) performed 1 year after resection of the primary tumor, in asymptomatic patients at high risk of developing peritoneal carcinomatosis (PC). Methods: Between 2012-2016, 33 patients without any sign of peritoneal recurrence on imaging studies were prospectively included in the study and underwent second-look surgery aimed at treating limited PC earlier and were prospectively recorded. They were selected based on 5 primary tumor-associated criteria: resected minimal synchronous macroscopic PC (n = 10), synchronous ovarian metastases (n = 2), positive peritoneal cytology (n = 2), pT4 primary tumors (n = 15) and perforation (n = 4). Results: PC was found and treated by cytoreduction plus HIPEC in 10 of the 33 (30.3%) patients, although it was detected in only 2/15 patients of the pT4 subgroup (13.3%). The patients without PC underwent complete abdominal exploration plus HIPEC. Median follow-up was 14.5 months. One patient died postoperatively at day 55. Severe morbidity rate (Clavien-Dindo III-V) was low (15.2%). The 3-year overall survival rate was 93% and the 3-year disease-free survival rate was 33%. Peritoneal recurrences occurred in 4 patients (12.1%), 2 of whom had macroscopic PC discovered at the second-look (20%), while the other 2 patients had no macroscopic PC (8.7%) (P = .04). Conclusions: The second look + HIPEC strategy in our series of patients at high risk of developing PC, allows its early detection and its treatment in 30.3% of cases, with a very low rate of peritoneal recurrence. It is important to continue evaluating the results to increase the accuracy of the inclusion criteria, especially the pT4 criterion that in this series has a low predictive power for the occurrence of PC (AU)

Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) with primary or secondary cytoreductive surgery in the treatment of advanced epithelial ovarian cancer.

BACKGROUND: Peritoneal dissemination is the most common route of spread of epithelial ovarian cancer (EOC). Cytoreductive surgery (CRS) followed by platinum-based systemic chemotherapy is the current standard treatment in advanced stages, with suboptimal results. The aim of this study is to analyze the outcome of advanced EOC treated with CRS plus hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) combined with systemic chemotherapy. METHODS: We analyze a cohort of women treated with CRS plus HIPEC for peritoneal carcinomatosis secondary to EOC from May 2007 to December 2014. We included both patients with peritoneal disease at first diagnosis of EOC and peritoneal recurrences after initial treatment. RESULTS: We performed 61 CRS with HIPEC procedures, 31 cases as primary treatment (4 as upfront therapy and 27 after neoadjuvant chemotherapy) and 30 as secondary treatment (recurrences). Median Peritoneal Carcinomatosis Index (PCI) was 9; the cytoreduction was optimal in 92% of the procedures. Severe morbidity (Grade III-IV of Clavien-Dindo classification) was 29.5%, without mortality. Median follow-up was 23 months and median disease-free survival (DFS) was 14 months (14 in primary surgery group and 17 in recurrence group, P=0.51). Median overall survival (OS) was 57 months; in primary surgery group, OS was 96.8% at 1 year, and 55% at 5 years, and median OS was not reached; OS in recurrence group was 89.3% at 1 year and 47.1% at 5 years, and median OS was 57 months. CONCLUSIONS: CRS with HIPEC is a treatment option for EOC with good results in terms of morbidity and survival, in experienced centers.