Perioperative Management of Gastric Cancer Patients Treated With (Sub)Total Gastrectomy, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Lessons Learned.

BACKGROUND: The PERISCOPE I study was designed to assess the safety and feasibility of (sub)total gastrectomy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin and docetaxel for gastric cancer patients who have limited peritoneal dissemination. The current analysis investigated changes in perioperative management together with their impact on postoperative outcomes. METHODS: Patients with resectable gastric cancer and limited peritoneal dissemination were administered (sub)total gastrectomy, CRS, and HIPEC with oxaliplatin (460 mg/m2) and docetaxel (escalating scheme: 0, 50, 75 mg/m2). Of the 25 patients who completed the study protocol, 14 were treated in the dose-escalation cohort and 11 were treated in the expansion cohort (to optimize perioperative management). RESULTS: A significant proportion of the patients in the dose-escalation cohort (n = 7, 50%) had ileus-related complications. In this cohort, enteral nutrition was started immediately after surgery at 20 ml/h, which was increased on day 1 to meet nutritional needs. In the expansion cohort, enteral nutrition was administered at 10 ml/h until day 3, then restricted to 20 ml/h until day 6, supplemented with total parenteral nutrition to meet nutritional needs. Ileus-related complications occurred for two patients (18%) of the expansion cohort. The intensive care unit (ICU) readmission rate decreased from 50 (n = 7) to 9% (n = 1; p = 0.04). CONCLUSION: The implementation of a strict nutritional protocol during the PERISCOPE I study was associated with a decrease in postoperative complications. Based on these results, a perioperative care path was described for the gastric cancer HIPEC patients in the PERISCOPE II study.

Systemic exposure of oxaliplatin and docetaxel in gastric cancer patients with peritonitis carcinomatosis treated with intraperitoneal hyperthermic chemotherapy.

In the PERISCOPE I study, gastric cancer patients with limited peritoneal dissemination were treated with systemic chemotherapy followed by (sub)total gastrectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with 460 mg/m2 hyperthermic oxaliplatin followed by normothermic docetaxel in escalating doses (0, 50, 75 mg/m2). In total, 25 patients completed the study protocol. Plasma samples were collected before the start of the HIPEC procedure, after oxaliplatin washing, after docetaxel washing and the following morning. Median peak plasma concentrations were 5.5∗10-3 mg/ml for oxaliplatin, 89∗10-6 mg/ml for docetaxel (dose 50 mg/m2) and 113∗10-6 mg/ml for docetacel (dose 75 mg/m2). The following morning median plasma concentrations were 32% and 4% of the measured peak concentrations for oxaliplatin and docetaxel, respectively. For both cytostatic agents, no correlation was found between intraperitoneal fluid concentration and peak plasma concentration. High doses oxaliplatin and docetaxel can be given intraperitoneally without causing potentially toxic systemic concentrations.

The metastatic pattern of intestinal and diffuse type gastric carcinoma - A Dutch national cohort study.

INTRODUCTION: The Lauren classification of gastric adenocarcinoma describes three histological subtypes, the intestinal, the diffuse and the mixed type carcinoma. The metastatic pattern of gastric adenocarcinoma by histological subtype has not been studied. METHODS: Gastric adenocarcinoma patients with metastatic disease at the time of diagnosis between 1999 and 2017 were identified through the Netherlands Cancer Registry. The Lauren classification was determined based on pathology reports archived in the Dutch Pathology Registry and was linked to individual cases in the Netherlands Cancer Registry. RESULTS: Among 8 231 newly diagnosed, metastatic and evaluable gastric adenocarcinoma patients, 57 % had an intestinal type carcinoma, 38 % patients had a diffuse type carcinoma and 5 % had a mixed type carcinoma. Intestinal type carcinomas more often metastasized to the liver (57 % versus 21 %, p < 0.0001) and lungs (13 % versus 7 %, p < 0.0001), whereas diffuse type carcinomas more often metastasized to the peritoneum (58 % versus 29 %, p < 0.0001) and bones (9 % versus 6 %, p < 0.0001). Patients with a diffuse type carcinoma had a worse survival perspective regardless of the number or the location of the metastases. CONCLUSION: In this national cohort study, metastatic gastric adenocarcinoma of the intestinal type had a predilection for the liver and that of the diffuse type for the peritoneum.

Treatment of PERItoneal disease in Stomach Cancer with cytOreductive surgery and hyperthermic intraPEritoneal chemotherapy: PERISCOPE I initial results.

BACKGROUND: The role of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer is unknown. This non-randomized dose-finding phase I-II study was designed to assess the safety and feasibility of HIPEC, following systemic chemotherapy, in patients with gastric cancer and limited peritoneal dissemination. The maximum tolerated dose of normothermic intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin was also explored. METHODS: Patients with resectable cT3-cT4a gastric adenocarcinoma with limited peritoneal metastases and/or tumour-positive peritoneal cytology were included. An open HIPEC technique was used with 460 mg/m2 hyperthermic oxaliplatin for 30 min followed by normothermic docetaxel for 90 min in escalating doses (0, 50, 75 mg/m2 ). RESULTS: Between 2014 and 2017, 37 patients were included. Of 25 patients who completed the full study protocol, four were treated at dose level 1 (0 mg/m2 docetaxel), six at dose level 2 (50 mg/m2 ) and four at dose level 3 (75 mg/m2 ). At dose level 3, two dose-limiting toxicities occurred, both associated with postoperative ileus. Thereafter, another 11 patients were treated at dose level 2, with no more dose-limiting toxicities. Based on this, the maximum tolerated dose was 50 mg/m2 intraperitoneal docetaxel. Serious adverse events were scored in 17 of 25 patients. The reoperation rate was 16 per cent (4 of 25) and the treatment-related mortality rate was 8 per cent (2 patients, both in dose level 3). CONCLUSION: Gastrectomy combined with cytoreductive surgery and HIPEC was feasible using 460 mg/m2 oxaliplatin and 50 mg/m2 normothermic docetaxel.

ANTECEDENTES: El papel de la cirugía citorreductora (cytoreductive surgery, CRS) combinado con la quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC) en el cáncer gástrico no está definido. Este estudio fase I-II no aleatorizado de escalado de dosis fue diseñado para evaluar la seguridad y la viabilidad de HIPEC, después de la quimioterapia sistémica, en pacientes con cáncer gástrico con diseminación peritoneal limitada. Además, se exploró la máxima dosis tolerada (maximum tolerated dose, MTD) de docetaxel intraperitoneal normotérmico en combinación con una dosis fija de oxaliplatino intraperitoneal. MÉTODOS: Se incluyeron pacientes con adenocarcinoma gástrico cT3-cT4a resecable con metástasis peritoneales limitadas y/o citología peritoneal positiva. Se utilizó una técnica HIPEC abierta con 460 mg/m2 de oxaliplatino hipertérmico (30 minutos) seguido de docetaxel normotérmico (90 minutos) en dosis crecientes (0, 50, 75 mg/m2 ). RESULTADOS: Entre 2014 y 2017, se incluyeron 37 pacientes. De los 25 pacientes que completaron la totalidad del protocolo del estudio, 4 pacientes fueron tratados en el nivel de dosis 1 (0 mg/m2 de docetaxel), 6 pacientes en el nivel de dosis 2 (50 mg/m2 ) y 4 pacientes en el nivel de dosis 3 (75 mg/m2 ). En el nivel de dosis 3, se produjeron dos casos de toxicidad limitante de dosis (dose-limiting toxicities, DLTs), ambas asociadas con un íleo postoperatorio. Posteriormente, otros 11 pacientes fueron tratados con el nivel de dosis 2, y no se produjeron más DLTs. La MTD de docetaxel intraperitoneal fue de 50 mg/m2 . Se registraron efectos adversos graves en 17 de 25 pacientes. La tasa de reoperación fue del 16% (n = 4) y la mortalidad relacionada con el tratamiento fue del 8% (n = 2; ambos en el nivel de dosis 3).

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus palliative systemic chemotherapy in stomach cancer patients with peritoneal dissemination, the study protocol of a multicentre randomised controlled trial (PERISCOPE II).

BACKGROUND: At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. METHODS: In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3-4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. DISCUSSION: The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. TRIAL REGISTRATION: clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

Using textbook outcome as a measure of quality of care in oesophagogastric cancer surgery.

BACKGROUND: Textbook outcome is a multidimensional measure representing an ideal course after oesophagogastric cancer surgery. It comprises ten perioperative quality-of-care parameters and has been developed recently using population-based data. Its association with long-term outcome is unknown. The objectives of this study were to validate the clinical relevance of textbook outcome at a hospital level, and to assess its relation with long-term survival after treatment for oesophagogastric cancer. METHODS: All patients with oesophageal or gastric cancer scheduled for surgery with curative intent between January 2009 and June 2015 were selected from an institutional database. A Cox model was used to study the association between textbook outcome and survival. RESULTS: A textbook outcome was achieved in 58 of 144 patients (40·3 per cent) with oesophageal cancer and in 48 of 105 (45·7 per cent) with gastric cancer. Factors associated with not achieving a textbook outcome were failure to achieve a lymph node yield of at least 15 (after oesophagectomy) and postoperative complications of grade II or more. After oesophagectomy, median overall survival was longer for patients with a textbook outcome than for patients without (median not reached versus 33 months; P = 0·012). After gastrectomy, median survival was 54 versus 33 months respectively (P = 0·018). In multivariable analysis, textbook outcome was associated with overall survival after oesophagectomy (hazard ratio 2·38, 95 per cent c.i. 1·29 to 4·42) and gastrectomy (hazard ratio 2·58, 1·25 to 5·32). CONCLUSION: Textbook outcome is a clinically relevant measure in patients undergoing oesophagogastric cancer surgery as it can identify underperforming parameters in a hospital setting. Overall survival in patients with a textbook outcome is better than in patients without a textbook outcome.

Outcomes after prophylactic gastrectomy for hereditary diffuse gastric cancer.

BACKGROUND: Patients with hereditary diffuse gastric cancer and a CDH1 mutation have a 60-80 per cent lifetime risk of developing diffuse gastric cancer. Total prophylactic gastrectomy eliminates this risk, but is associated with considerable morbidity. The effectiveness (removal of all gastric mucosa) and outcomes of this procedure were evaluated retrospectively. METHODS: All consecutive individuals undergoing a prophylactic gastrectomy for a CDH1 mutation or gastric signet ring cell foci at the authors' institute between 2005 and 2017 were included. RESULTS: In 25 of 26 patients, intraoperative frozen-section examination (proximal resection margin) was used to verify complete removal of gastric mucosa. All definitive resection margins were free of gastric mucosa, but only after the proximal margin had been reresected in nine patients. In the first year after surgery, five of the 26 patients underwent a relaparotomy for adhesiolysis (2 patients) or jejunostomy-related complications (3 patients). Six patients were readmitted to the hospital within 1 year for nutritional and/or psychosocial support (4 patients) or surgical reintervention (2 patients). Mean weight loss after 1 year was 15 (95 per cent c.i. 12 to 18) per cent. For the 25 patients with a follow-up at 1 year or more, functional complaints were reported more frequently at 1 year than at 3 months after the operation: bile reflux (15 versus 11 patients respectively) and dumping (11 versus 7 patients). The majority of patients who worked or studied before surgery (15 of 19) had returned fully to these activities within 1 year. CONCLUSION: The considerable morbidity and functional consequences of gastrectomy should be considered when counselling individuals with an inherited predisposition to diffuse gastric cancer. Intraoperative frozen-section examination is recommended to remove all risk-bearing gastric mucosa.

The value of inflammation markers and body temperature in acute diverticulitis.

AIM: To determine the diagnostic value of serological infection markers and body temperature in discriminating complicated from uncomplicated diverticulitis. METHODS: Patients in whom diverticulitis was pathologically or radiologically proven at presentation were included. Patients were classified as either complicated (Hinchey Ib, II, III and IV) or uncomplicated (Hinchey Ia) diverticulitis. The discriminative value of C-reactive protein (CRP), white blood cell (WBC) count and body temperature at presentation was tested. RESULTS: A total of 426 patients were included in this study of which 364 (85%) presented with uncomplicated and 62 (15%) with complicated diverticulitis. Only CRP was of sufficient diagnostic value (area under the curve 0.715). The median CRP in patients with complicated diverticulitis was significantly higher than in patients with uncomplicated disease (224 mg/l, range 99-284 vs 87 mg/l, range 48-151). Patients with a CRP of 25 mg/l had a 15% chance of having complicated diverticulitis. This increased from 23% at a CRP value of 100 mg/l to 47% for 250 mg/l or higher. The optimal threshold was reached at 175 mg/l with a positive predictive value of 36%, negative predictive value of 92%, sensitivity of 61% and a specificity of 82%. CONCLUSION: WBC count and body temperature are of no value in discriminating complicated from uncomplicated diverticulitis. Only CRP can be used as an indicator for the presence of complications, but a low CRP does not mean that complicated disease can safely be excluded. Therefore, radiological examination remains central in the diagnostic work-up of patients presenting with diverticulitis.

Does the presence of abscesses in diverticular disease prelude surgery?

BACKGROUND: Information on long-term outcome of patients treated conservatively for diverticular abscess is scarce. This study aims to compare diverticulitis patients with abscess to patients without abscess with regard to readmission, complications, and surgical treatment during a follow-up period of at least 12 months. METHODS: A chart review of all patients admitted for a primary manifestation of diverticulitis between January 2005 and January 2011 was performed. RESULTS: Fifty-nine patients with abscess and 663 without abscess were identified. Median follow-up was 28 months (range 12-103). Initial conservative management was achieved in 54 (91.5 %) patients with diverticular abscess and 635 (96.8 %) without abscess. Readmission occurred more frequently among patients with abscess (hazard ratio (HR) 2.6; confidence interval (CI) 1.51-4.33) with a first-year risk of 27.3 versus 10.7 % and second-year risk of 8.2 versus 4.6 %. Surgery was more frequently performed in patients with diverticular abscess (HR 2.3; CI 1.42-3.66). The first-year risk was 35.1 versus 16.6 % and second-year risk was 12.9 versus 2.4 %. The most frequent indication for surgery was persisting or recurrent disease. CONCLUSION: Patients with diverticular abscess have a higher risk of being readmitted and/or requiring surgical treatment. The pattern suggests that readmission and need for surgery are the results of an ongoing inflammation of the initial episode.