Impact of obesity after cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for rare peritoneal malignancies: Paradox of obesity or poor prognostic factor?

BACKGROUND: Obesity is a public health concern with an increasing occurrence worldwide. Literature regarding impact of obesity on results after management of peritoneal carcinomatosis is poor. Our aim was to compare postoperative and oncological outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for rare peritoneal malignancies according to the body mass index. METHODS: All the patients managed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for rare peritoneal malignancies (including mainly pseudomyxoma peritonei and peritoneal mesothelioma), between 1995 and 2020, were retrospectively included from the French national registry of rare peritoneal tumors. RESULTS: 1450 patients were retrospectively included (63.5 % female, mean age 54 ± 13 years). Patients were divided into two groups according to their body mass index: non-obese (n = 1248, 86 %) and obese (n = 202, 14 %). Overall morbidity was significantly lower in non-obese patients in comparison with obese patients (n = 532/1248, 43 % vs n = 106/202, 53 %, p = 0.009). Medical and surgical morbidities were significantly lower in non-obese patients in comparison with obese patients (423/1258, 34 % vs n = 86/202, 43 %, p = 0.02 and n = 321/1248, 26 % vs n = 67/202, 33 %, p = 0.003, respectively). One-, 5- and 10-year overall survivals were similar between non-obese and obese patients (95 %, 82 % and 70 % vs 94 %, 76 % and 63 %; p = 0.1). One-, 5- and 10-year disease free survivals were similar between non-obese and obese patients (84 %, 67 % and 61 % vs 79 %, 62 % and 56 %, p = 0.1). CONCLUSION: Obese patients have to be carefully managed after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for rare peritoneal malignancies. Some perioperative prophylactic treatments could be specifically implemented to reduce thromboembolic events, metabolic and wound complications.

Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Long term oncologic outcomes from the international PSOGI registry.

The laparoscopic approach for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (L-CRS + HIPEC) in highly selected patients was previously reported from the PSOGI registry with a demonstrable reduction in length of stay and post-operative morbidity. This study aims to update this international PSOGI registry with a larger cohort of patients and a longer follow-up period. METHODS: An international registry was designed through a networking database (REDCAP®). All centers performing L-CRS + HIPEC were invited through PSOGI to submit data on their cases. Variables such as demographics, clinical outcomes, and survival were analyzed. RESULTS: A total of 315 L-CRS + HIPEC cases were provided by 14 worldwide centers. A total of 215 patients were included in the L-CRS + HIPEC group. The median peritoneal cancer index (PCI) was 3 (3-5). The median length of stay was 7 days (5-10) and the major morbidity (Clavien-Dindo ≥3) was 6.1% after 30 days. The 5-year disease-free survival (DFS) per tumor origin was: 94% for PMP-LG, 85% for PMP-HG, 100% for benign multicyst peritoneal mesothelioma (MPM), 37.4% for colonic origin, and 54%(at 3 years) for ovarian origin. The 5 years overall survival (OS) per tumor origin was: 100% for PMP-LG, PMP-HG and MPM; 61% for colonic origin, and 74% (at 3 years) for ovarian origin. In addition, a total of 85 patients were analyzed in the laparoscopic risk-reducing HIPEC (L-RR + HIPEC). The median length of stay was 5 days (4-6) and the major morbidity was 6% after 30 days. The 5-year DFS per tumor origin was: 96% for perforated low grade appendiceal mucinous neoplasm (LAMN II) and 68.1% for colon origin. The 5 years OS per tumor origin was: 98% for LAMN II and 83.5% for colonic origin. CONCLUSIONS: Minimally invasive CRS + HIPEC is a safe procedure for selected patients with peritoneal carcinomatosis in specialized centers. It improves perioperative results while providing satisfactory oncologic outcomes. L-RR + HIPEC represents a promising strategy that could be evaluated in patients with high risk of developing peritoneal carcinomatosis into prospective randomized trials.

PIPAC nebulizer: How to test the new devices in the market, expert recommendations.

Pressurized intraperitoneal aerosol chemotherapy, named PIPAC, is now used in many centers around the world and as an intraperitoneal drug delivery system for treatment of peritoneal carcinomatosis. Recently, many of us have encountered problems during PIPAC procedures due to changes in material and production features of the original PIPAC nebulizer. Concomitantly, new PIPAC nebulizers proposed by other manufacturers are being launched on the market; which claim that they are the same as the original device in delivering PIPAC. However, these new devices are all different in terms of materials, technical characteristics and costs. We have considered that, to maintain the acquired results of PIPAC, we must ensure that the new systems are equivalent. The characteristics deemed essential by the expert group are as follows: 1: The nebulizer must be able to create droplets through an injector pressure between 10 and 20 bars, 2: The mean droplet size must be 3 micrometers, with 95% of the droplets between 0 and 10 micrometers, 3: The diffusion angle must be 70 degrees, which is the minimum.

Prognosis of poorly cohesive gastric cancer after complete cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (CYTO-CHIP study).

BACKGROUND: The incidence of gastric poorly cohesive carcinoma (PCC) is increasing. The prognosis for patients with peritoneal metastases remains poor and the role of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is controversial. The aim was to clarify the impact of gastric PCC with peritoneal metastases treated by CRS with or without HIPEC. METHODS: All patients with peritoneal metastases from gastric cancer treated with CRS with or without HIPEC, in 19 French centres, between 1989 and 2014, were identified from institutional databases. Clinicopathological characteristics and outcomes were compared between PCC and non-PCC subtypes, and the possible benefit of HIPEC was assessed. RESULTS: In total, 277 patients were included (188 PCC, 89 non-PCC). HIPEC was performed in 180 of 277 patients (65 per cent), including 124 of 188 with PCC (66 per cent). Median overall survival (OS) was 14.7 (95 per cent c.i. 12.7 to 17.3) months in the PCC group versus 21.2 (14.7 to 36.4) months in the non-PCC group (P < 0.001). In multivariable analyses, PCC (hazard ratio (HR) 1.51, 95 per cent c.i. 1.01 to 2.25; P = 0.044) was associated with poorer OS, as were pN3, Peritoneal Cancer Index (PCI), and resection with a completeness of cytoreduction score of 1, whereas HIPEC was associated with improved OS (HR 0.52; P < 0.001). The benefit of CRS-HIPEC over CRS alone was consistent, irrespective of histology, with a median OS of 16.7 versus 11.3 months (HR 0.60, 0.39 to 0.92; P = 0.018) in the PCC group, and 34.5 versus 14.3 months (HR 0.43, 0.25 to 0.75; P = 0.003) in the non-PCC group. Non-PCC and HIPEC were independently associated with improved recurrence-free survival and fewer peritoneal recurrences. In patients who underwent HIPEC, PCI values of below 7 and less than 13 were predictive of OS in PCC and non-PCC populations respectively. CONCLUSION: In selected patients, CRS-HIPEC offers acceptable outcomes among those with gastric PCC and long survival for patients without PCC.

The Delphi and GRADE methodology used in the PSOGI 2018 consensus statement on Pseudomyxoma Peritonei and Peritoneal Mesothelioma.

Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are currently under debate. To aid physicians involved in the treatment of these patients in clinical decision making, the PSOGI executive committee proposed to create a consensus statement on PMP and PM. This manuscript describes the methodology of the consensus process. The Delphi technique is a reliable method for attaining consensus on a topic that lacks scientific evidence through multiple voting rounds which feeds back responses to the participants in between rounds. The GRADE system provides a structured framework for presenting and grading the available evidence. Separate questionnaires were created for PMP and PM and sent during two voting rounds to 80 and 38 experts, respectively. A consensus threshold of 51.0% was chosen. After the second round, consensus was reached on 92.9%-100.0% of the questions. The results were presented and discussed in the plenary session at the PSOGI 2018 international meeting in Paris. A third round for the remaining issues is currently in progress. In conclusion, using the Delphi technique and GRADE methodology, consensus was reached in many issues regarding the treatment of PM and PMP amongst an international panel of experts. The main results will be published in the near future.

Appendiceal tumours and pseudomyxoma peritonei: Literature review with PSOGI/EURACAN clinical practice guidelines for diagnosis and treatment.

Pseudomyxoma Peritonei (PMP) is a rare peritoneal malignancy, most commonly originating from a perforated epithelial tumour of the appendix. Given its rarity, randomized controlled trials on treatment strategies are lacking, nor likely to be performed in the foreseeable future. However, many questions regarding the management of appendiceal tumours, especially when accompanied by PMP, remain unanswered. This consensus statement was initiated by members of the Peritoneal Surface Oncology Group International (PSOGI) Executive Committee as part of a global advisory role in the management of uncommon peritoneal malignancies. The manuscript concerns an overview and analysis of the literature on mucinous appendiceal tumours with, or without, PMP. Recommendations are provided based on three Delphi voting rounds with GRADE-based questions amongst a panel of 80 worldwide PMP experts.

Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for limited peritoneal metastasis. The PSOGI international collaborative registry.

INTRODUCTION: A laparoscopic approach for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (L-CRS+HIPEC) in highly selected patients has been reported in small cohorts with a demonstrable reduction in length of stay and post-operative morbidity. This study aims to analyse individual patient data from these international centres collected through the Peritoneal Surface Oncology Group International (PSOGI) L-CRS+HIPEC registry. METHODS: An international registry was designed through a networking database (REDCAP®). All centres performing L-CRS+HIPEC were invited through PSOGI to submit data on their cases. Patient's characteristics, postoperative outcomes and survival were analysed. RESULTS: Ten international centres contributed a total of 143 L-CRS+HIPEC patients during the study period. The most frequent indication was low grade pseudomyxoma peritonei in 79/143 (55%). Other indications were benign multicyst mesothelioma in 21/143(14%) and peritoneal metastasis from colon carcinoma in 18/143 (12,5%) and ovarian carcinoma in 13/143 (9%). The median PCI was 3 (2-5). The median length of stay was 6 (5-10) days, with 30-day major morbidity rate of 8.3% and 30-day mortality rate of 0.7%. At a median follow-up of 37 (16-64) months 126/143 patients (88.2%) were free of disease. CONCLUSIONS: Analysis of these data demonstrates that L-CRS+HIPEC is a safe and feasible procedure in highly selected patients with limited peritoneal disease when performed at experienced centres. While short to midterm outcomes are encouraging in patients with less invasive histology, longer follow up is required before recommending it for patients with more aggressive cancers with peritoneal dissemination.

Prospective correlation of the radiological, surgical and pathological findings in patients undergoing cytoreductive surgery for colorectal peritoneal metastases: implications for the preoperative estimation of the peritoneal cancer index.

AIM: The peritoneal cancer index (PCI) is one of the strongest prognostic factors in patients undergoing cytoreductive surgery (CRS) for colorectal peritoneal metastases. Using pathological evaluation, however, the disease extent differs in a large proportion of patients. Our aim was to study the correlation between the radiological (rPCI), surgical (sPCI) and pathological (pPCI) PCI in order to determine factors affecting the discordance between these indices and their potential therapeutic implications. METHOD: From July 2018 to December 2019, 128 patients were included in this study. The radiological, pathological and surgical findings were compared. A protocol for pathological evaluation was followed at all centres. RESULTS: All patients underwent a CT scan and 102 (79.6%) had a peritoneal MRI. The rPCI was the same as the sPCI in 81 (63.2%) patients and the pPCI in 93 (72.6%). Concordance was significantly lower for moderate-volume (sPCI 13-20) and high-volume (sPCI > 20) disease than for low-volume disease (sPCI 0-12) (P < 0.001 for sPCI; P = 0.001 for pPCI). The accuracy of imaging in predicting presence/absence of disease upon pathological evaluation ranged from 63% to 97% in the different regions of the PCI. The pPCI concurred with the sPCI in 86 (68.8%) patients. Of the nine patients with sPCI > 20, the pPCI was less than 20 in six. CONCLUSION: The rPCI and sPCI both concurred with pPCI in approximately two thirds of patients. Preoperative evaluation should focus on the range in which the sPCI lies and not its absolute value. Radiological evaluation did not overestimate sPCI in any patient with high/moderate-volume disease. The benefit of CRS in patients with a high r/sPCI (> 20) who respond to systemic therapies should be prospectively evaluated.

Sodium thiosulfate protects from renal impairement following hyperthermic intraperitoneal chemotherapy (HIPEC) with Cisplatin.

BACKGROUND: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to provide benefits in the management of peritoneal metastasis. Cisplatin (CDDP) is one of the most frequently used drugs for peritoneal infusion. A major restriction is that CDDP causes renal toxicity and acute renal failure, sometimes leading to chronic renal failure. The aim of the present study was to assess the impact of sodium thiosulfate (ST) in preventing renal impairment (RI) following HIPEC with CDDP. METHODS: This prospective study assessed the RI rates for all patients who underwent HIPEC with CDDP during two successive periods: without ST (nST Period; from November 2016 to September 2017) and with ST (ST Period; from October 2017 to March 2018). During the ST Period, patients received an ST infusion at 9 mg/m2 prior to HIPEC and at 12 mg/m2 at the end of the procedure. RI was defined by postoperative serum creatinine >1.6 times elevation of baseline value. The impact of ST treatment was evaluated by comparison of the RI rates between the two periods. RESULTS: During ST Period, none of 38 patients (0%) developed RI versus 11/35 patients (31.4%) during the nST Period (p < .005); 2 of whom required definitive hemodialysis. Baseline characteristics, background circumstances, indications and laboratory parameters before HIPEC were comparable between the two groups, as well as CDDP dose use during HIPEC. CONCLUSION: ST appears to be an effective drug for the prevention of the renal toxicity of CDDP used for HIPEC and should be used for all such procedures.

Treatment of primary and metastatic peritoneal tumors in the Covid-19 pandemic. Proposals for prioritization from the RENAPE and BIG-RENAPE groups.

The Covid-19 pandemic is profoundly changing the organization of healthcare access. This is particularly so for peritoneal neoplastic diseases, for which curative treatment mobilizes substantial personnel, operating room and intensive care resources. The BIG-RENAPE and RENAPE groups have made tentative proposals for prioritizing care provision. A tightening of the usual selection criteria is needed for curative care: young patients with few or no comorbidities and limited peritoneal extension. It is desirable to prioritize disease conditions for which cytoreduction surgery with or without associated hyperthermic intraoperative peritoneal chemotherapy (HIPEC) is the gold-standard treatment, and for which systemic chemotherapy cannot be a temporary or long-term alternative: pseudomyxoma peritonei, resectable malignant peritoneal mesotheliomas, peritoneal metastases of colorectal origin if they are resectable and unresponsive to systemic chemotherapy after up to 12 courses, first-line ovarian carcinomatosis if resectable or in interval surgery after at most six courses of systemic chemotherapy. Addition of HIPEC must be discussed case by case in an expert center. The prioritization of indications must consider local conditions and the phase of the epidemic to allow optimal peri-operative care.

[Treatment of primary and metastatic peritoneal tumors in the Covid-19 pandemic. Proposals for prioritization from the RENAPE and BIG-RENAPE groups]. / Prise en charge des tumeurs primitives et métastatiques du péritoine en période de pandémie CoViD-19. Pistes de réflexion et de priorisation du groupe RENAPE et BIG-RENAPE.

The Covid-19 pandemic is profoundly changing the organization of healthcare access. This is particularly so for peritoneal neoplastic diseases, for which curative treatment mobilizes substantial personnel, operating room and intensive care resources. The BIG-RENAPE and RENAPE groups have made tentative proposals for prioritizing care provision. A tightening of the usual selection criteria is needed for curative care: young patients with few or no comorbidities and limited peritoneal extension. It is desirable to prioritize disease conditions for which cytoreduction surgery with or without associated hyperthermic intraoperative peritoneal chemotherapy (HIPEC) is the gold-standard treatment, and for which systemic chemotherapy cannot be a temporary or long-term alternative: pseudomyxoma peritonei, resectable malignant peritoneal mesotheliomas, peritoneal metastases of colorectal origin if they are resectable and unresponsive to systemic chemotherapy after up to 12 courses, first-line ovarian carcinomatosis if resectable or in interval surgery after at most six courses of systemic chemotherapy. Addition of HIPEC must be discussed case by case in an expert center. The prioritization of indications must consider local conditions and the phase of the epidemic to allow optimal peri-operative care.

Development and internal validation of a diagnostic score for gastric linitis plastica.

BACKGROUND: There is no consensual definition for gastric linitis plastica (GLP). We aim to construct a diagnostic score to distinguish this rare tumor from usual gastric adenocarcinomas. METHODS: In this retrospective study, all patients who had gastrectomy for cancer between 2007 and 2017 in French tertiary centers were included. The outcome was a diagnosis of GLP based on pathological review of the surgical specimen. The diagnostic score was created by using variables that were most frequently associated with GLP using penalized logistic regression on multiply imputed datasets. We used discrimination measures to assess the performances of the score. Internal validation was performed using bootstrapping methods to correct for over-optimism. RESULTS: 220 patients including 71 linitis plastica (female 49%, median age 57 years) were analyzed. The six parameters retained in the diagnosis score were the presence of large folds and/or parietal thickening on at least one segment, pangastric infiltration and presence of gastric stenosis on the upper endoscopy, circumferential thickening on at least one segment and thickening of the third hyperechogenic layer on endoscopic ultrasound and the presence of signet ring cells on endoscopic biopsies. The area under the ROC curve (AUC) was 0.967 with a sensitivity of 94% [89.9-97.3] and a specificity of 88.7% [81.7-95.8] for a threshold of 2.75. After internal validation, the corrected AUC was 0.959. CONCLUSION: It is the first study validating a pre-therapeutic diagnostic score (Saint Louis linitis score) with an excellent ability to discriminate GLP from non-GLP adenocarcinomas. An external validation is necessary to confirm our data.

Perioperative FOLFOX 4 Versus FOLFOX 4 Plus Cetuximab Versus Immediate Surgery for High-Risk Stage II and III Colon Cancers: A Phase II Multicenter Randomized Controlled Trial (PRODIGE 22).

BACKGROUND: Perioperative chemotherapy has proven valuable in several tumors, but not in colon cancer (CC). OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of perioperative chemotherapy in patients with locally advanced nonmetastatic CC. METHODS: This is a French multicenter randomized phase II trial in patients with resectable high-risk T3, T4, and/or N2 CC on baseline computed tomography (CT) scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type patients, a third arm testing perioperative FOLFOX-cetuximab was added. Tumor Regression Grade (TRG1) of Ryan et al was the primary endpoint. Secondary endpoints were toxicity, perioperative morbidity, and quality of surgery. RESULTS: A total of 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped (lack of efficacy). The remaining 104 patients (control, n = 52; FOLFOX preop n = 52) represented our intention-to-treat population. In the FOLFOX perioperative group, 96% received the scheduled 4 cycles before surgery. R0 resection and complete mesocolic excision rate were 94% and 93%, respectively. Overall mortality and morbidity rates were similar in both groups. Perioperative FOLFOX chemotherapy did not improve major pathological response rate (TRG1 = 8%) but was associated with a significant pathological regression (TRG1-2 = 44% vs 8%, P < 0.001) and a trend to tumor downstaging as compared to the control group. CT scan criteria were associated with a 33% rate of overstaging in control group. CONCLUSIONS: Perioperative FOLFOX for locally advanced resectable CC is feasible with an acceptable tolerability but is not associated with an increased major pathological response rate as expected. However, perioperative FOLFOX induces pathological regression and downstaging. Better preoperative staging tools are needed to decrease the risk of overtreating patients.

Management of colorectal peritoneal metastases: Expert opinion.

When peritoneal metastases are diagnosed (strong agreement of experts): (i) seek advice from a multidisciplinary coordination meeting (MCM) with large experience in peritoneal disease (e.g. BIG RENAPE network); (ii) transfer (or not) the patient to a referral center with experience in hyperthermic intraperitoneal chemotherapy (HIPEC), according to the advice of the MCM. With regard to systemic chemotherapy (strong agreement of experts): (i) it should be performed both before and after surgery, (ii) for no longer than 6 months; (iii) without postoperative anti-angiogenetic drugs. With regard to cytoreductive surgery (strong agreement of experts): (i) Radical surgery requires a xiphopubic midline incision; (ii) no cytoreductive surgery via laparoscopy. With regard to HIPEC: HIPEC can be proposed for trials outside an HIPEC referral center (weak agreement between experts): (i) if surgery is radical; (ii) if the expected morbidity is "reasonable"; (iii) if the indication for HIPEC was suggested by a MCM, and; (iv) mitomycin is preferred to oxaliplatin (which cannot be recommended) for this indication.

Evaluation of a strategy using pretherapeutic fiducial marker placement to avoid missing liver metastases.

Background: Hepatic surgery is appropriate for selected patients with colorectal liver metastases (CRLM). Advances in chemotherapy have led to modification of management, particularly when metastases disappear. Treatment should address all initial CRLM sites based on pretherapeutic cross-sectional imaging. This study aimed to evaluate pretherapeutic fiducial marker placement to optimize CRLM treatment. Methods: This pilot investigation included patients with CRLM who were considered for potentially curative treatment between 2009 and 2016. According to a multidisciplinary team decision, lesions smaller than 25 mm in diameter that were more than 10 mm deep in the hepatic parenchyma and located outside the field of a planned resection were marked. Complication rates and clinicopathological data were analysed. Results: Some 76 metastases were marked in 43 patients among 217 patients with CRLM treated with curative intent. Of these, 23 marked CRLM (30 per cent), with a mean(s.d.) size of 11·0(3·4) mm, disappeared with preoperative chemotherapy. There were four complications associated with marking: two intrahepatic haematomas, one fiducial migration and one misplacement. After a median follow-up of 47·7 (range 18·1-144·9) months, no needle-track seeding was noted. Of four disappearing CRLM that were marked and resected, two presented with persistent active disease. Other missing lesions were treated with thermoablation. Conclusion: Pretherapeutic fiducial marker placement appears useful for the curative management of CRLM.