A Pocard

M Sardi

MD Rea Lo Dico
email: rea.lo-dico@aphp.fr

M Faron²

Y Yonemura

O Glehen

M Pocard

A Sardi

M Hübner

D Baratti

G Liberale

A Kartheuser

I De Hingh

P Sugarbaker

W Ceelen

B Moran

M Robella

F Quenet

L Sideris

D Goere

M Limbert

P Sammartino

D Morris

Psogi

J Abba

K Abboud

G Lorimier

P Ortega

with HIPEC for metastatic colorectal cancer: Results

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Combined Liver Resection and Cytoreductive Surgery with HIPEC for metastatic colorectal cancer: Results of a Worldwide analysis of 565 patients from the Peritoneal

Surface Oncology Group International (PSOGI) INTRODUCTION

A curative approach in patients with oligometastatic colorectal cancer can achieve "better than expected" long-term survival and provides the rationale for an extensive surgical approach in case of metastases limited in number and to one or a few organs [START_REF] Hellman | Oligometastases[END_REF] .

Liver metastases (LM) occur in 25-40% of patients with colorectal cancer (CRC) [START_REF] Nordlinger | Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial[END_REF] . The longterm outcomes of patients with LM undergoing systemic chemotherapy alone is poor, with a median overall survival (OS) of 16 months as reported in the Cairo trial [START_REF] Koopman | Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial[END_REF] , and up to 31 months with treatment intensification as shown in the TRIBE trial [START_REF] Cremolini | FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study[END_REF] . A meta-analysis by Franko et al. reported an OS of 19 months in patients with LM from CRC [START_REF] Franko | Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database[END_REF] . Curative management of LM is based on surgical resection, although in 70% of cases, LM will recur despite the use of multimodal and adjuvant chemotherapy [START_REF] Nordlinger | Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial[END_REF] .

Peritoneal metastases (PM) are present in 3.5-8.3% of patients with CRC at the time of diagnosis [START_REF] Lemmens | Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study[END_REF][START_REF] Segelman | Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer[END_REF][START_REF] Van Gestel | Metachronous peritoneal carcinomatosis after curative treatment of colorectal cancer[END_REF] , and are associated with poor survival, being as low as 6 months if left untreated [START_REF] Bengtsson | Natural history of patients with untreated liver metastases from colorectal cancer[END_REF] .

The presence of isolated PM in patients with CRC is prognostic of poor OS compared with isolated non-peritoneal metastases [START_REF] Franko | Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database[END_REF] . Using modern systemic chemotherapy, modest improvements in prognosis can be achieved with median OS in the range of 12-16 months [START_REF] Franko | Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database[END_REF][START_REF] Koppe | Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies[END_REF] .

Cytoreductive surgery (CRS) with intraperitoneal chemotherapy, including hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed as the only potentially curative treatment for PM of CRC origin, achieving a median OS of 31.6 months [START_REF] Verwaal | Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer[END_REF][START_REF] Baratti | Progress in treatments for colorectal cancer peritoneal metastases during the years 2010-2015. A systematic review[END_REF] . A median OS up to 41.7 months and a recurrence-free survival of 13.1 months and has also been recently reported in highly selected patients [START_REF] Quenet | A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7[END_REF] . The National Comprehensive Cancer Network (NCCN) guideline recommends that complete CRS combined with HIPEC can be considered in highvolume centers for selected patients with limited peritoneal metastases in whom R0 resection can be achieved [START_REF] Tanaka | Verifying the M1c category of CRC: analysis of the data from a Japanese multi-institutional database[END_REF] .

Simultaneous LM and PM from CRC has traditionally been considered a contraindication to any surgical approach because this disease presentation has been associated with very poor survival [START_REF] Fong | Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases[END_REF][START_REF] Glehen | Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study[END_REF] . However, smaller pilot series have reported prolonged survival, reaching up to 3 years in selected patients, after management of simultaneous colorectal LM and PM with CRS plus HIPEC combined with liver resection (LR). The authors claim that LM were not an absolute contraindication to a curative surgical management of PM and the concomitant treatment of both might indeed be possible [START_REF] Kianmanesh | Iterative cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis of colorectal origin with or without liver metastases[END_REF][START_REF] Izzo | Management of colorectal liver metastases in patients with peritoneal carcinomatosis[END_REF][START_REF] Chua | Peritoneal carcinomatosis and liver metastases from colorectal cancer treated with cytoreductive surgery perioperative intraperitoneal chemotherapy and liver resection[END_REF][START_REF] De Cuba | Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: Systematic review of all literature and meta-analysis of observational studies[END_REF][START_REF] Berger | Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with liver involvement[END_REF][START_REF] Delhorme | Peritoneal carcinomatosis with synchronous liver metastases from colorectal cancer: Who will benefit from complete cytoreductive surgery?[END_REF][START_REF] Navez | Surgical Treatment of Colorectal Cancer with Peritoneal and Liver Metastases Using Combined Liver and Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Report from a Single-Centre Experience[END_REF][START_REF] Lorimier | Curative cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis and synchronous resectable liver metastases arising from colorectal cancer[END_REF][START_REF] Pinto | Synchronous liver metastases and peritoneal carcinomatosis from colorectal cancer: different strategies for curative treatment?[END_REF] . However, to date, no standard management pathway has been established for patients with simultaneous LM and PM, especially if a major hepatectomy and extensive peritoneal CRS have to be performed. Moreover, there are currently no specific criteria to select patients with the highest potential for surgical success, nor guidelines concerning the timing of peritoneal and liver surgery.

The aim of this study was to assess the early outcomes and survival of CRC patients undergoing LR and peritoneal CRS with HIPEC for concomitant PM and LM. The secondary aim was to identify potential factors related to poorer outcomes, in order to establish a basis to guide the management of these patients, optimizing the selection of candidates for surgical treatment and determining the best sequence of surgical procedures.

PATIENTS AND METHODS

Data Collection

A prospectively maintained multi-institutional database was established using the PSOGI and BIG-RENAPE database networks from surgical teams of expert centers for colorectal PM performing CRS and HIPEC. This study was carried out in accordance with the precepts established by the Helsinki Declaration and the institutional review board for each center approved the study procedures. Using the databases of 33 international expert centers from 13 different countries, we identified and collected in a retrospective analysis all patients with concomitant PM and LM from CRC treated with LR and CRS with HIPEC between 1993 and 2017.

All background clinical, histological, operative and postoperative data for this study were prospectively collected, entered into a standardized central electronic database and analyzed retrospectively. We included only patients whose clinical records contained complete information such as age, Eastern Cooperative Oncology Group (ECOG) performance status, tumor markers, diagnostic techniques, AJCC stage group (VIII ed.) and histopathology of primary tumor, number and site of LM, surgical procedures used during CRS and LR including complications according to the Clavien-Dindo classification [START_REF] Dindo | Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey[END_REF] , Peritoneal Cancer Index (PCI) [START_REF] Jacquet | Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis[END_REF] , completeness of cytoreduction (CC) score [START_REF] Jacquet | Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis[END_REF] , HIPEC techniques and drugs, systemic chemotherapy and eventual drug-induced toxicity evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0) [START_REF] Basch | Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE)[END_REF] and last complete updated data on follow-up.

Indications for CRS plus HIPEC combined with LR were concomitant metastatic spread to peritoneum and liver from colorectal cancer in patients younger than 75 years of age with adequate cardiac, renal, hepatic and bone marrow function, ECOG performance status 0 to 1, written informed consent, resectable disease and for the present study patients in whom CRS had a likelihood of achieving residual disease measuring at least < 2.5 mm (CC1).

Contraindications for CRS plus HIPEC combined with LR were extra-abdominal disease, other malignancies, unresectable disease or patients with progressive disease after neoadjuvant chemotherapy and patients whose severe associated medical conditions made them unfit for the procedure. Ovarian metastases were considered a manifestation of peritoneal disease [START_REF] Evers | Indication for oophorectomy during cytoreduction for intraperitoneal metastatic spread of colorectal or appendiceal origin[END_REF] .

Operative treatment

Simultaneous resection was defined as LR and CRS plus HIPEC during the same operation (one step procedure) and separate procedures were defined as two-steps procedures. Detailed staging and evaluation of systemic chemotherapy eventually combined with biological or molecular treatment depended mainly on imaging findings including computed tomography (CT), magnetic resonance imaging (MRI) and positron emission CT (PET-CT). Staging laparoscopy was used mainly for histopathological sampling or when imaging failed to specify resectability. Patients were scheduled for CRS combined with HIPEC and LR according to a likelihood of achieving complete peritoneal cytoreduction (CC0/1) and LR, and dependent on the patient's general condition following discussion at a multidisciplinary meeting including surgeons, medical oncologists, and dedicated radiologists at each PSM center At laparotomy, the peritoneal spread was recorded according to the PCI [START_REF] Jacquet | Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis[END_REF] . Patients then underwent surgery with curative intent: CRS of peritoneal disease was performed with peritonectomy and visceral resection according to standardized procedure, albeit some surgical techniques may have varied among centers. Visceral resections and the other peritonectomy procedures were done depending on the distribution of malignancy in the peritoneal space; normal peritoneum was never excised. If macroscopically affected, the appendix and ovaries were systematically removed. HIPEC was administrated after completion of CRS using an open coliseum or closed technique according to the team's preference, to deliver the chemotherapy agent at 42-43°C for 30-90 min in a closed circuit.

The drugs employed and the duration of the intra-peritoneal chemotherapy was previously described [START_REF] Brigand | Peritoneal mesothelioma treated by cytoreductive surgery and intraperitoneal hyperthermic chemotherapy: results of a prospective study[END_REF][START_REF] Elias | Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases[END_REF] .

LR was performed according to the principles of oncologic radicality. Minor hepatectomy was defined as any LR of less than three hepatic segments, including atypical resection (metastasectomy, segmentectomy and bisegmentectomy), and radiofrequency ablation (RFA) for lesions measuring less than 2.5 cm and located far from the main vessels according to each team's preference. Major hepatectomy was defined as the LR of at least three hepatic segments, minor resection was defines as the segmentectomies (anatomical resections) and local ablation was defines as non-anatomical or limited resections (wedge resections, radiofrequency or cryotherapy).

Postoperative complications was defined as taking place within 90 days after surgery and operative mortality as death within 90 days after surgery or until hospital discharge. For 2staged surgeries we added up the length of stay for both hospital admissions.

The general approach across the centers was that patients requiring minor resections had simultaneous LR and peritoneal CRS and HIPEC, whereas in some cases major LR and CRS and HIPEC was performed in two steps: liver-first approach, when the LR was followed by CRS and HIPEC, and delayed LR when the CRS and HPEC was the first procedure.

Endpoints

The primary endpoint of the analyses was OS. OS was defined as the time from diagnosis of liver or peritoneal metastases to the time of death due to any cause. The secondary endpoints were relapse-free survival (RFS), postoperative morbidity/mortality at 90 days according to from first surgery, CRS and HIPEC or LR, to relapse, or death, whichever occurred first. RFS at 3 years was defined as the percentage of patients that were relapse-free at three years. In the case of two-steps procedures, the first surgical procedure date was considered as the first treatment day. Second colorectal cancers were considered as RFS events, whereas noncolorectal tumors were disregarded in the analyses.

Statistical Analysis

Quantitative variables were described as mean (+/-standard deviation) or median (inter quartile range) depending on the distribution and compared with Student's t-test or Wilcoxon's test. Qualitative variables were described as count (percentage) and compared with Chi square test or Fisher's exact test as appropriate.

Survival curves were calculated according to Kaplan-Meier and compared with the log-rank test. Median follow-up was calculated according to Schemper's method [START_REF] Schemper | A note of quantifying follow-up in studies of failure time[END_REF] .

The Cox proportional hazard model was used to determine factors influencing patient prognosis. Any variable achieving a p<0.2 in the univariable analysis was then entered in a Cox multivariable model. Backward variable selection based on Akaike's Information Criteria (AIC) was used to identify the subset of independent variables.

RESULTS

Patient Characteristics

Five hundred and sixty-five consecutive patients from 33 centers were screened (Fig. 1). Four hundred and ninety-one patients (91.9%) were treated with preoperative systemic chemotherapy before surgery given to treat PM and/or LM before CRS/HIPEC and LR. The average interval between diagnosis of liver or peritoneal metastases and combined surgery was 6 months. For 224 patients (41.9%), the PM were synchronous with the primary tumor, for 206 (38.6%) LM were synchronous with the primary tumor. Regarding the first choice of IP chemotherapy during HIPEC, oxaliplatin (55%), mitomycin-C (37%), and "other" (8%), were reported. Patient characteristics are summarized in Tables 1.

Treatment Related Data

Median PCI was 9.8 (SD: 7.4, range, 0-39), being ≥12 in 152 patients (Table 2). A complete CRS (CCR-0-1) was achieved in 534 (94.7%) patients. Four hundred and thirty seven patients (81.8%) underwent LR simultaneously with CRS and HIPEC, whereas 97 (18.2%) had twosteps procedures, among them 66 (12%) had liver-first approach (Fig. 1). The median number of LM was 2 (IQR: 1-3, range: 1-14). Major LR was performed in 41 patients (7.3%); fortyfive patients (8.4%) were treated with minor resection, and 337 (63.1%) with local ablation or with the association of two or more limited resections (Table 2).

Early Outcome

The overall severe postoperative complications (grades III-IV) occurred in 176 patients (32.9%) and surgical interventions for complications were required in 80 patients (15%). The overall postoperative mortality rate was 4.0% (n=23). Severe complications occurred in 141/437 (32.3%) patients who underwent a one-step procedure, and in 35/97 (35.7%) who underwent two-steps procedures. Briefly: if a liver-first approach was chosen, we observed 6 severe complications after LR (6.1%) and 21 after CRS and HIPEC surgery (21.6%); for patients receiving delayed LR we observed 6 complications after CRS and HIPEC surgery (6.1%) and 2 after LR (2.1%). The median duration of hospital stay was 24 days (SD: 14.6, range, 5-152 days). Simultaneous CRS and LR was associated with a shorter postoperative hospital stay than two-steps procedures (23 (SD:14.4) vs. 30 (SD: 23.0) days, respectively, P=0.1) (Table 3). In case of two-steps procedures the durations of the two stays were added to obtain a cumulative stay. The number of LM and the type of LR were not identified as being associated with the frequency of severe postoperative complications (Table 4).

Long-term Outcome

The median follow-up was 48.4 months (95% CI 44.2-56.2). The median OS was 47.6 months (95% CI 42.5-53.3), with 1-, 3-and 5-year OS rates being 93%, 64% and 39% respectively (Fig. 2). The median RFS was 19.4 months (95% CI, 17.4-20.7), with 1-, 2-and 3-year RFS rates being 74%, 37%, and 21% respectively (Fig. 2). For patients who underwent preoperative chemotherapy (91.9%), the average interval between diagnosis of liver or peritoneal metastases and combined surgery was 6 months. Four hundred and sixteen (77.9%) patients had a recurrence during the follow-up. The liver was the most frequent site of recurrences 41.1% (n=231). Among this group, 62/231 (27%) had isolated liver recurrence.

Fifty-four (10%) patients had isolated peritoneal recurrence, 213 (39.9%) patients had extraperitoneal recurrence, and 143 (26.8%) patients had both. Among the patients with extra-abdominal recurrence, 138 (24.4%) had pulmonary metastases, either isolated or in combination with other sites. Overall, 282 (49.9%) patients died during the follow-up period.

The sequence of the surgery had an impact on the survival (Fig. 3A andB). For patients treated with liver-first approach, the median OS and RFS were better than patients treated with CRS and HIPEC first or for patients who had one-step procedure (63.7, 52.6 and 44.8 months respectively for OS (P= 0.036), and 28.2, 17.1 and 17.8 for RFS, (P= 0.016)). Upon univariate analysis, PCI, adjuvant LR chemotherapy and surgical sequence, were identified as prognostic factors for lower OS. Moreover, our results have shown a trend towards a lower OS after use of different than oxaliplatin-based drugs for IP compound and modern systemic chemotherapy. At multivariate analysis, only PCI remained as a significant prognostic factor (Table 5). Kaplan-Meier curves for OS of all patients and stratified by surgical sequence are shown (Fig 3A). At univariate analysis, higher PCI and surgical sequence were both identified as greater prognostic factors for lower RFS than primary tumor side. These results were confirmed on multivariate analysis (Table 6). The Kaplan-Meier curves of all RFS patients, stratified by surgical sequence, are shown in Fig 3B.

DISCUSSION

The management of patients with liver and peritoneal metastases from CRC has undergone major improvements over the past few decades. Whereas OS did not exceed one year with classic systemic chemotherapy based on 5-FU [START_REF] Thomassen | Incidence, prognosis, and treatment options for patients with synchronous peritoneal carcinomatosis and liver metastases from colorectal origin[END_REF] , oxaliplatin and targeted therapies such as anti-angiogenic or anti-EGFR antibodies (for wild type RAS) have allowed extending the OS up to 2 years in selected patients [START_REF] Franko | Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database[END_REF][START_REF] De Cuba | Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: Systematic review of all literature and meta-analysis of observational studies[END_REF][START_REF] Varban | Outcomes associated with cytoreductive surgery and intraperitoneal hyperthermic chemotherapy in colorectal cancer patients with peritoneal surface disease and hepatic metastases[END_REF] . Recent studies have suggested that resection of liver and peritoneal metastases, combined with HIPEC, may increase OS up to 3 years, despite an increased risk of morbidity [START_REF] Kianmanesh | Iterative cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis of colorectal origin with or without liver metastases[END_REF][START_REF] Chua | Peritoneal carcinomatosis and liver metastases from colorectal cancer treated with cytoreductive surgery perioperative intraperitoneal chemotherapy and liver resection[END_REF] . Recently, the combination of three systemic chemotherapy agents (FOLFOXIRI regimen) has shown an increased OS of several months in metastatic CRC patients compared to classical chemotherapy regimens [START_REF] Cremolini | FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study[END_REF] , and some achieve OS similar to extensive surgery. However, the incidence of serious adverse events in patients treated with FOLFOXIRI plus bevacizumab is up to 20.4% [START_REF] Loupakis | Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer[END_REF] , which is comparable to perioperative morbidity of major surgery (5-28% for CRS and HIPEC [START_REF] Glehen | Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study[END_REF] and 5-20% for major liver resection) [START_REF] Imamura | One thousand fifty-six hepatectomies without mortality in 8 years[END_REF][START_REF] Jarnagin | Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade[END_REF][START_REF] Sano | One hundred two consecutive hepatobiliary resections for perihilar cholangiocarcinoma with zero mortality[END_REF] . This multicenter study is the largest series of selected patients with PM from CRC and simultaneous LM treated with LR, CRS and HIPEC. The present study shows that extended surgical management of multi-metastatic CRC is feasible with an acceptable morbidity and reasonably low postoperative mortality rates (31% and 4%, respectively). These morbidity and mortality rates are consistent with those reported after LM resection and similar to PM treatment alone [START_REF] Quenet | A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7[END_REF][START_REF] Kianmanesh | Iterative cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis of colorectal origin with or without liver metastases[END_REF][START_REF] Navez | Surgical Treatment of Colorectal Cancer with Peritoneal and Liver Metastases Using Combined Liver and Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Report from a Single-Centre Experience[END_REF][START_REF] Varban | Outcomes associated with cytoreductive surgery and intraperitoneal hyperthermic chemotherapy in colorectal cancer patients with peritoneal surface disease and hepatic metastases[END_REF] . We believe these low rates of morbidity were achieved by careful selection of patients: if LM required only minor LR, this was usually performed at same time as CRS + HIPEC. However, if LM required complex or major LR, especially in patients with suspected liver parenchyma damage through preoperative chemotherapy, resection of LM was mostly performed non-simultaneously to CRS and HIPEC. Interestingly, despite this approach, a major LR was not associated with an increased complication rate compared with minor LR. However, we suggest that this concept of two-steps procedures, already used in complex abdominal and liver surgeries, may represent a valuable tool to reduce patient morbidity and mortality rates. Despite this cautionary note, In light of the present data, it chould be concluded that when both LM and PM are resectable, extended surgery improves chances for selected patients to achieve favorable OS rates. Surprisingly, in this study, we found that for patients treated with liver first approach the median RFS was significantly better than other surgical sequence strategies. In order to further discuss available surgical sequence strategies [START_REF] Adam | Managing synchronous liver metastases from colorectal cancer: a multidisciplinary international consensus[END_REF] to be advocated in case of advanced CRC (liver metastases) with asymptomatic primary, a recent meta-analysis [START_REF] Gavriilidis | Simultaneous, Delayed and Liver-First Hepatic Resections for Synchronous Colorectal Liver Metastases: A Systematic Review and Network Meta-Analysis[END_REF] demonstrated that no significant differences in long-term survival and major morbidity were found amongst the simultaneous, delayed and liver-first approach. Moreover, the reverse strategy (so-called liver-first approach) was ranked as the potentially best treatment with respect to its relative efficacy on the basis of 5-year OS outcomes and postoperative complication rate compared to simultaneous or delayed LR.

Probably because the risk that LM becomes unresectable during the interval between two surgeries is real, some centers have chosen to realize liver-first approach. The better OS and RFS rates between the different strategies showed in this study suggested that the liver-first approach strategy might be an appropriate option for the surgical sequencing of this select group of patients. However, this conclusion is in contrast with the results obtained with the only experimental model known to assess PM growth after LR [START_REF] Lo Dico | Hepatectomy increases metastatic graft and growth in an immunocompetent murine model of peritoneal metastases[END_REF] . Furthermore, the patients who had liver-first approach and then never went on to receive CRS and HIPEC, because of the progression, are not included in the analysis. Thus, the cohort of patients treated by liverfirst approach and then by CRS and HIPEC represents a highly selected population of patients with better biology than those who never progress to the second step procedure. Limited peritoneal disease extent should be an advantage to explain better survival after liver first approach. Should be possible that the survival advantage was not related to the surgical sequence but to lower peritoneal tumor load. However, as shown in table 2, the difference between PCI values in function of the surgical sequence is very low and does not explain the result. More investigations are necessary in order to conclude.

A limitation of this study is the period of data collection from numerous institutions during which temporal trends such as the advent of modern systemic chemotherapy has also taken place. To minimize this bias, the analysis was stratified by time periods (before and after 2000) to discern the effect of modern oxaliplatin-based. No impact in OS and RFS was observed in the limited sample of only 56 (10%) of patients were treated with extended surgical approach before 2003. However, the small sample size could explain the nonsignificance of the result.

Despite the encouraging OS rates in our study, almost 50% of patients recurred within the first eighteen postoperative months. We also found an association between reduced RFS and severe complication events (HR = 1.19 [IC 95% 0.98-1.44], p = 0.081), which is in line with previous studies [START_REF] Simkens | Serious Postoperative Complications Affect Early Recurrence After Cytoreductive Surgery and HIPEC for Colorectal Peritoneal Carcinomatosis[END_REF] . However, we also found that OS was surprisingly not related to severe morbidity as an earlier recurrence was assumed to be related to shorter survival. Varban et al.

have also reported similar results [START_REF] Varban | Outcomes associated with cytoreductive surgery and intraperitoneal hyperthermic chemotherapy in colorectal cancer patients with peritoneal surface disease and hepatic metastases[END_REF] . Thus, these data suggest that careful selection of patients, less likely to experience severe postoperative complications, may allow for improved RFS.

Nevertheless, the association of complications and survival should be attentively considered when selecting any patient with LM and PM for surgery.

The promising long-term results of LM surgery from CRC over the past decade and recent trends towards increasing surgical aggressiveness (as illustrated by iterative resections of LM) [START_REF] Taylor | Survival after surgical resection of hepatic metastases from colorectal cancer: A systematic review and meta-analysis[END_REF] have formed the rationale for the surgical management of both LM and PM, given that CRS + HIPEC may also achieve excellent outcomes. Some series suggest that relatively long survival may be achieved with aggressive management, including the simultaneous resection of LM and PM [START_REF] Chua | Peritoneal carcinomatosis and liver metastases from colorectal cancer treated with cytoreductive surgery perioperative intraperitoneal chemotherapy and liver resection[END_REF][START_REF] Maggiori | Should patients with peritoneal carcinomatosis of colorectal origin with synchronous liver metastases be treated with a curative intent? A case-control study[END_REF][START_REF] Elias | A simple tumor load-based nomogram for surgery in patients with colorectal liver and peritoneal metastases[END_REF] . Previous findings were confirmed in the present study showing that OS is significantly prolonged up to 60 months in selected cases. However, a meta-analysis of de Cuba et al. showed that patients with synchronous PM and LM of CRC seemed to fare less well when compared to patients with isolated PM (pooled HR=1.24, 95%CI 0.96-1.60) [START_REF] De Cuba | Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: Systematic review of all literature and meta-analysis of observational studies[END_REF] .

Despite this, the authors also showed a tendency towards better OS in carefully selected patients with PM and LM who were treated with curative resection of both sites plus HIPEC compared to treatment with modern systemic chemotherapy alone.

The PCI is considered the most widely used tool to evaluate disease extent in peritoneal surface malignancies [START_REF] Glehen | Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study[END_REF][START_REF] Koh | Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis[END_REF][START_REF] Pestieau | Treatment of primary colon cancer with peritoneal carcinomatosis: comparison of concomitant vs. delayed management[END_REF][START_REF] Shehata | Peritoneal carcinomatosis from colorectal cancer and small bowel cancer treated with peritonectomy[END_REF] . Increased PCI is also recognized as an independent prognostic indicator for long-term outcomes in patients with PM from CRC [START_REF] Da Silva | Analysis of prognostic factors in seventy patients having a complete cytoreduction plus perioperative intraperitoneal chemotherapy for carcinomatosis from colorectal cancer[END_REF] and an inverse linear relationship between any point rise in PCI and OS has been demonstrated [START_REF] Faron | Linear Relationship of Peritoneal Cancer Index and Survival in Patients with Peritoneal Metastases from Colorectal Cancer[END_REF] . Similarly, we found that PCI was an independent prognostic factor for OS and RFS in patients undergoing simultaneous resection of LM and PM. This result is in line with previous Italian two-center study reporting worse outcomes in patients with peritoneal than non-peritoneal colorectal metastases. However, survival benefit may be obtained in selected patients with limited peritoneal involvement [START_REF] Baratti | Should a History of Extraperitoneal Disease Be a Contraindication to Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Cancer Peritoneal Metastases?[END_REF] . Whilst PCI also influences the likelihood of complete cytoreduction [START_REF] Verwaal | Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer[END_REF][START_REF] Yan | Cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma: non-mucinous tumour associated with an improved survival[END_REF] , in the present analysis, the quality of CRS was optimal in close to 95% of the patients, with a reasonable mean PCI of about 10. This finding is in line with the literature, as previous studies have shown that a large volume of disease was associated with poor long-term survival even if complete cytoreduction was achieved [START_REF] Pestieau | Treatment of primary colon cancer with peritoneal carcinomatosis: comparison of concomitant vs. delayed management[END_REF][START_REF] Da Silva | Analysis of prognostic factors in seventy patients having a complete cytoreduction plus perioperative intraperitoneal chemotherapy for carcinomatosis from colorectal cancer[END_REF] .

The concomitant presence of LM is considered a poor prognostic factor compared to patients with PM alone [START_REF] Glehen | Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study[END_REF][START_REF] De Cuba | Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: Systematic review of all literature and meta-analysis of observational studies[END_REF][START_REF] Elias | A simple tumor load-based nomogram for surgery in patients with colorectal liver and peritoneal metastases[END_REF] . Elias et al. reported that completely resected LM during CRS remained a negative prognostic factor for patients with PM of CRC [START_REF] Elias | Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study[END_REF] . However, Maggiori et al. suggested that in LM and PM, prolonged survival may still be achieved in highly selected patients with limited peritoneal disease (PCI <12) [START_REF] Maggiori | Should patients with peritoneal carcinomatosis of colorectal origin with synchronous liver metastases be treated with a curative intent? A case-control study[END_REF] . In our study, we also found that a PCI>12 was associated with a poor OS in both uni-and multivariate analysis. Therefore, the PCI itself could be a useful criterion for patient selection. In line with de Cuba et al., we also believe that, based on current data, there is no evidence to support an exclusion of patients with PM and LM from aggressive, potentially curative treatment [START_REF] De Cuba | Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: Systematic review of all literature and meta-analysis of observational studies[END_REF] . However, an accurate, extensive preoperative evaluation is mandatory before surgery, and thus a diagnostic laparoscopy may prove useful in avoiding unnecessary surgery in high PCI and simultaneous CRC LM patients [START_REF] Najah | A feasibility study of the use of computed virtual chromoendoscopy for laparoscopic evaluation of peritoneal metastases[END_REF] .

The recent results of the PRODIGE 7 [START_REF] Quenet | A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7[END_REF] , a prospective randomized multicenter phase III French trial, reopen the question concerning the benefit on survival outcomes given by the addition of HIPEC to the CRS compared to the CRS alone. Is it thus possible that CRS plus LR without HIPEC could have the same results of survival outcomes and lesser morbidity rates compared to the CRS plus LR with HIPEC? CRS plus LR without HIPEC has been reported in only rare and small series [START_REF] Desolneux | Cytoreductive surgery of colorectal peritoneal metastases: outcomes after complete cytoreductive surgery and systemic chemotherapy only[END_REF][START_REF] Allard | Is unexpected peritoneal carcinomatosis still a contraindication for resection of colorectal liver metastases?:Combined resection of colorectal liver metastases with peritoneal deposits discovered intra-operatively[END_REF] . Allard et al. showed that combined resection of LM and limited peritoneal deposits (median PCI: 2) accidentally discovered intra-operatively was associated with an 18% of 5-year OS rate and a median OS of 42 months [START_REF] Allard | Is unexpected peritoneal carcinomatosis still a contraindication for resection of colorectal liver metastases?:Combined resection of colorectal liver metastases with peritoneal deposits discovered intra-operatively[END_REF] . However, in our study combined resection of LM and PM with HIPEC is associated with a better OS of 47 months with 5-year OS rates being 38% in patients with a higher PCI (median PCI: 10).

These better results are probably associated with a better selection of patients and the intrinsic properties of IP chemotherapy: the cytotoxic effects to the hyperthermia and the high local concentration compared to the systemic chemotherapy. Our conclusion is that the option of resection without HIPEC may potentially be proposed in cases where there is concern that HIPEC may increase in morbidity.

Currently, two regimens are widely used open-abdomen Oxaliplatin ± Irinotecan with concurrent intravenous 5-fluorouracil and folinic acid, and open-or close-abdomen Mitomycin-C, alone or in combination with other drugs [START_REF] Baratti | Progress in treatments for colorectal cancer peritoneal metastases during the years 2010-2015. A systematic review[END_REF] . In this series we found that the use of Oxaliplatin vs other IP regimens had better outcomes. The improvement on the OS of the PM from CRC using modern Oxaliplatin-based chemotherapies is known. The role of the IP Oxaliplatine remains unclear. As previously reported most cytoreductive surgeons doing HIPEC with Oxaliplatin carried out the hyperthermic perfusion only for 30 min, and most of those doing HIPEC with MMC did it for 90 min. It is possible that the duration of hyperthermia, and not the drug itself could be responsible for survival difference [START_REF] Prada-Villaverde | The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery[END_REF] . However, in the same study patients considered with negative prognostic factors had better results in terms of survival if treated with IP Oxaliplatine. We considered that the presence of two metastatic sites, liver and peritoneum, in our population is a prognostic factor and this would explain the better result if treated with Oxaliplatin.

Despite analyzing prospectively maintained databases, this study is limited by its retrospective design resulting in some missing data. Furthermore, great heterogeneity in patient selection and operative techniques may have compromised our findings. However, despite these short-comings, this study represents the largest multicenter series, to date, and the data provided herein forms a basis for future prospective trials.

CONCLUSION

This multicenter study demonstrated the feasibility of the simultaneous treatment of colorectal cancer dissemination to the liver and peritoneum with liver resection, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in combination to systemic chemotherapy in selected patients, resulted in a 48-month median overall survival, with reasonable morbidity.

Even though this study suggests performing liver-first approach in the case of two-steps procedures, the exact timing of these individual complex treatment steps remains unknown.

Future studies assessing the feasibility of this surgical approach in a prospective, randomized setting, as well as further studies elucidating how best to control disease progression following disease recurrence, would be helpful in improving the care of patients with advanced colorectal cancer. One step (procedure) was defined as liver resection and cytoreductive surgery and hypertermic intraperitoneal chemotherapy during the same operation; Liver-first (approach) when the liver resection was followed by cytoreductive surgery and hypertermic intraperitoneal chemotherapy, HIPEC-first when liver resection was delayed. ) PM: Peritoneal metastases; CT: systemic chemotherapy; CEA: Carcinoembryonic antigen; CA19.9: Carbohydrate Antigen; HIPEC: hyperthermic intraperitoneal chemotherapy; Monoclonal antibodies: bevacizumab or anti epidermal growth factor receptor (EGFR) in K-RAS wild-type tumors; PCI: peritoneal cancer index; CCR: completeness of cytoreductive surgery, 0: no visible residual disease; 1: residual disease ≤2.5 mm; 2: residual disease >2.5 and ≤5 mm; CCR 3: residual disease >5 mm; EPIC: early postoperative intraperitoneal chemotherapy; LM: liver metastases; R0 resection: margin width > 1mm; R1 resection: margin width ≤ 1mm; CT: systemic chemotherapy. *Major hepatectomy was defined as the liver resection of at least three hepatic segments.

Fig. 1 :Fig. 2 :

 12 Fig.1: Flow Chart of patient selection and study groups selected for analysis of concomitant liver and peritoneal metastases from colorectal cancer (CRC) treated by Cytoreductive Surgery (CRS) and Hypertermic Intraperitoneal Chemotherapy (HIPEC) associated with Liver resection (LR). LM, liver metastases; PM, peritoneal metastases; CCR, completeness of cytoreductive resection; * Data from the global population; **Second surgical procedure for post-operative complications

Fig. 3 :

 3 Fig.3: Kaplan-Meier curve for Overall Survival (A) and Relapse Free Survival (B) in patients undergoing combined liver resection and cytoreductive surgery and hypertermic intraperitoneal chemotherapy for concomitant colorectal liver and peritoneal metastases by surgical sequence. One step (procedure) was defined as liver resection and cytoreductive surgery and hypertermic intraperitoneal chemotherapy during the same operation; Liver-first (approach) when the liver resection was followed by cytoreductive surgery and hypertermic intraperitoneal chemotherapy, HIPEC-first when liver resection was delayed.

Table 1 .

 1 Demographics and characteristics of primary tumor of patients with liver and peritoneal metastases from colorectal cancer treated by cytoreductive surgery and hypertermic intraperitoneal chemotherapy associated with liver resection.

		ALL	One step	Liver first	HIPEC first	p-value
	Age	54.8 (+/-11.7)	54.89 (+/-11.9)	54.6 (+/-10.2)	54.55 (+/-12.1)	0.98
	Age >60					0.82
	No	329 (63.3%)	269 (62.7%)	41 (65.1%)	19 (67.9%)
	Yes	191 (36.7%)	160 (37.3%)	22 (34.9%)	9 (32.1%)
	Gender					0.3
	Female	312 (58.5%)	248 (57%)	44 (66.7%)	20 (62.5%)
	Male	221 (41.5%)	187 (43%)	22 (33.3%)	12 (37.5%)
	Type of Surgery					0.17
	Laparoscopy	84 (26.7%)	59 (24.6%)	19 (37.3%)	6 (25%)
	Laparotomy	231 (73.3%)	181 (75.4%)	32 (62.7%)	18 (75%)
	Tumor side					0.97
	Right	177 (33.9%)	142 (33.4%)	22 (33.8%)	13 (40.6%)
	Left	271 (51.9%)	220 (51.8%)	35 (53.8%)	16 (50%)
	Rectum	67 (12.8%)	57 (13.4%)	7 (10.8%)	3 (9.4%)
	Multifocal	7 (1.3%)	6 (1.4%)	1 (1.5%)	0 (0%)
	T from the TNM					0.27
	T1 or T2	14 (3.6%)	11 (3.6%)	3 (6%)	0 (0%)
	T3	190 (49.5%)	146 (47.2%)	29 (58%)	15 (60%)
	T4	180 (46.9%)	152 (49.2%)	18 (36%)	10 (40%)
	N from the TNM					0.38
	N0	101 (23.3%)	76 (22.2%)	15 (25.9%)	10 (31.2%)
	N1	169 (39%)	130 (37.9%)	26 (44.8%)	13 (40.6%)
	N2 or N3	163 (37.6%)	137 (39.9%)	17 (29.3%)	9 (28.1%)
	Differentiation					0.075
	Good	85 (21.7%)	65 (21.2%)	17 (30.4%)	3 (10.3%)
	Moderate	225 (57.4%)	174 (56.7%)	28 (50%)	23 (79.3%)
	Poor	82 (20.9%)	68 (22.1%)	11 (19.6%)	3 (10.3%)
	Mucinous					0.24
	No	295 (81%)	223 (79.4%)	49 (89.1%)	23 (82.1%)
	Yes	69 (19%)	58 (20.6%)	6 (10.9%)	5 (17.9%)
	Synchronous PM					0.0017
	no	317 (60.7%)	249 (58.5%)	50 (76.9%)	18 (58.1%)
	yes	205 (39.3%)	177 (41.5%)	15 (23.1%)	13 (41.9%)
	Adjuvant CT					0.29
	No	134 (25.5%)	115 (26.9%)	12 (18.2%)	7 (21.9%)
	Yes	392 (74.5%)	313 (73.1%)	54 (81.8%)

Table 2 .

 2 Characteristics of peritoneal and liver metastases of patients treated by cytoreductive surgery and hypertermic intraperitoneal chemotherapy associated with liver resection.

		All	One step	Liver first	HIPEC first	p-value
	Peritoneal Metastases
	CEA pre HIPEC	28.4 (+/-70.2) 24.34 (+/-50.2)	44.75 (+/-126)	42 (+/-103)	0.097
	CA19.9 pre HIPEC	79.9 (+/-
		212.1)	88.34 (+/-224)	30.79 (+/-58.7)	86.51 (+/-272)	0.31
	Neoadjuvant CT					0.013
	pre-HIPEC
	No	119 (22.8%)	86 (20.2%)	23 (34.8%)	10 (32.3%)
	Yes
		404 (77.2%)	340 (79.8%)	43 (65.2%)	21 (67.7%)
	Monoclonal antibodies					0.87
	pre-HIPEC
	No	376 (70.3%)	305 (69.8%)	48 (72.7%)	23 (71.9%)
	Yes	159 (29.7%)	132 (30.2%)	18 (27.3%)	9 (28.1%)
	PCI	9.8 (+/-7.4)	10.07 (+/-7.6)	9.077 (+/-6.88)	7.552 (+/-4.48)	0.15
	PCI ≥12	152 (30.2%)	129 (31.5%)	19 (29.2%)	4 (13.8%)	0.13
	CCR					<0.0001
	0	472 (88.4%)	399 (91.3%)	46 (69.7%)	27 (87.1%)
	1
		62 (11.6%)	38 (8.7%)	20 (30.3%)	4 (12.9%)
	Mucinous					0.15
	No	304 (79.8%)	225 (77.9%)	55 (88.7%)	24 (80%)
	Yes
		77 (20.2%)	64 (22.1%)	7 (11.3%)	6 (20%)
	EPIC					0.087
	no	341 (91.2%)	268 (89.9%)	49 (96.1%)	24 (96%)
	yes
		28 (7.5%)	27 (9.1%)	1 (2%)	0 (0%)
	Intra peritoneal					0.14
	oxaliplatin
	No
		231 (43.2%)	180 (41.2%)	34 (51.5%)	17 (53.1%)
	Yes	304 (56.8%)	257 (58.8%)	32 (48.5%)	15 (46.9%)
	Adjuvant CT					0.0026
	post-HIPEC
	No	234 (44.9%)	176 (41.5%)	42 (63.6%)	16 (51.6%)
	Yes
		287 (55.1%)	248 (58.5%)	24 (36.4%)	15 (48.4%)
	Monoclonal antibodies					0.29
	post-HIPEC
	No
		461 (86.2%)	373 (85.4%)	61 (92.4%)	27 (84.4%)

Table 3 .

 3 Postoperative Outcomes at 90-days, according to Clavien-Dindo Classification of patients with liver and peritoneal metastases from colorectal cancer treated by cytoreductive surgery and hypertermic intraperitoneal chemotherapy associated with liver resection. Demartines N, Clavien PA: Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205-13, 2004.

	Type of Complication	Global outcomes	Complications by procedures
		No.	%	CRS + HIPEC	Liver surgery
	Details of postoperative complications	317	59.4%
	Hemoperitoneum	29	9.2%
	Global anastomotic leak	78	24.6%
	Enteric fistula	41	12.9%
	Pancreatic fistula	8	2.5%
	Biliary leak	10	3.2%
	Urinary fistula	16	5%
	Other	3	0.9%
	Intra-abdominal abscess	42	13%
	Wound infection	14	0.44%
	Peritonitis	3	0.9%
	Pleural effusion with drainage	45	14.2%
	Pneumonia	16	5%
	Respiratory distress	5	0.3%
	Pulmonary embolism	2	0.1%
	Ileus	5	0.3%
	Complications (Clavien Dindo)*
	0			217 (40.6%)	515 (96.4%)
	1			54 (10.1%)	8 (1.5%)
	2			87 (16.3%)	2 (0.4%)
	3			19 (3.6%)	2 (0.4%)
	3a			56 (10.5%)	3 (0.6%)
	3b			45 (8.4%)	0 (0%)
	4			48 (8.9%)	3 (0.6%)
	5			8 (1.5%)	1 (0.18%)
	90-day postoperative major	176	32.9%
	complications (grade III-IV)
	Reoperation

(78.1%)

Conflicts of interest:

.08] HIPEC: hyperthermic intraperitoneal chemotherapy; PCI: peritoneal cancer index; CCR: completeness of cytoreductive surgery, 0: no visible residual disease; 1: residual disease ≤2.5 mm; 2: residual disease >2.5 and ≤5 mm; CCR 3: residual disease >5 mm; EPIC: early postoperative intraperitoneal chemotherapy; CT: systemic chemotherapy; PM: Peritoneal metastases; LM: Liver metastases; Major hepatectomy was defined as the liver resection of at least three hepatic segments; R0 resection: margin width > 1mm; R1 resection: margin width ≤ 1mm; NS: Not significant. *Treatment after year 2000: the analysis was stratified by time periods (before and after 2000) to discern the effect of modern oxaliplatin-based. .04] HIPEC: hyperthermic intraperitoneal chemotherapy; PCI: peritoneal cancer index; CCR: completeness of cytoreductive surgery, 0: no visible residual disease; 1: residual disease ≤2.5 mm; 2: residual disease >2.5 and ≤5 mm; CCR 3: residual disease >5 mm; EPIC: early postoperative intraperitoneal chemotherapy; CT: systemic chemotherapy; PM: Peritoneal metastases; LM: Liver metastases; Major hepatectomy was defined as the liver resection of at least three hepatic segments; R0 resection: margin width> 1mm; R1 resection: margin width≤ 1mm; NS: Not significant. *Treatment after year 2000: the analysis was stratified by time periods (before and after 2000) to discern the effect of modern oxaliplatin-based.


Flora Devos

Léa Jilet

Naïm Bouazza

Frantz Foissac

Jean-Marc Tréluyer

Hélène Chappuy

Pierre-Yves Ancel

Léa

Identification and comparison of France to other countries of the teaching of research to nursing students: Results of an international survey of nursing educator

Keywords: teaching research, nursing students, international survey, scientific literacy, nursing curricula

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Scientific literacy, a concept developed by Durant in 1994, indicates the skills to accept the need for more information about a clinical situation, but also to seek, find and use scientific knowledge for that specific clinical problem (Durant, 1994;[START_REF] Laugksch | Initiation à la recherche en formation initiale infirmière en France : une étude descriptive transversale[END_REF]. The American Library Association defines a person with scientific knowledge as "a person who is able to recognize when information is needed and who has the ability to locate, evaluate, and effectively use needed information" (Association of College & Research Libraries, 2015).

Scientific literacy skills include knowledge of scientific databases, the findings of useable information and its understanding (ability to read a specific vocabulary) and finally the use of this new information in a corpus of knowledge for integration in a reflection about practice and a change of practice. Scientific literacy skills contribute to the transfer of scientific knowledge into practice by providing more independence and scientific reflection in nursing decision-making [START_REF] Valente | Research dissemination and utilization improving care at the bedside[END_REF], e.g. integrating a critical viewpoint on the purpose of the article read, methodological bias, method and design of the article. Scientific literacy skills are essential for nurses to use scientific evidence in their clinical practice. One way to develop these skills is through research education. Universities and schools of nursing around the world are the main vector for teaching research to undergraduate nursing students.

BACKGROUND

Learning theories are the main guide for educational systems, including nursing education.

Teachers know the general principles of these theories and can use them in different learning situations. However, none of these theories is perfect. Teaching new knowledge's or skills in a field, such as nursing research, must include learning through exploration according to Piaget's theories, reinforcing behavior according to the behaviorist movement but also using the internal process of the learner [START_REF] Piaget | Science of Education and the Psychology of the Child[END_REF][START_REF] Piaget | Sociological Studies[END_REF].

Existing literature does not state the content of research education. However, a systematic review of the educational strategy used to teach evidence-based practice at a bachelor's degree shows varied learning techniques but nursing students still struggle to see the relevance of research finding to nursing practice (Aglen, 2016). Another study reports that nursing students are dissatisfied with the teaching of research and want more practice-oriented teaching (Ax & Kincade, 2001). However, teaching research to undergraduate nursing students has a significant impact on students' research skills and minimizes barriers to evidence use after graduation (Hatala & Guyatt, 2002;Leach, Hofmeyer, & Bobridge, 2016;Porter et al., 2010). It is therefore important for schools and faculties of nursing ensure that future professionals have the scientific literacy skills to promote dissemination and transfer (Cheek, Gillham, & Ballantyne, 2005;Johansson, Fogelberg-Dahm, & Wadensten, 2010).

In France, the 2009 nursing education reform identified research as a needed skill and aimed to develop nurses' ability to use research in clinical reasoning [START_REF] Laugksch | Initiation à la recherche en formation initiale infirmière en France : une étude descriptive transversale[END_REF]. Since then, French nursing schools have been teaching research to students in the aim of promoting nursing as a scientific profession. But also to support the profession in an academic way. In this context, it is interesting to explore, 10 years after the reform of nursing studies in France, the similarities and differences between French research programs and those of other countries and the skills that these programs could enable students to acquire. Furthermore, nurses have always considered their profession as a passport to the world. It is therefore important that nursing education reflect the challenge of the globalization of nursing.

However, to our knowledge, no comparison has been conducted between France and other countries in term of nursing research training.

To investigate how scientific knowledge might be transferred into practice, it is necessary to determine how research is taught to undergraduate nursing students. However, little is known about what is taught to undergraduate nursing students around the world and how it is delivered, nor is it known if there are differences between France and other countries. The purpose of this study is to evaluate research education in schools (or universities) of nursing and to compare teaching in France and other countries.

METHOD Study Design

The design was a cross-sectional survey using a web-based questionnaire.

Survey Design

An online questionnaire was developed based on the American Library Association's publication on the scientific literacy skills of students and nurses in health care (American Library Association, 2013; Association of College & Research Libraries, 2015). Authors developed the survey questionnaire. Before starting the online survey, we performed a pilot evaluation of our questionnaire by sending it to a French nursing school. Two French nursing educators conducted this evaluation. This pilot evaluation assessed the understanding and acceptability of the questions, the relevance of the answers, and the time taken to complete the questionnaire, but no psychometrics data was collected. This pilot evaluation allows us to highlight five problem areas. Three areas concerned the understanding and choice of answers to questions 8, 12 and 15.7 and 2 areas concerned the relationship between the questions. The survey was then revised.

The questionnaire consisted of 17 questions (21 sub-questions) to explore 3 teaching topics.

The topics studied were the teaching of scientific databases (examples of database, use of simple or advanced research), Critical Reading of Articles and scientific English. The teaching of scientific English means the knowledge of an English vocabulary that facilitates the relationship with patients and the understanding of scientific data published in English.

These teachings were chosen because they enable nurses to be autonomous in answering a clinical question in their future practice with evidence-based data and because they are the first step towards scientific literacy. For each teaching, the number of hours of supervised work (class organized with a small group of students and aimed to practicing) and of lecture hours (class organized with all students corresponding to the first, second or third year) was requested. We also examined the tools made available to students by nursing schools or universities and the number of articles provided to the undergraduate students by the institution throughout nursing education. The characteristics of schools of nursing were asked through 11 questions.

Skip logic was used to reduce respondents' burden and avoid irrelevant questions. For example, if a respondent stated that his or her institution did not teach a course, the questionnaire automatically presented the questions of the next course and skipped all subquestions. A copy of the questionnaire is available in Supporting Information.

The survey was administered using GoogleForms (www.GoogleForms.com) between December 2018 and July 2019. This period was chosen to reflect the trade-off between obtaining usable data over a short period of time and a significant amount of participation time.

Settings and participants

All national and international schools or universities of nursing were eligible to participate in the survey. The usual methods were used to conduct the survey [START_REF] Van Selm | Conducting Online Surveys[END_REF]. These methods involved distributing the questionnaire by e-mail to respondents or making a general request in an electronic communication environment. But also, response time management which incorporates several incentives for respondents. As part of our study, emails containing an offer to participate in the survey and its explanation, as well as two links to the online questionnaire (in French and English) were sent to national or international nursing organizations in order to disseminate our survey by network. Nurses' organizations were approached as they have direct links with nursing schools and could easily disseminate our survey to nursing schools. In addition, several messages were published on social networks (Linked In and Facebook), requesting participation in the survey and its dissemination to schools or universities of nursing. Finally, French schools of nursing were contacted by direct e-mail using an index of French schools of nursing.

A total of 326 French nursing schools and 15 nursing organizations and their social network profiles were contacted. A reminder was sent 2 weeks after the first contact by email with the letter introducing the survey and the two links. This reminder was repeated every 3 weeks after the first contact until the end of the study. One participation per nursing school or university was requested.

Data collection

GoogleForms data were collected automatically. FD, LJ, FF, and NB at the end of the study managed the data.

Ethical considerations

Participation in the survey was voluntary and responses were anonymous. No incentives were offered for participation or dissemination of the survey. The questionnaire and the email included an introduction on the purpose, intent and use of the data. Completion of the questionnaire constituted implied consent to participate. Data were stored on passwordprotected computer, only the principal investigator knew the password. No information identifying the schools/universities (excluding the country) was collected.

Data analysis

All calculations were performed using version 3.4.2 of the R software.

Continuous data were presented as median and interquartile range, while a number and percentage represented categorical data. Unless otherwise indicated, categorical variables were compared by a Chi-square test or Fisher's exact test, as appropriate, and continuous variables were compared using a Student's t test or Wilcoxon-Mann-Whitney test, as appropriate. All statistical assessments were two-tailed and considered significant at the 0.05 level. If the analysis of the heading question of the teaching item was significant, the comparative analyze was continued on sub-items. A similar sub-groups analysis was repeated using only schools or universities of nursing with Associate or Bachelor level.

RESULTS

Respondent characteristics

A total of 245 nursing schools or universities participated. Respondents came from France (n=202, 82.4%), other European countries (n=17, 6.9%), North America (n=12, 4.9%) and Asia (n=14, 5.7%). Of the participating schools, 94.3% (n=231) were from non-Englishspeaking countries.

Research teaching in nursing schools or universities

Table 3 shows the description of each teaching topics and their comparison between France and the other countries.

Teaching of scientific databases Scientific databases were taught in 137 (56.8%) of nursing schools or universities. The teaching consisted of 5 [2; 10] hours of supervised work and 3 [2; 5] hours of lectures.

However, French schools of nursing teach significantly less database search strategies -i.e examples of database, use of simple or advanced research-than other countries, with 51.3% (n=102) and 83.3% (n=35) respectively (p=0.001). Furthermore, a significant difference was observed in the type of teaching of scientific databases between France and the other countries (p<0.0001). Indeed, the other countries teach the CINAHL database more frequently (71.4%, n=25 of 43 schools of nursing in the other countries) than schools of nursing in France (34.3%, n=35 of 202 French nursing schools).

Critical Reading of Article

Critical Reading of Article is taught in 70.1% of the nursing school or universities investigated with a significant difference (p=0.001) between France (n=131, 65.8 %) and other countries (n=38, 90.5 %). Teaching included 8 [4; 13] hours of supervised work and 4 [2; 7] hours of lectures.

Among the 10 items included in the Critical Reading of Article (CRA), the teaching of "bibliometry" principles such as the meaning of the Impact factor or the number of citations of an article (n=44, 26%) and the "applicability of results" (n=77, 45.6%) were not often reported by schools or universities of nursing (Table 3). Schools or universities of nursing in other countries were more likely to teach at least five CRA items than French schools of nursing (p=0.001). Seventy-five percent (n=127) of schools or universities of nursing distributed between 1 to 5 articles in the native language of nursing students during all years of education, with no significant difference between schools of nursing in France and those in other countries. However, schools or universities of nursing in other non-English-speaking countries were more likely to study articles in English than French nursing schools (p<0.0001). Indeed, 76.2% (n=100) of French schools of nursing did not study articles in English compared to 10.5% (n=4) of schools or universities of nursing in other non-Englishspeaking countries. The methodology of articles read by students is uniform. Indeed, 68%, 56.8% and 76.9% of the articles read respectively have a qualitative, quantitative and mixed methodology. No significant difference between French nursing schools and those in other countries was found (p=0.05). Students from nursing schools or universities in other countries studied systematic reviews (n=26, 68.4%) and meta-analyzes (n=15, 39.5%) significantly more than students from French schools of nursing (n=40, 45.9%, p=0.023 and n=26, 19.8%, p=0.023, respectively).

Scientific English

Scientific English (English vocabulary facilitating the relationship with patients and the understanding of scientific data published in English) was taught in 60.6 % (n=146) of the nursing schools or universities studied, with a significant difference between France (n=128, 64.3%) and other non-English-speaking countries (n=18, 42.9%; p=0.009). The teaching scientific English most often includes reading professional articles (n=109, 74.7% of nursing schools and universities). Only 28.8% of nursing schools or universities include the reading of scientific articles in the teaching of scientific English with a significant difference between France (n=30, 23.4%) and other non-English speaking countries (n=12, 66.7%, p<0.001).

Articles provided to nursing students (excluding the teaching of CRA) Most schools or universities of nursing (89.6%, n=216) reported providing scientific articles to students with no significant difference between France and other countries. The number of articles provided to nursing students is heterogeneous. However, most nursing schools in France offer 5 -10 articles during all years of training (n=47, 26.1%) while nursing schools or universities in other countries offer more than 30 articles (n=10, 27.8%). As with the results of teaching Critical Reading of Articles, most of the articles provided to nursing students in France were in their native language (n=152, 84.4%). In nursing schools or universities in other non-English speaking countries, articles provided to nursing students were as much in English (n= 17, 47.2%) as in both languages (native and English language) (n=16, 44.4%).

Access to articles through nursing schools or universities

Through nursing schools or universities, students have access to online and print journals (n=162, 66.1%). Access to articles by subscription is significantly different between France and other countries (p<0.0001). Nursing students in other countries were more likely to have access only to online articles (n=12, 28%) than nursing students in France (n=11, 5.4%).

Comparison of France and World teaching at a bachelor's level

This analysis give almost the same results as those obtained without excluding other university degrees. Indeed, only the question on the type of articles read and the questions on the teaching of scientific English changed their results (See Table 3).

DISCUSSION

This study evaluated the research education of 245 national and international nursing schools or universities. Our results show that most nursing schools reported teaching the 3 research teaching topics studied by our work (Scientific database, Critical Reading Teaching and Scientific English), but also provided articles to students and provided access to scientific knowledge. They show that scientific databases are taught in 56.8% of schools or universities of nursing and the PubMed database in 79.7% of schools or universities of nursing worldwide. The PubMed and CINAHL databases are the best-known and most comprehensive biomedical and nursing databases. Searching on PubMed provides enough information to solve a clinical issue, but CINAHL allows nurses or paramedics to access to specialized scientific and academic information [START_REF] Klem | Do Nursing Students Need Instruction in Both CINAHL and MEDLINE?[END_REF]. Although 70.1% of nursing schools or universities teach Critical Reading of Articles, the content of the teaching is highly varied (see Table 3). Our results show that 61.5% of non-English speaking schools of nursing did not study an article in English while teaching Critical Reading of Article. If students do not read in English while teaching of Critical Reading or Scientific English, they are likely to graduate without having read many articles in English, which represents a significant teaching gap because health knowledge sciences is published in English. In this way, and because English is currently the international language of research and people, it is crucial to teach English to nursing students [START_REF] Starkey | The critical factors that influence faculty attitudes and perceptions of teaching English as Second Language nursing students: A grounded theory research study[END_REF]. If registered nurses are not able to read articles in English, it is unlikely that their knowledge will be updated. Therefore, not teaching English could have a negative impact on patient care.

Our results highlight a wide heterogeneity in the teaching of research to nursing students around the world. In fact, although research is taught in most schools or universities of nursing, the composition of research teaching and the resources available for research differ from country to country.

These findings highlight the need to standardize the teaching of research to nursing students worldwide for two reasons. First, there is a need for nurses to be able to work, collaborate and communicate easily with each other and with other health professions on patient care. In addition, research is one of the main goals of the university. That is why we recommend that professionals who do research themselves teach research to nursing students through the university. In addition, the inclusion of nurses in a dynamic learning environment helps to limit the turnover of nurses [START_REF] Mahon | The Social Determinants of Nursing Retention in a Pediatric Hematology/Oncology Unit[END_REF]. Second, improving research education might increase evidence-based-nursing practice by promoting the development of nurses' scientific literacy skill in schools of nursing or universities. Scientific literacy skills can empower nurses and create a vocation among students [START_REF] Kaplan Jacobs | Information literacy as the foundation for evidence-based practice in graduate nursing education: a curriculum-integrated approach[END_REF]. It is therefore necessary to examine the competencies that nurses need after graduation. Research education is crucial for the development of skill in scientific literacy. Scientific literacy is a major lever for improving care practices with a long-term vision [START_REF] Ruzafa-Martínez | Effectiveness of an evidence-based practice (EBP) course on the EBP competence of undergraduate nursing students: A quasi-experimental study[END_REF]. Scientific literacy is important in valuing nursing care by giving credibility to decision arguments in nursing care choices. Given the wide variety of research teachings, some may not be able to offer scientific literacy skills to nursing students. As a result, the transfer of knowledge into practice may be more challenging.

It will be interesting to focus future research on the acquisition of research skills by nursing students by comparing, for example, skills assessment strategies. Similarly, the comparison of research teaching content using slides and course materials could be of interest.

Our study has some limitations. Firstly, few nursing schools or universities in countries other than France participated in the survey. It was therefore impossible to compare the teaching of research by country. Despite this under-representation of nursing schools or universities from countries other than France, our study compared research teaching in France and other countries with significant results. Second, no French nursing schools confers a university degree beyond the bachelor's degree. A subgroup analysis was performed by excluding schools that confer a degree beyond the bachelor's degree rather than adjusting for the level of education. Finally, our data collection instrument was not validated with psychometric data. Nevertheless, we carried out an assessment of the comprehension of our survey tool with two

French

  research is essential for the development of scientific literacy skills of nursing students. Our study showed a wide variety in the content of research education around the world. Standardization and reflection on the content of research education for students could lead to an increase in evidence-based care practices. FUNDING SOURCE This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. BIBLIOGRAPHY American Library Association, 2013. Information Literacy Competency Standards for Nursing. Association of College & Research Libraries, 2015. Framework for information literacy for higher education. Chicago. Durant, J., 1994. What is scientific literacy? Eur. Rev. 2, 83-89. https://doi.org/10.1017/S1062798700000922

  Table 1 shows the number of responses by country. Most respondents worked in a public institution (n=210, 85.7%) and 54.2% (n=133) were referent teachers for research education. Institutions have 270 [180; 380] students per year and 15 [11; 21] instructors. For most respondents, nursing education provided an Associate/Bachelor's level (n=184, 75.1%) and is based on a curriculum provided by their country's government or ministry (n=227, 95.8%). The total duration of the course was 36 [34; 36] months. Research was taught in most nursing schools or universities (n=240, 98.4%). Teachers of research courses were mainly professional masters (n=179, 73%) or a research masters (n=86, 35.1%). Only, 26.5% (n=65) of schools of nursing have teacher-researchers or teachers with a PhD in research. Table 2 presents demographics data.

Table 1 :

 1 Characterics of participating nursing schools or faculties.

	Items		All
		n	%	Md	[IQ]
	1. Completed by
	Instructor referent to research	133	54.2
	Instructor	66	27
	Director of training program	23	9.4
	Assistant director	23	9.4
	2. Status
	Public	210	85.7
	Private	23	9.3
	Associative	12	4.9
	9. Instructor with 2-year Master degree			4	[2; 8]
	10. Instructor with PhD degree			6	[3.5; 14.5]
	11.University level
	Associate/ Bachelor's	184	75.1
	1-year master's	52	21.2
	2-year master's	2	0.8
	None	7	2.9
	12. Degree level of teachers who teach the research
	courses
	Associate or bachelor	72	29.4
	Professional master	179	73
	Research master	86	35.1
	Professional doctorate	20	8.2
	Research doctorate	65	26.5

Table 3 :

 3 Description of research teaching and comparison between nursing schools in France and abroad *p< .05 ; † On PubMed and CINAHL answers ; ‡ On nursing schools which have answered 5 or more propositions.

		France	Other			All
	Items			countries	p
		n	%	n	%		n	%
	14.3 Databases taught					<0.0001* †
	PubMed	76	74.5	34	94.4		110 79.7
	CINAHL	35	34.3	25	71.4		60	43.8
	Others	51	50	12	34.3		63	46
	All	162		71			233
	14.4 Content of teaching
	Simple research	85	83.3	28	80		113 46.9
	Avanced research	68	66.7	32	91.4		100 41.5
	Filters	58	56.9	28	80		86	35.7
	MESH terms	21	20.58 24	68.6		45	19.1
	All	232		112			345
	15.3 Teaching of CRA included					0.001* ‡
	Statistics	62	47.3	34	89.5		96	56.8
	Bibliometry	30	23	14	36.8		44	26
	Study biases	66	50.4	30	78.9		96	56.8
	Consistensy of results	95	72.5	28	73.7		123 72.8
	Selection of study population	91	69.5	33	86.8		124 73.4
	Goal of the study	115 87.8	34	89.5		149 88.2
	Applicability of the results	48	36.6	29	76.3		77	45.6
	Article structure	103 78.6	29	76.3		132 85.8
	Internal validity	19	14.5	31	81.6		50	29.6
	External validity	15	11.5	29	76.3		44	26
	All	644		291			935
	15.5 Number of articles read in English					<0.0001*
	0	100 76.2	4	10.5		104 61.53
	[1-5[	27	20.6	17	44.7		44	26.03
	[5-10[	1	0.8	5	13.2		6	3.56
	[10-20[	0	0	7	18.4		7	4.14
	More than 20	0	0	4	10.5		4	2.36
	All	128		37			165
	15.7 Type of articles read
	Original articles	99	75.6	35	92.1	0.05	134 79.3
	Systematic review	60	45.9	26	68.4	0.023*	86	50.9
	Meta-analyzes	26	19.8	15	39.5	0.023*	41	24.3
	All	185		76			261
	16.1 Teaching included
	Reading professional articles	95	74.2	14	77.8		109 74.7
	Reading scientific articles	30	23.4	12	66.7	<0.001*	42	28.8
	All	125		26			151

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We would like to thank of all nursing schools, universities and organizations who have accepted to participate and/French ministry of health, FINE-Europe, Assistance Publique -Hôpitaux de Paris (AP-HP)