G Nasti

A Ottaiano

M Berretta

P Delrio

F Izzo

A Cassata

C Romano

G Facchini

D Scala

A Mastro

Iaffaioli Rv

Pre-operative

Keywords: Liver metastases, colorectal cancer, neoadjuvant, resection

Introduction

Colorectal cancer (CRC) is the second cause of cancer death in Europe and the third in USA. The expected incidence of CRC in Italy is 32000 cases/year with 16000 CRC-related deaths/year [1]. Twenty percent of patients have clinical evidence of hepatic metastases at diagnosis and about 50% of patients will develop liver metastatic disease later [START_REF] Jemal | Cancer Statistics[END_REF].

The standard treatment of CRC patients with hepatic metastases is systemic chemotherapy; however, 5-year survival is disappointingly poor despite recent advances. On the other hand, in patients who undergo immediate radical surgical resection of hepatic metastases, 5-year survival reaches 30-40%. Unfortunately, only 15-20% of patients with hepatic metastases are initially eligible for a radical surgical approach [START_REF] Scheele | Resection of colorectal liver metastases[END_REF][START_REF] Bismuth | Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy[END_REF].

Retrospective series show a clear advantage in terms of overall survival in patients who undergo hepatic resection with respect to patients treated only with chemotherapy [START_REF] Adson | Resection of liver metastases: when is it worthwhile?[END_REF][START_REF] Fong | Liver resection for colorectal metastases[END_REF][START_REF] Kato | Therapeutic results of hepatic metastases of colorectal cancer with special reference to effectiveness of hepatectomy: Analysis of prognostic factors for 763 cases recorded at 18 institutions[END_REF], but it is commonly felt that the advantage observed with surgery is at least partially due to patient selection (better performance status and smaller disease extension in patients treated with surgery). Furthermore, the majority of patients undergoing liver resection relapse after surgery. For this reason, new onco-surgery approaches have been investigated in recent years. A recent EORTC randomized controlled trial demonstrated a significant benefit in terms of progression-free survival in patients treated with peri-operative 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]. Furthermore, the introduction of novel biological agents (such as bevacizumab and cetuximab) has prompted a new interest in the multidisciplinary approach to colo-rectal liver metastases.

The rationale of neoadjuvant treatment in CRC

Pre-operative chemotherapy has the potentiality of i) rendering resectable hepatic metastases in patients with initially unresectable disease, ii) increasing the percentage of radical resections and iii) allowing limited hepatectomies in patients with initially resectable hepatic metastases, with the aim of reducing surgery-related morbidity and improving post-operative recovery, iv) hitting micro-metastases, v) offering a test of in vivo chemosensitivity which could possibly be useful for the determination of an optimal postoperative schedule.

Patient selection for primary liver resection of CRC metastases

The majority of patients with liver metastases are not eligible for radical surgical resection. In the past, the main contraindications for a surgical approach have been: > 4 metastases, presence of extra-hepatic disease and resection margins < 1 cm [START_REF] Ekberg | Determinants of survival in liver resection for colorectal secondaries[END_REF]. Subsequently, Bismuth et al. [START_REF] Bismuth | Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy[END_REF] have extended the above criteria allowing resection of more metastases and of multinodular or hilar metastases. Recently, a consensus group has proposed new guidelines for the evaluation of resectability of hepatic metastases (Table 1). Their unresectability criteria are: 1) hepatic disease that involves more than 50% of liver parenchyma or six segments, 2) extra-hepatic disease, 3) unfit patients [START_REF] Poston | Individualize the treatment of liver metastases from colorectal cancer using RAND appropriateness method: Oncosurge decision model-Results of a consensus detecting from the international task force group[END_REF]. However, consensus on the definition of resectability criteria and surgical attitude varies considerably among centres. The patients candidated for radical hepatic resection can be stratified into risk groups on the basis of clinical scoring systems [START_REF] Nordlinger | Surgical resection of colorectal carcinoma metastases to the liver : A prognostic scoring system to improve case selection, based on 1568 patients[END_REF][START_REF] Iwatsuki | Hepatic resection for metastatic colorectal adenocarcinoma: A proposal of a prognostic scoring system[END_REF][START_REF] Adam | Resection of non resectable liver metastases after chemotherapy: Prognostic factors and long-term results[END_REF][START_REF] Mala | Hepatic resection for colorectal metastases: Can preoperative scoring predict patient outcome?[END_REF], which use prognostic factors identified with multivariate analysis, such as the presence of positive lymph nodes, a < 12 month disease-free survival, the presence of more than one tumour, high preoperative CEA, a > 5 cm tumour. According to the above factors, the 5-year survival has been shown to range between 14 and 60%. The validity of such systems needs to be confirmed in further studies before their introduction into the clinical practice. More recently, Quispe et al. [START_REF] Quispe | Long-term overall survival (os) and prognostic factors of patients (pts) with surgery of liver metastases from colorectal cancer origin (lm/crc): Retrospective analysis of a Spanish single institution[END_REF] have highlighted the importance of some main risk factors which may affect prognosis of patients treated with primary liver metastasectomy. In this analysis, synchronic (vs metachronic) disease, presence (vs absence) of limphonodal spread and R1 or 2 (vs R0) resection were associated with poor 5 years overall survival.

Neoadjuvant chemotherapy in unresectable liver metastasis: is it a realistic option?

The optimal neoadjuvant chemotherapy regimen has not yet been determined. However, as in the metastatic setting, the combination of chemotherapy with biological agents seems the most effective approach for a neoadjuvant intent. The greater part of data currently available in the literature comes from retrospective analyses or from phase III studies on metastatic disease, in which it was observed that some patients initially treated with a palliative intent became susceptible to radical resection of their hepatic metastases (Table 2) [START_REF] Tournigand | FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomised GERCOR study[END_REF][START_REF] Goldberg | A randomised controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer[END_REF]. Phase III studies: The study of Tournigand et al. has evidenced a 54% OR rate for the combination of 5-FU/FA and OXA (FOLFOX) and of 56% for the combination of 5-FU/FA and IRI (FOLFIRI). Hepatic metastases treated with FOLFOX resulted resectable in 13% of cases, while those treated with FOLFIRI were resectable in 7% of cases [START_REF] Tournigand | FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomised GERCOR study[END_REF]. The study of Goldberg et al. has compared FOLFOX with a combination regimen of IRI and bolus 5-FU/FA (IFL) and with the association of OXA and IRI (IROX), evidencing an OR rate significantly higher for the FOLFOX regimen (45% vs 31% vs 35%, respectively). In this study the percentage of patients who subsequently underwent surgery with radical intent after FOLFOX (4.1%) was also higher than after IFL (0.75%) [START_REF] Goldberg | A randomised controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer[END_REF]. A recent phase III study published by the Gruppo Oncologico Nord Ovest (GONO) compared fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line chemotherapy in unresectable metastatic colorectal cancer. Response rates as assessed by an external panel was 34% (FOLFIRI) versus 60% (FOLFOXIRI) (P < .0001). Interestingly, the R0 resection rate of metastases in liverlimited disease was greater in the FOLFOXIRI arm (12% v 36%; P = .017). Progression Free Survival (PFS) and Overall Survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032) [18].

Retrospective analyses of single-centre series

The Bismuth study was the first to specifically estimate the role of neoadjuvant chemotherapy in patients with unresectable hepatic metastases. Three-hundred thirty patients with unresectable hepatic lesions (large dimensions, multiple nodules, hilar localization, extrahepatic disease) were analysed. Most of the patients were treated with oxaliplatin-containing regimens; after chemotherapy 53 patients (16%) underwent hepatic resection. Intraoperative mortality was not observed, while 14 patients (26%) suffered from post-operative complications. The 5-year survival of patients who underwent surgery was 40% which is comparable to that of patients candidate to immediate hepatic resection [START_REF] Bismuth | Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy[END_REF]. Subsequently, Adam et al. reported an update of the aforesaid data with an analysis of 701 patients; radical resection was possible in 14% of patients with a 5year survival of 35% [START_REF] Adam | Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal (liver) metastases[END_REF]. Another important retrospective study by Giacchetti et al. analyzed 151 patients initially considered unresectable for the presence of hepatic metastases of large dimensions (> 5 cm), multiple metastases (> 4 nodules), or metastases localized in the hepatic hilus. All patients were treated with an oxaliplatin-containing chemotherapy regimen and objective response rate was 59%. After chemotherapy, 51% of patients were considered resectable but only 38% of patients underwent radical resection. The median survival was 48 months for the resected patients and 15.5 months for the unresected ones [START_REF] Giacchetti | Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery[END_REF].

Recently, a study by Adam et al. evaluated long-term outcome after combining downsizing chemotherapy and rescue surgery to define prognostic factors of cure. All patients with initially unresectable colorectal liver metastases who underwent rescue surgery and had a minimum follow-up of 5 years were included. Cure was defined as a disease-free interval > or = 5 years from last hepatic or extrahepatic resection until last follow-up. One hundred eighty-four patients who underwent resection from 1988 to 2002 were evaluated.

Patients had a mean number of 5.3 metastases (bilobar in 76%), associated to extrahepatic disease in 27%.

Surgery was possible after one (74%) or more (26%) lines of chemotherapy. Five-and 10-year overall survival rates were 33% and 27%, respectively. Of 148 patients with a follow-up > or = 5 years, 24 patients (16%) were considered cured (mean follow-up, 118.6 months), six (25%) of whom were considered cured after resection of recurrence. Cured patients more often had three or fewer metastases less than 30 mm (P=0.03) responding to first-line chemotherapy (P=0.05). Multivariate analysis identified maximum size of metastases less than 30 mm at diagnosis, three or fewer metastases at hepatectomy, and complete pathologic response as independent predictors of cure [START_REF] Adam | Patients With Initially Unresectable Colorectal Liver Metastases: Is There a Possibility of Cure?[END_REF]. Although these retrospective studies highlight the suitability of an integrated approach for treatment of hepatic metastases from CRC, they clearly suffer from their intrinsic limitations.

Prospective studies

Recently some small prospective studies specifically dealing with the neoadjuvant approach in unresectable hepatic metastases from CRC have been published (Table 2) [START_REF] Alberts | Liver resection after 5-fluorouracil, leucovorin and oxaliplatin for patients with metastatic colorectal cancer (MCRC) limited to the liver: A North Central Cancer Treatment Group (NCCTG) phase II study[END_REF][START_REF] Quenet | Resection of previously unresectable liver metastases from colorectal cancer (LMCRC) afer chemotherapy (CT) with CPT-11/L-OHP/LV5FU (Folfirinox): A prospective phase II trial[END_REF][START_REF] Pozzo | Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients[END_REF]. Alberts et al. have evaluated 42 patients treated with FOLFOX-4 reporting a 62% OR rate, a 33% of hepatic resections and a median survival of 31.4 months in resected patients [START_REF] Adam | Patients With Initially Unresectable Colorectal Liver Metastases: Is There a Possibility of Cure?[END_REF]. In another study, Quenet et al. have evaluated 34 patients treated with a chemotherapy regimen containing three drugs, namely OXA, IRI and 5-FU, obtaining resection of hepatic disease in 37,5% of patients [START_REF] Quenet | Resection of previously unresectable liver metastases from colorectal cancer (LMCRC) afer chemotherapy (CT) with CPT-11/L-OHP/LV5FU (Folfirinox): A prospective phase II trial[END_REF]. Pozzo et al. treated 40 patients with FOLFIRI, obtaining an objective response in 47,5% of patients and resection of hepatic metastases in 27.5% of patients. The median survival of resected patients had not yet been reached after a median follow-up of 30.4 months [START_REF] Pozzo | Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients[END_REF].

Moreover, an important study by Benoist et al. analyzed 38 patients derived from a prospective monoinstitutional series of 586 consecutive patients treated for hepatic metastases from CRC. The authors' policy was to perform liver resection, including the sites of the disappeared liver metastases in patients with resectable metastases. In initially unresectable patients, resection or local ablation of all visible liver metastases was performed, leaving the disappeared liver metastases in the remnant liver. Of the 38 patients, 22 had unresectable liver metastases (multiple bilobar deposits in 20 patients and invasion of major liver vessels in 2 patients) while 16 patients had resectable disease. Complete radiological remission (cRR) was confirmed by liver examination and US during surgery in 15 patients who had initially resectable disease.

However, pathologic examination of the cRR resected areas showed the presence of viable tumour cells in 12 patients (80%). Recurrence was observed 1 year after liver resection in 10 patients (66.6%). After 1 year, 14 of 15 patients were alive. In initially unresectable metastases liver examination and intraoperative US confirmed that there were no remaining visible tumour at the site of 31 liver metastases that had a cRR; these lesions were not resected. At 1 year, 23 patients (73%) developed recurrences at the site of the unresected lesions [START_REF] Benoist | Complete response of colorectal liver metastases after chemotherapy: does it mean cure?[END_REF]. The study of Benoist et al showed that although radiological complete response may be a useful criterion for evaluating the efficacy of chemotherapy, it does not mean a potential cure. In fact, the study indicated that the planned curative resection should not be altered by radiographic responses and that a cRR in a lesion that cannot be resected because of its anatomic site affects the potential for surgical cure. In fact, viable cancer cells are still present in liver even if a cRR is documented by US and CT and are responsible of in situ relapse in disappeared areas. Pathologic complete response remains the goal of the neoadjuvant treatment. In light of these data, systemic chemotherapy with neoadjuvant intent in patients with initially unresectable liver metastases from CRC seems a potential curable option However, many questions remain unanswered: which is the optimal neoadjuvant regimen and how many cycles are more appropriate before surgery? The planned curative resection should be determined by radiogralogical response? Does the response to neoadjuvant chemotherapy indicate the continuation of the same therapy after surgery? We have no definitive answers to these questions. For these reasons, all patients with initially unresectable liver metastases from CRC should always be addressed by a multidisciplinary team to determine the best treatment plan.

Neoadjuvant chemotherapy in resectable liver metastasis: is it worthwhile?

Feasibility and effectiveness of neoadjuvant chemotherapeutic treatment in patients with initially resectable hepatic metastases is still debated. Perioperative morbidity after neoadjuvant treatment of liver metastases is a major issue, especially in patients with resectable disease. Several reports have recently raised the issue of the potential liver toxicity of pre-operative chemotherapy. To date a long-term control of benefits (i.e. disease free survival and overall survival) has not been carried out. Thus, all patients with resectable liver metastasis eligible for neoadjuvant chemotherapy require accurate risk/benefit evaluation. Gruenberger et al have evaluated 50 patients with resectable hepatic metastases (1 metastasis 30%; 2-3 metastasis 22%; > 4 metastases 48%) treated with a neoadjuvant regimen containing oxaliplatin (30 patients with XELOX, 20 patients with FOLFOX4). All patients underwent surgery and obtained hepatic resection R0, with no surgery-related deaths and a morbidity of 12%. At a preliminary follow-up, 58% of patients were diseasefree, 20% had relapsed and 22% had died [START_REF] Gruenberger | Neoadjuvant chemotherapy for resectable colorectal cancer liver metastasis: Impact on magnitude of liver resection and survival[END_REF]. In another study Taieb et al. studied 22 patients with resectable hepatic metastases treated with neoadjuvant chemotherapy according to the FOLFOX7 regimen.

Twenty patients (91%) obtained R0 hepatic resection [START_REF] Taïeb | Intensive systemic chemotherapy combined with surgery for metastatic colorectal cancer : results of a phase II study[END_REF]. Recently, feasibility and efficacy data of the phase III EORTC 40983 study have been reported. The study compared perioperative chemotherapy with Folfox regimen (six cycles before surgery and six cycles after) with surgery alone in 364 patients and showed that Folfox does not affect the mortality of hepatectomy for resectable colo-rectal liver metastases.

Reversible post-operative complications occurred more often after chemotherapy than after surgery (25% vs 16%; p=0.04). The rate of progression-free-survival at 3 years increased from 33.2% to 42.4% in the chemotherapy group, with an absolute increase in rate of progression-free survival at 3 years of 9.2% in patients undergoing resection [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]. This trial indicated that perioperative chemotherapy with Folfox is compatible with major liver surgery and reduces the risk of progression-free survival in resected patients.

Characteristic of results of neoadjuvant chemotherapy trials with resectable liver metastases are detailed in Table 3. On the other hand, there is accumulated data of specific hepatic toxicities in patients treated with neoadiuvant chemotherapy before liver surgery. Specifically, two main types of liver damage have been reported: vascular changes and chemotherapy-associated steatohepatitis (CASH) [START_REF] Vauthey | Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases[END_REF][START_REF] Fernandez | Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases[END_REF][START_REF] Adam | Impact of preoperative systemic chemotherapy on liver histology and outcome of hepatic resection for colorectal cancer liver metastases (CRLM)[END_REF]. Vauthey et al. analyzed the effects of preoperative fluoropyrimidine-based regimens (5-FU alone, irinotecan plus 5-FU, oxaliplatin plus 5-FU) on liver histology in 248 patients compared to 158 patients who did not receive preoperative chemotherapy. Oxaliplatin was associated with sinusoidal dilation (18.9% oxaliplatin vs 1.9% no chemotherapy, p < 0.001; odds ratio = 8.3) while irinotecan was associated with steatohepatitis (20.2% irinotecan vs 4.4% no chemotherapy, p < 0.001; odds ratio = 5.4). It is noteworthy that steatohepatitis was associated with increased 90-day mortality after hepatic surgery compared to patients who did not have steatohepatitis (14.7% vs. 1.6%, respectively; p = 0.001; odds ratio = 10.5), while vascular changes increased the risk of operative bleeding but not that of perioperative morbidity or mortality [START_REF] Vauthey | Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases[END_REF]. Fernandez et al studied the presence of non-alcoholic steatohepatitis (NASH) in 37 patients who underwent hepatic resection of CRC metastases. Thirteen patients received no neoadjuvant therapy, 10 received 5-fluorouracil only, and 14 received neoadjuvant irinotecan (n = 12), or oxaliplatin, or both (n = 4), in conjunction with 5-FU. A multivariate analysis showed that both irinotecan or oxaliplatin-based regimens and body mass index were independent risk factors for developing steatohepatitis [START_REF] Fernandez | Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases[END_REF]. Adam et al. reported results from a retrospective analysis in 92 patients who had liver resection for CRC hepatic metastases treated without (17 pts) and with chemotherapy based on 5-FU alone (23 pts) or associated with oxaliplatin (52 pts). Vascular changes were more frequent in the group treated with chemotherapy (52 vs 18%, p< 0.01). There was also a trend towards a higher incidence of fibrosis and centrolobular necrosis (CLN) in the chemotherapy group. FOLFOXtreated patients had less steatosis and fibrosis, equal sinusoidal changes but more CLN (35 vs 4%, p= 0.07) than 5-FU alone. The outcome of patients following liver resection was not affected by these histological changes.. However, prolonged preoperative chemotherapy (>12 cycles) was related to a longer duration of hospital stay (15 vs. 11 days, respectively; p=0.02) and was a risk factor for re-operation (11% vs. 0%, respectively; p=0.04) [START_REF] Adam | Impact of preoperative systemic chemotherapy on liver histology and outcome of hepatic resection for colorectal cancer liver metastases (CRLM)[END_REF]. Regenerative nodular hyperplasia (RNH) represents the worst evolutive stage of vascular lesions induced by chemotherapy in the liver. In a recent retrospective analysis conducted upon 107 patients, Whichert et al. evaluated the impact of RNH on postoperative morbidity. As result, patients who received prolonged courses of preoperative Oxaliplatin had an increased risk of RHN and associated postoperative hepatic morbidity (23% vs 11% observed in Oxaliplatin naive patients). Moreover, preoperative gamma-glutamil-transferase (GGT) > 30 U/L and a total bilirubin level > 15 mol/L resulted to be independent predictive factors of RHN development [START_REF] Wicherts | Liver regenerative nodular hyperplasia consecutive to preoperative chemotherapy: Impact on outcome of liver surgery for colorectal metastases[END_REF].

As a result of the above data, patients with resectable metastasis should be considered for neoadjuvant chemotherapy, but patients should not be overtreated to avoid chronic and progressive chemotherapyinduced liver damage, which could preclude curative surgery. Some liver injury predictive factors are emerging from literature [START_REF] Nordlinger | Benefits and risks of neoadjuvant therapy for liver metastases[END_REF], but a more reliable assessment remains an important area of clinical investigation. Furthermore, considering the lack of data on neoadjuvant chemotherapy in terms of overall survival, we do not know if benefits of pre-operative chemotherapy encompass the risk of potential liver toxicities in patients with initially resectable liver metastases. In this regard, the recent EORTC 40983 trial data seem to tilt the balance towards the benefits of pre-operative chemotherapy. Further clinical studies are warranted in this setting.

Neoadjuvant chemotherapy: increasing appeal with the introduction of biologic agents?

Recent studies have shown the remarkable therapeutic effectiveness of some biological agents in advanced CRC. In particular, bevacizumab, a monoclonal antibody anti-vascular endothelial growth factor (VEGF) and cetuximab, a monoclonal antibody anti-epidermal growth factor receptor (EGFR), are the most interesting molecules. They have evidenced important therapeutic properties and are leading to a dramatic change of the therapeutic standards in advanced CRC [START_REF] Hurwitz | Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer[END_REF][START_REF] Kabbinavar | Combined analysis of efficacy: the addition of Bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer[END_REF][START_REF] Giantonio | Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200[END_REF]. In the most impressive study, Hurwitz et al. randomized 813 patients with metastatic CRC receiving either the combination of IFL and bevacizumab or IFL alone. A significant advantage of IFL plus bevacizumab compared to IFL alone was reported in terms of OR (44,8 vs. 34.8; p=0.004) and median survival (20,3 vs. 15,6 months; p=0.001) [START_REF] Hurwitz | Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer[END_REF]. Analogous results have also been obtained in a study in which bevacizumab was associated either with 5-FU/LV or with FOLFOX in the second-line treatment of metastatic disease [START_REF] Kabbinavar | Combined analysis of efficacy: the addition of Bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer[END_REF][START_REF] Giantonio | Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200[END_REF]. It has been demonstrated that the association of standard drugs with bevacizumab in first-line and second-line treatment significantly increases the percentage of OR and the overall survival. Moreover, many studies indicate that bevacizumab does not increase toxicity correlated to chemotherapy, while bevacizumab-specific side effect are reported, such as proteinuria, hypertension, bleeding, wound healing delay, arterial thrombosis and gastrointestinal perforation [START_REF] Scappaticci | Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab[END_REF][START_REF] Ellis | Surgical resection after downsizing of colorectal liver metastases in the era of bevacizumab[END_REF][START_REF] Gruenberger | Bevacizumab, Capecitabine, and Oxaliplatin as neoadjuvant therapy for patients with potentially curable metatsatic colorectal cancer[END_REF]. The use of bevacizumab in the neoadjuvant setting may be associated with major adverse events, such as wound healing delays, bleeding and defects in liver regeneration at the time of surgery. Clinical trials of bevacizumab in metastatic colorectal cancer reported 10% of patients having wound healing complication after major unplanned or elective surgery while on therapy [START_REF] Gruenberger | Bevacizumab, Capecitabine, and Oxaliplatin as neoadjuvant therapy for patients with potentially curable metatsatic colorectal cancer[END_REF]. The main issue is the interval between neoadjuvant bevacizumab and hepatic resection. The first BEAT study was aimed at evaluating the safety of bevacizumab in a broader patient population using a variety of chemotherapy regimens, such as FOLFOX, CAPOX, FOLFIRI. The trial design mandated BEV to be stopped at least 6-8 weeks before metastasectomy; when appropriate BEV was restarted 28 days after surgery. 1927 patients were enrolled in the study; 63 had undergone metastectomy and 60 had liver resections. Median time from last BEV administration to surgery was 56 days and median follow-up was 15.4 months. Chemotherapy regimens used with BEV included FOLFOX (n=24), XELOX (n=16), and FOLFIRI (n=15). No wound healing delay or bleeding related to surgery was reported; 70% of patients reported no complications. One patient had concomitant myocardial infarction and portal vein thrombosis, possibly related to BEV therapy [START_REF] Michael | Feasibility of metastasectomy in patients treated with bevacizumab in first-line mCRC: Preliminary results from the First Beat-study[END_REF].

In NO16966 trial patients with metastatic colorectal cancer were randomly assigned to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point progression-free survival (PFS) was reached because bevacizumab had a significant effect on PFS (9,4 months versus 8,0 months, P=0.0023). Interestingly, 44/699 (6.3%) patients receiving BEV underwent R0 resection compared with 34/701 (4.9%) patients receiving placebo (p=NS). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077).

Response rates were similar in both arms. [START_REF] Saltz | Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study[END_REF]. Recently, Gruenberger et al. have reported the results of a single-center, phase II study designed to determine the feasibility, perioperative complication rate and potential impact on post-operative liver regeneration with neoadjuvant capecitabine and oxaliplatin (Xelox) plus bevacizumab in patients with potentially curable liver metastases. Fifty-six patients were accrued and objective response to neoadjuvant chemotherapy was observed in 41 patients (73%). Fifty-two patients underwent liver resection and no increased intraoperative bleeding events or wound-healing complications were observed. No postoperative mortality occurred and morbidity was encountered in 11 patients (20%). This trial demonstrated that in patients who received bevacizumab up to 5 weeks before liver resection, the rate of surgical, wound healing or bleeding complications were not increased compared with historical data for chemotherapy alone. [START_REF] Michael | Feasibility of metastasectomy in patients treated with bevacizumab in first-line mCRC: Preliminary results from the First Beat-study[END_REF]. Much more recently, Bouganim et al. carried out a retrospective analysis upon 60 patients treated with preoperative chemoterapy containing bevacizumab. Response was observed in 80% of patients. Overall survival rates at 12, 24, 36 and 48 months were, 100%, 86%, 74% and 66%, respectively. Median progression free survival was 14 months (13 in Irinotecan receiving population and 15 in Oxaliplatin group). No sudden death or bowel perforation were reported [START_REF] Bouganim | Perioperative chemotherapy with bevacizumab (BV) for liver metastases (LM) in colorectal cancer (CRC): McGill University pilot study[END_REF]. Additionally, in another recent study, resected liver specimens from patients in two prospective, non-randomized trials (5fluorouracil/oxaliplatin+/-bevacizumab) were analyzed retrospectively. Interestingly, bevacizumab decreased the severity of the sinusoidal obstruction syndrome and had no impact on hepatic steatosis and fibrosis. This analysis showed that bevacizumab could protect against the sinusoidal obstruction syndrome and provide the histological explanation for the safe use of bevacizumab prior to liver resection [START_REF] Klinger | Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases[END_REF].

Cetuximab, a chimeric monoclonal antibody targeting EGFR, has shown high activity in advanced colorectal cancer either alone or in combination and does not increase complications in surgery. Cetuximab has the advantage of a shorter half-life (10 days) with respect to bevacizumab; furthermore, there is no current evidence that EGFR-targeted drugs may affect wound healing and liver regeneration. Moreover, the favourable response rates observed in advanced disease suggest that liver metastases could be effectively downsized, thus rendering the drug potentially appealing in the neoadjuvant setting. To date, only one study specifically exploring the role of cetuximab therapy on resectability of colorectal cancer liver metastases has been published. The study was performed to determine the post-cetuximab resectability rate and to examine postoperative outcomes in a group of heavily pretreated patients. One hundred fifty-one patients with unresectable CLM resistant to initial chemotherapy and subsequently treated with systemic cetuximab were evaluated. Twenty-seven patients underwent surgery after a median of six cycles of cetuximab + irinotecan (20 of 27), oxaliplatin (four of 27), or both (one of 27). Eighteen patients (67%) had experienced treatment failure after at least two lines of chemotherapy before cetuximab. Twenty-five of the 27 patients who had surgery underwent hepatectomy. Postoperative mortality was 3.7% (one of 27), with a complication rate of 50%. Histopathologic liver abnormalities were found in nine patients (36%), without specific lesions attributable to cetuximab. After median follow-up of 16 months, 23 of 25 patients who underwent resection (92%) were alive, and 10 patients (40%) were disease free. Median overall (OS) and progression-free survival (PFS) from initiation of cetuximab therapy were 20 and 13 months, respectively. Thus, combination therapy with cetuximab increased resectability rates without increasing operative mortality or liver injury suggesting that this strategy benefits patients with previously refractory disease who respond subsequently to cetuximab. [START_REF] Adam | Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy[END_REF] Recently, preliminary data from a randomized phase II study of cetuximab plus FOLFOX6 or FOLFIRI (CELIM study, ASCO, 2009 Gastrointestinal Cancers Symposium, Abs. 296) demonstrated high response rates (85% and 66%, respectively) in neoadjuvant therapy of unresectable colorectal liver metastases. Forty percent of FOLFOX6 plus cetuximab patients underwent resection (37% R0), compared with 43% (35% R0) of FOLFIRI plus cetuximab patients and 43% (34% R0) of patients with KRAS wild-type tumors. In a combined analysis of both arms, the 67 patients with wild-type KRAS tumors achieved a response rate of 79%. [START_REF] Folprecht | Randomized multicenter study of cetuximab plus FOLFIRI in neoadjuvant treatment of non-resectable colorectal liver metastases (CLM)[END_REF]. Furthermore, interesting data are emerging from phase III studies non specifically designed for patients with liver metastases. Impressive improvement of the resectability rate in patients with initially unresectable liver metastases treated with cetuximab in association with both FOLFOX and FOLFIRI regimens has been observed.

In the CRYSTAL study the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer was investigated. A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone with a randomization procedure. The hazard ratio for progression free survival in the cetuximab-FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P = 0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P = 0.31). KRAS mutation was predictive of response (P = 0.03) but not of progression-free survival (P = 0.07) or overall survival (P = 0.44). Interestingly, the rate of surgery for metastases was higher in the cetuximab-FOLFIRI group than in the FOLFIRI group (7.0% vs. 3.7%), as was the rate of R0 resection with curative intent before disease progression (4.8% vs. 1.7%; odds ratio for cetuximab-FOLFIRI, 3.02; 95% CI, 1.45 to 6.27; P = 0.002). With regard to only liver-confined disease, a rate of curative liver resection was achieved in 4.5% for FOLFIRI alone vs 9.8% for cetuximab-FOLFIRI [START_REF] Van Cutsem | Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer[END_REF]. In the OPUS study, patients were randomized to cetuximab plus FOLFOX-4 (n=169) or FOLFOX-4 alone (n = 168) as first-line treatment for metastatic disease. The ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR = 61% v 37%; odds ratio = 2.54; P = .011) and a lower risk of disease progression (hazard ratio = 0.57; P = .0163) compared with FOLFOX-4 alone. The addition of cetuximab to FOLFOX-4 was associated with an approximate doubling of the R0 resection rate from 2.4% (four of 168 patients) for FOLFOX-4 alone to 4.7% (eight of 169 patients) for cetuximab plus FOLFOX-4. [START_REF] Bokemeyer | Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer[END_REF]. Garufi et al. tested the combination of cetuximab, Irinotecan, Oxaliplatin, 5FU and Folinic Acid followed by surgery in 45 patients with unresectable colorectal liver metastasis and an encouraging 63% complete resection rate was achieved [START_REF] Garufi | POCHER (preoperative chemotherapy for hepatic resection) with cetuximab (Cmab) plus CPT-11/5fluorouracil (5FU)/leucovorin(FA)/oxaliplatin (L-OHP) (CPT-11-FFL) in unresectable colorectal liver metastases (CLM)[END_REF].

In conclusion, these data prompt the use of biologic agents in the neoadjuvant setting and open a real opportunity for pursuing curative resection also in patients with initially unresectable liver metastases. Both cetuximab and bevacizumab appear equally effective in combination with chemotherapy. The addition of cetuximab should be preferred in patients with wild-type KRAS tumors. Data from CRYSTAL and OPUS are pooled from subgroup analysis within large phase III studies in the metastatic setting and thus, they suffer of statistical pitfalls. Prospective, ad hoc trials are warranted in the near future in order to assess the effective role of biologic agents in the neoadjuvant setting and establish which targeted agent is the preferred combination partner for specific chemotherapy.

Table 1 : Controindications for the hepatic resection of colorectal cancer metastases: Before consensus:

 1

	>4 metastases
	Extrahepatic disease

included in clinical scoring systems:

	Positive lymphnodes
	Disease-free survival<12 months
	More than a tumor
	Elevated preoperative CEA
	Tumor with dimensions more than 5 cm

Table 2 . Characteristics and results of neoadjuvant chemotherapy including patients with unresectable liver metastases from colorectal cancer.

 2

	Author (year)	Therapy	Phas e	n. patient s	Prospectiv e	Specificall y designed	OR rate	Survival (% or median)	% resectabilit y
	Bismuth et al (1996)	FU/FA/oxa cronomodulate d	II	53	No	No	NR	40% at 5 years	16

Table 3 . Characteristics and results of neoadjuvant chemotherapy trials in patients with resectable liver metastases from colorectal cancer

 3

	Author	Therapy Phase Patients	Prospectiv	Specially	OR	Survival	%
	(Year)		number	e	designed	rate	(% or	resectability
							median)
		II	50	yes	yes	70%	Study
		XELOX
	Gruenberger et al (2004)	and FOLFOX					start:2003, 48% alive at	100
		-4
							the time of
							publication
		II	22	yes	yes	77%	89% at 2
	Taeib et al. (2005)	FOLFOX -7					years	91
		II	56	yes	yes	73%	NR
	Gruenberger et al (2008)	Xelox Bevacizu mab +	evaluabl (19 pts					95
			e)
		III	182	no	yes	43% Not reached
	Nordlinger et al (2008)	FOLFOX -4	(171 pts					93
			evaluabl

Conclusions

The addition of biological agents to chemotherapy, such as bevacizumab and cetuximab, and the improvements of surgical techniques have opened a new scenario in the management of colorectal liver metastases. For many years, the diagnosis of liver metastases from CRC was characterized by a dismal prognosis. Chemotherapy and surgery were two worlds which ignored each other. Recently, the EORTC trial has demonstrated that perioperative chemotherapy (Folfox regimen) is feasible and improves progression free survival in patients with resectable liver metatsases. Chemotherapy and surgery can finally work together. In the unresectable setting the association of chemotherapy with bevacizumab and cetuximab is particularly promising in improving resectability rate. In particular, K-RAS is a molecular response predictive factor that could be particularly useful in selecting the best treatment option in patients with unresectable liver disease.

Challenges for the immediate future are represented by: the definition of the role of biological agents as neoadjuvants, the assessment of biological markers of response to pre-operative chemotherapy, and the assessment of the best chemotherapy liver toxicity profile.


INTRODUCTION

Because of the multiple advantages of simulation and of the breakthroughs made in the improvement of their performances, the use of simulators has spread in a large number of application fields. Indeed, the main qualities of simulations are that they allow low cost repeatable testing of sensitive systems or of systems whose price forbids a full size test. Computer simulation also enables to model systems of high complexity and huge scale, such as the evaluation of natural systems or the study of structures as vast as a whole building. The use of computer simulators mainly prevents people and materials from runnig unnecessary risks, and prevents from engaging expensive machinery, and it enables the repetition of the same phenomenon as many times as necessary. Coupled with the continuous growth in the computing power, computer simulation gives totally satisfiying results in terms of exactness, in comparison to the real observations.

Current simulators have different priorities depending on their missions. This could be the physical accuracy of the results given, or the immersing capacity in the virtual world proposed to the user, by visual and sound aspects or any kind of methods used in virtual reality developments. Currently, the simulators are used for several missions, they evaluate prototypes, train people, predict some natural and physical phenomena or are physical phenomena or are used for purely ludic applications.

Crisis simulation is a domain whose needs perfectly meet the use of computer simulators. Indeed, their goal is often to assess the effects of industrial accidents, natural disasters or spiteful accidents. Therefore, the impossibility of realizing numerous full size tests led to the creation of several crisis simulators. However, the evaluation of the effects is not the only interest of the use of crisis simulators. In France, the legislation concerning plants classified for environment protection I.C.P.E., is based on two fundamental texts (the 19th July 1976 law and it 21st September 1977 decree of application) imposes on factory managers, potentially dangerous towards their environment, to maintain an Internal Operation Plan P.O.I. that describes the procedures to be set up to control the accidents until the plant is in a safe state. This legislation forces the adoption of three principles: creating and maintainming the P.O.I.s, training the personnel to follow the plans and setting up P.O.I.s in crisis situations. That is why we have developed our simulator, called 3D Virtual P.O.I., that meets problems linked to e-learning, as well as the necessity to build a simulator operational in a crisis situation. In this article, we will present the way we developed this software as well as the software as it was delivered to the customer. We listed two great types of architecture used in the design of crisis simulators. Some simulators exploit a geo-Accident Simulation: Design and Results

V. Idasiak & P. David

Laboratoire Vision et Robotique, Bourges, France

ABSTRACT: The French legislation regulates the functioning of factories that may be dangerous towards their environment. This legislation imposes the creation of an Internal Operation Plan (P.O.I.) on the plant managers. Those plans describe the proceedings that have to be implemented in case of an accident. Within a framework involving our laboratory and a gas company we have designed a software to create, maintain and execute P.O.I.s . In this paper, in addition to the software functionalities, we present our design method, as well as the used tools. Both are related to the problems of computing the design process of a P.O.I. and its exploitation in crisis situations. The approach is structured around the UML and the © MATLAB tool for both physical simulation and 3D environment management. The final software is developed in Java and uses the API Java-VRML EAI. This solution is currently in use at our partner's plants and it has completely revolutionized their way of managing P.O.I.s. graphical database (S.I.G) coupled with a physical engine which runs a mechanical model. The results of the simulation are presented to the user by means of a graphical interface that could be, depending the case, two or three dimensional. For instance, this type of architecture was used for a forest fire simulator. The second class of architecture is composed of an iterative database that communicates with the S.I.G. in order to present the running of the simulation by a multi-view system. This type of simulator is widely used for the simulation of hazardous materials (Hazmat) and for applications such as city crisis. Technically speaking, our tool is closer to the first type of architecture insofar as the S.I.G. is expressed with a 3D world that accurately represents the real studied plants. In our case, the mechanical model is limited to a simple behavioral model. The user controls and communicates with the simulator thanks to a 2D control window and a visualisation window in 3D. With "3D Virtual P.O.I." the setting up of the virtual dynamic world that represents the industrial installations permits to immerse the user in the replica of reality. Thanks to beacons we also obtain the technical information about the functional and security systems referred to in the P.O.I.. It is possible to consult information sheets, to simulate accidents (for example gas leakages, ignited or not, explosions). With the main interface developed in Java, the user can deploy the means of fighting against the disaster. The tool memorizes all the events and decisions and thus builds an accident report or a crisis resolution scenario, in order to improve the initial P.O.I.. The design process of the simulator is based on a method constructed by our team. Within the framework of this contract, we mainly included two stages of this method. In this article we will highlight those two points after having raised up the interaction between the industrial origins of the project and the competences and development of our team. Then, we will detail the characteristics of the simulator. Last, we will present the final tool and the impact of its use on the P.O.I. management, before concluding on the work done and the future improvements.

DESIGNING PROCESS

Industrial issues

The gas storage sites of the partner company of this project must respect the French legislation about I.C.P.E.s. It was thus necessary for them to equip their factories with a tool, capable of updating their P.O.I.s, but also that could be a precious help in conducting the plans in crisis situations. The product that we had to design was to reach an industrial level of quality for the triple mission of the simulator: teaching, training and the operational management of accidents.

The design of an industrial tool requires [START_REF] Göransson | Usability Design: a framework for designing usable interactive systems in practise[END_REF] to allow the different actors of the project and the future users to intervene at each step of the development process. To minimize its cost, we employed a method centered on the end-user, which led us to apply an incremental method based on the study of a prototype tool (Fig. 1).

Main developments applied to the project

Our research team worked on an integrated step aiming at using the support of specification and design teams to provide models to the teams in charge of the reliability studies and reciprocally. It consists in finding shared tools usable by the two specialities to improve the dialogue between them, and thus to create reliable design methods. During the realization of the simulator, the use of this method brought us some help at two levels, that is to say for the implementation of the tool and also for the contruction of the P.O.I.s. The employed method allows to create an application the nearest from the specifications. But it has in addition led to the modification of the specifications and to the evaluation of the modeled phenomenons. This step led us for instance to highlight the need of coherence between each behavioral event and their effects in the 3D interface, and moreover to create the behavioral model of each simulated entity. The deployed method rests mainly on two principles: the extraction of the dysfunctional behavior of the components from a UML functional analysis, and the modeling in  Matlab blocks of the failure modes highlighted in an FMEA.

Specificities of the simulator as regards its mission

We considered the exploitation constraints of this type of software, such as the necessity of having a high power of representation, the necessity of being independent as regards the operating system, to allow the consultation from a CD ROM or a website. Knowing that the sofware should allow: the automatic or semi-automatic addition of information or graphical representation, this without using others phases of development. Therefore we reused works and methods employed for e-learning [START_REF] Schaerf | JubilEasy: Build a personalized 3D visit of Rome[END_REF], [START_REF] Ewing | A framework for intelligent Virtual Training Environment: the steps from specification to design[END_REF] for the design of the static 3D part and the treatment of multiformat information. As far as the dynamic part is concerned, for instance the simulation engine, we adapted former works about remote controlled systems and reliable industrial systems [START_REF] Benali | A design of Adaptative Teleoperation Application[END_REF], [START_REF] Idasiak | Safety and reliability in the design of computers network for manufacturing[END_REF].

Use and impact of our method on the simulator design

As the P.O.I. already contains use cases and accident management scenarios, an adaptation towards the use cases and sequence diagrams in UML was naturally done. This allowed us to start the first step of our method, that is to say the synthesis of an FMEA from the functional data found in the sequence diagrams. Traditionally, FMEAs are built from functional analysis. The use of sequence diagrams in order to create an FMEA is totally justified because we observed that it was possible to find the same information about the studied system in both formats. Indeed, FMEAs are used to study the non-realization or the unsatisfaction of the system's functions. The construction of the FMEA is based on the results of the functional analysis because it identifies the functions of the system in the different phases of its lifecycle. Those phases can be found in the sequence diagrams because they describe the different functions in the whole lifecycle. The external elements and their behaviour are also searched; those elements being identified in the sequence diagrams by the entities of "actor" type. The relationships between the actors and the diverse components were also modeled. Finally, the functional analysis makes it possible to identify all the functions of the system, these are the functions which are described by each use case represented by the sequence diagrams. This treatment which creates the FMEA is realised by an algorithm that we developed and whose instructions are described in the following lines.

Input of the algorithm:

• Set of the Actors noted A • Set of the Objects noted O A ∩ O = ∅ • Set of the messages noted M
The elements of M are couples (x,y) where x, y ∈ A ∪ O, x is the sender of the message and y its receiver.

• C and E are two empty sets Creation of a table whose first line is composed of 9 boxes that indicate, the name of the object or actor, the failure mode, the cause(s), the effect(s), the severity, the probability, the risk, the means of detection, the technical solutions.

∀i ∈ A ∪ O and ∀ md ∈ MD ∀ m ∈ M, if m[2] = i, C = C + m[1] ∀ m ∈ M, if m[1] = i, E = E + m[2] Creating a line = {i, md, C, E, ∅, ∅, ∅, ∅, ∅
The algorithm has been implemented in XML using the transformation language XSLT. XSLT allows to specify how to generate an XML tree (or HTML in our case) from a source tree itself written in XML. In order to realise the specification of the next XSL (norm that includes XSLT) we used rules that associated selectors to a form to be generated (in our case the HTML structure). The selectors are the objects that we search thanks to pointers on the XML nodes. The existing rules on the selectors are setting off the construction of the file.

The use of this method during the prototyping phase (described in section 3) allowed to quickly validate the dysfunctional modes that had an interest for the simulation and highlighted the necessity to add new tools in the method. There is a profusion of dysfunctional modes to study, thus a necessity to create a standard Matlab box and a step to introduce the dysfunction in the prototype.

Technological solutions

The interface prototype is based on the analysis of the use cases and the main scenarios. It is divided into two ways of access: the information consultation and the accidents simulation. The functionalities of the information consultation mode as well as the access to technical information or security data and other procedures are totally included in the simulation mode. It quickly appeared interesting to allow an optimised access to this information without having to run the simulation mode, much more expensive in term of resources. The main offered functionalities have been regrouped by the emerging center of interest that we saw in the scenarios and classified by temporal criteria (placing of the accident, settings of the climatic aspects, adding graphic elements …). In parallel, the elaboration of the chosen architecture has been guided by the functionalities accepted by the end-users and the exploitation contrainsts that exists in the crisis management center and in the production plants. A tree based structure of HTML file, generated from an extraction of the database of P.O.I.s, both guarantee the coherence of the information and a fast access to the multiformat documents. The application, accessible from a Web browser, associated with the Blaxxun contact 3D plugin, is deployed with the Java language. The interface with the 3D VRML world is realised thanks to the API Java-VRML EAI [START_REF] Dit | 3D technology for the Worl Wide Web[END_REF]. The advantages of employing a 3D interface in place of 2D views have been discussed in publication like [START_REF] Cory | Utilization of 2D, 3D, or 4D CAD in construction communication documentation[END_REF]. The 3D rendering of this product brings the user in an immersing experience of accident scenarios. Thanks to this technology the user understands the geographical aspects of each case much more rapidly than with a simple 2D plan. The 3D environment gives immediately an idea of the installation's dimensions and how the equipments are placed. The details of the viewing window are enough precise to simulate things as the orientation of flames. Moreover the 3D aspects allow to represent easily elements that are far to be insignificant, like the flames high. Finally one plan in 3D shape presents things that would need several 2D plans. For instance in order to represent a gas pipeline, at least two 2D plans are required (one representing the layout of the pipeline and one for the transverse section of the pipe), whereas a single one is necessary in 3D models. The use of 3D view is therefore more effective to enhance the power of representation and the navigation in the virtual environment. The dynamic simulation part, developed with the formalism of statecharts, is naturally built from the specifications expressed by the collaboration diagrams which merge the different scenarios of each use case. This stage, we also have modeled the dysfunctional behaviors of the diverse objects that appear in the scenarios. We inserted the state that models the dysfonctional behavior thanks to security analysis of the materials as the FMEAs. With the use, they will allow to study the impacts of supplementary accidents or of the unavailability of some equipment during the simulation.

Finally, the software needs to be ready to receive new equipment or to produce new scenarios: a setting at the beginning of the application allows to add some new elements and graphic objects as well as new types of events. Whereas the types of event are simple textual information specific to the job of the end-user, the graphic objects are much more complex. They respect the class diagram of Figure 2, in which we define two types of objects: the simple graphic objects and the event generator objects or objects which have an impact on the physical pa-rameters managed by the simulator. For instance, some of them impact the capacity of fighting a fire by consuming the water reserve. It is a permanent request for the end-user to know the state of the water reserve in real time, and the impact of each means of fire fighting or gas refreshment on this reserve. When we add an object that consumes water the simulator automatically calculates the next state of the reserves. The graphic objects also have proper methods for the visualisation of their dynamic behaviour, their geographic position in the scene depending on the three axis and to the rotation around the vertical axes. The « child shape » class models the tree based architecture VRML and is not managed by the software. By construction it is the VRML engine that realises the graphic operations. It is easy to add some objects. This operation consists in selecting an item in a skeletal list. After a validation, the graphic part is loaded in the VRML file directly in the browser and appears immediately. The insertion position in the interface is the one of the avatar. Therefore, it is a very intuitive command. The static and dynamic attributes are loaded in the Java simulator. The interface described in section 4 offers the user a means to run the application in real time. All modifications of the position and orientation parameters are automatically written in the positioning vector of the VRML file. The modification of the dynamic behaviour involves the posting of the graphic elements (water, color, …) associated with the main object.

PROTOTYPING

Influence of the prototyping

For the prototyping of the dynamic part, we have chosen to represent only a fraction of the whole site: the one constituted by the storage area, two storage spheres and three cisterns, plus the area of loading and unloading of the cisterns-coaches. This step uses three formalisms:

The state diagrams model the accident scenario in conformity with the P.O.I., the virtual VRML world is in charge of representing the physical behaviour of the components in order to make the scenarios rapidly understandable by the users. The Simulink part manages the whole simulation, that is to say the interaction with the user, the calculations and the relationships between the two other formalisms and the transmission of the states' values of the stateflow for the animation of the 3D model.

After the validation of the model by the end-user, the Java code of the software has been generated semi-automatically from the stateflow and simulink diagrams. That brought more coherence between the final product and the prototype.

Figure 3 shows the main window of the project in Matlab. The diagram shows the links between the various blocks with the sending of data and events. In a preoccupation with the ergonomics, a single color identifies the blocks related to the same elements (cold colors for water and gas; hot colors for the flames, the temperature and the explosion …).

The stateflow part, Figure 4, saved us a considerable time in the development of the dynamic behaviors to simulate. Note that if we consider the final mission of the simulator only basic behaviors have been modeled.

In order to validate the relevance of our stateflow models, we instrumented them, aiming at memorizing the changings of state of our components on a simulated scale of time. This enabled us to compare the dynamic evolutions obtained with the scenarios expressed in the specifications. We have also generated new scenarios. This property was preserved in the final code, with a list of events.

Limits explored and highlighted by the prototype

In parallel with the project, we have tried out some models of thermal or gas diffusion (Fig. 4) and dysfonctional models (Fig. 4). Some limits appeared, in particular, the complexity to directly calculate, starting from this formalism, a reliability level. We are now translating this work in the AltaRica Data Flow language [START_REF] Arnold | The AltaRica language and its semantics[END_REF], [START_REF] Bouissou | Reliability & performance evaluation[END_REF], in order to offer, for each scenario, a calculation of a success rate. We apply for this work our method that deducts the construction of Mode Automata [START_REF] Rauzy | Mode Automata and their compilation into Fault tree[END_REF] from FMEA and functional analysis. With this method we are also able to build Stochastic Petri Nets. All those developments will be dealt with in a future communication. From the FMEA we transpose the failure modes in our simulink model to introduce the main dysfunction (identified by the calculation of the risk) in the system model. We note that this manner of proceeding allows to introduce, since the conception, the impacts of some failure modes and thus to foresee at this step the setting up of mechanism for error recovery or fault avoidance.

Figure 3. ©Matlab model of the dynamic prototype

Prototyping of the graphic aspect

The animations showing the effects of the gas leakages or the flames are realised by coupling simulink diagrams with the "scale" parameter of the VRML "shape" node selected. The simplicity for setting up a cyclic signal generator in simulink makes this operation very fast. We made the effect of bubbles or flames with three groups of elementary shapes, connected with periodic signals out of phase by Π/3. The effect is symbolic, but it is suf-ficient for the software and really low cost in terms of computing resources.

The interface with the 3D world uses a part of the API Java-VRML EAI. It constitutes a limiting factor for this prototype in the framework of this project. However, if it is not possible or easy to add dynamically 3D objects or to modify parameters such as the transparency, this will be done in the next version of the conception cycle. Two types of files are extracted from a data base of P.O.I.s . The first type contains for each object: a single label common to all P.O.I.s, the simulator and the VRML files; the photographs of the real installations and of the mobile equipments; a technical report; finally, technical plans can be referred. Those files are automatically analysed and start the construction of the Web pages. These files appear in the "technical information" window (Fig. 5 --). Access to this information is very intuitive by the addition of "proximity sensors" on the referred objects. During the movement into the 3D world, if the cursor points a graphic object, a label appears. A simple click starts the posting of information.

The second type of extracted files is essentially composed of a single label and physical caracteristics of the simulation. They are loaded by the Java applet and inform it about the initial parameters of the object that the user can handle.

The interface of the simulator is composed of five panels (Fig. 5);

The "initialization" panel gives the state of the loading of the initialization files. They gather the basic information about the simulator, and al-low the insertion of the localization of the files of simple objects, event objects and water objects. Thus, all 3D VRML models can be added into the simulator, after a declaration phase. The syntax of the loaded files is verified; no error of parameter file can be accepted. A color indicates a loading error.

The "dreaded event" interface allows the selection of an accident from a list of four possible leakages: ignited gas LPG, not ignited gas LPG, ignited liquid LPG and not ignited liquid LPG. After the choice of the localization and the size of the leakage, the simulation can be run from this panel. The "water" gauges indicate in real time all the information about the cumulated flows, the autonomy and the time passed since the occurrence of the accident.

The "event" panel memorizes all the actions that occured during the simulation. For each action the time when which they appear is noted. When the applet starts, it is possible to fix the starting time .

The "device" window allows the selection and the dynamic addition of devices declared during the initialization. A control block provides the means to move the selected object along the x, y or z axis or to rotate it around the z axis. We have also introduced a cursor that permits to modify the importance of the movement in order to improve long displacements and precision in the installation.

The activation, the stop and the dynamic removal of objects are also carried out through the orders available on this panel. Finally, the direction and the strength of the wind are also modifiable .

Impact on the P.O.I. document creation

The P.O.I.s are designed to be utilized in crisis situation that are not yet critical. They are created to limit and describe how to treat restricted accident. Therefore dramatic accident like explosions are not described in Virtual P.O.I because the operation that those cases need are presented in other type of document like P.P.I.s (Particular Intervention Plan), or Red Plans, which were not the goal of the end user. In France the only document which is accepted by the legal institutions to manage P.O.I.s is a document on paper. The use of Virtual P.O.I. leads to the creation of a documentation database more precise and clear. First the software makes it easy to try many scenarios of accident, therefore it is simple to highlight which of them are relevant and to justify the establishment of a formal document made in paper format. By using screen printings from Virtual P.O.I. the formal documents are also more suitable, because they present a realistic perception of the environment impacted by the crisis treated. Finally Virtual P.O.I. has two advantages for the legal document creation, which are the detection and the selection of the scenarios studied on the one hand, and the integration of interesting views and information about the crisis states and resolution on the other hand.

User experience and reuse

The software uses very instinctive functionalities for the establishment of the scenarios. Moreover the navigation in the interface and the placement of new objects is very intuitive. All those aspects make the software very easy to be used. After roughly twenty minutes of explanation a new user can start to simulate a first accident scenario. The software has two main functionalities in training, the first is to allow to discover the plant, and the second to conduct accident scenarios in it. Thanks to the fact that the navigation system is very standard, a simple visit of the plant which is very useful for future workers, can be made without experience of the software. The software is therefore easy to deploy for a mission of training. To use the software to follow a real crisis development and to use it as a tool for decision-making aid, a preliminary experience of the software would be very useful.

The direct reuse that we could imagine for our simulator are in the field of the management of P.O.I.s for oil, chemical or petrochemical industries. The design methods and the techniques that we used can be adapted to represent special phenomenon for those technologies. For instance if we would like to reuse those works for a transfer in oil industry, we should proceed identically. A preliminary risk analysis should be performed to identify the accident scenarios and their impacts. Therefore new dangerous phenomenon should be highlighted like boilovers, bleves, toxic smokes or large fires. Heating effects should be supported by colorizing the environment of flames respecting a value scale, solid remains should be added after an explosion by a simple object creation. Those remains could have the effect of a physical barrier and could also carry out a heating information. Liquid leakages (Ignited or not ) should be also represented and indication about the maximum flow and quantity of lost oil could be integrated.

CONCLUSION

This article presented the options chosen for the development of the simulator. This has highlighted the particular technological choices that we have employed to solve the problem of P.O.I. manage-ment, but it has also raised up the use of a general design step stressing the taking into account of the dysfonctional behavior. This method, that aims at integrating the dependability analysis in the conception operations, will be the topic of a future communication in which we will better underline the methodological aspects. The simulator that we presented has shown capabilities for its mission of managing P.O.I.s in gas plant, but it could be deployed for more types of industrial plants or public buildings. It is in reality a tool for testing and setting up emergency plans for any kind of situation. Our current work about this tool consists in trying to introduce smart agents in the simulations, in order to model technicians or firemen that follow orders to solve the crisis, or just panicked people.

Figure

  Figure 1. Design process

Figure 2 .

 2 Figure 2. Dynamic graphic object class diagram

Figure 4 .

 4 Figure 4. reduced dynamic model of the plant

Figure 5 .

 5 Figure 5. 3D virtual P.O.I. interface in simulation mode

4. 2

 2 Impact of the use of 3D Virtual P.O.I.