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Colorectal cancer is a frequent disease with an increasing incidence. Its prognosis improved recently because of progress in diagnostic and therapeutic procedures. Rationale and guidelines for colorectal cancer screening using the faecal occult blood test in the average risk population and screening recommendations for high risk groups are presented, as well as diagnostic and therapeutic principles. Because of the efficacy of the new chemotherapy regimens, the availability of biotherapies and the fact that surgery can potentially cure more and more patients, colorectal cancer management needs to be multidisciplinary.

Immune glomerulonephritis (GN) initially develop as a result of inappropriate immune response, either inadequately directed to self-antigens, or unable to effectively eliminate a foreign antigen. This abnormal immune response leads to the formation of circulating immune complexes, auto-antibodies or self-reactive effector T cells that target glomerular antigens or to the inappropriate regulation of IgA producing lymphocytes (Berger disease) or helper T lymphocyte sub populations (minimal change nephrotic syndrome). In most of the cases, the initial immune injury induces an inflammatory response. However, it is the extent of the interstitial fibrosis which is genetically controlled, that conditioned the evolution of the initial glomerular injury to glomerular sclerosis and progressive renal failure. Recent data on the pathogenesis of the most frequent GN are reported: IgA nephropathy, membranous nephropathy and minimal change nephrotic syndrome. Recent significant advances in the pathophysiology of those glomerular diseases have shed considerable light on the understanding of the underlying disease even if they do not have immediate therapeutic implications.

The 5-year risk of progression after complete resection of liver metastases is of 50% to 75%. Trials which have evaluated adjuvant systemic chemotherapy using 5FU--folinic acid, sometimes in association with intra-arterial chemotherapy, are not powerful and did not demonstrate a clear survival benefit. It is strongly recommended to participate to clinical trials. An adjuvant chemotherapy with the LV5FU2 regimen during 6 months is a reasonable option if the patient has not been included in a trial (professional agreement). A preoperative chemotherapy is not recommended if liver metastases are considered as right away resectable but it should be discussed if resectability is uncertain and/or in case of pejorative factors (professional agreement). If metastases resection has been facilitated or made possible by pre-operative chemotherapy, post-operative resumption of this chemotherapy should also been discussed (professional agreement).

A prospective phase II study was performed to determine the feasibility, efficacy and safety of arterial hepatic infusion (HAI) using pirarubicin combined with intravenous chemotherapy.From December 1991 to April 1994, 75 patients with unresectable colorectal metastases confined to the liver were included in this multicenter study to receive intra-arterial hepatic pirarubicin and a systemic monthly regimen of 5-fluorouracil (5-FU) and folinic acid. Sixty-four patients were analyzed in the intention-to-treat analysis and 61 in the per-protocol analysis.Tolerance of this regimen was rather good; however, functional catheter problems were observed in 29 patients (45%) resulting in failure of HAI in 21 cases (33%) after a median of three cycles; vomiting grade 3 was present in 12.5% of patients, neutropenia grade 4 in 23% and alopecia grade 3 in 19%. The overall response rate was 31.9% in intention-to-treat analysis, and 39.3% in per-protocol analysis. Extrahepatic progression was reported in only 21.7% of patients. Time to hepatic progression and extra-hepatic progression was 8.3 and 15 months, respectively, in intention-to-treat analysis, and 11 and 18 months, respectively, in per-protocol analysis. Median survival was 19 and 20 months in intention-to-treat analysis and per-protocol, respectively.In our study, the combination of intra-arterial pirarubicin and intravenous chemotherapy demonstrated some efficacy and good tolerance in the treatment of isolated colorectal liver metastases. This treatment seems to prevent extra-hepatic spread and prolong survival time. The results of this study have to be confirmed by new trials using more active systemic chemotherapy.

Cryptosporidiosis is a common cause of diarrhea in patients with AIDS but remains one of the most challenging AIDS-related conditions to treat. We therefore carried out an open, uncontrolled, prospective study to evaluate the efficacy of oral paromomycin for the treatment of chronic diarrhea due to Cryptosporidium in 24 successive patients infected with human immunodeficiency virus. Twenty-two of the 24 patients responded clinically, with complete remission occurring in 18 cases and marked reduction of the diarrhea occurring in four. Clearance of cryptosporidia from stools and/or intestinal biopsy specimens occurred within 2-4 weeks. Furthermore, all 18 patients who achieved complete remission gained weight. Ten patients relapsed either during administration of maintenance therapy or after discontinuation of treatment, but diarrhea resolved again after increasing or restarting paromomycin therapy in all but two. Paromomycin appeared to be an active and well-tolerated treatment for cryptosporidiosis in patients with AIDS. Efficacy is dose-related, and continuous maintenance therapy is required to prevent relapses. These data suggest that paromomycin might be given as first-line therapy in AIDS-related cryptosporidiosis, but this should be confirmed by the findings of a controlled, randomized trial.

Colorectal cancer (CRC) is the second leading cause of cancer death in Western countries, and although the treatment of advanced CRC has progressed substantially, the improvements in response rates have not always been translated into a significant survival benefit. Until recently, the standard therapy for advanced CRC was a variety of biomodulated 5-fluorouracil (5-FU) regimens. 5-FU was used as first- or second-line therapy, and a different 5-FU regimen was used second line if first-line 5-FU therapy failed. Typically, the survival times for these patients were short and their quality of life poor. In recent years, a variety of new agents have emerged that have demonstrated activity in the treatment of advanced CRC. Of these, irinotecan (CPT-11) and oxaliplatin in combination with 5-FU and folinic acid (FA) have yielded the most promising results. However, only CPT-11 combined with either bolus or high-dose infusional 5-FU/FA, in randomized phase III studies, has demonstrated an increased response rate and median time to progression, producing a significant and clinically relevant survival advantage. In 2 randomized phase III studies, oxaliplatin/5-FU/FA demonstrated a clear increase in response rate over 5-FU/FA alone but failed to demonstrate a survival advantage. CPT-11 was approved by the Food and Drug Administration in April 2000 for the first-line treatment of advanced CRC in combination with 5-FU/FA.

Background We have investigated the efficacy, safety and quality of life profiles of three therapeutic combinations [irinotecan + leucovorin (LV)/5-fluorouracil (5-FU), oxaliplatin + LV/5-FU and irinotecan +oxaliplatin] in patients with metastatic colorectal cancer after failure of a 5-FU-based regimen, or whose disease had progressed within 6 months of the end of treatment. Patients and methods One hundred and one patients were randomised to receive either: (i) irinotecan 180 mg/m2 on day 1 followed by an LV 200 mg/m2 infusion, before a 5-FU 400 mg/m2 bolus followed by a 5-FU 600 mg/m2 infusion (LV5FU2 regimen), on days 1 and 2 every 2 weeks; (ii) oxaliplatin 85 mg/m2 on day 1 followed by the LV5FU2 regimen on days 1 and 2 every 2 weeks; or (iii) oxaliplatin 85 mg/m2 followed by irinotecan 200 mg/m2, both on day 1 every 3 weeks. The primary end point was overall response rate (ORR). Results The intention-to-treat ORRs were 11.4% [95% confidence interval (CI) 3.2–26.7), 21.2% (95% CI 9.0–38.9) and 15.2% (95% CI 5.1–31.9), respectively, in the three arms. Tumour growth control was ≥60% for all three combinations and overall survivals were 12.2 months (95% CI 9.2–16.0), 11.5 months (95% CI 9.0–14.1) and 11.0 months (95% CI 8.1–12.2), respectively. All patients were evaluable for safety. Main grade 3–4 toxicity was neutropenia (33 to 39% of patients). Conclusions Thus, second-line treatment with irinotecan/LV5FU2, oxaliplatin/LV5FU2 or irinotecan/oxaliplatin, provides good tumour growth control and survival coupled with an acceptable safety profile.

To prospectively evaluate efficacy and tolerance of the 5-fluorouracil + folinic acid + cisplatin (LV5FU2-P) combination in the treatment of unresectable pancreatic carcinoma.Between March 1998 and June 2000, 35 patients, mean age 61 years (37-75), with advanced (n=2) or metastatic (n=33) pancreatic cancer and initial performance status (WHO) of 0 (n=9), 1 (n=14) or 2 (n=12) were enrolled in the study. Two consecutive groups of patients were treated twice monthly, the first group (n=19) received the LV5FU2 regimen: a 2 hour-infusion of leucovorin 200 mg/m(2), 5-FU bolus 400 mg/m(2), followed by 22-hour continuous infusion of 5-FU 600 mg/m(2) on 2 consecutive days and cisplatin 50 mg/m(2) on day 2. The second group (n=16) received a simplified schedule with bolus leucovorin 40 mg/m(2), 5-FU bolus 400 mg/m(2) on day 1, followed by 5-FU 2400 mg/m(2) 48-hour infusion and cisplatin 50 mg/m(2) on day 2. Clinical symptoms and performance status were monitored together with weight changes. Tumor assessment was performed every 2 months.Three patients (9%) exhibited grade 4 neutropenia and grade 3 toxicity occurred in 31% of the patients (neutropenia: n=3, thrombocytopenia: n=1, vomiting: n=3, mucositis: n=3, diarrhea: n=1). There were no treatment-related deaths. Objective response was observed in 10 patients (29%, 95% confidence interval: 20-40%) including one complete response. Median progression-free survival and overall survival were 4.5 and 9 months, respectively. Six-months and 1-year survival rates were 70% and 25%, respectively. Weight gain was observed in 40% of the patients and performance status improved in 50%.LV5FU2-P regimen is active and well tolerated. It should be compared to gemcitabine as a first line therapy in advanced and metastatic pancreatic cancer.

Surgical resection is now well accepted as the standard treatment in 10 to 20% of patients with liver metastases. Tumor ablative techniques have been developed in recent years. The basic idea is to use them in patients with a limited number of intrahepatic deposits that are not totally resectable. Several papers published in 2001 have addressed cryotherapy. Cryotherapy can be considered an effective method for local destruction of liver metastases up to 3 to 4 cm in diameter but is also associated with a significant rate of complications. In many centers, cryoablation has now been replaced by radiofrequency ablation, the most widely used method for ablation of unresectable liver metastases. It can be performed during laparotomy, at laparoscopy, or percutaneously. Tumors less than 3 cm in their greatest diameter can be destroyed with one placement of the needle electrode. Metastases larger than 3 cm require several placements. Both cryotherapy and radiofrequency ablation are effective methods to induce necrosis of liver metastases. It is likely that in the near future, most patients with liver metastases will receive a multimodality treatment: a local treatment such as surgical resection or tumor ablation, and a general treatment such as hepatic infusional or systemic chemotherapy. Trials published in 2001 have shown that oral prodrugs of fluorouracil were probably equivalent to fluorouracil bolus administration. Regimens containing oxaliplatin or irinotecan have also been evaluated for efficacy and tolerance and by the intravenous route alone or in combination with hepatic artery infusion. Effective systemic chemotherapy regimens have resulted in increased survival rates and improved quality of life and in some cases have allowed resection of initially unresectable liver metastases.

1. Digestive oncology – a changing fieldDigestive cancer accounts for a quarter of all cancers and con-siderable knowledge of the particular features of these disordersis required for correct treatment. Digestive oncology (DO) is amajor field of activity for hepato-gastroenterologists (HGE), whoare involved at all stages, from screening to diagnosis, follow-up,tumour evaluationandpalliativetreatment.HGEhavealsorecentlybeen recruited to multidisciplinary teams, due to their consider-able competence in the management of digestive cancers. OverallDO accounts for more than 50% of all admissions to most gas-troenterology (GI) departments. In Belgium, France and Germany,HGE withspecific,recognizedcompetenceareallowedtoadminis-ter chemotherapy and targeted therapies. In these countries, suchcompetence isconsideredtobeattainedaftertwoyearsoftrainingwith an additional course and certification controlled by special-ists in oncology. HGE work in close collaboration with the otherspecialists responsible for managing digestive cancer, as part ofmultidisciplinary teams. Together, Belgium, France and Germanyaccount for 40% of the European population (about 200 millionEuropean citizens). The system works well in these countries andit is not clear why other European countries have not also electedto allow HGE to perform these functions after specific training.Chemotherapy and targeted therapies are no more complex toadminister than other drugs regularly prescribed by HGE, suchas immunosuppressants, antiviral treatments and anti-TNF treat-ments.The reasonsforthissituationmaybehistorical,demographicoreven political.1.1. Historical aspectsWhen 5FU (fluorouracil Roche lb), the first antineoplastic drug,was discovered 50 years ago, HGE expressed great scepticism con-cerning its utility. However, the situation changed in the 1990s

4058 Background: Ramucirumab (RAM) added to paclitaxel (PTX) resulted in statistically significantly improved overall survival, progression-free survival and response rate for previously treated pa...

4076 Background: RAINBOW, a global, randomized, double-blind, phase 3 trial demonstrated significant improvements in overall survival (OS), progression-free survival (PFS), and response rate in met...

3549 Background: Prognostic value of KRAS mutations in resected colon adenocarcinoma remains debated. We examined the prognostic impact of KRAS exon 2 mutations in stage III patients receiving adju...

e15155 Background: Based on old studies, streptozocin (STZ), used to treat gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), is known to have some renal toxicity. We investigated the renal...

3589 Background: IV chemotherapy (chemo) downsizes LM-CRC in most pts. Yet less than 15% of those with previously unresectable LM and prior chemo undergo successful complete macroscopic LM resectio...

PURPOSE: To compare the efficacy and safety of orally administered capecitabine (Xeloda; Roche Laboratories, Inc, Nutley, NJ), a novel fluoropyrimidine carbamate designed to mimic continuous fluorouracil (5-FU) infusion but with preferential activation at the tumor site, with that of intravenous (IV) 5-FU plus leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer. PATIENTS AND METHODS: We prospectively randomized 602 patients to treatment with capecitabine 1,250 mg/m2 administered twice daily days 1 to 14 every 3 weeks, or to the 4-weekly Mayo Clinic regimen (5-FU/LV) until disease progression or unacceptable toxicity. RESULTS: The primary objective, to demonstrate at least equivalent response rates in the two treatment groups, was met. The overall response rate was 18.9% for capecitabine and 15.0% for 5-FU/LV. In the capecitabine and 5-FU/LV groups, respectively, median time to disease progression was 5.2 and 4.7 months (log-rank P = .65); median time to treatment failure was 4.2 and 4.0 months (log-rank P = .89); and median overall survival was 13.2 and 12.1 months (log-rank P = .33). The toxicity profiles of both treatments were typical of fluoropyrimidines. However, capecitabine led to significantly lower incidences (P < .00001) of stomatitis and alopecia, but a higher incidence of cutaneous hand-foot syndrome (P < .00001). Capecitabine also resulted in lower incidences (P < .00001) of grade 3/4 stomatitis and neutropenia, leading to a lower incidence of grade 3/4 neutropenic fever and sepsis. Only grade 3 hand-foot syndrome (P < .00001) and uncomplicated grade 3/4 hyperbilirubinemia (P < .0001) were reported more frequently with capecitabine. CONCLUSION: Oral capecitabine achieved an at least equivalent efficacy compared with IV 5-FU/LV. Capecitabine demonstrated clinically meaningful safety advantages and the convenience of an oral agent.

International audience; Germline specific point mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3) are associated with autosomal dominant human skeletal dysplasia and craniosynostosis syndromes. Mutations identical to the germinal activating mutations found in severe skeletal dysplasias have been identified in certain types of cancer: at low frequency in multiple myeloma and cervix carcinoma and at high frequency in bladder carcinoma. We analysed, by SSCP and sequencing, the prevalence of FGFR3 mutations in 116 primary tumours of various types (upper aerodigestive tract, oesophagus, stomach, lung and skin). The regions analysed encompassed all FGFR3 point mutations previously described in severe skeletal dysplasia and cancers. No mutations were detected in the tumour types examined, suggesting that FGFR3 mutations are restricted to a few tumour types, the evidence to date suggesting that they are very specific to bladder carcinomas.

The aggressiveness of poorly-differentiated neuroendocrine tumors is similar to small-cell lung cancer within a median survival of 6 months without treatment. Most patients have metastatic disease and poor condition at the time of diagnosis, and cannot be approached surgically with curative intent. Moertel et al. [Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin, Cancer 1991;68:227--232] reported an objective response rate of 67% with a chemotherapy regimen combining etoposide plus cisplatin, with a median survival of 19 months and a median time to progression of 11 months. Since this publication, this regimen has been considered as the reference treatment for poorly-differentiated neuroendocrine tumors. A French retrospective study has recently confirmed the high chemosensitivity of those tumors. However, the prognosis remains poor with a 2-year survival lower than 20% and other therapeutic approaches should be developed.

PURPOSE: To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer. PATIENTS AND METHODS: A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points. RESULTS: The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX). CONCLUSION: All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.

Delayed diarrhea is the main toxicity of irinotecan at the currently recommended dose of 350 mg/m 2 30-minute intravenous infusion, once every 3 weeks. This phase II, multicenter, open-label, randomized study was primarily designed to evaluate the effect of a 15-day Tiorfan (racecadotril) treatment on the incidence and severity of irinotecan-induced delayed diarrhea. One hundred thirty-six patients with metastatic colorectal cancer who failed to respond to a 5-fluorouracil-based treatment received 714 cycles of irinotecan. The patients were randomly allocated either to group A (68 patients) and received Tiorfan (300 mg/day) from DO to D15 or to group B (68 patients) with no prophylactic treatment. Delayed diarrhea occurred in 197 of 355 cycles (55%) in Group A and 203 of 344 cycles (59%) in Group B. grade III-IV diarrhea was reported in 17 of 40 compliant patients (42%) in group A and 31 of 68 evaluable patients (45%) in group B. No difference was observed between the two groups for delayed diarrhea characteristics, incidence, or severity. The response rate in 99 evaluable patients was 12.1% (6.4%-20.2%). This study has shown that Tiorfan given prophylactically at 300 mg/day has no effect on delayed diarrhea.

This study reports on six cases of deficiency in the human complement regulatory protein Factor H (FH) in the context of an acute renal disease. Five of the cases were observed in children presenting with idiopathic hemolytic uremic syndrome (HUS). Two of the children exhibited a homozygous deficiency characterized by the absence of the 150-kD form of Factor H and the presence, upon immunoblotting, of the 42-kD Factor H-like protein 1 (FHL-1) and other FH-related protein (FHR) bands. Southern blot and PCR analysis of DNA of one patient with homozygous deficiency ruled out the presence of a large deletion of the FH gene as the underlying defect for the deficiency. The other four children presented with heterozygous deficiency and exhibited a normal immunoblotting pattern of proteins of the FH family. Factor H deficiency is the only complement deficiency associated with HUS. These observations suggest a role for FH and/or FH receptors in the pathogenesis of idiopathic HUS.

Summary Background In phase II trials, irinotecan is active in patients with advanced colorectal cancer, but the survival and clinical benefit of irinotecan compared with secondline fluorouracil by continuous infusion is not known. Methods 267 patients who had failed to respond to firstline fluorouracil, or whose disease had progressed after treatment with first-line fluorouracil were randomly allocated irinotecan 300–350 mg/m 2 infused once every 3 weeks or fluorouracil by continuous infusion. Treatment was given until disease progression, unacceptable toxic effects, or the patient refused to continue treatment. The primary endpoint was survival, while progression-free survival, response rate, symptom-free survival, adverse events, and quality of life (QoL) were secondary endpoints. Findings 133 patients were randomly allocated irinotecan and 134 were allocated fluorouracil by continuous infusion. Patients treated with irinotecan lived for significantly longer than patients on fluorouracil (p=0·035). Survival at 1 year was increased from 32% in the fluorouracil group to 45% in the irinotecan group. Median survival was 10·8 months in the irinotecan group and 8·5 months in the fluorouracil group. Median progression-free survival was longer with irinotecan (4·2 vs 2·9 months for irinotecan vs fluorouracil, respectively; p=0·030). The median pain-free survival was 10·3 months and 8·5 months (p=0·06) for irinotecan and fluorouracil, respectively. Both treatments were equally well tolerated. QoL was similar in both groups. Interpretation Compared with fluorouracil by continuous infusion second-line irinotecan significantly improved survival in patients with advanced colorectal cancer.

Background/Aims: Lipiodol chemoembolization is a widely used method of treatment in patients with unresectable hepatocellular carcinoma, but its efficacy is still debated. The aim of our study was to assess the efficacy of lipiodol chemoembolization in patients with unresectable hepatocellular carcinoma. Methods: Seventy-three patients with unresectable hepatocellular carcinoma, but without severe liver disease or portal vein occlusion, were randomly assigned to receive either repeated lipiodol chemoembolization (lipiodol, cisplatin (2 mg/kg), lecithin, and gelatin sponge injected into the hepatic artery) plus tamoxifen (40 mg) or tamoxifen alone. The maine end-point was survival. Results: The 37 patients in the lipiodol chemoembolization group received 104 courses (median 3 per patient). By 1 September 1996, 58 patients had died: 30 in the lipiodol chemoembolization group and 28 in the tamoxifen group. There was no difference in survival between the two groups ( p =0.77). The relative risk of death in the lipiodol chemoembolization plus tamoxifen group as compared to the tamoxifen group was 0.92 (95% confidence interval 0.55 to 1.56). At 1 year, survival was 51% and 55%, respectively. An objective tumoral response was more frequently observed in the lipiodol chemoembolization group than in the tamoxifen group (24 versus 5.5%, respectively, p =0.046). Lipiodol chemoembolization caused two deaths and induced signs of liver failure in 51% of the patients assigned to this treatment. Conclusion: In our randomized study, lipiodol chemoembolization did not improve the survival of patients with unresectable hepatocellular carcinoma treated with tamoxifen.

Background and purpose : Clinical trials have demonstrated that high dose radiation therapy and daily cisplatin (CDDP) could increase local control and survival in carcinoma from various sites. The present phase I–II study has combined high dose radiation therapy and daily CDDP at escalating dosages. Methods : From August 1994 to December 1995, 23 patients with non-resectable carcinoma of the pancreas were enrolled in a phase I–II multicentric, pilot study to test the toxicity and the effectiveness of high dose radiotherapy and daily cisplatin (CDDP) at escalating dosages. A dose of 6 mg/sqm/day of CDDP was selected for the phase II step since no grade IV toxicity occurred in any patient in the phase I step. Results : Toxicity was considered fairly acceptable. At the time of analysis, the 23 patients who entered the study had clear evidence of evolutive disease either locally or distantly in the liver. It is suggested that high dose radiotherapy (60 Gy continuously) and daily CDDP have little effect on local control of the tumor and survival, and only a moderate effect on pain. Conclusions : In unresectable, apparently non-metastatic cancers of the pancreas, there is an urgent need for new agents or new combinations of agents to be tested.

Summary Background There is conflicting evidence on the efficacy of regional adjuvant chemotherapy, via portal-vein infusion (PVI), after resection of colorectal cancer. We undertook a randomised controlled multicentre trial to investigate the efficacy of PVI (500 mg/m 2 fluorouracil plus 5000 IU heparin daily for 7 days). Methods 1235 of about 1500 potentially eligible patients were randomly assigned surgery plus PVI or surgery alone (control). The patients were followed up for a median of 63 months, with yearly screening for recurrent disease. The primary endpoint was survival; analyses were by intention to treat. Findings 619 patients in the control group and 616 in the PVI group met eligibility criteria. 164 (26%) control-group patients and 173 (28%) PVI-group patients died. 5-year survival did not differ significantly between the groups (73 vs 72%; 95% CI for difference -6 to 4). The control and PVI groups were also similar in terms of disease-free survival at 5 years (67 vs 65%) and the number of patients with liver metastases (79 vs 77%). Interpretation PVI of fluorouracil, at a dose of 500 mg/m 2 for 7 days, cannot be recommended as the sole adjuvant treatment for high-risk colorectal cancer after complete surgical excision. However, these results cannot eliminate a small benefit when PVI is used at a higher dosage or in combination with mitomycin.

Over the last 10 years important advances have been made in the treatment of patients with advanced colorectal cancer, particularly with surgery either alone or in combination with radiotherapy. Furthermore, despite early scepticism, several chemotherapy studies have now reported significant clinical benefits with 5-FU-based regimens and promising results have also been reported with newer agents such as raltitrexed and irinotecan. Taken together these advances now enable a significant proportion of patients to undergo treatment which will improve their quality of life, prolong survival and even result in cure in certain cases. Patients with advanced colorectal cancer can only benefit from these important advances, however, if a truly multidisciplinary approach to patient care is adopted which requires integration of the roles of the surgeon, medical oncologist and radiotherapist.

The Gastrointestinal Tract Cancer Liaison Office (GITCLO) was developed in an attempt to organise the increasing body of clinical research in gastrointestinal tumours in Europe. This paper represents an analysis, by tumour localisation, of the trials collected for the second edition of the GITCLO booklet. The list of co-operative groups, chairmen and study co-ordinators is given with their respective telephone and telefax numbers. A total of 84 trials were collected, conducted by 46 co-operative groups in 14 countries. For each organ and stage of disease, a summary of concepts investigated is given with the references of the study co-ordinator. Obviously, too many questions are raised at the same time. In colorectal cancer, for example, a total of 41 trials exploring 22 concepts are currently open for patients' registration. We hope that the present attempt to clarify the situation of clinical research in the field of gastrointestinal cancers in Europe will speed up therapeutic progress in the best interest of the patients.

Purpose: Accelerated fractionation was used to shorten overall treatment time to increase locoregional control and cause-specific survival. Methods and Materials: Eighty-eight patients with cancer of the esophagus ineligible for surgery were entered in the study between 1986 and 1993. Neoadjuvant chemotherapy was given to 64% of patients. Accelerated radiotherapy using the concomitant boost technique delivered a median dose of 65 Gy in a median overall treatment time of 32 days. Results: The 3-year acturial local control rate in patients with T1, T2, and T3 tumors was 71%, 42%,and 33%, respectively. The 3-year cause-specific survival rates were 40%, 22%, and 6%, respectively. Sixteen percent of patients experienced Grafe 3 esophagitis. Late toxicity included esophageal stenosis and pulmonary fibrosis in 8% and 9% of the patients, respectively. Multivariate analysis demonstrated that T stage and overall treatment time were prognostic factors for cause-specific survival. T stage and neoadjuvant chemotherapy were independent prognostic factors for locoregional control. Conclusion: These findings suggest that accelerated giben in an overall treatment time of

3599 Background: Optiliv allowed complete macroscopic resection (R0-R1) of previously unresectable LM-CRC in 28% of the pts, despite failure of 1-3 prior chemotherapy protocols (Lévi et al. Proc ASCO GI 2013). Purpose: To assess tolerability and efficacy of Optiliv according to previous chemotherapy exposure. Methods: Pts received iv Cet (500 mg/m²) and chronomodulated or conventional HAI of Irinotecan (180 mg/m²), 5-Fluorouracil (2800 mg/m²), and Oxaliplatin (85 mg/m²) q2 wks. Liver surgery was performed according to q6wks multidisciplinary reviews. Pts were categorized according to Optiliv as 2nd (N=29 pts) vs 3rd-4th chemotherapy line (N=35 pts). Results: Pt characteristics were similar in both groups. Overall, there were 22F and 42 M, aged 33-76 years, with good PS (0/1/2: 40/22/2) and predominantly liver lesions. LM-CRC were bilateral in 51 pts (79.7%), with a median of 10 metastases (1-50), 6 segments involved (1-8), and largest diameter of 52 mm (15-172). 61 pts (2nd line, 27; 3rd-4th line, 34) received a median of 6 courses (1-15). Grade 3-4 toxicities per pt were similar in both groups except for abdominal pain (2nd line, 15% vs 3rd-4th line, 35%, p=0.07), diarrhea (7% vs 24%, p=0.09), thrombocytopenia and febrile neutropenia (0 vs 9%, p=0.25). Four CR were achieved in 2nd line (15%) vs none in 3rd-4th line. Respective objective response rates were 63% and 38% (p=0.05). R0-R1 resections were performed in 11/27 pts (41%) on 2nd line vs 6/34 pts (18%) on 3rd-4th line (p=0.06), resulting in respective median progression-free survival (PFS) of 14.2 months [7.8 - 20.7] vs 7.3 [5.5 - 9.1] (p=0.002). Median overall survival (OS) was not reached at 3 years in the pts on Optiliv as 2nd line vs 15.2 months in the more heavily pretreated pts (pnd lineas compared to 3rd-4th line. Optiliv now deserves upfront testing. Clinical trial information: NCT00852228.

466 Background: Multiple, large and bilateral LM-CRC can be downsized with chemotherapy (chemo) and resected with curative intent in ~15% pts (Adam et al. 2004). The complete resection rate (R0+R1) may be increased with Cet addition, triplet chemotherapy, chronomodulated delivery (Chrono) and hepatic artery infusion (HAI) (Bouchahda et al. 2009; Kemeny et al. 2009; Garufi et al. 2010; Goere et al. 2010). Purpose: To increase the R0+R1 rate from 15% to 30% in pts with unresectable KRAS wt LM-CRC despite failure of 1-3 prior chemo protocols. Methods: 64 pts received iv Cet (500 mg/m²) and Chrono (18 pts) or conventional (Conv, 46 pts) HAI of Irinotecan (180 mg/m²), 5-Fluorouracil (2800 mg/m²), and Oxaliplatin (85 mg/m²) q2 weeks. Liver surgery was performed according to q6wks multidisciplinary meetings. Results: There were 22F and 42 M, aged 33-76 years, with good PS (0/1/2: 40/22/2). Liver lesions were bilateral in 50 pts (78.1%), with a median of 10 metastases (1-50) and largest diameter of 52 mm (15-172). Five courses (1-13) were given to 61 pts (3 never treated), as 3-4th line for 35 pts (54.6%). Grade 3-4 toxicities per pt were neutropenia (40%), abdominal pain (26%), fatigue (18%) and diarrhea (16%). Tumor response (RECIST) was achieved in 28 pts (2 CR, 26 PR), with an objective response rate of 46% [95%CL, 33-58]. Disease control rate was 95% [90-100]. The main endpoint was met, with R0-R1 resections in 19/61 pts, for an overall complete macroscopic resection rate of 28% [17-39]. R0+R1 resections were performed in 33.3% Chrono pts and 25.6% Conv pts, with worse initial prognosis for the Chrono pts (>6 segments involved, 50% vs 9%; > 9 metastases, 75% vs 27%). Median progression-free and overall survival were 8.7 months [6.9-10.5], and 25.7 months [14.2-37.2] respectively. Conclusions: The combination of intravenous Cet and triplet hepatic artery infusion safely doubled the expected rate of complete resections of LM-CRC, despite prior failure of systemic chemo. This most effective treatment option now deserves upfront testing. Clinical trial information: NCT00852228.

To compare dynamic contrast-enhanced subtraction (DCES) and T2-weighted spin-echo (SE) magnetic resonance (MR) imaging in the differentiation of fibrosis from recurrence during the follow-up of treated colorectal neoplasms.Forty-one patients with 39 malignant and 16 benign lesions confirmed by means of surgery (n = 23), biopsy (n = 24), or 12-month follow-up examination (n = 8) underwent DCES MR imaging and T2-weighted SE MR imaging. Enhancement of an abnormal pelvic structure within the first 90 seconds on DCES images or high signal intensity on T2-weighted SE images was considered indicative of malignancy.Sensitivity, specificity, and positive and negative predictive values were, respectively, 97%, 81%, 93%, and 100% for DCES MR imaging and 77%, 56%, 81%, and 56% for T2-weighted MR imaging. The number of correctly classified lesions was significantly higher with DCES imaging compared with T2-weighted imaging (Por = .006).DCES imaging is more accurate than T2-weighted SE imaging for differentiating fibrosis from recurrence during the follow-up of treated colorectal neoplasms.

In an open phase III study, octastatin was given as a continuous subcutaneous (s.c.) infusion to 35 patients (mean age 62 years) with malignant neuroendocrine gastro-intestinal tumours and the carcinoid syndrome. The wash-out was often incomplete because of the advanced stage of disease. The starting dose of 1.5 mg/24 h was increased up to 3.0 mg/24 h at 3 months in some patients. The carcinoid syndrome disappeared in 20% of patients at 3 months and in 23% at 6 months, with 43 and 45% of patients, respectively, experiencing an improvement. The mean Karnovsky index increased by10% in 40% of patients at 3 and 6 months. Urinary 5-hydroxyindoleacetic acid (U-5-HIAA) levels at 3 months normalised in 1 patient, fell in 20% (by50%; p = 0.0021) and stabilised in 66%. The respective values at 6 months were 1, 17% (p = 0.023) and 60%. There was also a significant decrease in plasma chromogranin levels at 3 months (p = 0.042), which did not persist at 6 months. Tumour size fell (by50%) in 1 patient by 6 months but this patient had undergone chemoembolisation one month prior to the start of the study. Most patients had tumour size stabilisation (76 and 68%) or progression (20 and 24%) at 3 and 6 months, respectively. Dose escalation from 1.5 to 3.0 mg did not significantly improve clinical, biochemical or tumour responses. The treatment was well tolerated with minor adverse events. In an open pilot phase II study of 19 patients (mean age 58 years), patients were given high dose somatuline with a maintenance dose of 12,000 mg/day in 4 divided s.c. injections. U-5-HIAA, which was elevated in 13 patients with a mean of 444 mumol/day before the start, was reduced to 58% of baseline at 3 months, 68% at 6 months (p = 0.04), 66% at 9 months and 75% at 12 months (p = 0.14). P-chromogranin was elevated in 18 patients, with a mean of 5,300 micrograms/l before the start, and was reduced to 52, 55, 63 and 64% of the baseline at 3, 6 (p = 0.039), 9 and 12 (p = 0.013) months, respectively. In the responding patients, apoptosis was induced.

The intratumoral (i.t.) delivery of anticancer drugs aims at controlling tumor growth and thereby provides palliative treatment for liver neoplasms. Mitoxantrone is a good candidate for local or regional administration because (1) its metabolism is mainly hepatic, (2) it has a steep dose-response curve for multiple solid tumors, and (3) its fixation in tissues is sustained without vesicant effects after extravasation. We compared the tolerance, pharmacokinetics, and antitumor effects of mitoxantrone on hepatic VX2 tumors in rabbits treated with i.t. intraarterial hepatic (i.a.h.) or i.v. mitoxantrone, i.t. ethanol; or i.t. 0.9% NaCl and in control animals. Tumor growth rates (TGRs) were evaluated at 9 days after treatment. Myelosuppression was the limiting toxicity of i.v. mitoxantrone at 1.5 mg/kg (maximal tolerated dose, MTD), but neither i.t. nor i.a.h. administration led to hematologic toxicity at the same dose. The mitoxantrone retained in tumors after i.t. administration was seen as blue-stained areas of complete necrosis according to histologic analysis. Pharmacokinetic parameters showed a significantly decreased systemic exposure to the drug after both regional treatments, although the i.a.h. route appeared to have an edge over the i.t. route. TGRs were significantly reduced after i.t. mitoxantrone (81 +/- 62%), i.a.h. mitoxantrone (337 +/- 110%), and i.t. ethanol treatments (287 +/- 117%) as compared with control values (886 +/- 223%; p0.01). Treatment with i.v. mitoxantrone (816 +/- 132%) had no antitumor effect, nor did NaCl injections (868 +/- 116%). Mitoxantrone given i.t. induced the highest antitumor effects, resulting in a 3.5-fold reduction in TGRs as compared with i.a.h. mitoxantrone and i.t. ethanol treatments (p0.02). Treatment with i.t. mitoxantrone provided efficient antitumor therapy without producing major side effects. This method should be considered as palliative treatment for nonresectable liver tumors and other localized malignancies.

Two cases of colonic carcinomas with multidirectional differentiation are presented. Both tumors showed light microscopic and immunohistochemical evidence of areas of adenocarcinomatous, squamous cell carcinomatous, and neuroendocrine differentiation. Only six similar cases have been previously reported. These highly malignant tumors support the recent concept of a multipotential stem cell within the mucosa of the gastrointestinal tract capable of differentiation in several directions.

Background FOLFOX is standard adjuvant therapy for stage III colon cancer (CC). Adding cetuximab to FOLFOX benefits patients with metastatic KRAS wild-type (wt) CC. The addition of cetuximab to mFOLFOX6 in the adjuvant setting in the US N0147 trial, failed to show a benefit (1). PETACC8 assessed the potential benefit of cetuximab added to FOLFOX4. Methods Patients with informed consent and centrally determined KRAS wt CC were randomized 28-56 days following resection. They received 12 biweekly cycles of oxaliplatin 85 mg/m2 on d1, with leucovorin 200 mg/m2, 5FU 400 mg/m2 bolus IV, then 22-hr IV 5FU 600 mg/m2 on d1 and d2 (FOLFOX4), without (Arm A) or with (Arm B) weekly cetuximab 250 mg/m2 (loading dose 400 mg/m2, cycle 1). Primary endpoint was disease-free survival time (DFS). Secondary endpoints included overall survival, treatment compliance and safety. Planned accrual of 1,407 KRAS wt patients provided a 90% power to detect a hazard ratio (HR) of 0.75 with 2-sideda = 0.05; an interim analysis was planned after 65% of the events. Results 1,602 KRAS wt patients were included in the interim analysis (Arm A, 811; Arm B, 791) with a median follow-up of 39.6 months at the time of the interim analysis. No difference was seen between the arms for DFS (HR 1.05, 95% CI 0.85-1.29; p = 0.66); the conditional power to have a positive result at the end of the study under a HR of 1.75 was lower than 1%. 3-yr DFS was 78.0% (95% CI 74.8-80.8) in Arm A and 75.1% (95% CI 71.7-78.1) in Arm B. The frequency of any AE grade ≥ 3 was significantly increased in Arm B (66.2% Arm A vs 80.9% Arm B; RR: 1.22, 95% CI 1.15-1.30). Diarrhea, vomiting, mucositis, skin disorders (grade ≥ 3) and failure to complete 12 cycles were also significantly higher in Arm B. Conclusions The primary analysis of this randomized phase III trial has not shown a benefit for adding cetuximab to FOLFOX4 in patients with resected stage III KRAS wt CC. Subgroup and biomarker analyses are still ongoing. Supported by Merck-Serono, Sanofi-Aventis.

Long term survival data from EORTC study 40983 : Perioperative chemotherapy for resectable liver metastases from colorectal cancer

Introduction CPT-11 showed modest activity and tolerability in metastatic pancreatic adenocarcinoma (MPA). We developed a new strategy to improve efficacy and tolerability of CPT-11 based regimen in MPA patients (pts). Methods Chemotherapy-naive pts with histologically proven MPA, bilirubin levels Results Between 2007 and 2011, 98 pts were enrolled (males: 59, median age: 62 years, PS 0: 32%). Median follow-up was 23 months. Grade 3-4 toxicities per pts (%) in arm A/B were diarrhea 13/0, nausea-vomiting 11/4, neutropenia 51/25, and febrile neutropenia 4/0. No toxic death occurred. Response rate were 40 and 11% as disease control rate (CR + PR + SD) were 73 and 52% in arm A and B, respectively. The primary endpoint of the trial was met with rate of PFS at 6 months of 48% (95% CI: 33-63) in arm A while in arm B PFS was 30% (95% CI: 17 - 44). One year PFS was 23% (95%CI: 11.5-36) and 11% (95% CI: 4-21), respectively. Conclusion FIRGEM strategy is feasible and efficient with a manageable toxicity profile in good condition pts with MPA. A phase III trial comparing this strategy with the FOLFIRINOX triplet therapy focusing on quality of life should now be performed.

4087 Background: The DCF regimen is superior to 5-FU-Cisplatin in term of response rate (RR) and overall survival (OS) in advanced gastric cancer, but is also more toxic. Oxaliplatin is better tolerated and can effectively replace cisplatin in AGC patients (pts). We hypothesize that incorporating Docetaxel into a simplified FOLFOX regimen should be a tolerable and efficient option, and could facilitate the use of this drug in 1st line in AGC. Methods: TFOX regimen was given biweekly as follow: Docetaxel (50mg/m2), oxaliplatin (85mg/m2), leucoverin (400mg/m2) and 5FU continuous infusion 48h (2400mg/m2). Main inclusion criteria were: pts with histollogically proven metastatic or locally advanced gastric or oesogastric junction adenocarcinoma, previously untreated, PS≤2. Using Fleming design the primary end point was response rate, needing a sample size of 40 pts. Results: Between 02/2008 and 07/2011, 41 pts with AGC were enrolled (oesogastric junction: 17 pts, diffuse type: 22 pts, metastatic: 37 pts); mean age was 53.5 years (31-73), 26 pts were male. PS 0/1/2: 11/24/6 pts, 14 pts had a relapse after a R0 resection. The total number of cycles administered was 310 (mean 7.6 cycles/pts) and 90% of pts received at least 4 cycles. No toxic death occurred. Grade 3-4 toxicities were observed in 20 pts (48%). Grade 3-4 toxicities were neutropenia (29%) febrile neutropenia (7%), neurotoxicity (10%), asthenia (10%). ORR was 63% (n=26) [IC95% 48-78], with 2 complete responses. Disease control rate (CR+PR+SD) was 78% (n=32) [IC95% 65-90]. Median progression free survival and overall survival were 6.5 months [IC95% 5.02-10.85] and 12.1 months [IC95% 7.25-15.28], respectively. Conclusions: TFOX is effective with a manageable toxicity profile in first line treatment for AGC pts. Tolerability of this regimen compares favourably with DCF reported tolerability. TFOX may be an alternative option for intensive 1st line treatment and should now be evaluated in randomized trials.

3562 Background: In the CRYSTAL and OPUS studies, adding cetuximab (cet) to first-line chemotherapy (CT) improved clinical benefit in patients (pts) with KRAS wild-type (wt) metastatic colorectal cancer. In a pooled analysis of these trials the benefit of treatment according to whether pts had liver-limited disease (LLD) or non-LLD was analyzed. Methods: Cox‘s proportional hazards model for overall survival (OS) and progression-free survival (PFS) or logistic regression model for best overall response and R0 resection were used on individual pt data, stratified by study. Likelihood ratio tests were used to explore interactions. Results: Adding cet to CT significantly improved PFS and overall response rate (ORR) in LLD pts, and OS, PFS and ORR in non-LLD pts and increased R0 resection rates (table). No treatment-by-study interactions were found. Treatment effects did not vary significantly by LLD status (PFS p=0.60, OS p=0.68, ORR p=0.0737, R0 resection p=0.71). However LLD vs non-LLD pts had improved outcome in each treatment arm: PFS, CT hazard ratio, HR=0.74, p=0.0910; CT + cet HR=0.66, p=0.0309; OS, CT HR=0.70, p=0.0091; CT + cet HR=0.74, p=0.0388; ORR, CT odds ratio=1.20, p=0.47, CT + cet odds ratio=2.32, p=0.0015; R0 resection, CT odds ratio=3.15, p=0.0496, CT + cet odds ratio=3.82, p=0.0018. Kaplan Meier survival plots will be shown. Conclusions: The OS benefit from adding cet to CT is more pronounced in non-LLD pts, thus strengthening the value of cet in palliative treatment.LLD status is associated with improved prognosis and may be predictive for response in pts receiving CT + cet, facilitating potentially curative resection. More pts (with R0 resection and longer follow-up) may be needed to confirm an OS benefit from CT + cet in LLD pts. [Table: see text]

TPS3634 Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) regulate angiogenesis and are overexpressed in CRC. RAM is a fully human IgG1 monoclonal antibody that inhibits binding of VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. In a preclinical study, antiangiogenic and antitumor effects were observed when DC101, an antibody that targets murine VEGFR-2, was administered to mice bearing human colon cancer xenografts. Antitumor activity for RAM has been demonstrated in a Ph I study in pts with solid tumors over a wide range of RAM dose levels and in a Ph II study with RAM + mFOLFOX-6 as 1st-line therapy in pts with mCRC. Methods: This ongoing, randomized, double-blind, placebo-controlled Ph III study includes mCRC pts with measurable or nonmeasurable disease and ECOG performance status of 0-1 who have experienced disease progression during or within 6 months following 1st-line therapy with BEV, OXALI, and any FP. Randomization is stratified by geographic region, KRAS status, and time to progression after initiation of 1st-line therapy. Pts are randomized 1:1 to either RAM 8 mg/kg or PL every 14 days. Pts in both arms receive FOLFIRI (irinotecan: 180 mg/m2, folinic acid: 400 mg/m2, 5-fluorouracil: 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46-48 hours). The primary endpoint is overall survival (OS). The sample-size estimate assumes 85% power to detect at least a 2.5-month median OS difference (HR = 0.8) between treatment arms with a 1-sided alpha of 0.025. Secondary endpoints include progression-free survival, tumor response, safety, pharmacokinetics, immunogenicity, and correlations between biomarkers and clinical outcome. CRC tissue and blood collection is mandatory for biomarker analyses. As of 05 January 2012, 238 of 1050 planned pts have been enrolled from 100 sites in North America, South America, Europe, Asia, and Australia.

3547 Background: HAI of chronomodulated (Chrono) irinotecan (I), 5-Fluorouracil (F) and oxaliplatin (O), or flat O combined with iv F-leucovorin allowed secondary metastases resections and prolonged survival in patients (pts) with CRC liver metastases despite prior chemotherapy failure (Bouchahda, Cancer 2009; Goere, Ann Surg 2010). Purpose: To prospectively evaluate safety and efficacy of combining iv Cet with HAI of IFO in pts with CRC liver metastases. Methods: This Phase II trial involved previously treated pts with unresectable CRC liver metastases. Pts received iv Cet (500 mg/m²) and Chrono or conventional HAI of I (180 mg/m²), F (2800 mg/m²), and O (85 mg/m²) q2 weeks. Liver metastases were resected if adequately downstaged. Results: Planned accrual of 60 pts was reached on 01/24/2012. 3 pts were not treated, 9 are ongoing. 48 consecutive treated pts (18F, 30 M; aged 32-76 years) are fully assessed and monitored. They had PS 0-1 (98%), bilobar liver lesions (69%), a median of 8 metastases (1-50; largest diameter, 57 mm – 15-172). Prior chemotherapy involved one (43%), or two or three (57%) lines. A median of 5 protocol courses (1-13) was given. Main grade 3-4 toxicities per pt were neutropenia (40%), abdominal pain (15%), fatigue (15%), nausea (15%), diarrhea (13%) and sensory neuropathy (4%). Objective response rate was 44% [30-58], with 6% radiological complete responses. Disease control rate was 85%. Secondary liver surgery was performed in 15 pts (31.3%).One pt with 25 metastases (1-6 cm) in all liver segments had pathologic complete response in 24 lesions removed through three-stage hepatectomy. She currently has an off treatment disease-free survival of 17+ months.With a follow up of 4 to 47 months, median progression-free survival is 14.2 months [9.7-18.8], 1- and 2-year survival rates are 92.8% and 59.2% respectively. Conclusions: OPTILIV offers a safe and unusually effective treatment option for patients with CRC liver metastases after failure of systemic chemotherapy within a coordinated medico-surgical strategy.

3508 Background: This study evaluates the benefit of combining peri-operative chemotherapy and surgery for patients with liver only metastases from colorectal cancer (LM) deemed resectable on pre-operative imaging. The PFS results, the primary endpoint, were reported (ASCO 2007). We now report on the secondary endpoint overall survival (OS) results, after a median follow-up of 8.5 years. Methods: Between September 2000 and July 2004, 364 patients (pts) with up to 4 LM were randomized between peri-operative FOLFOX4 (oxaliplatin 85mg/m² and LV5FU2), 6 cycles before and 6 cycles after surgery, (CT arm), and surgery alone (S arm). OS was compared between arms using a 2-sided non-stratified log-rank test at the 0.05 level of significance (intent-to-treat analysis). Results: 182 pts were randomized in each arm (CT arm and S arm) of which 171 were eligible (CT and S) and 152 underwent resection (CT and S). In the CT arm, 171 received preop CT and 115 received postop CT. At a median follow-up of 8.5 years, 221 deaths were reported (61 % of all randomized pts). Causes of death in CT arm were cancer relapse (85 pts), complication of surgery (2 pts), other causes (16 pts) and unknown cause (4 pts), and in S arm, cancer relapse (99 pts), complication of surgery (2 pts), other causes (11 pts) and unknown cause (2 pts). Observed median OS was higher in CT arm: 61 months (CT) vs. 54 months (S) in all randomized pts and 64 months (CT) vs. 55 months (S) in eligible pts. The 5 year OS rate was 51.2% (CT) vs. 47.8% (S) (all randomized) and 52.4% (CT) vs. 48.3% (S) (eligible pts). There was no significant difference in OS between arms (HR=0.88, 95% CI 0.68-1.14, p=0.34) (all randomized). After progression, second line treatment with chemotherapy was given in 59 % (CT) and 77% (S) of the pts with cancer progression and repeat surgery in 46% (CT) and 40% (S), respectively. Conclusions: Peri-operative chemotherapy with FOLFOX4 improves PFS but does not significantly improve OS over surgery alone. A potential benefit may have been diluted by second treatment lines and by more deaths unrelated to cancer in the CT arm.

561 Background: Three Db Pbo controlled studies were conducted with IV Afl in metastatic cancer patients [colorectal (CRC) Afl+FOLFIRI (WCGC 2011 abstract O-0024), lung (LC) Afl+docetaxel (WCLC 2011, abstract 511) and pancreatic (PC) Afl+gemcitabine (WCGC 2009 abstract O-0006)]. Each study used the same weekly Afl dose intensity (4 mg/kg q2w for CRC and PC; 6mg/kg q3w for LC). A safety meta-analysis of anti-VEGF class adverse events (AE) was performed on data from these studies. Methods: A fixed-effect logistic regression model was used, including study, treatment and study-by-treatment interaction factors as covariates to test the consistency of treatment effect across studies for each of the considered AE. When no evidence of heterogeneity of treatment effects was found across studies, relative risks (RR) and 95% confidence intervals (CI) were estimated. Summary incidences (% of patients [pts]) and RR are presented for NCI grade 3-4 events. Results: Safety data from total of 2,662 pts (Afl: 1,333; Pbo: 1,329) were included for analysis (Table). Among pts treated with Afl, 0.4 and 0.5% experienced grade 4 hypertension and nephrotic syndrome, respectively. Conclusions: The addition of Afl to concurrent chemotherapies did not increase the risk of VTE. The risk of grade 3-4 anti-VEGF class AEs was increased when adding Afl to concurrent chemotherapies. This increased risk was statistically significant (**) only for hypertension, proteinuria and hemorrhage. Further analyses, when more data are available, should improve the precision of these results. Studies were sponsored by Sanofi NCT00561470 , NCT00532155 , and NCT00574275 . [Table: see text]