Poster Discussions

Annals of Oncology 20 (Supplement 7): vi17–vi28, 2009

doi:10.1093/annonc/mdp283poster discussions

PD-0001. RELATIONSHIP BETWEEN KRAS STATUS ANDEFFICACY OF FOLFOX6 1 CETUXIMAB OR FOLFIRI 1 CETUXIMABIN FIRST-LINE TREATMENT OF PATIENTS WITH METASTATICCOLORECTAL CANCER (MCRC): THE CECOG/CORE1.2.001 TRIAL

Ocvirk J1, Vrbanec D2, Beslija S3, Koza I4, Ciuleanu T5, Papamichael D6, Wrba F7,Messinger D8, Zielinski C9, Brodowicz T9

1Institute of Oncology, Lujbljana, Slovenia, 2University Hospital Rebro, Zagreb,Croatia, 3Institute of Oncology, Clin. Center of Sarajevo University, Bosnia-Herzegovina, 4National Cancer Institute, Bratislava, Slovakia, 5InstitutulOncologic, Cluj-Napoca, Romania, 6Bank of Cyprus Oncology Center, Nicosia,Cyprus, 7Clinical Institute of Pathology, Medical University of Vienna, Austria,8Biometrics, Datamanagement, Mannheim, Germany, 9Clin. Division ofOncology, Dep. of Medicine I and Cancer Center, Medical University of Vienna,Austria

Background: Subgroup analyses from the phase II CECOG/CORE1.2.001 trial haveshown that patients with KRAS wild-type tumors experience significantly betterprogression-free survival and overall survival, compared with patients with KRASmutant tumors, when treated with cetuximab plus standard chemotherapy in 1st linemCRC . Here we provide survival data according to KRAS status from a post-studysurvival update and report on other potential predictive factors for overall survival.

Methods: Impact of KRAS status and other possible predictive factors for overallsurvival was reassessed with multivariable Cox proportional hazard methods.

Results: A total of 117 (77%) of the 151 patients comprising the intent-to-treatpopulation had KRAS-evaluable tissue available for the analyses. 53% (n=62) oftumors were KRAS wild-type (34/57 in the FOLFOX6 + cetuximab arm and 28/60 inthe FOLFIRI + cetuximab arm). In patients with KRAS wild-type tumors, overallsurvival was significantly improved at a median follow-up of 29 months whencompared with patients with KRAS mutant tumors (median 20.8 vs 15.9 months;hazard ratio [HR]=1.62; p=0.0296). When the data were analyzed according totreatment arm, overall survival in the FOLFOX6 + cetuximab arm was statisticallysignificantly longer for patients with KRAS wild-type tumors compared with patientswith KRAS mutant tumors (median 22.5 vs 15.2 months; HR=2.06; p=0.0201);however, no significant survival difference based on KRAS mutation status was notedfor the FOLFIRI + cetuximab arm. In addition to KRAS wild-type status (vs KRASmutant status), the strongest independent predictors for prolonged survival were grade2/3 acne-like rash (vs grade 0/1) during the first 6 weeks of treatment (HR=0.465;95%CI: 0.274–0.788; p=0.0044) and no previous treatment versus previous neo-/adjuvant treatment (HR=0.321; 95%CI: 0.170–0.605; p=0.0004).

Conclusions: This updated survival analysis has shown that patients with KRAS wild-type tumors who are treated with cetuximab plus standard chemotherapy experiencea significantly improved overall survival compared with patients who have KRASmutant tumors, confirming results obtained from previous studies. As well as KRASstatus, the cetuximab-related grade 2/3 acne-like rash that occurs in the early stages oftreatment appears to be an independent predictor for prolonged survival.

PD-0002. EXTENSIVE LIVER-DOMINANT COLORECTAL (CRC)METASTASES FAILING MULTIPLE LINES OF SYSTEMICCHEMOTHERAPY TREATED BY 90Y RADIOEMBOLISATION: AMATCHED-PAIR ANALYSIS

Ricke J, Ruhl R, Seidensticker M, Dudeck O, Pech M, Amthauer HRadiology and Nuclear medicine, Magdeburg, Germany

Background: With continued evolution of systemic chemotherapy and biologicalagents, the prognosis for patients presenting with metastatic CRC continues toimprove. Median survival with contemporary standard-of-care chemotherapyregimens exceeds 20.0 months from time of diagnosis. However, despite theseadvances, liver metastases continue to present a life-limiting prognosis for CRCpatients. This prospective study assessed the safety and efficacy of 90Y-resinmicrosphere therapy in patients exhibiting extensive progressive CRC liver-dominantmetastases following multiple lines of systemic chemotherapy/biological agents,compared to matched historical control patients who received best supportive careand/or chemotherapy.

Method: A matched-pair analysis for overall survival was conducted in patients withextensive CRC liver metastases (>20% liver involvement) to evaluate the benefit of 90Y-resin microspheres as salvage therapy. Patients were matched on established prognosticcriteria: tumour load, synchronous/metachronous metastases, alkaline phosphatase(ALP) increase and CEA >200 U/mL. Tumour progression following systemicchemotherapy was confirmed via imaging (CT/MRI), ALP, tumour markers (CEA)and/or clinical symptoms. Toxicities and adverse events post-90Y-microsphere therapywere documented. Overall survival for 90Y-microsphere therapy and control were

calculated via Kaplan-Meier analysis from last progression on chemotherapy prior to90Y-microsphere therapy to date of death. The effect of all prognostic factors(clinical history, Karnofsky performance status, disease presentation andchemotherapy history) on overall survival was assessed using Multivariate Coxproportional hazards (SAS, Carey, NC).

Results: 58 patients were recruited (29 received 90Y-microsphere therapy; 29 control)with extensive liver tumour involvement: median (range) 30% (20–50%) vs. 25%(10–75%) respectively. Patients received a median (range) of 4 (2–7) vs. 3 (2–8) priorlines of chemotherapy respectively. Lack of 90Y-microsphere therapy (HazardRatio=4.0) was the only parameter found to be a significant contributor to theprognosis for overall survival of CRC patients failing standard-of-care chemotherapy(p<0.001). None of the prognostic factors contributed to the proportional hazardsmodel. Patients receiving 90Y-microsphere therapy following chemotherapy failuresurvived significantly longer than control patients (median survival: 8.3 vs. 3.5 monthsrespectively; p<0.001). This benefit was clearly evident at 3 months post 90Y-microsphere therapy (97% vs. 59% survival) and sustained through 12-months followup (24% vs. 0% survival). Patients receiving 90Y-microsphere therapy followingchemotherapy failure showed increased tumour stabilisation compared to controls(median PFS: 5.5 vs. 2.1 months respectively, p<0.001). Other than reduced Karnofskystatus and increased tumour markers due to progression, one case of thrombopeniaand sepsis (3%), one case of abdominal pain (3%), and three possible cases ofradiation-induced liver disease [RILD] (10%) following 90Y-microsphere therapy werereported. RILD was medically managed and not a life-threatening event (mediansurvival: 9.8 months; range: 9.0–16.6 months).

Conclusions:90Y-microsphere therapy provides a compelling alternative for patientswho have failed multiple lines of systemic chemotherapy for whom liver-dominantdisease is the life-limiting condition. The therapy provides substantial clinical benefit asevidenced by significant increased liver disease stabilization and prolonged overallsurvival in patients for whom there are limited treatment options.

PD-0003. LOCAL TREATMENT FOR RECURRENT COLORECTALHEPATIC METASTASES AFTER PARTIAL HEPATECTOMY

van der Pool A1, Lalmahomed Z2, de Wilt J1, Eggermont A1, Ljzermans J2,Verhoef C1

1Erasmus University MC- Daniel den Hoed Cancer Center, Rotterdam,Netherlands, 2Erasmus University MC, Netherlands

Background: Liver metastases develop in 50-60% of patients with colorectal cancer andsurgical resection currently represents the best treatment with a 5-year survival of30-50%. Despite the curative intent, more than 60% will suffer from recurrence afterliver resection, the liver being the most common location. Since liver resection hasbecome safer through improvements in surgical techniques and per-operativemanagement, repeat hepatic resection is being more frequently performed in patientswith hepatic recurrences. Recent technologic advances have also made local ablativetreatments for liver tumors accessible. The objective of this study was to determine theoutcome of local treatment modalities in patients with recurrent intra-hepaticcolorectal liver metastases after partial liver resection.

Methods: Between 1984 and 2007, more than 500 patients were operated on forcolorectal liver metastases in our unit. A total of 51 patients, 34 men and 17 womenwith a median age of 60 (range 37-78) years, were treated for hepatic recurrence(s) afteran initial partial hepatic resection. Surgery was considered as the primary treatmentoption for eligible patients. Patients who were poor candidates for surgery weretreated with radiofrequency ablation (RFA), 2 open and 8 percutaneous procedures.Stereotactic body radiation therapy (SRBT) was given as an outpatient, emerginglocal treatment option for patients with intra-hepatic recurrences not eligible forsurgery or RFA.

Results: The median disease-free interval between initial hepatectomy and the hepaticrecurrence was 11 (range, 3-78) months. Neoadjuvant chemotherapy was given to 11patients (22%). Surgical treatment was performed in 36 patients (70%), RFA in 10patients (20%) and SRBT in 5 patients (10%). Median hospital stay was 7 (range, 3-62)days with a morbidity of 16% without in hospital death. None of the patientsreceived adjuvant chemotherapy. There was no difference in recurrence or survivalbetween the 3 treatment modalities. Disease-free survival and overall 5-year survivalwas 30,4% and 35,1% with an estimated median disease-free and overall survival of 14and 37 months, respectively. Patients with a disease-free interval between firsthepatectomy and hepatic recurrence less than 6 months did not survive 3 years.

Conclusion: Resection, RFA and SRBT can be performed safely in patients withrecurrent colorectal liver metastases and offer a survival that seems comparable toprimary liver resections of colorectal liver metastases.

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PD-0004. LATERAL LYMPH NODE DISSECTION FOR ADVANCEDRECTAL CANCER

Akihiro K, Saito N, Sugito M, Ito M, Nishizawa YNational Cancer Center Hospital East, Kashiwa, Chiba, Japan

Backgrounds: Although lateral lymph node dissection (LLD) is one of the standardprocedures for middle or lower advanced rectal cancer in Japan, it is rarely performedin other countries.

Purpose: This study examined to clarify indication and benefit of LLD for rectal cancer.

Methods: A total of 261 patients who underwent curative surgery with LLD for rectalcancer between 1992 and 2003 were reviewed. Lateral lymph nodes were definedas lymph nodes located outside the pelvic plexus, along the internal iliac and commoniliac vessels and the obturator vessel. Clinical significance of LLD was investigatedin clinicopathological parameters.

Results: Positive lateral lymph nodes were found in 47 patients (18%). Multivariateanalysis disclosed a significantly increased incidence of lateral lymph node metastasis inextranodal tumor deposits, lymphatic invasion, lower rectal cancers of an analcanal, T3-T4 and poorly differentiated or mucinous adenocarcinoma. The five-yearsurvival rate for 261 patients was 73.9%. The survival of patients with positive laterallymph nodes was significantly worse than that of Stage III patients with negativelateral lymph nodes (47.1 vs. 67.5%, P<0.05). Multivariate analysis showedsignificantly worse prognosis in perirectal lymph node metastasis, preoperative serumCA19-9, extranodal tumor deposits, non sphincter preservative surgery, lower rectalcancers of an anal canal and lymphatic invasion. During the median follow-up time of6.5 years, recurrence developed in 106 patients (40.6%): 72 patients (33.6%) withoutlateral lymph node metastasis and 34 patients (72.3%) with lateral lymph nodemetastasis (P<0.0001). Local recurrence was found in 40 patients (15.3%): 28 patients(13.1%) without lateral lymph node metastasis and 12 patients (25.5%) with laterallymph node metastasis (P<0.05). However, multivariate analysis disclosed thatlower rectal cancers, preoperative serum CA19-9, perirectal lymph nodemetastasis and lymphatic invasion were significantly associated with an increased localrecurrence.

Conclusion: LLD may be needed for patients with T3-T4 lower rectal cancers of analcanal because of the greater provability of positive lateral lymph nodes. According tomultivariate analysis, perirectal lymph node metastasis and CA19-9 and lymphaticinvasion were important predictor in both survival and local recurrence.

PD-0005. SAFETY AND EFFICACY OF BEVACIZUMAB (BEV) ANDCHEMOTHERAPY IN ELDERLY PATIENTS WITH METASTATICCOLORECTAL CANCER (MCRC): RESULTS FROM THE BEATOBSERVATIONAL COHORT STUDY

Van Cutsem E1, Rivera F2, Berry S3, Kretzschmar A4, Michael M5,DiBartolomeo M6, Mazier M7, Canon J8, Georgoulias V9, Peeters M10,Bridgewater J11, Cunningham D12

1University Hospital Gasthuisberg, Leuven, Belgium, 2Hospital Marques deValdecilla, Santander, Spain, 3Sunnybrook Odette Cancer Centre, University ofToronto, Toronto, Canada, 4HELIOS-Klinikum Berlin, Robert Rossle Klinik derCharite, Berlin, Germany, 5Peter MacCallum Cancer Institute, Melbourne,Australia, 6Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,7Parexel, Paris, France, 8Centre Hospitalier Notre Dame Reine Fabiola,Charlerio, Belgium, 9University General Hospital, Heraklion, Greece, 10UniversityHospital, Gent, Belgium

Background: Addition of BEV to chemotherapy prolongs overall survival (OS) andprogression-free survival (PFS) in 1st- and 2nd-line treatment of patients (pts) withmCRC. Subgroup analyses from a recent pooled analysis of BEV pivotal studies[Kabbinavar et al, JCO 2009] have shown that older (‡65 years) and younger (<65years) pts derive similar PFS and OS without a difference in the risk–benefit profile. Weevaluated the safety and efficacy of BEV + chemotherapy by age group in pts whoparticipated in BEAT (Bevacizumab Expanded Access Trial).

Methods: Details of BEAT have been reported previously [Berry et al, ASCO 2008].We analyzed the effect of age on adverse events (AEs) of interest for BEV in pts aged<65, 65–74, and ‡75 years. The effect of age on survival was assessed using a Coxregression.

Results: Of the 1914 pts enrolled in BEAT, half received BEV + oxaliplatin-basedtherapy (FOLFOX, bFOL, XELOX, other), 35% received BEV + irinotecan-basedtherapy (FOLFIRI, IFL, XELIRI) and the remainder received BEV + monotherapy(5-FU bolus, 5-FU infusion, capecitabine). 1286 (67%) pts were <65 years, 499 (26%)were 65–74 years and 129 (7%) were ‡75 years. Median PFS appears to be similar forthe 3 age categories (Table). Given the small number of pts who were 75 or older,we limited our comparison to those between <65 and ‡65 years; the hazard ratio for age‡65 vs. <65 years (reference) was 1.18 (95% CI 1.04–1.33; p<0.05). BEV-targeted safetywas similar in those aged <65, 65–74 and ‡75 years.

Conclusions: These results show that older pts with mCRC can derive similar benefitfrom BEV + chemotherapy as younger pts without a substantial increase in toxicity andsuggest that age alone should not preclude effective treatment.

Age group, years

All(n=1914)

<65(n=1286)

65–74(n=499)

‡75(n=129)

Safety, n (%)Gastrointestinal perforation 37 (1.9) 22 (1.7) 11 (2.2) 4 (3.1)Arterial thromboembolism 29 (1.5) 14 (1.1) 10 (2.0) 5 (3.9)Grade 3/4 bleeding 44 (2.3) 33 (2.6) 9 (1.8) 2 (1.6)New/worseninghypertension

572 (29.9) 354 (27.5) 180 (36.1) 38 (29.5)

Survival, monthsMedian PFS 10.8 10.8 11.2 10.0Median OS 22.7 23.5 22.8 16.6

PD-0006. WHAT IS THE BEST TIMING TO PERFORM SURGERY OFMETASTASES IN COLORECTAL CANCER?

Perez Staub N1, Chibaudel B1, Paye F1, Taieb J2, Gayet B3, Bourges O1,Andre T2, Tournigand C1, Louvet C1, de Gramont A1

1Hopital Saint Antoine, Paris, France, 2Hopital Pitie Salpetriere, France,3Institut Mutualiste Montsouris, France

Background: Operable patients can achieve 25-30% 5-year survival rate with surgery.In addition, neoadjuvant Folfox has proven some efficacy over surgery alone(EORTC ASCO 2007). However, it can be limited by toxicities or not feasible in case ofearly relapse after folfox therapy. Unresectable patients can become resectable due totumor response with chemotherapy but waiting for the best tumor response is notneeded (Perez-Staub N, ASCO 2006) and also can be a problem in case of completeresponse.

We report here the results in pts resectable at presentation and in pts who underwentsurgery after chemotherapy in phase 2 and 3 studies.

Methods:We retrospectively analysed 167 pts who underwent R0/R1 surgery, 46 pts atpresentation in a phase 2 study testing a combination of Folfox followed by Folfiri(MIROX, Taieb JCO 2005), and 121 pts who underwent a salvage surgery after Folfoxtreatment in OPTIMOX1 (Tournigand, JCO 2006) and OPTIMOX2 (Maindrault-Goebel, ASCO 2007) after updating the survival.

Results: Patients baseline characteristics were (MIROX/OPTIMOX%): median age 56/62 yrs, PS 0 50/73, adjuvant CT 20/12 (none with oxaliplatin), metachronousmetastasis 41/21, ‡ 2 met sites 11/18, liver met 78/88, lung met 11/19, other met 17/10,two-stage surgery 9/10, second surgery after relapse 39/22, R0 resection 91/ 85.

114 among 142 evaluable patients had a response to FOLFOX (80%).

Median time from randomisation to surgery was 8 mths in the OPTIMOX group.

In the MIROX group, 46% had surgery of metastases before chemotherapy.

Median disease-free survival from R0/R1 surgery was 18.6 months in MIROX group vs9.4 months in OPTIMOX group (p=0.006). Median overall survival was 104.8 monthsin MIROX group vs 42.6 months in OPTIMOX group (p=0.02). No differencewas found between OPTIMOX pts resected before 6 months (n=44) and after (n=77)in OS (46.5 vs 49.9 months, p=0.85) or in DFS (11.3 vs 9.4 months, p= 0.39).

Conclusion: We can recommend 1) an immediate surgery when feasible, especially inpts previously exposed to adjuvant folfox 2) to perform a trial comparing adjuvantand neoadjuvant chemotherapy 3) not to delay salvage surgery in case of tumorresponse.

PD-0007. A PHASE 2 STUDY OF IMC-11F8, A MONOCLONALANTIBODY DIRECTED AGAINST THE EGFR, IN COMBINATION WITHMFOLFOX6 CHEMOTHERAPY IN THE FIRST-LINE TREATMENT OFADVANCED OR METASTATIC COLORECTAL CARCINOMA

Tabernero J1, Cervantes A2, Delaunoit T3, Hendlisz A4, Youssoufian H5, Zhul J5,Marshall K5, Rowinsky E5, Sastre Valera J6

1Hospital Universitario Vall d’Hebron, Barcelona, Spain, 2Hospital ClinicoUniversitario de Valencia, Valencia, Spain, 3Centre Hospitalier, Jolimont Lobbes,Haine-Saint Paul, Belgium, 4Institut Jules Bordet, Brussels, Belgium, 5ImCloneSystems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Branchburg,New Jersey, USA, 6Hospital Universitario San Carlos, Madrid, Spain

Background: IMC-11F8 is a fully human IgG1 mAb designed to robustly block ligandbinding to the EGFR, thereby inhibiting downstream signaling that promotes cancergrowth and survival. In preclinical studies, IMC-11F8 has demonstrated antitumoractivity comparable or superior to that associated with the chimeric anti-EGFR mAbcetuximab, and since IMC-11F8 is fully human, it is anticipated that itspharmacokinetic (PK) and toxicity profiles may be more favorable than those ofcetuximab. As an IgG1 construct, IMC-11F8 has also been shown to induceantibody-dependent cell-mediated cytotoxicity against tumor cells. In a previous Phase1 trial, IMC-11F8 monotherapy was well-tolerated; its PK profile supported flatdosing on an every-2-week schedule, and objective antitumor activity was noted.

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Methods: This study enrolled patients with unresectable mCRC who had received noprior anticancer therapy for metastatic disease. Since patient enrollment occurredbefore knowledge of the KRAS-dependent effects of EGFR-targeted mAbs, eligibilitywas irrespective of KRAS mutation status. All enrolled patients received IMC-11F8 atan absolute dose of 800 mg combined with mFOLFOX6 chemotherapy (oxaliplatin/leucovorin/5-fluorouracil) every 2 weeks. Radiographic assessment of tumor responsewas performed every 8 weeks. Patients continued to receive all study treatments untildocumentation of progressive disease, toxicity necessitating discontinuation, orwithdrawal of consent.

Results: A total of 44 patients have been enrolled and treated; 14 have discontinuedtherapy to date. Patients have received a mean of eight doses of IMC-11F8 (range, 1-18), spanning a mean 18.8 weeks of therapy (range, 2.0 to 44.3). A total of 27 (68%) of40 patients for whom response data are available have experienced an objectiveresponse. All of the remaining 13 patients experienced disease stabilization through atleast the initial 8 week treatment cycle; thus the disease control rate is 100%. Seven(16%) patients have undergone surgical resection with curative intent of previouslyunresectable disease. With a median follow-up time of 11.1 months, the medianPFS has not been reached. IMC-11F8-related adverse events (AE) were reported for 33of 44 patients (75%). 23 patients (52%) experienced IMC-11F8-related rash,including seven (15.9%) with related rash of Grade 3. Other related AEs affecting morethan 10% of the population were paronychia (22.7%), asthenia (15.9%), conjunctivitis(13.6%), dry skin (13.6%), and skin fissures (13.6%); most of these events wereGrade £ 2. One patient experienced a Grade 2 hypersensitivity reaction during Cycle 2.Adverse events related to mFOLFOX6 were consistent with the known toxicity profileof this regimen. Retrospective analysis of KRAS mutation status is pending.

Conclusions: The combination of mFOLFOX6 and IMC-11F8 has been well tolerated.Skin rash, generally mild and manageable, has been the most notable IMC-11F8-relatedadverse event; further, there is no indication that the addition of IMC-11F8exacerbated the toxicity of mFOLFOX6 chemotherapy. Evidence of antitumor activity,including a preliminary objective response of 68%, a surgical resection rate of 16%,and an intriguing PFS duration, has been observed in this population irrespective ofKRAS mutation status.

PD-0008. CLINICAL STUDIES VERIFY PERFORMANCE OF THEBLOOD-BASED SEPTIN 9 DNA METHYLATION ASSAY FOR THEDETECTION OF COLORECTAL CANCER

Horns T2, Lofton-Day C1, deVos T1, Schuster M2, Sledziewski A1, Wandell M1,Rosch T3

1Epigenomics, Inc. 1000 Seneca St, Ste 300 Seattle, WA 98101, USA,2Epigenomics AG, Kleine Prasidenten Str. 1, 10178 Berlin, Germany,3Universitatsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg,Germany

Introduction: Colorectal cancer (CRC) is the second leading cause of cancer deathsdespite a survival rate of over 90% when detected early. Currently, less than half ofguideline eligible individuals are willing to undergo regular screening for CRC,typically using colonoscopy or stool based tests, highlighting the need for a new testthat will drive patient compliance. We previously identified and validated methylatedSeptin 9 DNA as a blood-based biomarker for all stages of CRC. Here we show data ofthe latest multi-center case control study and progress of the ongoing prospectiveclinical validation study PRESEPT.

Methods + Results: A new clinic-ready assay for Septin 9 DNA methylation in bloodplasma was used to further validate the biomarker for colorectal cancer detection.Two prospective case control studies with 518 samples were performed. The first study(269 subjects) tested blood samples from 97 patients with CRC, and 172 individualswithout colorectal cancer as confirmed by colonoscopy. The new assay detected 72of 97 cancer cases (74% sensitivity) with 92% specificity. The second case control study,composed of an entirely independent set of blood plasma samples from 249 subjects,confirmed the performance observed in the first study. In this study the clinic-optimized Septin 9 assay identified 63 of 91 colorectal cancer patients of all stages (69%sensitivity) with 89% specificity. In these two independent studies, the performance ofthe optimized assay was statistically equivalent to the performance of the researchassay previously used in a 2006 study of over 300 subjects, which demonstrateda sensitivity of 72% at a specificity of 90%. Further, we report the current status of thePRESEPT study. PRESEPT is a multi-center clinical study sponsored by Epigenomicsto prospectively evaluate the clinical performance of methylated Septin 9. It is oneof the first studies to evaluate the performance of a non-invasive test to indicatepresence of colorectal cancer in colorectal cancer screening guidleline-eligibleindividuals in a standard blood sample. The study is designed to enroll up to 7,500subjects aged 50 or older at average to increased risk for colorectal cancer who havebeen scheduled for a screening colonoscopy at multiple clinical sites in the U.S. andGermany. This population is expected to harbor about 50 cases of undetectedcolorectal cancer. Enrollment for the study is expected to be finished in 2009 and Septin9 testing of the prospectively collected samples by an independent clinical laboratorywill follow.

Conclusions:With more than 3000 patient plasma samples tested, methylated Septin 9DNA is one of the most extensively studied blood-plasma marker for the detectionof colorectal cancer. A commercially available blood based test for colorectal cancer has

the potential to change the CRC screening landscape since it eliminates patientinvolvement in sample collection, which has been shown to reduce compliance to thestool based tests, and allows more direct testing through a simple blood draw ina physician’s office during a routine exam.

PD-0009. COMPLETE RESPONSE RATE TO NEOADJUVANTCHEMORADIOTHERAPY IN LOCALLY ADVANCED RECTAL CANCERMAY BE IMPROVED BY ALTERING INTERVAL TO SURGERY

Dhadda A1, Zaitoun A2, Bessell E2

1Castle Hill Hospital, Hull, United Kingdom, 2Nottingham University Hospital,Nottingham, United Kingdom

Background: The pathological complete response (pCR) rates to neoadjuvant chemo/radiotherapy in locally advanced rectal cancer have not been dramatically improved bythe addition of newer combination chemotherapy agents. Our previous work hasshown that the median tumour volume-halving time, for locally advanced rectalcancers, to neoadjuvant chemo/radiotherapy is 14 days1. Based on this it would appearthe current standard interval of 6-8 weeks to surgery following completion ofradiotherapy may not be sufficient for larger tumours.

Methodology: The original study involved 106 patients with locally advanced rectalcancer treated with preoperative long course chemo/radiotherapy at NottinghamUniversity Hospital. Patients were treated with CT planned radiotherapy to a dose of50Gy in 25 fractions over 5 weeks with or without concurrent capecitabinechemotherapy at a dose of 825mg/m2/bd/day. The tumour volumes were measured onCT images by two independent observers and compared to careful pathologicalvolumes assessed by a single pathologist. 94 patients went on to have surgery with12 remaining irresectable. Based on the calculated median tumour volume-halvingtime of 14 days it was calculated that the current interval of 6-8 weeks would only allowa tumour of less than 25cm3, regressing at the median rate, adequate time to regresscompletely by the time of surgery. Hence, the data was analysed for tumours <25cm3

and >25cm3 to ascertain the pCR rates in these patients.

Results: Of the original cohort of 106 patients there were 10 pCRs (9%). On multiplelinear regression analysis only the original tumour volume, tumour volume-halvingtime and interval to surgery was found to be significantly related to thepathological volume (p<0.0001). There were 10 patients with tumours <25cm3 out ofthe original cohort. Four of these patients had a pCR (40%). The pCR rate in patientswith tumours >25cm3 was only 6% (6/96). This was highly significant on chi-squaretest (p<0.001 v2= 12.1). Of the pCRs in patients with tumours >25cm3 3 of the6 (50%) had intervals greater than 10 weeks to surgery (range 10 – 40 weeks).

Conclusions: The pCR response rate may well be increased by individualising theinterval to surgery, using the original tumour volume and tumour volume-halvingtime, to allow tumours adequate time to regress. This has to be balanced againstpotential repopulation/regrowth of poorly responding tumours during the interval. Aspatients with a pCR have been shown to have improved long term outcomes2 thismay well have significant clinical implications.

References:

1. Dhadda AS, Zaitoun AM, Bessell EM. Regression of rectal cancer with radiotherapywith or without concurrent capecitabine – optimising the timing of surgicalresection. Clin Oncol 2008 Nov 20

2. Capirci C, Valentini V, Cionini L et al. Prognostic value of pathological completeresponse after neoadjuvant therapy in locally advanced rectal cancer: long-termanalysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys. 2008 Sep 1;72(1):99-107.

PD-0010. STROMA PRODUCTION AND DOWNREGULATION OFSMAD4 CORRELATES WITH POOR SURVIVAL FOR STAGE I-IICOLON CANCER PATIENTS

Mesker W1, Liefers G1, Morreau H2, Tanke H3, Tollenaar R1

1Dept of Surgery, Leiden University Medical Center, Leiden, The Netherlands,2Dept of Pathology, Leiden University Medical Center, Leiden, The Netherlands,3Dept of Molecular Cell Biology, Leiden University Medical Center, Leiden,The Netherlands

Background: Recent models on metastatic invasion focus on the tumor-‘‘host’’interface, in particular the role of the stromal tissue. The biological meaning of thestromal compartments are thought to be part of the process of wound healing, butthere is also strong emphasis that CAF’s (cancer-associated fibroblasts) are importantpromotors for tumor growth and progression. Assuming these models are correctwe anticipated that changes in the proportion of stroma in the primary tumor couldreflect progression. We therefore investigated if the amount of intra-tumor stromacould be applied as a candidate marker to identify patients for adjuvant therapy.

Methods: In a first study we have investigated the proportion of intra-tumor stroma,on heamatoxylin-eosin (H&E) stained histological sections in a set of 122 patients(stage I-III) and distinguished between patients with a high amount of stroma(stroma-high) and patients with less stroma (stroma-low).

The second study is based on stage I-II patients only, a subgroup of patients who mightbenefit from adjuvant therapy. We have analyzed 135 stage I-II colon cancerpatients for the proportion of tumor related stroma and for TGFb-R2, SMAD4 and

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b-catenin, markers involved in pathways related to stromal production andepithelial-to-mesenchymal transition (EMT).

Results: The first study showed five-year survival rates for stroma-high versus stroma-low of respectively for OS: 15.2% and 73.0% and for DFS: 12.1% and 67.4% (OSp<0.0001, HZ 3.73; DFS p<0.0001, HZ 4.18). In a multivariate Cox regression analysis,the amount of stroma remained an independent variable when adjusted for either stageor for tumor status and lymph-node status (OS: p<0.001, OS: p<0.001).

For the second study of 136 analyzed patients 35 (25.7%) patients were stroma-highand 101 (74.3%) stroma-low. Significant differences in survival were observed betweenthe two groups, with stroma-high patients showing poor survival (OS p<0.0001,HZ 2.59; DFS p=0.0002, HZ 2.31).

A high-risk group was identified with stroma-high and SMAD4 loss (OS p=0.008, HZ7.98, CI 4.12-15.44, DFS p=0.005, HZ 6.57, CI 3.43-12.56); 12 of 14 (85.7%)patients died within 3 years. In a logistic-regression analysis a high proportion ofstroma and SMAD4 loss were strongly related (HZ 5.42, CI 2.13-13.82, p<0.001).

Conclusions: Conventional haematoxylin-eosin stained tumor slides contain moreprognostic information than previously fathomed. This can be unleashed by assessingthe tumor-stroma ratio. The combination of analyzing the tumor-stroma ratio andstaining for SMAD4 results in an independent parameter for confident prediction ofclinical outcome.

PD-0011. FINAL RESULTS OF A MULTICENTRE PHASE II TRIALEVALUATING CETUXIMAB IN COMBINATION WITH FOLFIRINOX ASFIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER(MCRC) PATIENTS

Samalin E1, Desseigne F2, Thezenas S1, Bibeau F1, Viret F3, Mineur L4, AssenatE1, Bleuse J1, Portales F1, Crapez E1, Ychou M1

1CRLC Val d’Aurelle, Montpellier, France, 2Centre Leon Berard, Lyon, France,3Institut Paoli Calmette, Marseille, France, 4Institut Sainte-Catherine, Avignon,France

The aim of this phase II trial was to evaluate the efficacy and safety of cetuximab incombination with FOLFIRINOX as first line treatment in mCRC pts irrespective ofEGFR status.

Methods: Pts received cetuximab IV 400 mg/m2 initial dose, then 250 mg/m2/weekplus FOLFIRINOX (oxaliplatin 85 mg/m2 d1, irinotecan 180 mg/m2 d1, leucovorin200 mg/m2 d1, 5FU 400 mg/m2 bolus, and 2400 mg/m2 infusion over 46 hours, d1)every 2 weeks. G-CSF was administered as primary prophylactic treatment on d7-d12.Eligibility criteria included: measurable and non resectable mCRC, age 18-75 years,PS 0 or 1, no prior chemotherapy for advanced disease. The primary endpoint wascomplete response rate. Secondary endpoints were the objective response rate (OR),response duration, PFS, toxicity and OS. Detection of point mutations in codons12 and 13 of the KRAS gene were retrospectively analyzed.

Results: 42 pts were included and treated (at least 1 cycle). Median age was 60 years(32-76), 52% were male and 78% were PS 0. Primary tumor was not resected in44% pts and 83% of metastases were synchronous. Five pts received less than 4 cyclesand were not evaluable for the first tumor assessment: 4 due to toxicity including 1toxic death (neutropenic septicemia) and 1 for local progression (occlusion) after thefirst cycle. Among 37 evaluable pts, 27 completed the final assessment: 5 achieveda complete response (CR), 29 PR, 2 SD and 1 PD as the best response. The OR rate was91.9% (95%CI: 78%-98%). The complete response rate was 13.5% (95%CI: 4%-29%).35/37 pts were evaluable for KRAS genotyping (34% mutated pts). The OR rate andPFS for KRAS mut and wild-type pts were: 100% and 8.2 months vs 87% and 10months (NS), respectively. 40 pts were evaluable for safety after the first 4 cycles. Grade3-4 toxicities: neutropenia 39%, vomiting 10%, diarrhea 52%, anorexia 24%,asthenia 32%, cutaneous 17%. 28 pts (67%) had 2nd line chemotherapy, 14 withbevacizumab (12 with FOLFIRI) and 13 (31%) had 3rd line (7 with bevacizumab).

Conclusions: These data show the feasibility of this new therapeutic combination infirst line mCRC pts and suggest a high response rate. The influence of KRAS statuswas not demonstrated, probably due to the effectiveness of the FOLFIRINOX regimenand the low number of pts evaluable for this subgroup analysis.

PD-0012. LONG-TERM RESULTS OF TRANSANAL ENDOSCOPICMICROSURGERY FOR RECTAL TUMORS

Richter P, Gach T, Kulig J, Nowak W, Szura MJagiellonian University, Krakow, Poland

Purpose: The study analyzes single centre’s experience in the use of transanalendoscopic microsurgery for selected rectal tumors.

Patients and methods: From April 1996 to December 2006, 195 TEM procedures wereperformed. The study group consisted of 78 patients with rectal adenomas and 82patients with rectal cancers, aged 33 to 85 years. The criteria of inclusion for rectal

adenomas were: plane adenomas up to 50 percent of circumference of the rectum,distance from anal verge 2 to 20 cm. The criteria of inclusion for preoperativelyrecognized rectal cancer were: low risk rectal cancer, no lymph node metastases,diameter of tumor less than 4 cm, distance from anal verge from 3 to 15cm. Thepatients were identified from a prospective database.

Results: The diameter of the lesions varied from 8 to 70mm (mean – 28mm). The meandistance from anal verge was 8.6 cm (range 2 to 18cm). Hospital stay ranged from 1 to23 days (average – 4 days). Average follow up was 12.1 months for rectal adenomas(range, 1 – 111.3 months) and 36 months for rectal cancers (range 1 – 128.4 months).Overall morbidity after TEM was 21.9%. Serious complications were observed in 6cases (3.8%). There were no cases of postoperative mortality. Recurrences wereobserved in 11 cases (13.9%) of adenomas and 8 cases (9.6%) of cancers. Mean time torecurrence was 11.7 months. Recurrence rate was significantly lower for tumors up to4cm in diameter, located over 5 cm from anal verge, excised radically.

Conclusions: TEM is a useful and safe technique for treatment of selected rectaladenomas and low risk rectal cancers. The authors recommend transanal endoscopicmicrosurgery because of the small number of serious complications and acceptableamount of recurrences.

PD-0013. DETECTION OF KRAS MUTATIONS IN CLINICALPRACTICE: A COMPARISON OF TWO DIFFERENTMETHODOLOGICAL APPROACHES

Carotenuto P1, Roma C1, Rachiglio A1, Ventola M1, Tatangelo F2, Botti G2,Ciardiello F3, Normanno N1,4

1Pharmacogenomic Laboratory, CROM – Centro Ricerche OncologicheMercogliano, Avellino, Italy, 2Surgical Pathology Unit, INT Fondazione‘‘G.Pascale’’, Naples, Italy, 3Dip. Medico Chirurgico di Internistica Clinica eSperimentale ‘‘Magrassi e Lanzara’’, Seconda Universita di Napoli (SUN),Naples, Italy, 4Cell Biology and Biotherapy Unit, INT Fondazione ‘‘G.Pascale’’,Naples, Italy

Background: Several retrospective studies demonstrated that metastatic colorectalcarcinoma (mCRC) patients carrying activating mutations of the KRAS gene do notrespond to treatment with the anti-epidermal growth factor receptor (EGFR)antibodies cetuximab or panitumumab. Following these results, the EuropeanMedicines Agency (EMEA) approved anti-EGFR antibodies only for treatment ofmCRC patients with wild-type KRAS. Therefore, assessment of KRAS mutations ismandatory for the choice of the most appropriate therapy in mCRC. The most widelyused method to detect KRAS mutations is PCR amplification followed by directsequencing. However, the limited sensitivity and the time consuming nature ofsequencing has prompted the development of alternative methods that are faster, easierto perform, and more sensitive. In this study, we compared in a small cohort ofpatients the standard PCR/sequencing technique and a commercially available KRASmutation detection assay (Therascreen� K-RAS Mutation Kit) based on Real-Time PCR.

Methods: The sensitivity of Therascreen� K-RAS Mutation Kit (DxS, Manchester) andof a standard PCR/direct sequencing approach were compared by performing bothtests on genomic DNA from the HCT116 cell line, which carries the KRAS mutationG38A, mixed with wild-type DNA from HT29 cells. Both techniques were also used toassess KRAS mutational status by using fixed, paraffin-embedded CRC tumoursamples that were evaluated by pathologists to assess the percentage of tumor cells.

Results: The analysis of DNA samples containing limiting dilutions of mutated DNA inwild type DNA confirmed that the Therascreen� kit is able to detect mutations whenthe mix contains 1% of mutated alleles. This sensitivity is higher as compared withthe standard PCR/sequencing protocol, which was able to detected mutations when themix contained at least 10% of mutated DNA. By using the standard PCR/sequencingapproach, we detected XX mutations in 130 CRC patients (39.4%) that werescreened at our Institution. We next compared the sensitivity of the two techniques in40 samples with an adequate content of tumor cells (>60%). In this cohort of patients,the Therascreen� assay and the PCR/direct sequencing method were both able todetect 17 mutations (42.5%). However, we found one patient in which the Therascreenwas able to identify a mutation (G35T) while the PCR/sequencing method none, andadditional patients mutated at the PCR/sequence (G34T) and wild type accordingto the kit. Finally, we compared the ability of the two techniques to detect mutations ina selected number of patients (n=8) with a percentage of tumor cells/sample rangingbetween 30% and 50%, for which dissection to enrich for tumor cells was notpossible to perform. The Therascreen� kit identified mutations in 2 patients while thePCR/sequencing method recognized one mutation in this subset.

Conclusions:Our results suggest that although Therascreen� has a higher sensitivity ascompared with the standard PCR/sequencing approach, in samples with adequatepercentage of tumour cells the ability of the two techniques to detect KRAS mutationsin mCRC patients is similar. However, the Therascreen� kit might have a highersensitivity in samples with suboptimal levels of tumor cells content (<50%).



PD-0014. IMPROVED SELECTION OF PATIENTS FOR HEPATICSURGERY OF COLORECTAL LIVER METASTASES WITH FDG-PET: ARANDOMIZED MULTICENTRE STUDY

Ruers T1, Wiering B2, Paul K3, van der Sijp J4, Roumen R5, de Jong K6,Comans E7, Pruim J8, Dekker H9, Oijen W10

1Dept Surgery, The Netherlands Cancer Institute, Amsterdam, Netherlands,2Surgery, Radboud University Nijmegen Medical Centre, Nijmegen,Netherlands, 3MTA, Radboud University Nijmegen Medical Centre, Nijmegen,Netherlands, 4Surgery, VUmc, Amsterdam, Netherlands, 5Surgery, MMC,Veldhoven, Netherlands, 6Surgery, UMC Groningen, Groningen, Netherlands,7Nuclear Medicine, VUmc, Amsterdam, Netherlands, 8Nuclear Medicine, UMCGroningen, Groningen, Netherlands, 9Radiology, Radboud University NijmegenMedical Centre, Nijmegen, Netherlands, 10Nuclear Medicine, RadboudUniversity Nijmegen Medical Centre, Nijmegen, Netherlands

Objectives: Careful selection of patients who may benefit from surgical treatment ofcolorectal liver metastases is critical. Staging by PET with FDG is thought to be betterthan conventional staging. Evidence that the addition of FDG-PET leads to superiorclinical results and improved clinical management in these patients are lacking. Inthis randomised controlled trial, we investigated whether the addition of FDG-PET isbeneficial and reduces the number of futile laparotomies.

Methods: 150 patients with colorectal liver metastases selected for surgical treatmentby imaging with CT scan were randomly assigned to CT imaging only (n=75) or CTimaging plus FDG-PET (n=75). Primary outcome measure was futile laparotomy,defined as any laparotomy that did not result in complete tumour treatment, thatrevealed benign disease or that did not result in a disease free survival period longerthan 6 months.

Results: Clinical characteristics were similar for both groups. The number of futilelaparotomies was 34 (45%) in the group without PET and 21 (28%) in the group withPET, the relative risk reduction was 38% (95%, CI=4%-60%).

Conclusions: Addition of FDG- PET to the work-up for surgical resection of colorectalliver metastases prevents unnecessary surgery in one out of six patients.

PD-0015. RAF KINASE INHIBITOR PROTEIN (RKIP) IS NOTA PREDICTIVE FACTOR IN PATIENTS WITH K-RAS WILD-TYPEMETASTATIC COLORECTAL CANCER (MCRC) TREATED WITHCETUXIMAB OR PANITUMUMAB

Saletti P1, Molinari F2, Zlobec I3, Lugli A3, De Dosso S1, Tornillo L3, TerraccianoL3, Mazzucchelli L2, Frattini M2

1Oncology Institute of Southern Switzerland, Bellinzona, Switzerland, 2IstitutoCantonale di Patologia, Locarno, Switzerland, 3Institute of Pathology, UniversityHospital, Basel, Switzerland

Background: Both monoclonal antibodies (MoAbs) cetuximab and panitumumabtarget and inhibit the epidermal growth factor receptor (EGFR), a tyrosine kinasereceptor that controls cell proliferation and survival through two main signalingpathways: the Ras-RAF-MAPK axis and the PI3K-PTEN-AKT. The role of MAPKpathway in the resistance to these drugs (following K-Ras or BRAF mutations) is widelyaccepted. RKIP blocks MAPK through direct interaction with RAF proteins (mainlyRAF-1 and, in a lesser extent, BRAF). In CRC, RKIP acts as a metastasis suppressor: itsloss or reduced expression correlate with chemo-resistance in cancer cell lines,increased metastasis growth and poor survival. Due to its implication in the RAS-RAFpathway, we hypothesized that RKIP could represent a predictive marker of outcome inpatients (pts) treated with anti-EGFR MoAbs.

Methods: Pts with mCRC who had EGFR expression in their primary tumour ‡1% byimmunohistochemistry (IHC) and treated with cetuximab- or panitumumab-basedregimens were retrospectively analyzed for both K-Ras and BRAF point mutations inexons 2 and 15 (direct sequencing) and RKIP expression (IHC). The response toEGFR-targeted therapies was assessed according to RECIST criteria. Statisticalevaluations were performed using the two-sided Fisher’s exact test.

Results: Forty-three pts (26 men, 17 women) were evaluated, 2 of them were treatedwith upfront cetuximab, the others had failed at least one prior chemotherapy regimen.Nine pts (21%) experienced partial response (PR), while 34 were classified as non-responders (NR, i.e. those pts who had stable or progressive disease). K-Ras statusstrongly linked to response (p= 0.02), as all 14 pts (33%) with mutated K-Ras were NR.BRAF mutations were detected in 4 pts, all of them were NR. BRAF was not anindependent predictive marker of EGFR-targeted therapies efficacy (p = 0.56). K-Rasand BRAF mutations were mutually exclusive. By analyzing both K-Ras and BRAFstatus, we found that all 18 pts with either K-Ras or BRAF mutations were NR, whilstthose with both genes wt profile experienced a PR in 9/25 (36%, p= 0.005) cases.

Overall, RKIP was evaluable in 40 pts, and positive expression was found in 33 (82.5%)cases. Focusing on K-Ras/BRAF wild-type tumors, RKIP protein expression wasassessable in 24 cases. In this group, RKIP had a positive staining in 18 (75%) cases andnegative expression in 6. Of these, 13/18 (72%) RKIP positive and 2/6 (33%) RKIPnegative pts did not respond to anti-EGFR- based therapy. Statistical analysis showedthat RKIP expression did not correlate with resistance to anti-EGFR-based therapy inK-Ras/BRAF wt pts (p = 0.15).

Conclusions: Our analysis failed to demonstrate a role of RKIP in predicting theresponse in patients with mCRC treated with anti-EGFR MoAbs. Conversely, inagreement with previous reports, our results confirm that pts carrying K-Ras or BRAFmutations are unlikely to benefit from anti-EGFR based therapy.

PD-0016. FOLFOXIRI (IRINOTECAN, OXALIPLATIN, INFUSIONAL5FU/LV) VS FOLFIRI AS FIRST-LINE TREATMENT OF METASTATICCOLORECTAL CANCER (MCRC): UPDATED RESULTS AFTER 5YEARS FOLLOW UP AND RISK-STRATIFIED ANALYSIS

Falcone A1,7, Vasile E1, Loupakis F1, Cupini S1, Baldi G1, Fornaro L1, Stasi I1,Salvatore L1, Brunetti I2, Fabbri M3, Chiara S4, Granetto C5, Ribecco A6,Andreuccetti M1, Masi G1

1U.O. Oncologia Medica, Azienda USL 6 di Livorno, Istituto Toscano Tumori,Livorno, Italy, 2U.O. Oncologia Medica 1, Azienda Ospedaliera-UniversitariaPisana, Istituto Toscano Tumori, Pisa, Italy, 3U.O. Oncologia B, Dipartimento diMedicina Sperimentale, Universita di Roma ‘‘Sapienza’’, Roma, Italy, 4U.O.Oncologia Medica, Istituto Nazionale Tumori, Genova, Italy, 5U.O. OncologiaMedica, Ospedale S. Croce e Carlo, Cuneo, Italy, 6S.C. Oncologia Medica,Azienda Sanitaria di Firenze Istituto Toscano Tumori, Italy, 7U.O. OncologiaMedica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, IstitutoToscano Tumori, Pisa, Italy

Background: As we previously reported (J Clin Oncol 2007) the GONO-FOLFOXIRIregimen compared to FOLFIRI demonstrated significant improvements in responserate (60% vs 34%, p<0.001), secondary radical resection (R0) of metastases (15% vs6%, p=0.03), progression-free survival (9.8 vs 6.9 months, p=0.006) and overallsurvival (22.6 vs 16.7 months, p=0.03) after a median follow up of 18.4 months.

Methods:We updated overall survival (OS) and progression-free survival (PFS) data ofthe 244 randomized patients after a median follow up of 60.6 months (mos) and weused a risk-stratified analysis according to the Kohne prognostic model (WBC,performance status, number of sites of disease, and alkaline phosphatase) (Ann Oncol2002) to determine if treatment outcomes differ in specific patient subgroups.

Results: The updated results confirm a significant improvement for FOLFOXIRI interms of PFS (median 9.8 vs 6.8 mos, HR=0.59, p<0.0001) and OS (median 23.4 vs 16.7mos, HR=0.74, p=0.026 and 5-years survival rate 15% vs 8%). There is a PFS and OSbenefit from FOLFOXIRI also excluding from the analysis the R0 patients (median PFS9.5 vs 6.6 mos, p=0.0001 and median OS 20.2 vs 15.9 months, p=0.12). Furthermore,among the R0 pts there are no differences in either PFS or OS according to treatmentarms. Finally, with regard to the risk-stratified analysis, FOLFOXIRI results in longerPFS and OS than FOLFIRI in all risk subgroups with Hazard-Ratios for low,intermediate and high risk groups respectively of 0.68, 0.56 and 0.44 for PFS and of0.90, 0.58 and 0.78 for OS.

Conclusions: These results demonstrate that the GONO-FOLFOXIRI regimen isassociated also with a better long term outcome compared to FOLFIRI (with anabsolute benefit in survival at 5 years of 7%) and that the superiority of FOLFOXIRI isnot only related to the increased rate of R0 surgery of metastases, but also to a betterpalliative effect which does not seem to be limited to some specific subgroup.

Partially supported by ARCO Foundation.

PD-0017. RECTAL CANCER WITH SYNCHRONOUS RESECTABLEMETASTASES: WHICH IS THE BEST STRATEGY?

Bachet J1,2, Ksiaa M1, Declety G1, Mitry E1, Lepere C1, Benoist S1, Vaillant J1,Housset M3, Penna C1, Nordlinger B1, Rougier P1

1Ambroise Pare Hospital, Boulogne Billancourt, France, 2ADEBIOPHARM ER48, France, 3Hopital Europeen Georges Pompidou, France

Introduction: There is no consensus concerning the therapeutic strategy in patientswith rectal cancer and synchronous metastases (RCSM). The aim of this study was toassess if the optimal treatment of the primary rectal tumor influence the possibility ofsecondary resection of metastases.

Patients and Methods: Medical files of all patients followed for a RCSM betweenDecember 1997 and December 2007 were retrospectively reviewed. Atmultidisciplinary meetings, resectability of metastases was established in 33 out of 80patients (41%). Characteristics of patients were: median age 59.0 years (range 30.1 to77.8); upper rectal tumor n=8 (24%), middle n=6 (18%) and lower n=19 (58%);number of metastastic site: one n=31 (94%), two n=2 (6%).

Results: 10 patients (30%) had primary tumor resection without pre-operativetreatment and 23 patients (70%) after pre-operative treatment: radiotherapy n=4(12%), radio-chemotherapy n=18 (55%), chemotherapy alone n=1 (3%). All patientswho received pre-operative treatments had T3-T4Nx stage at diagnosis. Surgery was anabdominoperineal resection in 6 patients (18%) and a low anterior resection in 27patients (82%); all resections were R0 (without microscopic invasion). Resection ofmetastases was performed in all patients: in the same time that the primary tumorresection (one stage) n=12 (36%); after resection of primary tumor (two or morestages) n=21 (64%). Adjuvant and/or interval chemotherapy was administered in 12 of13 patients (92%) who had one stage resection and 16 of 20 patients (80%) who hadtwo or more stages resection.



All One stage Two or more stages

Patients 33 12 (36%) 21 (64%)Liver metastases : 29 (88%) 9 (75%) 20 (95%)Right / Left / bilobular 9 / 9 / 11 0 / 5 / 4* 9 / 4 / 7’’Locally peitoneal carcinosis 3 (9%) 3 (25%) 0Lung Metastases 3 (9%) 0 3 (14%)

*liver resection and controlateral per-operative radiofrequency ablation n=2‘‘liver resection and controlateral per-operative radiofrequency ablation n=2

After a median follow-up of 71.4 months (range 11.5 to 128.5) since diagnosis and 64.7months (range 9.1 to 122) since resection of metastases, relapses occurred in 21 patients(64%), and 15 patients (45%) died. Relapse free survival after resection of metastaseswas 9.5 months [95% CI: 5.8-29.6] with 28% relapse free at 5 years. Overall survival was47.5 months [95% CI: 21.7-] after resection of metastases, and 62.1 months [95% CI:27.9-] after initial diagnosis; 51% of patients were alive at 5 years.

Conclusion: In patients with RCSM, when multidisciplinary approach is respected,secondary metastases resection is not compromised by an optimal treatment ofprimary rectal tumor.

PD-0018. DOUBLE BLIND RANDOMIZED PHASE II STUDY WITHRADIATION 1 5-FLUOROURACIL 1/- CELECOXIB FOR RESECTABLERECTAL CANCER

Debucquoy A1, Lambrecht M1, Roels S1, Goethals L2, Libbrecht L3,Van Cutsem E5, Geboes K3, Penninckx F6, Andre D6, William H M4, Karin H1

1Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven,Belgium, 2Department of Radiation Oncology, AZ Groeninge, Kortrijk, Belgium,3Department of Pathology, University Hospital Gasthuisberg, Leuven, Belgium,4Department of Radiation Oncology, David Geffen School of Medicine, UCLA,Los Angeles, CA, USA, 5Department of Digestive Oncology, University HospitalGasthuisberg, Leuven, Belgium, 6Department of Abdominal Surgery, UniversityHospital Gasthuisberg, Leuven, Belgium

Purpose: To assess the feasibility and efficacy of the addition of celecoxib topreoperative chemoradiation for patients with locally advanced rectal cancer ina double blind randomized phase II study.

Materials and methods: Thirty-five patients with locally advanced rectal cancer weretreated with preoperative radiation (45Gy; 1.8 Gy/fraction, 5days/week) combinedwith 5-fluorouracil (225 mg/m2) and celecoxib (2x400 mg/day) or placebo.Pathological response and the toxicity of the treatment were evaluated, as well as theexpression of COX-2 and Ki67 in the tumor tissue and IL-6 in plasma samples aspossible molecular correlates and predictors of response to treatment.

Results: A trend towards a better response was seen in the celecoxib arm with 61% ofresponders compared to 35% in the placebo arm (p=0.13). Also T downstaging and Ndownstaging were slightly higher in the celecoxib treatment arm. Plasma IL-6 levels andintratumoral COX2 or Ki67 were altered by chemoradiation but there was noadditional effect of celecoxib and these markers were therefore not useful in identifyingsubpopulations of patients who could benefit from this treatment. There was no effectof adding celecoxib to chemoradiation in terms of additional toxicity and it seemed tohelp mitigate therapy-related pain.

Conclusions: The addition of celecoxib to preoperative chemoradiation is feasible forpatients with locally advanced rectal cancer and might help mitigate treatment-relatedpain. The possible positive effect on pathological response, as suggested by our results,needs to be clarified by further clinical studies.

PD-0019. COMPARATIVE IMAGING EVALUATION BEFORESURGICAL RESECTION OF LIVER METASTASIS IN COLORECTALCANCER PATIENTS: FIRST RESULTS OF ITALIAN PROMETEOSTUDY

Rojas Llimpe F1, Di Fabio F1, Ercolani G2, Giampalma E3, Serra C4,Castellucci P5, Pini S1, Mutri V1, Golfieri R3, Martoni A1, Pinna A2, Pinto C1

1Medical Oncology Unit, S.Orsola-Malpighi Hospital, Bologna, Italy, 2Generaland Liver Surgery Unit, S.Orsola-Malpighi, Bologna, Italy, 3Radiology Unit,S.Orsola-Malpighi Hospital, Bologna, Italy, 4Medicine Unit, S.Orsola-MalpighiHospital, Bologna, Italy, 5Nuclear Medicine Unit, S.Orsola-Malpighi Hospital,Bologna, Italy

Background: The aim of the study was to define the specific diagnostic accuracy ofdifferent imaging techniques in patients (pts) with resectable colorectal cancer livermetastasis (CLMs).

Methods: Consecutive pts with, potentially resectable CLMs afferent to theMultidisciplinary Liver Team of Bologna Sant’Orsola Malpighi Hospital performed, inthe 3 weeks prior to liver surgery, computed tomography scan (CT), magneticresonance diffusion-weighted (MR-DW), and liver contrast-enhancedultrasonography (CEUS1). Liver contrast-enhanced ultrasonography was alsoperformed intra-operatively (CEUS2). All the imaging exams were performedaccording to the standard operative procedures.

Results: From December 2007 to January 2009, thirty-two out of 54 pts enrolled in thePROMETEO study underwent liver resection. The pt characteristics were: 21 (66%)males, 11 (34%) females; 21 (66%) synchronous metastasis, 11 (34%) metachronousmetastasis; 17 (53.1%) neoadjuvant chemotherapy; 8 (25%) previous liver surgery; 4(12.5%) previous loco-regional treatment. One-hundred and one liver lesions wereresected; the median number lesions per patient was 2 (range 1-10). All lesions werestudied with CT and CEUS1, 98 (97%) with CEUS2, 91 (90.1%) with PET and 91(90.1%) with MR-DW. Five lesions at pathological examination were non-metastasis(1 hamartoma, 1 steatosis, 1 giant-cell reaction, 2 necrosis). Only 3 lesions were notdetected by all imaging techniques (in one pt. previously treated with chemotherapyand radiofrequency).

CT % CEUS1 % CEUS2 % PET % MR %

Accuracy 81/101 79 82/101 81 90/98 92 51/91 67 75/91 82Sensitivity 77/96 80 82/96 85 87/93 93.5 59/86 69 74/86 86Positive Predictive value 77/78 99 82/87 94 87/89 98 59/62 95 74/78 95Specificity 4/5 80 0/5 0 3/5 60 2/5 40 1/5 20Negative predictive value 4/23 17 0/14 0 3/9 33 2/29 7 1/13 8

Conclusions: These results show that CT, CEUS1 andMR-DW have a good accuracy inthe detection of liver metastasis in patients who are candidates for resection. CEUS2presents the best accuracy.

PD-0020. MSI STATUS IS A PROGNOSTIC FACTOR BUT NOTA PREDICTIVE FACTOR OF 5FU- CHEMOSENSITIVITY IN ADJUVANTSETTING FOR PATIENTS WITH COLORECTAL CANCER

Des Guetz G, Schischmanoff O, Nicolas P, Perret G, Morere J, Uzzan BHopital Avicenne, Bobigny, France

Purpose: Adjuvant chemotherapy (CT) for colorectal cancer (CRC) is always based on5FU, alone or in combination with oxaliplatin. Microsatellite instability (MSI) isa prognostic factor in CRC. Whether it predicts the effect of adjuvant CT on OverallSurvival (OS) and Relapse Free Survival (RFS) is controversial.

Material and Methods: Studies were identified through PubMed, Embase and ASCOproceedings with keywords combination (colorectal cancer, chemotherapy, MSI).We used a fixed effect model, due to lack of heterogeneity between studies.

Results: AMA was performed for treated and non treated MSI population on 7 studies.Statistical calculations were performed on 7 studies representing 3690 patients;mean age: 65.5 years; 810 stage II and 2444 stage III (75%). MSI- high (MSI-H) wasfound in 454 patients (14% of the global population), microsatellite stable (MSS) in2871. A total of 1444 patients received 5FU-based chemotherapy, whereas 1518 patientsdid not.

For MSI-H patients, there was no statistically significant difference for RFS whether ornot they received chemotherapy (5 studies); HR RFS: 0.96 (95% CI: 0.62-1.49); HROS (6 studies) 0.70 (95% CI: 0.44-1.09; p = 0.12). Elsewhere, we found a significantinteraction between MSI status (MSI-H or MSS) and therapeutic status suggestinga lesser benefit for MSI-H than for MSS patients (HR interaction RFS: 0.77 [95% CI:0.67-0.87]).

Conclusion: We found a better prognostic for MSI-H compared to MSS patientswithout treatment but similar RFS for MSI-H patients treated by 5FU compared withuntreated, showing that MSI is a good prognostic factor but not a predictive factorof chemosensitivity.

PD-0021. TOPICAL APPLICATION OF VITAMIN K1 CREAM FORCETUXIMAB-RELATED SKIN TOXICITIES

Ocvirk J, Rebersek MInstitute of oncology Ljubljana, Slovenia

Background: Cetuximab is licensed for the first-line treatment of patients (pts) withEGFR-expressing KRAS wild-type metastatic colorectal cancer (mCRC) and for thetreatment of head and neck cancer. Skin toxicities, including acne-like rash, pruritus,dry skin, desquamation, hypertrichosis, and nail disorders are seen inapproximately 80% of pts treated with cetuximab and, unless properly managed, canresult in dose reductions and treatment delays. Therefore the effective management ofskin toxicities is essential to maximize treatment efficacy and maintain quality oflife. Preclinical studies have shown that vitamin K reactivates EGFR-mediated signaltransduction after the inhibition via EGFR receptor antagonists. The aim of ourstudy was to assess the efficacy of topical vitamin K1 cream in the treatment ofcetuximab-related acne-like rash.

Methods: Between Jan 2007 and Aug 2008, 79 pts with mCRC received weeklycetuximab plus chemotherapy. A cream containing urea and 0.1% vitamin K1 wasapplied topically when acne-like rash (NCI CTCAE version 3) developed. Pts weremonitored weekly for ‡12 wks.

Results: 69 (87%) pts developed an acne-like rash 1.2 wks (median, range 1–4 wks)after start of cetuximab infusions: grade 3 (n=20, 25%), grade 2 (n=38, 48%), grade 1(n=11, 14%). Twice-daily application of vitamin K1 cream resulted in a gradual



decrease in skin toxicity. Median time to improvement was 1.2 wks. Median time todownstaging of the rash by ‡1 grade was 2.3 wks. No dose reductions or treatmentdelays were needed for pts with grade 1/2 rash; 5/20 pts with grade 3 rash requireda dose reduction. Topical clindamycin was applied concomitantly in 12/20 and 2/38 ptswith grade 3 and grade 2 acne-like rash, respectively. Topical use of vitamin K1 creamwas not associated with any toxicities.

Conclusions: These findings confirm the efficacy of topical vitamin K1 cream in themanagement of cetuximab-related acne-like rash. Studies are underway to furtherinvestigate this therapeutic approach.

PD-0022. RESULTS FROM THE CELIM STUDY: CETUXIMAB PLUSFOLFOX6 OR CETUXIMAB PLUS FOLFIRI AS NEOADJUVANTTREATMENT FOR NONRESECTABLE COLORECTAL CANCER LIVERMETASTASES

Kohne C1, Grunberger T2, Bechstein W3, Hartmann J4, Lang H5, Lordick F6,Herrmann T6, Stohlmacher J7, Frilling A8, Raab H1, Liersch T9, Ockert D10,Konopke R7, Weitz J6, Folprecht G7

1Klinikum Oldenburg GmbH, Oldenburg, Germany, 2University Hospital Vienna,Vienna, Austria, 3University Hospital Frankfurt, Frankfurt, Germany, 4UniversityHospital Tubingen, Tubingen, Germany, 5University Hospital Mainz, Mainz,Germany, 6University Hospital/NCT Heidelberg, Heidelberg, Germany,7University Hospital Carl Gustav Carus, Dresden, Germany, 8University HospitalZurich, Zurich, Switzerland, 9University Hospital Gottingen, Gottingen, Germany,10Krankenhaus der Barmherzigen Bruder, Trier, Germany

Background: Nonresectable liver metastases from colorectal cancer may be renderedresectable by effective chemotherapy (CTx), potentially offering curative therapy.Combination of CTx with cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody, is known to substantially improve response rates.

Methods: In this phase II multicenter study, patients (pts) with nonresectablecolorectal liver metastases were randomized to receive cetuximab plus FOLFOX6 (armA) or cetuximab plus FOLFIRI (arm B). Pts were stratified by: reason fornonresectability (technically nonresectable vs at least 5 liver metastases); use of PETscans at initial staging; and EGFR status. Eight cycles (�4 months) of pre-operativetherapy were planned, and in the event of persistent nonresectability, multidisciplinaryevaluation was scheduled every 4 cycles. Responses were confirmed according toRECIST criteria or by resection. A central blinded imaging review was also performed,in which surgeons evaluated CTx/MRI scans for resectability at baseline and 4 months.Liver metastases were defined as resectable if at least 50% of surgeons selected‘‘resectable’’ or ‘‘exploration’’.

Results: Between December 2004 and March 2008, 56 pts were randomized to arm Aand 55 pts to arm B. Median age was 63 years. Fifty-five percent of pts were technicallynonresectable, 18% were initially staged with PET, and 73% had EGFR-positivetumors (as determined by immunohistochemistry). Ninety-nine pts were evaluable forKRAS mutation status; 70 pts (71%) had KRAS wild-type (wt) tumors. 16% of ptshad received adjuvant CTx and 13% had undergone previous liver resection. Toxicitiesof Grade 3 or above were reported in 72% of pts during pre-operative CTx, themost frequent being skin toxicity (33%), neutropenia (23%), and diarrhea (14%).Neuropathy (Grade 2 or above) occurred in 10% of pts (20% arm A). Five fatal eventsoccurred (two during pre-operative CTx, one during post-operative CTx, and twopost-operatively). Confirmed response rates were 70% in all pts with KRAS wt tumors(95% CI: 58–81%) and 43% (95% CI: 24–63%) in pts with KRAS mutant tumors (68%arm A, 57% arm B). Thirty-four percent of pts underwent R0 resection and 46%had macroscopically complete liver resection and/or radiofrequency ablation. Mediantime to intervention was 5 months. In the retrospective surgical review, scans frombaseline and 4 months were available for 75 pts (68% of randomized pts). Betweenthese timepoints, 32% changed from ‘‘nonresectable’’ to ‘‘resectable’’ and 6% from‘‘resectable’’ to ‘‘nonresectable;’’ 61% remained unchanged according to the imagingreview.

Conclusions: The combination of standard CTx and cetuximab produces highresponse rates (70% in pts with KRAS wt tumors), leading to a marked increase inresectability (as determined by blinded surgical review) and an encouraging rate of liverresection.

PD-0023. MODEL-BASED PREDICTION OF DEFECTIVE DNAMISMATCH REPAIR USING CLINICOPATHOLOGICAL VARIABLES INSPORADIC COLON CANCERS

Sinicrope F, Foster N, French A, Thibodeau S, Sargent D, O’Connell MMayo Clinic, Rochester, MN, USA

Background: Defective DNA mismatch repair (MMR) results in microsatelliteinstability (MSI) and is detected in approximately 15% of sporadic colon cancers.MMR status has been shown to provide prognostic and predictive information inprimary colon cancers. We sought to develop a model to predict MMR deficiency insporadic colon cancer patients using clinical and pathological data.

Methods: TNM stage II and III colon carcinomas (n= 982) were studied from six 5-fluorouracil-based adjuvant therapy trials conducted by the North Central CancerTreatment Group. MMR status in tumors had been analyzed by MSI (using mono-

and dinucleotide markers) or by immunohistochemistry for MMR proteins (hMLH1and hMSH2). Tumor infiltrating lymphocytes (TILs) was determinedmorphologically and categorized in a patient subset (n= 326) as mean number of TILsper high power field (HPF): 0-1, 2-4, 5-8, > 9. Logistic regression and a recursivepartitioning and amalgamation (RPA) analysis was used to identify importantpredictive factors of MMR status. Factors explored included age, gender, histologicgrade, tumor site, stage, lymph node metastases, T-stage, and TILs.

Results: Defective MMR was found in 147 (15%) cancers. Tumor site was the mostimportant predictor of MMR status followed by histologic grade. Distal tumors hada low likelihood of defective MMR (3% rate overall; 13/ 468), whereas proximal tumorshad a greater likelihood of defective MMR (26%; 130/ 506). For patients with proximaltumors, the addition of histologic grade and gender increased the prediction ofdefective MMR (Table 1). Using tumor site, histologic grade, and gender, the logisticregression model showed excellent discrimination (c-statistic = 0.81). In the patientsubset including TILs (n=326), a model including tumor site, TILs, and gender showedeven better discrimination (c-statistic = 0.86), along with increased positive predictivevalue (PPV). Specifically, proximal site, female gender and TILs (> 2) yielded a PPV of81% for detecting defective MMR (Table 2).

Table 1 (N=982)

Clinicopathological Variables DefectiveMMR(PPV)

Likelihood ofDefective MMR

Distal site 13/468 (3%) LowProximal, well/moderate*, male 26/177 (15%) AverageProximal, well/moderate*, female 35/158 (22%) IncreasedProximal, poor/undifferentiated,

male23/80 (29%) Increased

Proximal, poor/undifferentiated,female

46/91 (51%) High

*tumor differentiation

Table 2 (N=326)

ClinicopathologicalVariables

DefectiveMMR (PPV)

Likelihood ofdefective MMR

Distal site 4/148 (3%) LowProximal, TILs (0-1) 22/131 (17%) AverageProximal, male, TILs (‡2) 10/20 (50%) HighProximal, female, TILs (‡2) 22/27 (81%) High

Conclusions: Defective MMR is rare in distal colon cancers. The combination ofproximal site, poor differentiation, and female gender resulted in a 51% likelihood ofdefective MMR. Substituting TILs (> 2) for tumor grade in a patient subset increasedthe PPV to 81%. Analysis of these tumor features is feasible in routine histologicalsections and can facilitate referral for MMR testing.

PD-0024. IMPACT ON QUALITY OF LIFE OF CETUXIMAB PLUSFOLFIRI IN THE FIRST-LINE TREATMENT OF PATIENTS WITHMETASTATIC COLORECTAL CANCER (MCRC): RESULTS FROM THECRYSTAL TRIAL

Lang I1, Aleknaviciene B2, Zolotukhin S3, Komissarenko V4, Garcia-Alfonso P5,Jurga L6, Moiseyenko V7, Filipczyk-Cisarz E8, Zubel A9, Van Cutsem E10

1National Institute of Oncology, Budapest, Hungary, 2Vilniaus UniversitetoOnkologijos Institutas, Vilnius, Lithuania, 3Donetsk Regional Oncology Centre,Donetsk, Ukraine, 4Krivoy Rog Oncology City Centre, Krivoy Rog, Ukraine,5Hospital Universitario Gregorio Maranon, Madrid, Spain, 6Onkologicka klinika,Trnava, Slovakia, 7NN Petrov Research Institute of Oncology, Saint Petersburg,Russia, 8Dolnoœlaskie Centrum Onkologii, Wroclaw, Poland, 9Merck Serono,Darmstadt, Germany, 10University Hospital Gasthuisberg/Leuven, Leuven,Belgium

Background: Assessing quality of life is important to evaluate the impact of treatmenton patients with mCRC and to inform clinical decision-making. The randomizedcontrolled phase III CRYSTAL trial compared cetuximab plus FOLFIRI with FOLFIRIalone in the first-line treatment of patients with epidermal growth factor receptor-expressing mCRC. The primary endpoint was progression-free survival; quality of lifewas one of the secondary endpoints.

Methods: Patients were randomized 1:1 to cetuximab (400 mg/m2 initial dose then 250mg/m2/wk) plus FOLFIRI q2w (irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-FUbolus 400 mg/m2, 5-FU infusion 2400 mg/m2 over 46 h) (n=599) or FOLFIRI alone(n=599). The EORTC QLQ-C30 (version 3.0) questionnaire was used to assessquality of life. Patients were asked to complete the questionnaire at baseline, every 4cycles, and at final tumor assessment. Patients with at least 1 evaluable EORTCQLQ-C30 questionnaire who were also included in the intention-to-treat populationwere evaluable for assessment. The primary quality of life analysis focused on GlobalHealth Status and Social Functioning scales using a pattern-mixture model that



included the drop-out pattern. Descriptive statistics were provided for each multi-itemscale considering quality of life changes over time.

Results: The addition of cetuximab to FOLFIRI significantly reduced the risk ofprogression (HR=0.85; p=0.0479); patients with KRAS wild-type tumors in thecetuximab plus FOLFIRI group had a 32% (HR=0.68) reduced risk of progressing.Questionnaire completion compliance rates were similar between treatment groups.Pattern-mixture analyses showed no statistically significant differences between the twotreatment groups for changes from baseline on the Global Health Status (p=0.29)and Social Functioning (p=0.39) scales. No statistically significant differences wereobserved when treatment groups were compared in terms of quality of life score overtime, with the exception of nausea/vomiting in favor of the cetuximab plus FOLFIRIgroup at week 16 (10.2 vs 13.3; p=0.0129), week 32 (9.3 vs 12.5; p=0.0488) and week40 (7.6 vs 12.5; p=0.0194).

Conclusions: In the first-line treatment of patients with mCRC, cetuximab plusFOLFIRI significantly prolongs progression-free survival compared with FOLFIRIalone. The progression-free survival benefit is even more pronounced for patients withKRAS wild-type tumors. Skin reactions related to cetuximab had no impact onthe EORTC QLQ-C30 Social Functioning scale — no clinicallymeaningful or statistically significant differences were observed between the treatmentgroups.

PD-0025. LONG TERM TREATMENT RESULTS IN PATIENTS WITHLOCALLY ADVANCED RECTAL CANCER AFTER PREOPERATIVERADIOTHERAPY 25 GY RANDOMIZED FOR SHORT VERSUS LONGINTERVAL TO SURGERY

Richter P1, Kulig J1, Nowak W1, Pach R1, Kowalska T2, Pszon J2

1Jagiellonian University, Krakow, Poland, 2Oncology Institute, Krakow, Poland

Background and patients: Contemporary approach to the treatment of locallyadvanced rectal cancer is composed of multimodal therapy. Surgery still remains themost crucial treatment modality and is usually combined with radiotherapy andchemotherapy. Although results of many randomized trials has been already published,the impact of preoperative radiotherapy on long term treatment results has not beenproved unequivocally yet. The aim of this study was to assess the long termtreatment results in patients with locally advanced rectal cancer (stage II and III acc. toUICC/AJCC) undergoing short course hyperfractionated preoperative radiotherapy5x5 Gy and subsequently surgical treatment after short or long time interval. 235patients with rectal cancer localized in middle and low rectum and operated on in the1st Department of General and Gastrointestinal Surgery in Cracow between 1999and 2007 were included in the scientific protocol and followed up to obtain the dataon long term treatment results.

Methods: Patients included in the study were randomly assigned to groups withdifferent time interval between the end of radiotherapy and surgery: 101 pts wereoperated on 7-10 days after completion of radiotherapy and 134 pts were operated on4-5 weeks after radiotherapy.

Endorectal ultrasound, CT scan of the abdomen and pelvis, rectoscopy and chest X-raypicture were performed to establish the clinical stage of rectal cancer beforerandomization. All patients were operated on by the same surgical team and accordingto the same surgical standards (TME, excision of minimum 12 lymph nodes, R0resection). Both groups were homogenous with regard to age, sex, tumour localization,clinical staging, resection margins and extent of lymphadenectomy. Long termtreatment results (systemic and local recurrence rate and overall survival) weredescribed after the mean follow up period - 3 years (0.05-8.4 years). In additiondownstaging rate after radiotherapy was assessed in both analysed groups andtreatment results in patients who responded to irradiation were compared with thosein patients without any benefits after combined treatment. Caplan-Meier method andlog-rank test was used to compare survival curves and Chi-square test to comparequalitative data.

Results: Statistically significant decrease in systemic recurrence rate (3.7% vs. 11.9%,p=0.017) but not in local recurrence rate (3% vs. 2%, p=0.629) were observed inpatients with rectal cancer operated on after longer time interval between radiotherapyand surgical treatment. Time period between completion of radiotherapy and surgerydid not influenced overall survival after 3 years. Downstaging rate was significantlyhigher in the group with longer time- interval to surgical treatment (30.6% vs. 14.9%respectively, p=0.005). Significantly improved 3-year survival was observed in patientswho responded to preoperative radiotherapy in comparison with those who did notbenefit from combined treatment (95% vs. 75%, p=0.036).

Conclusion: Longer time interval between the end of preoperative short coursehyperfractionated radiotherapy 25 Gy and surgical treatment leads to decrease insystemic recurrence rate and increase in downstaging rate but did not prolong theoverall survival in patients with locally advanced rectal cancer. Prolonged 3-yearssurvival is observed only in patients who respond to preoperative irradiation i.e. whendownstaging is affirmed.

PD-0026. SURVIVAL BENEFIT OF THE INFERIOR MESENTERICARTERY (IMA) ROOT NODAL DISSECTION AND EXTENDED PELVICSIDEWALL DISSECTION (PSD) IN T3T4 LOWER RECTAL CANCERSURGERY.

Yasuno M, Sugihra KTokyo Medical and Dental University, Tokyo, Japan

Background: In Japan, the standard surgical approach for T3T4 lower rectal cancer hasbeen total mesorectal excision (TME) combined with high ligation of the inferiormesenteric artery (IMA) and extended pelvic sidewall dissection (PSD) since the late1970s. Sometimes, IMA root nodal dissect ion combined with left colic arterypreservation has been underwent in Japan. In the surgical approach for lower T3T4rectal cancer, IMA root nodal dissection with/without high ligation of the IMA, andextended PSD have remained controversial. The aim of this study was to assess theimpact of IMA root nodal dissection and PSD on survival in patients with T3T4 lowerrectal cancer.

Method: Date on 653 consecutive patients who underwent curative resection forpT3T4 lower rectal cancer, with IMA root nodal dissect ion and extended PSD, wereidentified from date base in 12 institutes between 1991 and 1998. Survival of patientswith involvement of lymph nodes along the IMA proximal to the origin of the left colicartery (root nodes, station 253) through the bifurcation of the superior rectal artery(trunk nodes, station 252), and lymph nodes along the iliac vessels and obturatornerves (lateral lymph nodes) was determined. One hundred fifteen patients (17.6%)had received adjuvant radiotherapy. Sphincter saving operation was performed in 294patients (45.0%).

Results: The mean number of nodes examined per patients was 46.4. The meannumber of the positive lymph nodes was 2.5. The incidence of metastasis to root nodes(station 253) was 3.4% of the patients. Trunk nodal (station 252) involvementoccurred in 14.8% of the patients. Positive lateral lymph nodes were found in 18.1% ofthe patients. Lymph nodal metastases occurred more frequently in patients with pT4lower rectal cancer. The 5-year survival and disease free survival rates of patientswith metastases to root nodes (station 253) were 36.9% and 26.3%. The 5-year survivaland disease free survival rates of patients with metastases to trunk nodes (station 252)were 52.7% and 47.8%. The 5-year survival and disease free survival rate of patientswith lateral lymph nodal involvement were 42.8% and 34.8%. IMA root nodaldissection would improve the 5 -year survival rate of patients with pT3T4 lower rectalcancer by 1.2%. PSD would improve the 5-year survival rate of patients with pT3T4 lower recta l cancer by 7.7%. (‘‘improvement of the 5-year survival rate’’ ="rate ofpositive lymph nodal metastases" ‘‘5-year survival rate of patients with positivelymph nodal metastases’’).

Conclusion: The incidence of metastasis to root nodes was low, and IMA root nodaldissect ion (high ligation) should not be highly beneficial because of the poorprognosis in patients with IMA root node positive T3T4 lower rectal cancer. On theother hands, PSD should be indicated for patients with T3T4 lower rectal cancerbecause of the greater provability of the positive lateral lymph nodes.

PD-0027. TRENDS IN SCREENING FOR COLORECTAL CANCER INFRANCE

Viguier J1, Calazel-Benque A2, Pivot X3, Morere J4, Blay J5, Coscas Y6, RousselC7, Eisinger F8

1Chru Trousseau, Tours, France, 2Capio clinique du Parc, France, 3CHUBesancxon, France, 4Hopital Avicenne, France, 5Hopital Edouard Herriot, France,6Clinique de la Porte de Saint-Cloud, France, 7Roche, 8Institut Paoli-Calmettes,France

Purpose: In France, after a pilot population-based screening programme in 23 districts(2002-2003), a national organized programme was progressively implemented startingin 2005. The EDIFICE 2 survey was conducted in 2008, 3 years after EDIFICE 1, toprovide a better understanding of French people’s participation in colorectal screeningprogrammes and to assess the evolution between the two periods.

Methods: This second nationwide observational study, EDIFICE 2, was conducted inJanuary 2008 among a representative sample of 1801 subjects aged between 40 and 85years old and a representative sample of 600 general practitioners (GPs). The analysisfocused on the target population of the national screening programme (50-74 yearsold).

Results: In 2008, 38% of subjects between 50 and 74 years (N=928) had undergonea screening test for colorectal cancer (including fecal test or colonoscopy) versus 25%in 2005 (p<0.05); Only 30% of GPs had systematically recommended the test versus18% in 2005 (p<0.05); 32% of the unscreened population (N=575) planned to undergoa test. Colorectal cancer screening increased significantly in all age groups, especiallybetween 65 and 69 years, and for both sexes. A most significant increase can beobserved in districts with pilot programme (+21%). Factors influencing the probabilityof screening were: being encouraged by the family circle, living in a couple, theexistence of a case of cancer (especially colorectal cancer) in the family circle, fear ofcolorectal cancer. The main reasons for not performing the screening were: not feelingconcerned, no recommendation by the GP, carelessness, no symptoms and fear ofexams or results.



Conclusion: The objective rate of participation (50%) can be reached by motivatingthe unscreened population already planning to perform a test. The results in the pilotdistricts show the effectiveness of an organization of the screening. This trend ofincreasing testing will probably be confirmed in the future if the reasons for non-attendance in an organized programme are addressed.

PD-0028. EVALUATION OF MSPATH SCORE COMPARED TOREVISED BETHESDA GUIDELINES FOR DETECTING LYNCHSYNDROME IN A CONSECUTIVE SERIES OF 223 COLORECTALCARCINOMAS

Julie C1, Beauchet A1, Tresallet C1, Brouquet A1, Muti C1, Coulet F2, Boileau C1,Nordlinger B1, Rougier P1, Emile J1, Radvanyi H1

1CHU Ambroise Pare, Boulogne, France, APHP, EA 4340, 2CHU Tenon, Paris,France, APHP

Background: The Bethesda guidelines (BG) for Lynch syndrome were developed topreselect patients for microsatellite instability (MSI) testing before germline mutationscreening. Among the 5 revised criteria, 1 focuses on particular pathology features.MsPath score (MsPS), based on site of the tumor, age at diagnosis and pathologyfeatures was recently shown to predict high-MSI (MSI-H) tumors in patientsdiagnosed before age 60 years. Our aim was to compare this score with the BG fordetecting Lynch syndrome in unselected patients.

Methods: A consecutive series of 223 resected colorectal invasive adenocarcinomasfrom 214 patients was collected in our institution. All tumors were reviewed by a seniorpathologist. Familial history, pathology features, site and age at diagnosis wereobtained. MSI analysis was performed for all tumors. Germline mutations in themismatch repair genes pointed by immunohistochemistry were searched for patientswith MSI-H tumor.

Results: MsPS was >or=1 in 105 patients (49%). Ninety patients (42%) met the BG.Twenty-one patients (9.8%) had MSI-H tumors. Germline testing identified8 mutations (3.7%) (MSH2, n=5; MLH1, n=2; MSH6, n=1). The specificity of MsPS>or=1 for predicting MSI was 54%. The BG failed to identify 2 of the 8 probands. Allpatients with Lynch syndrome had MsPS >or=2.3. The sensitivity and the specificity ofMsPS >or=1 in combination with MSI for detecting Lynch syndrome were 100% and93.7%, versus 75 and 98.5% for the BG.

Conclusion: In our study, the MsPS identified all the patients with germline mutation,since a quarter of them were missed by the BG. Futhermore, MsPS increased onlyslightly the number of patients who should be tested for MSI (49% versus 42% for theBG). These data suggest that MsPS could replace BG for preselecting patients for MSItesting and are arguments for the detection of Lynch syndrome by the pathologists.Further studies in larger series are needed to confirm these data and to determinea MsPS value which would increase the specificity with no decreasing the sensitivity.

PD-0029. EGFR GENE COPY NUMBER AND KRAS STATUSANALYSIS IN PATIENTS WITH LOCALLY ADVANCED RECTALCANCER TREATED WITH PREOPERATIVE CHEMO-RADIOTHERAPY

Bengala C1, Bettelli S2, Ponti G1, Bertolini F1, Sartori G2, Fontana A1, Malavasi N1,Del Giovane C1, Zironi S1, Luppi G1, Conte P1

1Division of Medical Oncology, University Hospital, Modena, Italy, 2Institute ofPathology and Cell Biology, University Hospital, Modena, Italy

Background: Gene copy number (GCN) of EGFR has been suggested to be a predictivefactor of response to Cetuximab in patients (pts) with metastatic colorectal cancer(mCRC); moreover K-ras mutation has been associated with resistance to cetuximab inmCRC. We have shown that both biomarkers correlate with pathological response topreoperative chemoradiation + cetuximab in locally advanced rectal cancer. Howeversome concern exists on the possible prognostic role of the two biomarkers.

Methods: In order to analyse the possible prognostic role of EGFR GCN and K-RASstatus we have retrospectively reviewed the clinical outcome of patients with locallyadvanced rectal cancer treated with preoperative radiation therapy (RT) + 5-FU givenas iv c.i. during the RT. Tumor specimens were characterized for EGFR GCN by FISHand K-RAS status was evaluated by PCR-based DNA sequencing. High GCN wasconsidered an EGFR/nuclei ratio > 2.9 or CEP7 polisomy > 50%. Pathological responsewas evaluated by Dworak’s tumor regression grade (TRG). Disease-free survival andoverall survival were also evaluated.

Results: So far 113 patients have been evaluated. TRG 4 and TRG 3-4 were achieved in15.6% and 35.1% of the pts respectively. Twenty-three (20.5%) and 20 pts (17.9%) hadan EGFR/nuclei ratio > 2.9 and CEP7 polisomy > 50%. Moreover 17 pts (19%) hada K-RAS mutation. No statistically significant correlation was observed betweenpathological response and EGFR/nuclei ratio (p: 0.69) or CEP7 polisomy (p: 0.89).Moreover the correlation between K-RAS status and pathological response was notstatistically significant (p: 0.22). Disease-free and overall survival of the entirepopulation at 4 years was 79% and 84.5% respectively. The correlation between EGFRGCN and risk of relapse or death was not statistically significant (p: 0.85 and p: 0.43respectively), as well as the correlation between K-RAS status and risk of relapse ordeath (p: 0.56 and p: 0.29 respectively).

Conclusion: Our data shown that EGFR GCN and K-RAS status are not prognosticfactors in locally advanced rectal cancer treated with preoperative 5-FU plus radiationtherapy.

PD-0030. CETUXIMAB WITH IRINOTECAN/FOLINIC ACID/5-FU ASFIRST-LINE TREATMENT IN ADVANCED GASTRIC CANCER:A NON-RANDOMISED MULTI-CENTER AIO PHASE II STUDY

Moehler M1, Trarbach T2, Seufferlein T3, Kubicka S4, Lordick F5, Geissler M6,Daum S7, Siebler J1, Galle P1, Kanzler S1, AIO Group G1

1University of Mainz, Mainz, Germany, 2University Essen, Essen, Germany,3University Halle, Halle, Germany, 4University of Hannover, Hannover, Germany,5University Heidelberg, Heidelberg, Germany, 6Klinik Esslingen, Esslingen,Germany, 7Charite University Center Berlin, Berlin, Germany

Background: Cetuximab has demonstrated high efficacy in combination withirinotecan-based therapies in metastatic colorectal cancer. Irinotecan/folinic acid/5-FU(IF) may be an effective alternative to cisplatin-based regimens in advanced gastriccancer. We therefore conducted a phase II AIO study to evaluate the tolerability andefficacy of cetuximab combined with IF as first-line treatment in patients withadvanced gastric cancer.

Methods: Patients (pts) were eligible as follows: previously untreated adenocarcinomaof the stomach or oesophagogastric junction, ECOG performance status (PS) < 2,measurable lesions and adequate organ functions. Pts received weekly cetuximab (firstdose 400 mg/m2, subsequent doses 250 mg/m2) combined with chemotherapyconsisting of irinotecan (80 mg/m2) plus 24 hours continuous infusion of sodiumfolinic acid (Na-FA: 200 mg/m2) and 5-FU (1500 mg/m2) on days 1, 8, 15, 22, 29 and36 of a 50-day cycle. Treatment was continued until tumor progression and tumorassessments were performed every 2nd cycle.

Results: Between Aug 2006 and Sep 2007, 49 pts were enrolled: 71% were males,median age was 63 years (range 33-77), median PS was 0 (65% pts), 69% of pts and31% of pts had gastric and oesophagogastric junction carcinomas, respectively. Themedian treatment duration was 15.2 weeks (range 1.1-69.1). Grade 3/4 toxicities werediarrhoea (17% pts), skin reactions (13% pts), anorexia (9% pts), anaemia and fatigue(7% pts), allergic reactions, leucopoenia and neutropenia (4% pts each). Among 48 ptsevaluable for response, the overall response rate (CR + PR) was 42% (CR 4%/PR 38%)and the tumour control rate was 73%. Median progression-free and overall survivaltimes were 8.5 months (36.6 weeks; 95% CI 30.1; 48.1) and 16.6 months (71.1 weeks;95% CI 50; 93.4), respectively.

Conclusion: Cetuximab plus IF was well tolerated and encouraging survival data wereobserved. Cetuximab combined with chemotherapy in advanced or metastatic gastriccancer is under further investigation in an ongoing phase III trial.

PD-0031. BILIARY TRACT CANCER: A JOINT CANCER DATABASEANALYSIS

Deutsch YE1, Soares H2, Herna S1, Macintyre J1, Sleeman D1, Levi J1, Wen B1,Montero AJ1, Ribeiro A1, Gomez C1, Rocha-Lima C1

1Division of Hematology/Oncology, University of Miami Miller School of Medicineand Sylvester Comprehensive Cancer Center, Miami, Florida, USA, 2MountSinai Medical Center, Miami Beach, FL, USA

Background: Biliary tract cancer is the second most common primary hepatobiliarycancer. Surgery is the only potentially curative therapy, but only 10-30% are eligible.The roles of radiation, chemo-radiation, and chemotherapy are not well established.The objective of this analysis is to assess the outcome of patients with biliary tractcancer managed with surgery, chemotherapy, radiation, and/or chemo-radiation.

Methods: A retrospective analysis of patients with cancer of the biliary tract diagnosedbetween 1997 and 2007 was performed. Patients were identified from the joint tumorregistry database at University of Miami Hospital, Sylvester Comprehensive CancerCenter and Jackson Memorial Hospital. The information extracted included:demographics, stage, pathology, treatment (surgical management, adjuvant andpalliative therapy) and survival. Data on organ function and performance status (PS)were not available.

Results: A total of 800 patients were diagnosed with biliary cancer. The site of cancerwas the bile duct in 351 patients, the gallbladder in 173, and ampulla of vater in 239.334 patients (95.2%) with adenocarcinomas of the bile duct – cholangiocarcinoma –were analyzed. The mean age at diagnosis of bile duct cancer was 65 (range 26-92). 55%of patients were male. 22% of patients presented with stage I, 18% with stage II, 21%with stage III, 26% with stage IV, and 13% were unknown. Potentially curative surgicalresection was performed in 45% of the patients. 24% received chemotherapy, 20%received radiation, and 14% received chemo-radiation in combination. The overallmedian survival (MS) of all patients was 13 months - 22, 16, 14, and 10 months forstages I, II, III, and IV respectively. Surgery provided an overall survival benefit for allstages (24 vs. 9 months, p<.001), including stage III (n=31/71, 20 vs. 10 months,p=.026) & stage IV (n=28/88, 23 vs. 6 months, p<.001). Chemotherapy offered a trendto survival benefit for patients with stage IV (13 vs. 6 months, p=.06) and combinedstages III & IV (13 vs. 10 months, p=.07). Combination chemo-radiation hada significant survival benefit in stage IV (19 vs. 6 months, p=.022) and in combinedstages III & IV (14 vs. 10 months, p=.026). Due to the small number of patients, the



benefit of chemotherapy, radiation therapy alone, and chemo-radiation in the adjuvantsetting was not analyzed.

Conclusions: Chemotherapy and chemo-radiation had a positive impact on survivalin patients with late stage cholangiocarcinoma. Surgery improved survival in bothearly and advanced stages. The lack of data on performance status and organ functiondid not allow factoring these variables in the analysis.

PD-0032. IMPACT OF 1ST LINE AND 2ND LINE PFS DEFINITIONSWITHIN A RANDOMIZED PHASE III TRIAL IN PTS WITH METASTATICPANCREATIC ADENOCARCINOMA (MPA)

Bonnetain F1, Methy N1, Seitz J2, Mitry E3, Ychou M4, Gasmi M5, Raoul J6,Mariette C7, Rougier P3, Bedenne L1, Dahan L2

1FFCD INSERMU866, Dijon, France, 2CHRUMarseille AP-HM, France, 3HopitalAmbroise Pare (AP-HP), France, 4Centre de lutte contre le cancer Val d’aurelle,France, 5Hopitaux Nord de Marseille (AP-HM), France, 6Centre de lutte contre lecancer Eugene Marquis, France, 7CHRU Lille, France

Background: The FFCD phase III trial in pts with MPA comparing LV5FU2-P followedby Gemcitabine (arm A) versus the opposite sequence (arm B) had failed todemonstrate a significant difference in median OS and PFS. The aim of this ancillarystudy was to investigate definitions of 1st and 2nd line PFS and their impacts on results.

Methods: From 08/2003 to 05/2006, 202 pts with measurable MPA, PS 0-2, non priorCT were included in 33 centers, 102 in arm A and 100 in arm B. PFS1 in 1st linewas defined as time interval between randomization and progression (P) or death (D)during the 1st line. Alive patients without P have been censored at the beginning of 2nd

line or at the last FU. PFS2 in 2nd line was defined as time interval betweenrandomization and P or D during the 2nd line. Alive patients without P during 2nd linehave been censored at the last FU. For patients receiving only one line, PFS2 wasdefined as time interval between randomization and first P or D. Survival curves hasbeen estimated using Kaplan Meier and compared using log-rank Tests. Strict ITT andmodified ITT (ie pts receiving 2 lines) analyses were performed.

Results: Amongst the 202 pts after a median follow-up of 44 months, 69 pts (45 pts dueto P) in Arm A and 55 pts (48 pts due to P) in Arm B have received a 2nd line.Median PFS was respectively equal to 3.4 months in Arm A and 3.5 months in Arm B(Stratified Log-Rank p = 0.78). For PFS1 we observed 77 and 93 events respectively inArm A and B. Median PFS1 was equal to 4.0 months in Arm A and 3.5 months inArm B (Stratified Log-Rank p = 0.57). For PFS2 we observed 99 and 100 eventsrespectively in Arm A and B. Median PFS2 was equal to 5.0 months in Arm A and 5.8months in Arm B (Stratified Log-Rank p = 0.68). Restraining PFS2 amongstpatients receiving 2 lines (N = 124 pts), we observed 67 and 55 events respectively inArm A and B, median PFS2 was equal to 6.3 months in Arm A and 8.8 months inArm B (Stratified Log-Rank p = 0.03).

Conclusions: Our results suggest that PFS2 for patients receiving 2 lines was longerwhen pts received Gemcitabine in 1st line. To be clinically meaningful definition ofPFS1 and PFS2 should be optimized regarding censoring rules. New definitions shouldbe proposed and assed.

PD-0033. EFFICACY OF HIGH-DOSE CONFORMALRADIOTHERAPY (CRT) COMBINED TO TRANSARTERIALCHEMOEMBOLIZATION (TACE) FOR SINGLE HEPATOCELLULARCARCINOMA (HCC) NODULES INELIGIBLE FOR SURGERY ORRADIOFREQUENCY ABLATION (RFA)

Mornex F1, Maillard E2, Cuinet M3, Marion D3, Wautot V1, Trepo C2, Zoulim F2,Merle P2

1Radiotherapy, Centre Hospitalier Lyon Sud, France, 2Hepatology, Hotel-Dieu,Lyon, France, 3Radiology, Hotel-Dieu; Hospices Civils de Lyon, France

Background:We previously showed that CRT could sterilize small size HCCs (< 5 cm)(Mornex et al., Int. J. Radiat. Oncol. Biol. Phys. 2006). Concerning large size HCCs(> or = 5 cm), CRT alone is less efficient, and TACE brings modest benefit on tumourresponse and survival rates.

Objectives: The aim of our study was to demonstrate that association of CRT + TACEcould give substantial local control rates for small as well as for large size HCCs.

Methods: Open single arm phase-2 study. TACE was performed at day-1(hyperselective injection of 100 mg cisplatin or 50 mg doxorubicin / lipiodol emulsion+ embolization) and CRT at day-7 [45 to 54 Gy with photons X >10 MV, 3 Gy/day, 5fractions/week, total dose calculated following the dose volume histograms (DVH)].Patients (pts) had single HCC nodule with or without concomitant macroscopicvascular invasion, diagnosed following AASLD guidelines. All HCCs were ineligible forsurgery or RFA. The primary endpoint was objective response rate as defined by liver-adapted RECIST criteria at contrast-US and dynamic CT-scan, and secondary end-points were time to progression (TTP), survival and toxicity. All the pts gave theirinformed consent.

Results: So far, 26 consecutive eligible patients have been enrolled in intent-to-treatstrategy. All pts were treated and 24 were assessable for the primary endpoint: 19 malesand 7 females, aged of 73 +/- 7 years, Child-Pugh A (n=23) or B (n=3), with singleHCC nodule of 58.8 +/- 29.1 mm (range, 25-140), and vascular invasion in 4 cases

(portal, suprahepatic or inferior cava vein). Response were 18 complete (CR), 7 partial(PR), and 1 progression (PD). After 16.7 +/- 12.2 mo (range, 3-47) of follow-up, localcontrol was 96%, and distant relapse rate of 50% in CR pts with TTP of 9.3 +/- 5.9months (distant hepatic relapse or visceral metastasis). The overall survival ratereached 70% (78% in CR; 50% in PR with median value of 15 mo), and progression-free survival of 39% (44% in CR and 25% in PR). Concerning toxicity, liver functionsslightly worsened with a mean Child-Pugh score values of 5.6 +/- 0.9, 6.3 +/- 1.6, 6.7 +/-2.2, 7.0 +/- 2.4, 6.5 +/- 1.8 and 6.2 +/- 1.6 at mo-0, 1, 3, 6, 9 and 12 respectively. Threepatients developed digestive bleeding and one patient ischemic biliary stenosis,although absence of grade 4 toxicity following Soma-Lent scale.

Conclusion: Our preliminary data show that combination of CRT and TACE can giveexcellent tumour response rates and prolonged local control for inoperable single HCCnodules of small as well as of large size, and encouraging survival rates. CR is a goodpredictive factor of overall and progression-free survival. Toxicity is acceptable inChild-Pugh A patients. Controlled trials comparing TACE to TACE + CRT arewarranted for single large size HCCs.

PD-0034. EVALUATION OF EARLY PREDICTIVE 18F-FDG-PETASSESSMENT IN ADVANCED ESOPHAGOGASTRIC JUNCTION ANDGASTRIC CANCER PATIENTS TREATED WITH CETUXIMAB-CONTAINING THERAPY

Di Fabio F1, Pinto C1, Rojas Llimpe F1, Castellucci P2, Fanti S2, Mutri V1,Giaquinta S1, Di Tullio P1, Pini S1, Compagnone G3, Martoni A1

1Medical Oncology Unit, S.Orsola-Malpighi Hospital, Bologna, Italy, 2NuclearMedicine Unit, S.Orsola-Malpighi Hospital, Bologna, Italy, 3Medical PhysicsUnit, S.Orsola-Malpighi Hospital, Bologna, Italy

Background: 18F-FDG-PET/CT (PET) was reported to predict the pathologicalresponse during preoperative chemotherapy in esophagogastric junction (GEJ) orgastric (G) cancer pts. The aim of this study is to evaluate the usefulness of an earlychange in PET at several time-points in predicting response to cetuximab-containingtherapy in pts with advanced GEJ or G cancer.

Methods: We evaluated 51 pts with locally advanced/metastatic GEJ or Gadenocarcinoma who underwent a first line cetuximab-treatment in two Italian phaseII studies. Twenty nine pts (GEJ/G = 5/24; locally advanced/metastatic = 2/27) receivedcetuximab in combination with cisplatin/docetaxel (DOCETUX study) and 22 pts(GEJ/G = 2/20; locally advanced/metastatic = 3/19) received cetuximab in combinationwith FOLFIRI (FOLCETUX Study). PET scans were performed at baseline, and inFDG-avid pts, again on day 21 in the DOCETUX study and on day 42 in theFOLCETUX study. Metabolic response was defined as a decrease in maximumstandard uptake value (SUV) ‡35% on the basis of our previous study (Di Fabio et al.,Gastric Cancer 10:221-227, 2007). Objective response, according to RECIST criteria,was assessed by CT scan at baseline and every 6 weeks.

Results: Five pts (10.2%) had FDG non-avid tumor (all pts with signet cell carcinoma).In the 46 FDG-avid tumor pts, the median SUV at baseline was 10.3 (range 5.0 – 36.4).The response rate (RR) was significantly higher in pts with a drop >/=35% in SUVfrom baseline to day 42: 83% (10/12 pts) in metabolic responders vs. 25% (2/8 pts) innon-metabolic responders (p= 0.019). In contrast, the SUV change at day 21 did notcorrelate with objective response: RR 57.1% (8/14 pts) in metabolic responders vs.41.7% (5/12 pts) in non-metabolic responders (p= 0.695). The RR in non-avid tumorpts was 20% (1/5 pts).

Conclusions: Our study suggests that in advanced gastric cancer pts with FDG-avidtumor the PET predicts objective response at day 42, but not at day 21. A PET responseassessment can provide an opportunity to change the treatment in non-responder pts.Prospective trials defining the role of PET in gastric cancer are warranted.

PD-0035. SCREENING PROGRAM FOR CIRRHOSIS ANDHEPATOCELLULAR CARCINOMA (HCC) IN TWO AREAS WITHA CLUSTER OF HCC

Barni S1, Bottelli R2, Mazzoleni M3, Colombo S4, Petrelli F1, Cabiddu M1,Del Poggio P4

1Oncology Dept. Treviglio Hospital, Treviglio, Italy, 2Medicine Dept. AngeraHospital, Italy, 3General Pratictioner Fara D’Adda, Italy, 4Hepatology UnitTreviglio Hospital, Treviglio, Italy

Background: International Guidelines recommend ultrasound (US) surveillance ofcirrhotic patients for the early detection of HCC, but no study has addressed theproblem if a specific program of their identification by General Practitioner (GP) canimprove the diagnosis and prognosis of HCC.

Method: Two Northern Italian Health Districts located in Varese and BergamoProvinces with 45.000 and 200.000 inhabitants and with a high prevalence of HCC wereselected.

Seventy-two out of 167 GP received a specific training program to improve skills in thediagnosis of cirrhosis. They were instructed to screen all HCV, HBsAg, alcoholic andoverweight/diabetic patients with physical exam, abdominal US, cell blood count andAST/ALT determination. Cirrhosis was suspected on clinical ground or in the presenceof two US signs or one US sign plus a platelet count less than 130 x 103. The diagnosis



was subsequently validated in 2 hospital based hepatology-oncology centers of thedistricts with usual clinical, histologic, US and elastographic criteria. All the confirmedcirrhotics patients were enrolled in a surveillance program with active recall of thepatients and high quality US examinations. Briefings with GP were also periodicallyheld to check for the congruity of the program.

Results: The program started in January 2005: a total of 513 cirrhotics patients wereidentified and confirmed: 297/215 M/F, mean age: 69, (range 37-87), 36,4% werepreviously unknown. The most prevalent aetiology was HCV (57%), followed byalcohol (23%), HBV (12%) and cryptogenic/NASH (8%). Functional status was: 83%Child A, 13% B, 4% C.

An interim analysis was performed in October 2008: 45 cases of HCC were foundduring surveillance (3.8% /year of surveillance), 36 (80%) received potentially curabletreatment (15% resected, 7,6% PEI, 46% RFA, 11,5% TAE). Stage (BarcelonaClassification Liver Cancer) and therapy of these HCC were compared to allconsecutive cases of HCC (43) referred in the same period by untrained GP (group B).

HCC FOUND WITHIN (A) AND OUTSIDE (B) THE SCREENING PROGRAM

N�residual

BCLCA1-3

A4 B C-D ablative theror resected

no tumor

A) 45 32 (70%) 4 (9%) 6 (14%) 3 (7%) 80% 69%B) 43 15 (35%) 4 (9%) 8 (19%) 16 (38%) 46% 28%

(The differences between the two groups were significant: Chi Square test p<0.01)

Conclusions: 1) Liver cirrhosis is underdiagnosed in a significant proportion of cases(36%). 2) A screening program of cirrhotic patients by GP, followed by USsurveillance, can lead to earlier diagnosis and more effective treatment of HCC. This ismore important in the era of new biologic agents.

PD-0036. EXTENDED RESECTION FOR ADVANCED GASTRICCANCER: A MONOCENTRIC EXPERIENCE AT SAN SALVATOREHOSPITAL

Sisti V1, Nisi M1, Catalano V2, Cicetti M1, Goffi L1, Tamburini A1, Tinti A1,Bonanno L1, Corinaldesi F1, Lucertini M1, Fiume I1, Baldelli A2, Giordani P2,Graziano F2, Zingaretti C1

1General, Oncological and Vascular Surgery. San Salvatore Hospital. Pesaro,Italy, 2Medical Oncology. San Salvatore Hospital. Pesaro, Italy

Background: Complete surgical resection (R0) of the primary tumor and regionallymph nodes is the treatment of choice for gastric cancer. To achieve curative resection,patients may require resection of contiguous organs. We analyzed our experience withextended multiorgan resection in patients with advanced gastric cancer.

Methods: From January 1998 to December 2008, 570 patients underwent gastricresection for cancer at our Department. Standard curative surgical treatment for anyprimary site of disease was total gastrectomy associated with D2 lymphadenectomyextended to the 3rd level 12p/b nodes (D2/D3). One hundred-sixteen patients (20.3%)received primary resection and had one or more organ resected in addition to thestomach. Data from these patients were entered in a prospectively recorded database.Patients with follow-up less than 12 months (n=9), pathologic findings different fromadenocarcinoma (n=11), synchronous cancer (n=9), symultaneous portocavalshunt or bypass for hepatic artery aneurysm (n=2) were excluded from analysis.Survival rates were calculated according to the Kaplan-Meier method.

Results: Eighty-five patients underwent gastrectomy for gastric carcinoma, 52 patients(61%) were male, median age was 74 years (range 30-87). Tumor location was upperthird in 25 patients (29.4%), middle third in 21 patients (24.7%), lower third in 23patients (27.1%), diffuse in 6 patients (7.0%), gastric stump in 10 patients (11.8%).The pathologic examination showed a pT1 stage in 6 patients (7.0%), pT2 in 11patients (12.9%), pT3 in 49 patients (57.7%), pT4 in 19 patients (22.4%). For whatconcern the nodal stage, pN0 was found in 32 patients (37.7%), pN1 in 29 patients(34.1%), pN2 in 13 patients (15.3%), pN3 in 11 patients (13.0%). Complete surgicalresection (R0) was achieved in 75 (88.2%) patients. The median number ofexamined lymph nodes was 31 (range, 4-80). Gastrectomy was associated with oneorgan resected in 62 (73%) patients, or >1 organ resected in 23 (27%) patients. Themost common organs resected were spleen alone (n=44), spleen/pancreas (n=9),transverse mesocolon (n=8), colon (n=5), liver (n=2) duodenocefalopancreasectomy(DCP) (n=1), DCP/colon (n=1), multiorgan resection (n=12), other organs (n=3).Major non-fatal surgical complications and mortality were 4.7% and 1.2%,respectively. After a median follow-up of 47 months, the overall 5-year survival rate was47.7%. For patients who achieved R0 resection and those with high-risk tumors(pT3N+ and pT4Nx), 5-year survival rates were 57.6% and 41.8%, respectively.

Conclusions: Long-term survival following gastrectomy with additional organresection is possible and can be performed with minimal morbidity and mortality.Extensive radical surgery with curative intent (R0 resection) is mandatory to improveprognosis.

PD-0037. LYMPH NODE STAGING IN BILIARY TRACT CANCERUSING [18F] FDG POSITRON EMISSION TOMOGRAPHY (PET): ACOMPARISON STUDY WITH CT

Kato A, Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Yoshitomi H,Furukawa K, Mitsuhashi N, Takeuchi D, Takayashiki T, Suda K, Takano S,Miyazaki MDepartment of General Surgery, Chiba University, Chiba, Japan

Background: Surgical resection is the only curative treatment strategy for biliary tractcancer. Therefore, preoperative evaluation of lymph node staging is important forappropriate management of the patients with biliary tract cancer. The aim of this studywas to evaluate the value and limitations of [18F] FDG positron emissiontomography (PET) for detection and lymph node staging of biliary tract cancercompared with computed tomography (CT).

Patients and Methods: One hundred twenty-two patients with adenocarcinoma of thebiliary tract cancer who underwent preoperative FDG-PET and CT scan wereevaluated retrospectively. Final diagnosis for primary tumors and lymph nodemetastases were established by means of histopathological examination in all patients.The underlying biliary diseases in these patients were intrahepatic cholangiocarcinomain 15 patients, extrahepatic chalangiocarcinoma in 66 patients, gallbladder carcinomain 31 patients, and carcinoma of the papilla Vater in 10 patients.

Results: For primary tumors, FDG-PET showed a sensitivity of 100% for intrahepaticcholangiocarcinoma, 60% for extrahepatic cholangiocarcinoma, 86% for gallbladdercarcinoma, and 40% of papilla Vater carcinoma. Visual analysis of FDG-PET resultedin higher sensitivity for diagnosis of intrahepatic cholangiocarcinoma than that ofextrahepatic cholangiocarcinoma. We found no significant correlation between thediagnostic accuracy and pathological characteristics of primary tumors such as tumordifferentiation and depth of invasion. However, the rate of detection for extrahepaticcholangiocarcinoma by FDG-PET is related to the maximum diameter of the tumor.In regional lymph node metastases in patients with biliary tract cancer, FDG-PETshowed 32% sensitivity, 97% specificity, and 65% accuracy, whereas CT scan showed39% sensitivity, 89% specificity, and 65% accuracy. Overall accuracy of FDG-PET wasnot significantly different from that of CT for regional lymph node metastases inpatients with biliary tract cancer. However, the specificity of FDG-PET for regionallymph node metastases was significantly higher than that of CT. For para-aortic lymphnode metastases, PET and CT had the same sensitivity, specificity, and accuracy.

Conclusion: FDG-PET is accurate as CT for the detection of regional lymph nodemetastases in patients with biliary tract cancer. Furthermore, the low sensitivities ofFDG-PET and CT were insufficient to allow decision making on the staging of lymphnode metastases before surgery. However, the high specificity of FDG-PET forlymph node metastases appeared valuable, and the presence of lymph node onFDG-PET may have a clinically significant impact on the choice of surgicalresectability.

PD-0038. A MULTICENTER PHASE II STUDY OF INDUCTIONCHEMOTHERAPY WITH FOLFOX-4 AND CETUXIMAB FOLLOWED BYRADIOTHERAPY AND CETUXIMAB IN LOCALLY ADVANCEDESOPHAGEAL CANCER (LAEC)

De Vita F1, Orditura M1, Vecchione L1, Innocente R2, Martinelli E1, Farella A6,Pinto C3, Chiarion Sileni V4, Ruol A5, Pacelli R6, Vaccher E2, Pini S3, Ciardiello F1

1Medical Oncology - Second University of Naples, Italy, 2Dept. of Radiotherapy& Oncology,CRO - Aviano, Italy, 3Medical Oncology - Azienda Ospedaliera,Bologna, Italy, 4Medical Oncology - Azienda Ospedaliera, Padova, Italy,5Surgical Oncology - University of Padova, Italy, 6Dept. of Radiotherapy,Federico II University, Naples,Italy

Background: Preoperative CRT improves the survival of pts with EC when comparedwith surgery alone. Epidermal growth factor receptor (EGFR) is overexpressed in 30-90% of EC and is associated with poor prognosis, providing the rationale for using theanti-EGFR monoclonal antibody Cetuximab (C). The purpose of the study was toinvestigate the efficacy, toxicity and feasibility of C with FOLFOX- 4 regimen asinduction CT followed by C and RT in pts with LAEC in a multicenter setting.

Methods: Eligibility criteria: resectable, locally advanced (uT3 or uN1, T4 if deemedresectable) squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the esophagus;staged by EUS, CT and PET scan; age 18-70y; PS <2; normal organ functions. All ptsreceived induction treatment with C at a starting dose of 400 mg/m2 and furtherweekly infusion at a maintenance dose of 250 mg/m2 and 4 cycles of FOLFOX-4 everytwo weeks. Post-induction EUS and CT scans were performed, while a PET scanwas repeated early before second cycle of CT: pts without PD were given daily RT(180cGy fractions to 5040cGy) with concurrent weekly C. Post RT, EUS plus biopsies,CT scan and PET were performed. At wk 18, pts without PD had esophagectomy.A Simons two stage design was used. Primary endpoint was histopathologicalresponse rate.

Results: Up to January 2009, 41 pts, 31 men, were enrolled from 4 institutions; medianage 59 y (35-70y); AC 12; SCC 29; stage II 15, stage III 26 pts. At this time 32/41 ptswere evaluable. The most frequent grade 3/4 toxicity of chemoradiotherapy wereskin (32%), neutropenia (29%) and esophagitis (9%); 10 pts had no resection (9progressive disease,1 patient’s refusal). Of 22 operated pts, 17 pts (77%) had RO-resection, 5 pts had palliative surgery. 2 pts died due to complications after surgery



(1 after > 30 days). The pathological response rate was 68 %, with a completehistopathological remission recorded in 6 pts (27%); 17 pts (53%) are still alive withoutresidual or recurrent disease.

Conclusions: These results suggest the feasibility of incorporating Cetuximab intoa preoperative regimen for LAEC pts and an encouraging antineoplastic activity with68% histopathological responders.

PD-0039. NUMBER OF LYMPH NODES EXAMINED AMONGPATIENTS WITH GASTRIC CANCER: VARIATION BETWEENDEPARTMENTS OF PATHOLOGY AND CLEAR PROGNOSTIC IMPACTIN NODE-NEGATIVE DISEASE

Dassen A1, Lemmens V2, vd Wurff A3, Brenninkmeijer S4, Lips D1, Bosscha K1

1Jeroen Bosch Hospital,’s-Hertogenbosch, Netherlands, 2Eindhoven CancerRegistry, Comprehensive Cancer Centre South (IKZ), Netherlands, 3St ElisabethHospital, Department of Pathology, Tilburg, Netherlands, 4TweeStedenHospital, Department of Surgery, Tilburg, Netherlands

Gastric cancer is still one of the leading cancers in incidence and mortality throughoutthe world. In the Netherlands, overall 5-year survival is 18%. The only curativetreatment is surgery with (partial) gastric resection and lymph node dissection.According to several studies and guidelines a resection with at least 15 lymph nodesshould be performed for proper staging and disease control. There is no consensusabout the extent of lymph node dissection worldwide however.

In this perspective, we conducted a retrospective study in the Southern part of theNetherlands to evaluate the amount of lymph nodes dissected and examined itsrelation to survival.

All patients resected for primary gastric cancer without evidence for distant metastasis,diagnosed between 1999 and 2007 in the Dutch Southern Cancer Registry area wereincluded (N=880). The area includes 10 hospitals on 15 locations, which are served by6 departments of pathology. The median number of lymph nodes was described bydepartment of pathology, nodal status (N0 vs N+) and period of diagnosis (1999-2001vs 2002-2003 vs 2004-2007). Follow-up of vital status was complete for patientsdiagnosed between 1999 and 2004. Differences in 5-year crude survival rates betweennode-negative patients with fewer than the total median number of nodes examinedvs. patients with more nodes examined were analysed by means of a log-rank test.Furthermore, the ratio between the number of metastatic and evaluated lymph nodeswas calculated, and divided into 4 groups: N-ratio 0 (0%), N-ratio 1 (0,1-19%),N-ratio 2 (20-29%), and N-ratio 3 (‡30%).

The median number of lymph nodes examined was 7. Among patients with N0 disease,the median number was 6, while among patients with N+ disease it was 8. Between1999-2001 and 2004-2007, the median number of nodes examined increased from6 to 8. The median number of nodes examined varied between the departments ofpathology from 5 to 9.

Among patients with N0 disease and < 7 nodes examined, 5-year survival was 57%compared to 73% among patients with ‡7 nodes examined (p=0.01). Using N-ratio,patients with N-ratio of 0% had higher 5-year survival rates (58%) compared topatients with a higher N-ratio (N-ratio3: 5-year survival 11%, p<0.001). Risk of dyingwas strongly correlated with N-ratio.

In our region insufficient number of lymph nodes are dissected and/or examined. Thedifference in lymph nodes examined between the departments of pathology couldlead to differences in stage distribution and survival. Attempts to improve nodalassessment seem to be mandatory.

PD-0040. LONGITUDINAL ANALYSIS OF QUALITY OF LIFE (QOL)WITHIN A RANDOMIZED PHASE III TRIAL IN PATIENTS WITHMETASTATIC PANCREATIC ADENOCARCINOMA (MPA)

Bonnetain F1, Maillard E1, Seitz J2, Mitry E3, Ychou M4, Gasmi M5, Raoul J6,Mariette C7, Bedenne L1, Dahan L2

1FFCD INSERMU866, Dijon, France, 2CHRUMarseille AP-HM, France, 3HopitalAmbroise Pare (AP-HP), France, 4Centre de lutte contre le cancer Val d’aurelle,France, 5Hopitaux Nord Marseille AP-HM, France, 6Centre de lutte contre lecancer Eugene Marquis, France, 7CHRU Lille, France

Background: The FFCD phase III trial in pts with MPA comparing LV5FU2-P followedby gemcitabine (arm A) versus the opposite sequence (arm B) had failed todemonstrate a significant difference in median OS. To longitudinally compare QoLaccording to treatment sequence we have explore definitions of time until definitivedeterioration (TUDD) of QoL scores according to minimal clinically importantdifference (MCID) cut off.

Methods: From 08/2003 to 05/2006, 202 pts with measurable MPA, PS 0-2, non priorCT were included in 33 centers, 102 in arm A and 100 in arm B. QoL wasevaluated using EORTC QLQ-C30 every 8 wks up to death. We focused analyses on the

following scores: Global Health (GH), Emotional functioning (EF), Physicalfunctioning (PF) Fatigue (FA) and Pain (PA). TUDD were estimated using KaplanMeier, and compared using log-rank tests. They were defined as the time intervalbetween randomization and the first occurrence of a decrease in QLQ-C30 score >= 5points without any further improvement in QoL score >= 5 points or any furtheravailable QoL data. These analyses were repeated using a 10 points MCID, and byincluding deaths as event. We have also studied TUDD of at least of one of the GH, EF,PF, FA or PA scores. Univariate and multivariate Cox analyses were performed toinvestigate prognostic factors of TUDD

Results: Amongst the 202 pts, 179 had completed at least one QoL questionnaire (89%)and the mean number of available QoL data was 3 (SD: 2.14). Using a 5 points MCID aswell as 10 points, TUDD of the 5 scores did not differ according to treatment arm.About 25% of patients reported definitive score deteriorations‡ 5 points and 15%‡ 10points. Including death as event for a 5 points MCID, median TUDD of GH scorewas 5.2 months (4.3-6.2) in Arm A and 6.1 months (5.1-6.1) in Arm B (log rankp=0.50). Median TUDD of FA score was 4.8 months (3.5-6.3) in Arm A and 5.6months (4.2-7.7) in Arm B (log rank p=0.76). Median TUDD of at least of one of theGH, EF, PF, FA or PA scores was 3.7 months (2.4-4.7) in Arm A and 3.7 months(2.5-5.1) in Arm B (log rank p=0.94) Median TUDD of scores was reached aftermedian PFS and at median time of 2nd line PFS. While treatment had no impact,multivariate Cox model showed that tumor localization and progression wereindependently associated with TTDU (p < 0.05)

Conclusions: We have investigated QoL analyses modalities using survival techniquesdealing with binding drop out missing data and with an easier clinical interpretationof results. Progression seems to negatively impact QoL.

PD-0041. LONGITUDINAL ANALYSIS OF THE QUALITY OF LIFE(QOL) WITHIN A RANDOMIZED PHASE III TRIAL: OCTREOTIDEVERSUS PLACEBO FOR THE PATIENTS HAVING ADVANCEDHEPATO-CELLULAR CARCINOMA (HCC)

Dumas F1, Barbare J2, Aparicio T3, Bouche O4, Lombard-Bohas C5, Faroux R6,Seitz J7, Raoul J8, Bedenne L9, Bonnetain F10

1Universite ParisV-Descartes, Paris, France, 2Delegation a la RechercheClinique et a l’Innovation. Centre Hospitalier Universitaire Amiens Nord, 3Serviced’hepatogastroenterologie CHU AP-HP Bichat, 4Serviced’hepatogastroenterologie CHRU Reims, 5Service d’hepatogastroenterologieCHRU Lyon, 6Service d’hepatogastroenterologie, CH La Roche sur Yon,7Service d’hepatogastroenterologie, CHRU Marseille AP-HM, 8Centre regionalde lutte contre le cancer Eugene Marquis, 9Federation Francophone deCancerologie Digestive, Institut National de la Sante et de la RechercheMedicale U866, 10Biostatistics and methodological unit of FederationFrancophone de Cancerologie Digestive, Institut National de la Sante et de laRecherche Medicale U866

Background: The primary objective of this ancillary study is to longitudinally compareQoL. Secondary objective was to explore definitions of time until definitivedeterioration (TUDD) of QoL scores according to minimal clinically importantdifference cut off (MCID).

Methods: Inclusion criteria were age > 18 years, diagnosis of HCC with CLIP 0 – 3 andto be ineligible for curative treatments. Patients (pts) were randomized 1:1 to receiveoctreotide (30 mg, every 4 weeks for 2 years or until death) or placebo (2 mL NaCl).QoL was evaluated using EORTC QLQ-C30 every 4 weeks up to 24 months. Wefocused analyses on the following scores: Global Health (GH), Mental Health (EF),Physical Health (PF) and Pain (P). Firstly mean differences of QoL scores between lastavailable measurement and inclusion were compared using Wilcoxon test. SecondlyTUDD were estimated using Kaplan Meier, and compared using log-rank tests.They were defined as the time interval between randomization and the first occurrenceof a decrease in QLQ-C30 score of ‡ 5 points without any further improvement inQoL score of ‡ 5 points or any further available QoL data. These analyses were repeatedusing a 10 points MCID, and by including deaths as event.

Results: Between July 2002 and October 2003 135 pts in octreotide and 137 pts inplacebo arm were included. Mean differences of QoL did not differed betweenoctreotide and placebo arm. Using a 5 points MCID, TUDD of GH score is significantlylonger in the placebo group (stratified log rank p= 0.033); median was 2.3 (95% CI :1.37-3.66) vs 4 months (2.23-5.7). Using a 10 points MCID, TUDD of GH scorediffered, median time was 2.5 (1.9- 3.73) for the octreotide and 4.7 months (2.73 – 5.8)for the placebo group (stratified log rank p=0.026). Including death as event for a 10points MCID, median was 2.4 (1.83-3.17) for octreotide and 4.1 months (2.5-5) forplacebo group (stratified log rank p=0.012),

Conclusion: These results suggest that octreotide could have a negative effect on globalQoL. We have investigated QoL analyses modalities using survival techniquesdealing with binding drop out missing data and with an easier clinical interpretationof results.



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