1Dr Efraim Idelevich MD, PhD Gastro-intestinal Oncology Unit Phase II study of Erbitux, CisPlatin, Epirubicin, Leucovorin with UFT (E-PELUF) as neoadjuvant treatment in patients with gastric cancerDr Efraim Idelevich MD, PhDGastro-intestinal Oncology UnitInstitute of OncologyKaplan Medical Center
2Neoadjuvant CT of Gastric & EG Junction Cancer Positive Trials: MAGICFrench FNLCC/FFCD trialMRC/OEO2 (British study)Negative Trials: INT 0113 (US study)Dutch trialERTC trial
3Idelevich E, et al. Acta Oncol 2007; 46(3): 324-329 Phase II study of cisPlatin, Epirubicin, LV and UFT (PELUF) as first-line chemotherapy in metastatic gastric cancerIdelevich E, et al. Acta Oncol 2007; 46(3):
4PELUF regimen for Metastatic Gastric Cancer (MGC) Cisplatin 60 mg/m2 and epirubicin 50 mg/m2 ivUFT 300 mg/m2/d with LV 30 mg/d in two divided doses (day 1 afternoon to day 22 morning)1-week rest periodDayAll patients received ondansetron and dexamethasone for prevention of emesis before administration of cisplatin and epirubicinCycles repeated every 4 weeks until disease progression, unacceptable toxicity, or patient refusal of further treatmentIdelevich E, et al. Acta Oncol 2007; 46(3):
5PELUF in MGC: Efficacy Response n=39 Complete response, n (%) Partial response, n (%)Overall response, % [95% CI]Stable disease, n (%)Progressive disease, n (%)TTP (months)MOS (months)1-year survival rate, % [95% CI]2 (5)13 (33)38 [24-52]16 (41)8 (21)6.59.536 [21-51]Idelevich E, et al. Acta Oncol 2007;46:
6PELUF in MGC: Tolerability Cycles with adverse eventsn (%) (n=196)Patients with adverse eventsn (%) (n=39)Adverse eventGrade 3Grade 4LeukopeniaNeutropeniaAnemiaThrombocytopeniaDiarrheaNausea/vomitingMucositis31 (16%)27 (14%)3 (1.5%)2 (1%)12 (6%)15 (8%)7 (4%)6 (3%)0 (0)6 (15%)4 (10%)2 (5%)1 (3%)3 (8%)0 (0)No hand–foot syndrome was reportedIdelevich E, et al. Acta Oncol 2007;46(3):
7review The role of UFT in advanced Gastric Cancer Aykan N, Idelevich EAnnals of Oncology, Volum 19, 6, June 2008,
8MGC: New-generation combinations RegimenResponse rateMedian OS(months)Adverse events (grade 3/4 >10%)FOLFIRI + Erbitux1Cetuximab 400 mg/m2 d1 then 250 mg/m2 weeklyIrinotecan 180 mg/m2 d1LV 1000 mg/m2 d1,25-FU 400 mg/m2 bolus mg/m2 CI d1,2 q2wORR 44%CR 12%TTP 8 moOS 16 mo(expected)Neutropenia 42%Acne-like rash 21%PELUF + Erbitux may achieve similar resultsPinto C, et al. Ann Oncol 2007;18:510–517
9MGC: New-generation combinations RegimenResponse rateMedian OS(months)Adverse events (grade 3/4 >10%)Cispaltin+Docetaxel + Erbitux1Cetuximab 400 mg/m2 d1 then 250 mg/m2 weeklyCisplatin 75 mg/m2 d1Docetaxel 75 mg/m2 d1q3wORR 41%TTP 5 moOS 9 moNeutropenia 44.4%Acne-like rash 21%No toxic death was observed72 ptsPELUF + Erbitux may achieve similar resultsPinto C, et al. Br J Cancer 2009;101(8):
11Mutation detection of K-ras in MGC Of the 52 cancers, K-ras mutations were found in 5 (9.6%).1The presence of K-ras mutation were found in 13.3% (32pts).2K-ras mutation were found in 11% of examined specimens.3Liu ZM et al. Mutation detection of KRAS by high-resolution melting analysis in Chinese with gastric cancer. Laboratory Center, Dalian Medical University, , PR ChinaPark SR et al. Predictive factors for the efficacy of cetuximab plus chemotherpay as salvage therapy in metastatic gastric cancer patients. Center for Gastric Cancer, Research Institute and Hospital, National cancer Center, Republic of KoreaIdelevich E. unpublished data, GI Oncology Unit, Institute of Oncology, Kaplan Medical Center
12Three cycles repeated every 4 weeks, followed by gastrectomy. E-PELUF regimen (Phase II study). Neoadjuvant CT with CisPlatin, Epirubicin, oral UFT & Leucovorin and Erbitux for resectable gastric and EGJ CancerCisplatin 60 mg/m2 and Epirubicin 50 mg/m2 iv, Erbitux 500 mg/m2UFT 300 mg/m2/d with LV 30 mg/d in two divided doses (day 1 afternoon to day 22 morning)1-week rest periodDayDay 1 Erbitux Day15 ErbituxThree cycles repeated every 4 weeks, followed by gastrectomy.Primary study objective: R0 resection rate, following neoadjuvant chemotherapy (PELUF-E) regimen in combination with Erbitux.Secondary study objectives: Safety profile, Overall Survival, Disease Free Interval, Overall Response Rate, Comparison results of this treatment with historical control group of pts, which did not receive neoadjuvant chemotherapy.
13E-PELUF : Patient characteristics ValueNo. of evaluable patientsMedian age, years (range)Male / female, n (%)ECOG performance status, n (%)1Weight loss n (%)0-5 kg> 5-10 kg> 10 kgClinical staging, n (%)T3 N0T2 N1T3 N1K-RAS status n (%)WildMutatedB-RAF status n (%)HER2 status n (%)Positive (+3)Negative2964.7 (45–80)20 (69%) / 9 (31%)6 (20%)23 (80%)5 (17%)22 (76%)2 (7%)1 (3%)26 (90%)16 (89%)2 (11%)1(6%)17 (94%)Clinical staging assessments included endoscopy&biopsy, endoscopic ultrasonography (EUS), computed tomography scan of chest&abdomen, and 18F-flurodeoxyglucose positron emission tomography (FDG-PET)Clinical statC
14Objective response Response No. of patients (%) (n=29) Complete responsePartial responseStable diseaseProgressive disease1(4%)12 (41%)11 (38%)5 (17%)Tumor response was assessed after the 3d treatment cycle. Assessments included endoscopy, endoscopic ultrasonography, computed tomography scan of chest and abdomen, and 18F-flurodeoxyglucose positron emission tomography (FDG-PET).
15Patients with adverse events NCI-CTCAE grade% (n=29) TolerabilityPatients with adverse events NCI-CTCAE grade% (n=29)Adverse eventGrade 3Grade 4Skin rashNeutropeniaAnemiaThrombocytopeniaDiarrheaNauseaVomitingMucositisHypomagnesemiaPerforation2014437106One treatment related death observed due to grade 5 neutropenia
16Surgery Twenty eight patients underwent surgery. 17 with partial gastrectomy, 8 patients total gastrectomy, three patients with intra-abdominal metastases, recognized at time of surgical exploration, did not undergo resection.Twenty (80%) had an R0 and 5 (20%) had an R1 resection.Postoperative complications occurred in 11 patients (46%). These included wound infection and anastomotic leakage.No patients died during the postoperative period.
17Postoperative treatment All 25 “resected” patients received adjuvant therapy: 20 chemotherapy, 5 chemoradiotherapy.Five patients (17%) had metastatic disease (MD).Staging of these 5 (17%) patients were identified as T3N1M0 disease before starting neoadjuvant chemotherapy. Intra-abdominal metastases were diagnosed at time of surgery in 3 patients. In two cases pathological examination identified T3N3(M1) and T3N1M2 diseases.All these 5 patients received palliative chemotherapy.
18Pre- and post-treatment stagea Pre-treatmentb Post-treatmentcn (%)T3 N0 M0T2 N1 M0T3 N1 M0T0 N0 M0T(any)N3T(any)N(any)M12 (7)1 (3)26 (90)-4 (14)3 (11)15 (54)1(4)1 (4)4 (13)aStage grouping according to the International Union Against Cancer, 5th editionbStaged by endoscopic ultrasonography, CT scan, (PET FDG) scancStaged by pathological examination
19Survival & Pattern of Disease Recurrence After a median follow-up of 24 months 20 patients (69%) were alive. 9 of whom showed no disease recurrence.No local recurrence (LR) observed in group of patients who underwent R0 resection,1 patient of R1 resection group suffers from LR and systemic metastases,10 patients from metastatic disease.Median overall survival was not reached yet.
20Summary & Conclusions The study is still ongoing. Data presented support the role of oral fluoropyrimidines as logical replacement for 5-FU in the treatment of gastric cancer.The biological agents are at the doorstep.The preliminary results of the study show that addition of erbitux to PELUF combination in patients with K-ras wild type gastric cancer has the promising activity.