Presentation on theme: "Phase II study of Erbitux, CisPlatin, Epirubicin, Leucovorin with UFT (E-PELUF) as neoadjuvant treatment in patients with gastric cancer Dr Efraim Idelevich."— Presentation transcript:
Phase II study of Erbitux, CisPlatin, Epirubicin, Leucovorin with UFT (E-PELUF) as neoadjuvant treatment in patients with gastric cancer Dr Efraim Idelevich MD, PhD Gastro-intestinal Oncology Unit Institute of Oncology Kaplan Medical Center
Neoadjuvant CT of Gastric & EG Junction Cancer Positive Trials: MAGIC French FNLCC/FFCD trial MRC/OEO2 (British study) Negative Trials: INT 0113 (US study) Dutch trial ERTC trial
Phase II study of cisPlatin, Epirubicin, LV and UFT (PELUF) as first-line chemotherapy in metastatic gastric cancer Idelevich E, et al. Acta Oncol 2007; 46(3):
PELUF regimen for Metastatic Gastric Cancer (MGC) Day week rest period Cisplatin 60 mg/m 2 and epirubicin 50 mg/m 2 iv UFT 300 mg/m 2 /d with LV 30 mg/d in two divided doses (day 1 afternoon to day 22 morning) Idelevich E, et al. Acta Oncol 2007; 46(3): All patients received ondansetron and dexamethasone for prevention of emesis before administration of cisplatin and epirubicin Cycles repeated every 4 weeks until disease progression, unacceptable toxicity, or patient refusal of further treatment
PELUF in MGC: Efficacy Idelevich E, et al. Acta Oncol 2007;46: 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) [21-51]
PELUF in MGC: Tolerability Adverse eventGrade 3Grade 4Grade 3Grade 4 Leukopenia Neutropenia Anemia Thrombocytopenia Diarrhea Nausea/vomiting Mucositis 31 (16%) 27 (14%) 3 (1.5%) 2 (1%) 12 (6%) 15 (8%) 7 (4%) 6 (3%) 2 (1%) 0 (0) 6 (15%) 4 (10%) 2 (5%) 1 (3%) 3 (8%) 2 (5%) 4 (10%) 1 (3%) 0 (0) Idelevich E, et al. Acta Oncol 2007;46(3): Cycles with adverse events n (%) (n=196) Patients with adverse events n (%) (n=39) No hand–foot syndrome was reported
review The role of UFT in advanced Gastric Cancer Aykan N, Idelevich E Annals of Oncology, Volum 19, 6, June 2008,
MGC: New-generation combinations Regimen Response rate Median OS (months) Adverse events (grade 3/4 >10%) FOLFIRI + Erbitux 1 Cetuximab 400 mg/m 2 d1 then 250 mg/m 2 weekly Irinotecan 180 mg/m 2 d1 LV 1000 mg/m 2 d1,2 5-FU 400 mg/m 2 bolus mg/m 2 CI d1,2 q2w ORR 44% CR 12% TTP 8 mo OS 16 mo (expected) Neutropenia 42% Acne-like rash 21% 1.Pinto C, et al. Ann Oncol 2007;18:510–517 PELUF + Erbitux may achieve similar results
MGC: New-generation combinations Regimen Response rate Median OS (months) Adverse events (grade 3/4 >10%) Cispaltin+Docetaxel + Erbitux 1 Cetuximab 400 mg/m 2 d1 then 250 mg/m 2 weekly Cisplatin 75 mg/m 2 d1 Docetaxel 75 mg/m 2 d1 q3w ORR 41%TTP 5 mo OS 9 mo Neutropenia 44.4% Acne-like rash 21% No toxic death was observed 72 pts 1.Pinto C, et al. Br J Cancer 2009;101(8): PELUF + Erbitux may achieve similar results
Mutation detection of K-ras in MGC Of the 52 cancers, K-ras mutations were found in 5 (9.6%). 1 The presence of K-ras mutation were found in 13.3% (32pts). 2 K-ras mutation were found in 11% of examined specimens. 3 1.Liu ZM et al. Mutation detection of KRAS by high-resolution melting analysis in Chinese with gastric cancer. Laboratory Center, Dalian Medical University, , PR China 2.Park 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 Korea 3.Idelevich E. unpublished data, GI Oncology Unit, Institute of Oncology, Kaplan Medical Center
E-PELUF regimen (Phase II study). Neoadjuvant CT with CisPlatin, Epirubicin, oral UFT & Leucovorin and Erbitux for resectable gastric and EGJ Cancer Day Day 1 Erbitux Day15 Erbitux 1-week rest period Cisplatin 60 mg/m 2 and Epirubicin 50 mg/m 2 iv, Erbitux 500 mg/m 2 UFT 300 mg/m 2 /d with LV 30 mg/d in two divided doses (day 1 afternoon to day 22 morning) Three 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.
E-PELUF : Patient characteristics CharacteristicValue No. of evaluable patients Median age, years (range) Male / female, n (%) ECOG performance status, n (%) 0 1 Weight loss n (%) 0-5 kg > 5-10 kg > 10 kg Clinical staging, n (%) T3 N0 T2 N1 T3 N1 K-RAS status n (%) Wild Mutated B-RAF status n (%) Wild Mutated HER2 status n (%) Positive (+3) Negative (45–80) 20 (69%) / 9 (31%) 6 (20%) 23 (80%) 5 (17%) 22 (76%) 2 (7%) 1 (3%) 26 (90%) 16 (89%) 2 (11%) 16 (89%) 2 (11%) 1(6%) 17 (94%) C Clinical stat Clinical staging assessments included endoscopy&biopsy, endoscopic ultrasonography (EUS), computed tomography scan of chest&abdomen, and 18F-flurodeoxyglucose positron emission tomography (FDG-PET)
Objective response Response No. of patients (%) (n=29) Complete response Partial response Stable disease Progressive disease 1(4%) 12 (41%) 11 (38%) 5 (17%) Tumor response was assessed after the 3 d treatment cycle. Assessments included endoscopy, endoscopic ultrasonography, computed tomography scan of chest and abdomen, and 18F- flurodeoxyglucose positron emission tomography (FDG-PET).
Tolerability Adverse eventGrade 3Grade 4 Skin rash Neutropenia Anemia Thrombocytopenia Diarrhea Nausea Vomiting Mucositis Hypomagnesemia Perforation Patients with adverse events NCI-CTCAE grade% (n=29) One treatment related death observed due to grade 5 neutropenia
Surgery 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.
Postoperative 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.
Pre- and post-treatment stage a n (%) T3 N0 M0 T2 N1 M0 T3 N1 M0 T0 N0 M0 T(any)N3 T(any)N(any)M1 2 (7) 1 (3) 26 (90) (14) 3 (11) 15 (54) 1(4) 4 (13) Stage Pre-treatment b Post-treatment c a Stage grouping according to the International Union Against Cancer, 5 th edition b Staged by endoscopic ultrasonography, CT scan, (PET FDG) scan c Staged by pathological examination
Survival & 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.
Summary & 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.