1. Dr 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 cancer
Dr Efraim Idelevich MD, PhD
Gastro-intestinal Oncology Unit
Institute of Oncology
Kaplan Medical Center

2. 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

3. Idelevich 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 cancer
Idelevich E, et al. Acta Oncol 2007; 46(3):

4. PELUF regimen for Metastatic Gastric Cancer (MGC)
Cisplatin 60 mg/m2 and epirubicin 50 mg/m2 iv
UFT 300 mg/m2/d with LV 30 mg/d in two divided doses (day 1 afternoon to day 22 morning)
1-week rest period
Day
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
Idelevich E, et al. Acta Oncol 2007; 46(3):

5. PELUF 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)
6.5
9.5
36 [21-51]
Idelevich E, et al. Acta Oncol 2007;46:

6. PELUF in MGC: Tolerability
Cycles with adverse events
n (%) (n=196)
Patients with adverse events
n (%) (n=39)
Adverse event
Grade 3
Grade 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%)
0 (0)
6 (15%)
4 (10%)
2 (5%)
1 (3%)
3 (8%)
0 (0)
No hand–foot syndrome was reported
Idelevich E, et al. Acta Oncol 2007;46(3):

7. review The role of UFT in advanced Gastric Cancer
Aykan N, Idelevich E
Annals of Oncology, Volum 19, 6, June 2008,

8. MGC: New-generation combinations
Regimen
Response rate
Median OS
(months)
Adverse events (grade 3/4 >10%)
FOLFIRI + Erbitux1
Cetuximab 400 mg/m2 d1 then 250 mg/m2 weekly
Irinotecan 180 mg/m2 d1
LV 1000 mg/m2 d1,2
5-FU 400 mg/m2 bolus mg/m2 CI d1,2 q2w
ORR 44%
CR 12%
TTP 8 mo
OS 16 mo
(expected)
Neutropenia 42%
Acne-like rash 21%
PELUF + Erbitux may achieve similar results
Pinto C, et al. Ann Oncol 2007;18:510–517

9. MGC: New-generation combinations
Regimen
Response rate
Median OS
(months)
Adverse events (grade 3/4 >10%)
Cispaltin+Docetaxel + Erbitux1
Cetuximab 400 mg/m2 d1 then 250 mg/m2 weekly
Cisplatin 75 mg/m2 d1
Docetaxel 75 mg/m2 d1
q3w
ORR 41%
TTP 5 mo
OS 9 mo
Neutropenia 44.4%
Acne-like rash 21%
No toxic death was observed
72 pts
PELUF + Erbitux may achieve similar results
Pinto C, et al. Br J Cancer 2009;101(8):

11. 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
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
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
Idelevich E. unpublished data, GI Oncology Unit, Institute of Oncology, Kaplan Medical Center

12. Three 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 Cancer
Cisplatin 60 mg/m2 and Epirubicin 50 mg/m2 iv, Erbitux 500 mg/m2
UFT 300 mg/m2/d with LV 30 mg/d in two divided doses (day 1 afternoon to day 22 morning)
1-week rest period
Day
Day 1 Erbitux Day15 Erbitux
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.

13. E-PELUF : Patient characteristics
Value
No. of evaluable patients
Median age, years (range)
Male / female, n (%)
ECOG performance status, n (%) 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 (%)
HER2 status n (%)
Positive (+3)
Negative 29
64.7 (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 stat C

14. 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 3d treatment cycle. Assessments included endoscopy, endoscopic ultrasonography, computed tomography scan of chest and abdomen, and 18F-flurodeoxyglucose positron emission tomography (FDG-PET).

15. Patients with adverse events NCI-CTCAE grade% (n=29)
Tolerability
Patients with adverse events NCI-CTCAE grade% (n=29)
Adverse event
Grade 3
Grade 4
Skin rash
Neutropenia
Anemia
Thrombocytopenia
Diarrhea
Nausea
Vomiting
Mucositis
Hypomagnesemia
Perforation 20 14 4 3 7 10 6
One treatment related death observed due to grade 5 neutropenia

16. 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.

17. 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.

18. Pre- and post-treatment stagea
Pre-treatmentb Post-treatmentc
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) -
4 (14)
3 (11)
15 (54)
1(4)
1 (4)
4 (13)
aStage grouping according to the International Union Against Cancer, 5th edition
bStaged by endoscopic ultrasonography, CT scan, (PET FDG) scan
cStaged by pathological examination

19. 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.

20. 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.