Adjuvant chemotherapy with Cisplatin, Etoposide,

Fluorouracil and Leucovorin (CEFL) for

gastric carcinomaM.Papadakou1, E.Xydakis1, E.Makropoulou1,

M.Bonios1, C.Boukis1, T.Kakavoulis2, C.Karaliotas3, G.Panagos1

1Department of Medical Oncology, Agii Anargiri Cancer Hospital, Kifisia2Department of Surgery, Agia Olga General Hospital, Nea Ionia3Department of Surgery, Korgialeneio-Benakeio General Hospital, Athens

Greece

Gastric cancer constitutes a major health problem

worldwide• It represents the 4th most common

cancer, with 934.000 new cases annually• and the 2nd most common cause of

death from cancer, with 700.000 deaths per year

• Gastric cancer accounts for 8.6% of all new cancer cases and is responsible for 12.1% of all cancer deaths worldwide

Management of patients with gastric cancer remains a challenge for

oncologists •Surgical resection remains the

only curative treatment•However, the majority of patients

develop locoregional and/or distant metastases after curative resection

•Five-year OS rate for all patients ranges between 20% and 35%

•The most important predictors for relapse and survival are the stage of disease and the completeness of surgical resection

•Especially, patients with stage III disease have very poor prognosis, with long-term survivors not exceeding 15% after surgical treatment

Systemic adjuvant chemotherapy aims at treating occult micrometastatic

disease• Monotherapy with mitomycin C or 5-FU,

or various combinations of 5-FU, mitomycin C and anthracyclines were used

• In most of these trials, adjuvant chemotherapy failed to show significant benefit in RFS and OS

• In some trials, however, there was a trend towards improvement of survival

In this study, we used a combination of cisplatin, etoposide, 5-FU and

leucovorin • Cisplatin, etoposide and 5-FU as single

agents have shown significant activity in advanced gastric cancer, with response rates 26%, 15%, and 21%, respectively

• Cisplatin and etoposide appear to have synergistic cytotoxic activity probably overcoming multidrug resistance

• In vitro synergy of 5-FU with cisplatin and etoposide has been demonstrated

Between January 1997 and February 2006 33 consecutive patients were

enrolled

• Histologically proven stage III gastric adenocarcinoma• Radical curative surgery within the previous 8 weeks• Age between 18 and 74 years• WHO performance status ≤ 2• WBCs ≥ 4.000/μL• Neutrophils ≥ 2.000/μL• Platelets ≥ 100.000/μL• Bilirubin ≤ 1.5 UNL• SGOT and SGPT ≤ 2.0 UNL• Serum Creatinine ≤ 1.25 UNL

Eligibility criteria included:

Treatment• Cisplatin 30 mg/m2 on days 1-3 with pre- and post-

hydration• 5-FU 300 mg/m2 on days 1-3 in continuous 24-hour

infusion• Leucovorin 100 mg twice a day on days 1-3 bolus iv• Etoposide 90 mg/m2 on days 1-3• Cycles were repeated every 28 days• G-CSF 5μg/kg sc was given on days 5-11• Erythropoietin was given when hemoglobin level

decreased below 11g/dL• Toxicity was graded according to WHO scoring

system and appropriate dose adjustments were made in the presence of severe hematological and/or non-hematological toxicities

• All patients were planned to receive 6 cycles of CEFL

Follow-up evaluation• Patients were evaluated every 4 months

for the first 2 years, every 6 months for the next 2 years, and yearly thereafter

• Follow-up examinations included complete history, physical examination, complete blood cell counts, serum biochemistry, CEA, CA 19-9, chest X-ray and abdominal ultrasonography

• Upper gastrointestinal endoscopy and CT scans were performed upon completion of therapy and yearly thereafter

Patients: Enrolled/Evaluable 33/30Gender: Male/ Female 21/12Age (years): Average (range) 63 (42-

74)Location of primary tumor:Cardia/Corpus/Antrum 4/21/8Type of gastrectomy: Total/Subtotal

22/11

Histology: Intestinal/Diffuse/Mixed 15/13/5Primary tumor size: T2/T3/T4a 4/26/3Regional lymph node metastases: N0/ N1/ N2 3/9/21Stage: IIIA/ IIIB 16/17

Toxicity-1• All patients but 3 received 6 cycles of

chemotherapy• One patient with stage IIIA disease denied

continuation of treatment after the 3rd cycle• He relapsed at 23 months and died at 33

months from enrollment of disease progression• Two patients developed neutropenic fever after

their 3rd and 5th cycle• They died of sepsis despite the treatment given• These patients were 68 and 72 years old and

both had stage IIIB disease• One of them had a complicated postoperative

course that delayed his starting adjuvant chemotherapy

Toxicity-2• Two patients developed grade 2

thrombocytopenia after their 1st cycle• Doses of cisplatin and etoposide were

reduced by 20% in the subsequent cycles• Two more patients developed grade 2

anemia without need for blood transfusions• Non-hematological toxicities included

nausea, vomiting, stomatitis, diarrhea, and peripheral neuropathy

• However, grading of these toxicities didn’t exceed score 1 and didn’t require dose modifications

Results-1• Mean follow-up duration for evaluable

patients was 31 months (range 6 to 114+)• Fifteen (50%) patients have relapsed so far• Mean RFS was 31 months (6 to 114+)• 1 patient had only locoregional relapse• 10 patients developed distant metastases

(liver 4, lung 2, bone 2, brain 1, paraaortic lymph nodes 1)

• 4 patients had both locoregional relapse and liver metastases

Results-2•Although relapse rate for both

stage III subgroups was practically equal (53% and 47% for IIIA and IIIB, respectively), stage IIIA patients seemed to have better prognosis as their mean RFS was 37 months, while the mean RFS for stage IIIB was 25 months (p>0.05)

Results-3

Kaplan – Meier cumulative relapse free survival of patients with stage III gastric cancer and adjuvant CEFL chemotherapy

Results-4• Mean OS of all patients was 35 months

(range 4 - 114+)• Mean OS of adequately treated patients

was 35 months (range 6 - 114+)• Mean OS for stage IIIA patients was 42

months, while for IIIB it was 27 months, again without statistical significance (p>0.05)

• Age at diagnosis and sex didn’t have any prognostic value

Results-5

Kaplan – Meier cumulative overall survival of patients with stage III gastric cancer and adjuvant CEFL chemotherapy

• Poor survival of patients with gastric cancer after curative surgical resection is indicative of the need for adjuvant therapy

• Three early studies from Japan showed improvement of 5-year OS with the use of systemic adjuvant chemotherapy with either mitomycin C alone or mitomycin C-containing regimens

• Many subsequent trials failed to demonstrate significant survival benefit from the administration of adjuvant chemotherapy with various regimens, although some of these showed a trend towards improvement of survival

• In many of these studies, serious methodological problems were encountered, like incοrrect staging, delay in starting therapy, use of relatively inactive agents or combinations, and small number of patients per arm

• Four metanalyses were conducted in an effort to elucidate the role of adjuvant chemotherapy which demonstrated a small, but statistically significant reduction of recurrences as well as improvement in OS

• The most recent one, which included data of 3,118 patients, demonstrated a 28% survival benefit for the adjuvant chemotherapy group

• Greater benefit was seen in trials conducted in Asians as well as in patients with lymph node involvement

Two recent pivotal prospective randomized trials had changed

the strategy of the management of patients with

resectable gastric cancer

US intergroup trial INT 0116• Total of 603 high-risk patients• Randomly assigned to receive either surgery

alone or adjuvant chemoradiotherapy• The administration of adjuvant

chemoradiotherapy produces significant improvement of RFS as well as OS

• This positive results led to the establishment of postoperative chemoradiotherapy as a new standard of care in high-risk patients with gastric cancer in many oncological centres

British MRC Adjuvant Gastric Cancer Infusional Chemotherapy (MAGIC)

trial • 503 patients with resectable gastric or esophageal adenocarcinoma

• Randomly assigned to surgery alone or to 3 cycles of ECF chemotherapy before and 3 after resection

• Preoperative chemotherapy led to significant downstaging of primary tumors and lymph node metastases

• After a median follow-up 3 years, PFS and OS of patients in the chemotherapy arm were significantly improved

• The perioperative chemotherapy is regarded as standard treatment option by many oncologists, mainly in the UK

Despite these a pressing need to identify more

active regimens remains in order to improve the

outcome of patients with advanced gastric cancer

CEFL combination chemotherapy appears to be very effective and probably superior to ECFWe suggest that it should be incorporated in the perioperative treatment of high-risk patients with gastric cancerProper selection of eligible patients and vigorous supportive care are essential to diminish toxicity of this regimen