Hintergrund: Mit einer medianen Überlebenszeit von 5,6 Monaten (Burris, 1997) sind die Ergebnisse der Monotherapie mit Gemcitabin (Gem) weiterhin unbefriedigend. Präklinisch und klinisch nachgewiesene Synergismen zwischen Gem/5-FU, Gem und Oxaliplatin (Ox) sowie Ox /5-FU bei gleichzeitig nicht-überlappendem Toxizitätsprofil bilden die Rationale für den Einsatz dieser Kombinationstherapie.

Einleitung: Kombinationen von Irinotecan (CPT11) mit Folinsäure/5-Fluorouracil (FA/5-FU) (ILF) zeigten gute antitumorale Aktivität beim metastasierten kolorektalen Karzinom. Erste Daten lassen ebenfalls eine Wirksamkeit beim metastasierten Magenkarzinom vermuten.

Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy. Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m−2 over 30 min), oxaliplatin (65 mg m−2) and 5-FU (1500 mg m−2 over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure. Response rates were 19% (95% CI: 6–32%) and 23% (95% CI: 9–37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6–12.4) and 9.9 months (95% CI: 7.5–12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia. Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.

BACKGROUND:Combinations of gemcitabine-oxaliplatin, gemcitabine-5-fluorouracil (5-FU) and 5-FU-oxaliplatin have synergistic activity and nonoverlapping adverse effect profiles. This trial assessed efficacy and safety of the triple combination gemcitabine-oxaliplatin and infusional 5-FU in patients with locally advanced (n=11) or metastatic (n=32) pancreatic adenocarcinoma.PATIENTS AND METHODS:A total of 43 eligible patients were treated with intravenous infusions of gemcitabine (900 mg/m2 over 30 min), followed by oxaliplatin (65 mg/m2 over 2 h) and 5-FU (1500 mg/m2 over 24 h) on days 1 and 8 of a 21-day cycle.RESULTS:Among all 43 patients, the tumor response rate was 19% [95% confidence interval 7% to 30%]. Nine patients were nonassessable for response because they did not complete the first two cycles of chemotherapy due to rapid disease progression, early death or treatment refusal. One patient was lost to follow-up. Median time to progression and overall survival were 5.7 and 7.5 months. Principal grade III/IV toxic effects were leucopenia in 11 (2%), thrombocytopenia in 13 (2%), nausea in 13 (0%), anorexia 16 (7%) and sensory neuropathy in 18 (0%) of patients. Unexpected cardiotoxicity was observed in this trial.CONCLUSION:Response rates and survival of the three-drug combination compare favorably with single-agent gemcitabine, but do not exceed results for doublets.

An open-label randomised comparison of efficacy and tolerability of irinotecan plus high-dose 5-fluorouracil (5-FU) and leucovorin (LV) (ILF) with etoposide plus 5-FU/LV (ELF) in patients with untreated metastatic or locally advanced gastric cancer. One cycle of ILF comprised six once-weekly infusions of irinotecan 80 mg m−2, LV 500 mg m−2, 24-h 5-FU 2000 mg m−2, and ELF comprised three once-daily doses of etoposide 120 mg m−2, LV 300 mg m−2, 5-FU 500 mg m−2. In all, 56 patients received ILF and 58 ELF. Median age was 62 years, Karnofsky performance 90%, and disease status was comparable for both arms. The objective clinical response rates after 14 weeks treatment (primary end point) were 30% for ILF and 17% for ELF (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.29–1.13, P=0.0766). Overall response rates over the entire treatment period for ILF and ELF were 43 and 24%, respectively (RR 0.56, 95% CI 0.33–0.97; P=0.0467). For ILF and ELF, respectively, median progression-free survival was 4.5 vs 2.3 months, time to treatment failure was 3.6 vs 2.2 months (P=0.4542), and overall survival was 10.8 vs 8.3 months (P=0.2818). Both regimens were well tolerated, the main grade 3/4 toxicities being diarrhoea (18%, ILF) and neutropenia (57%, ELF). The data from this randomised phase II study indicate that ILF provides a better response rate than ELF, and that ILF should be investigated further for the treatment of metastatic gastric cancer.

4129 Background: Combinations of gemcitabine (GEM)/5-FU, GEM/oxaliplatin (LOHP) or 5-FU/LOHP work synergistically in pancreatic and/or colorectal malignancies, and have non-overlapping safety profiles. This phase II-study was designed to evaluate the efficacy and safety of the triple combination GEM/LOHP/5-FU in patients (pts) with advanced or metastatic carcinoma of the gallbladder. Methods: One-stage, multicentre phase II study. Eligibility criteria: chemonaive pts with histologically proven advanced, recurrent or metastatic gallbladder carcinoma (ECOG 0–1; expected survival >3 months; measurable disease; adequate renal, hepatic and bone marrow function). According to the results of our previous phase I-study (Proc ASCO 2003, # 1298), pts were treated with GEM 900mg/m2 as a 30-min infusion, followed by LOHP 65 mg/m2 (2-hr infusion) after a 30 min rest and 5-FU 1500 mg/m2 (24-hr-infusion) on d 1, 8, every 3 weeks. Planned sample size: 35 response evaluable patients. The primary endpoint was tumor response, secondary endpoints were toxicity, median survival, the one-year-survival rate, clinical benefit and quality of life. Results: At time of abstract submission, median follow-up of 35 enrolled pts is 9.8 months. Pt. characteristics: m/f: 11/24, median age 61 (range 42–81), ECOG 0/1: 24/11 (69/31%) pts, locally advanced/metastatic disease 1/32 (3/91%) pts. Analysis of tumor response is still pending. Grade III/IV (NCI-CTC) toxicities occurred in 36/3% of 191 cycles and were: leucopenia 3/1%, neutropenia 4/1%, thrombocytopenia 4/1%, anemia 2/0%, nausea 1/0%, sensory neuropathy 4/0%, asthenia 1/0%, elevated bilirubin 2/0%, AP 4/0%, or elevated SGOT/SGPT 1/0%, edema 1/0%, infection 1/0%, dyspnoe 1/1%. Median survival of all pts is 9.9 months (95% CI: 7.5–11.5), the one-year-survival-rate is 30 % (95% CI: 16–47). Conclusions: GEM/LOHP/5-FU combination therapy is tolerated well in patients with gallbladder cancer. The promising survival data has to be confirmed in a phase III study. (Supported by grants from Eli Lilly and Company, Indianapolis, IN, USA and Sanofi-Synthelabo, Paris, France). [Table: see text]

4064 Background: Combinations of irinotecan (CPT11) with continuous folinic acid (FA) and 5-fluorouracil (5-FU) have shown promising activity in advanced or metastatic gastric cancer (AGC). We prospectively evaluated toxicity, efficacy and survival of CPT11/FA/5-FU (arm A) versus Etoposide/FA/5-FU (ELF; arm B) in AGC. As ELF was not inferior to FAMTX or Cisplatin/5-FU in a recent EORTC trial, ELF served as control arm. Methods: Metastatic or locally advanced adenocarcinoma of the stomach or gastroesophageal junction; performance status (PS) 0–2; no prior chemotherapy. Patients (pts) were eligible and randomized to arm A with CPT11 80 mg/m2, FA 500 mg/m2, 24h-5-FU 2000 mg/m2, d 1,8,15,22,29,36, q7w or to arm B with E 120 mg/m2, FA 300 mg/m2, 5-FU 500 mg/m2, d1–3+22–24, q6w. Results: From Nov 2000 to Apr 2003, (A/B) 56/58 pts were randomized. Median age (61/63 y), gender, distribution of tumors of gastric origin and esophageal junction, rate of surgical pretreatment (52/53%), PS, localization and numbers of metastatic sites were comparable for both arms. Median treatment duration were 14.1 (0.1–90) and 6.4 (0.3–61) weeks. All pts were eligible and evaluable for toxicity, 48/52 pts for response in A/B, respectively. Grade 3/4 toxicity per pt for A/B (%): neutropenia 7/47, neutropenic fever 7/7, diarrhoea 20/0, nausea 16/7, emesis 7/5, asthenia 2/7, 1 death occurred in A due to pt incompliance after 5 days diarrhoea, 2 deaths due to cerebrovascular events in B. Best overall response (% of pts) for A/B: CR 4/0, PR 40/17, NC 14/12, tumor control rate (CR+PR+NC) 58/29. Median progression-free time for A/B: 129 (CI95% 8–693) and 63 (0–545) days. Overall survival has not yet been reached. Conclusions: CPT11/FA/5-FU is highly effective in advanced or metastatic gastric cancer. CPT11/FA/5-FU can safely be given on an outpatient basis with proper management of adverse events. Cardiovascular deaths occurred only with ELF. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Germany