Adjuvant chemotherapy strategies

Older adjuvant cytotoxic regimes such as the triplet of doxorubicin, mitomycin and 5-fluorouracil (AMF) for six cycles to treat pancreatic and papillary cancers showed no overall survival advantage beyond two years, although there was a 1 and 2 year relapse-free survival advantage favouring chemotherapy over surgery alone.!7!

In addition to the survival advantage shown ESPAC-1, the Charité Onkologie (C0NK0-001) study!8] published in 2007 demonstrated a survival benefit with adjuvant gemcitabine over surgery alone. Patients with R0 or R1 resections were assigned to observation alone or gemcitabine delivered at 1000mg/ m2/ week (days 1, 8 and 15 of a 28 day cycle) for a total of six cycles. There was a trend toward an improved median overall survival (22.8 vs. 20.2 months p=0.06) as well as a statistically significant improvement in disease-free survival (13.4 vs. 6.9 months p <0.001) over surgery alone. Importantly the rate of 5-year survival was significantly better in those patients receiving adjuvant gemcitabine over observation alone (21% vs. 9%).

In the largest adjuvant pancreatic trial to date, ESPAC-3I9"10] involved 1088 patients with R0-or R1 resected pancreatic adenocarcinoma, randomising patients into either observation alone, 5-FU/LV, or gemcitabine. Notably the 5-FU was delivered as five bolus doses (425mg/m2 with leucovorin 20mg/ m2 days 1-5 of a 28 day cycle) rather than as an infusion. 551 patients received 5-FU and 537 received gemcitabine with treatment for a total of six months. The observational arm was discontinued after the outcome of the C0NK0-001 trial was made available. At a median follow up of 34.2 months after 753 deaths, there was no advantage seen between the intervention arms (23.0 vs. 23.6 months p=0.39). 12 and 24 month survival was 78.5% and 48.1% respectively in those who received 5-FU with 80.1%

and 49.1% respectively in the gemcitabine arm. The side effect profile however favoured gemcitabine in terms of grade 3-4 toxicity and hospitalisation. Grade 3 and 4 mucositis was seen in 10% of patients who received 5-FU (compared with no patients on gemcitabine). Grade 3-4 diarrhoea was also significantly higher in the 5-FU group. The gemcitabine treated group did however experience higher rates of grade 3 and 4 thrombocytopenia, although the absolute risk of this remained small (1.5 vs. 0%) (p=0.003). Quality-of-life was also comparable.

Thus, survival outcomes were not significantly improved by gemcitabine over 5-FU group in ESPAC-3. This outcome differs to that seen in the advanced setting.[13] One reason could be that the 5-FU intensity was greater in ESPAC-3 than that seen in the Burris et al. trial.

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