Following the concept that the actual survival of pancreatic cancer patients can only be significantly improved by sequential poly-chemotherapy (EOSPC) in order to add one or two further progression free-survival times (PFST), in addition to the potential antitumoral effects of a first- or second-line therapy we studied the therapeutic efficacy of a third- or fourth-line chemotherapy with irinotecan alone, or in combination with oxaliplatin and high dose 5-FU/FA respectively, in a pilot study in 17 patients. Follow-up was performed on the basis of clinical investigations, imaging methods and the course of tumor markers, mainly CT and CA 19-9. The overall response rate in these cases of third/fourth-line therapies was 1 PR, 4 MR, 6 SD in the imaging methods compared to 5 PR, 2 MR and 5 SD on the basis of the tumor marker courses in the serum. The median PFST amounted to 4 months. Side effects could be seen as reported in the literature. Only in 1 patient did treatment have to be stopped due to irinotecan-induced gastrointestinal symptoms. Our data might suggest that combinations are more effective than irinotecan alone. However, further studies have to demonstrate whether irinotecan alone or in combination with e.g. oxaliplatin and 5-FU/FA will be more effective. The results suggested that irinotecan alone or in combination might also be used as third- and fourth-line therapeutical trials in exocrine pancreatic cancer in order to improve the survival time of these patients based on efficacy orientated sequential poly-chemotherapy (EOSPC).