Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patientswith colorectal cancer and increased preoperative risk (ASA 3 and 4) - Protocol of a controlled clinical trial developed by consensus of an international study group - Part one: rationale and hypothesis

General design. Presentation of a novel study protocol to evalue the effect iveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoper ative infectious complications and sub-optimal recovery from operation in p atients with colorectal cancer and increased preoperative risk (ASA 3 and 4 ). The rationale and hypothesis are presented in this part of the protocol of the randomised, placebo controlled, double-blinded, single-centre study performed at an - university hospital (n = 40 patients for each group). Objective: Part one of this protocol describes the concepts of three major sections of the study: - Definition of optimum and sub-optimal recovery aft er operation. Recovery, as an outcome, is not a simple univariate endpoint, but a complex construction of mechanistic variables (i.e, death, complicat ions and health status assessed by the surgeon), quality of life expressed by the patient, and finally a weighted outcome judgement by both the patien t and the surgeon (true end-point). Its conventional early assessment withi n 14-28 days is artificial: longer periods (such as 6 months) are needed fo r the patient to state: "I am now as well as I was before". Identification of suitable target patients: - the use of biological response modifiers (im mune modulators) in addition to traditional prophylaxes (i. e. antibiotics, heparin, volume substitutes) may improve postoperative outcome in appropri ate selected patients with reduced host defence and increased immunological stress response, but these have to be defined. Patients classified as ASA 3 and 4 (American Society for Anaesthesiologists) and with colorectal cance r will be studied to prove this hypothesis. Choice of biological response m odifier: - Filgrastim has been chosen as an example of a biological respons e modifier because it was effective in a new study type, clinic-modelling r andomised trials in rodents, and has shown promise in some clinical trials for indications other than preoperative prophylaxis. It has also enhanced h ost defence and has been anti-inflammatory in basic research. Conclusion: The following hypothesis will be tested in patients with operat ions for colorectal cancer and increased preoperative risk (ASA 3 and 4): i s the outcome as evaluated by the hermeneutic endpoint (quality of life exp ressed by the patient) and mechanistic endpoints (mortality rate, complicat ion rate, relative hospital stay, assessed by the doctor) improved in the g roup receiving filgrastim prophylaxis in comparison with the placebo group? Quality of life will be the first primary endpoint in the hierarchical, st atistical testing of confirmatory analysis.