Title: Phase II study of up-front chemotherapy and neo-adjuvant shortcourse radiotherapy for resectable rectal carcinoma.~Short Title/Acronym: COLORE~Protocol Code: IRST154.01~Phase: 2~Study Design: Phase II, open-label, single-arm, multi-centre study.~STUDY PRODUCT,DOSE,ROUTE,REGIMEN AND DURATION OF ADMINISTRATION:~Neoadjuvant Treatment (pre-operative chemo-radiotherapy regimen):~FOLFOX4* 2 cycles (WK1+WK3) - Tomotherapy** (WK5) - FOLFOX4* 2 cycles (WK7+WK9)~* Oxaliplatin 85 mg/m2 iv: day 1 Levofolinate 100 mg/m2 iv: day 1-2 5-fluorouracil 400 mg/m2 iv in bolus and 600 mg/m2 iv infusion over 22h: day 1-2 Every cycle will last 2 weeks (approximately 48 hours of treatment infusion and 12 days of rest).~** 25 Gy in 5 consecutive fractions, one fraction per day in 5 days on CTV (Clinical Target Volume) at the isodose of the 95% of the total dose. The treatment plan will be elaborated at the work-station dedicated to the Helicoidal Tomotherapy. The treatment could be planned also with linear accelerator with IGRT-IMRT technique or VMAT technique.~Restaging (week 11)~Surgery (week 12-16) with Total Mesorectal Excision (TME)~End Of Treatment (week 16-32)~Adjuvant therapy (The maximum interval between surgery and start of adjuvant therapy should be 8 weeks):~FOLFOX4* 8 cycles (every 2 weeks)~Study Duration: about 5 years. Enrollment period: 36 months. Treatment period: about 8 months. Follow-up: 1 year.~OBJECTIVES~Primary objectives:~Step A: to evaluate the feasibility and safety of the chemoradiotherapy regimen.~Step B: to evaluate the proportion of patients with pathological complete remission after combined radio-chemotherapy.~Secondary objectives (of Step B):~To evaluate the safety of the neo-adjuvant treatment~To determine pathological down-staging~To evaluate the rate of R0 resection~To evaluate the sphincter saving resection rate~To evaluate median disease free survival and overall survival~To evaluate the correlation between biomarker, pathological response and outcome (auxiliary\subsidiary Biological Study)~NUMBER OF SUBJECT:~· Step A: a maximum of 6 patients. 6 evaluable patients are needed to assess toxicity. If 1 toxicity resulting in discontinuation of treatment will be observed in 6 patients, the treatment can be considered safe (with a confidence > 90%).~If 2 or more toxicity resulting in discontinuation of treatment on 6 patients, the study will be stopped because not safe and another type of radiotherapy schedule must be designed.~· Step B: a total of 50 patients is required to be recruited in 2 years (including patients enrolled in Step A).~The goal is to achieve a proportion of at least 15% of patients with a complete pathological response with the new radiochemotherapeutic treatment.~STATISTICAL METHODOLOGY:~The primary analysis will be performed on the ITT (Intention-To-Treat) population, while the secondary analysis will be conducted on the PP (Per Protocol) population.~The number and percentage of treated patients undergoing grade 1 to 4 adverse events (CTC-AE, version 4.0) will be tabulated in the ITT and PP population. No statistical inference will be performed.~Step A: Patients, tumor characteristics and toxicity events observed will be described.~Step B: The proportion of patients with pathological Complete Response will be calculated. Safety profile will be analyzed. OS (Overall Survival) and DFS (Disease Free Survival) will be estimated with Kaplan-Meier method (Kaplan El, Meier P., J Am Stat Assoc 1958).~No interim analysis will be performed. The 95% confidence intervals should also be provided.
Phase II study of up-front chemotherapy and neo-adjuvant shortcourse radiotherapy for resectable rectal carcinoma.~Study Design: Phase II, open-label, single-arm, multi-centre study.~STUDY PRODUCT,DOSE,ROUTE,REGIMEN AND DURATION OF ADMINISTRATION:~Neoadjuvant Treatment (pre-operative chemo-radiotherapy regimen):~FOLFOX4* 2 cycles (WK1+WK3) - Tomotherapy** (WK5) - FOLFOX4* 2 cycles (WK7+WK9)~* Oxaliplatin 85 mg/m2 iv: day 1 Levofolinate 100 mg/m2 iv: day 1-2 5-fluorouracil 400 mg/m2 iv in bolus and 600 mg/m2 iv infusion over 22h: day 1-2 Every cycle will last 2 weeks (approximately 48 hours of treatment infusion and 12 days of rest).~** 25 Gy in 5 consecutive fractions, one fraction per day in 5 days on CTV (Clinical Target Volume) at the isodose of the 95% of the total dose. The treatment plan will be elaborated at the work-station dedicated to the Helicoidal Tomotherapy. The treatment could be planned also with linear accelerator with IGRT-IMRT technique or VMAT technique.~Restaging (week 11)~Surgery (week 12-16) with Total Mesorectal Excision (TME)~End Of Treatment (week 16-32)~Adjuvant therapy (The maximum interval between surgery and start of adjuvant therapy should be 8 weeks):~FOLFOX4* 8 cycles (every 2 weeks)~Study Duration: about 5 years. Enrollment period: 36 months. Treatment period: about 8 months. Follow-up: 1 year.~NUMBER OF SUBJECTs:~· Step A: a maximum of 6 patients. 6 evaluable patients are needed to assess toxicity. If 1 toxicity resulting in discontinuation of treatment will be observed in 6 patients, the treatment can be considered safe (with a confidence > 90%).~If 2 or more toxicity resulting in discontinuation of treatment on 6 patients, the study will be stopped because not safe and another type of radiotherapy schedule must be designed.~· Step B: a total of 50 patients is required to be recruited in 2 years (including patients enrolled in Step A).~The goal is to achieve a proportion of at least 15% of patients with a complete pathological response with the new radiochemotherapeutic treatment.