Multicenter Phase 2 Trial: a Tailored Strategy for Locally Advanced Rectal Carcinoma

A Randomized Multicenter Phase 2 Study: a Tailored Strategy for Locally Advanced Rectal Carcinoma

The purpose of this study is to determine whether the tailored management of locally advanced rectal carcinoma can improve the oncologic and functional outcome.

Locally advanced rectal carcinoma raise the issue of both the oncological control, local and general, and the therapeutic morbidity. Surgery alone can cure only one out of two patients, radiochemotherapy improves the local control but the metastatic risk remains about 30% with enhanced postoperative morbidity and poor functional results. The tumor response to preoperative treatment is the major prognostic factor which revealed the aggressiveness of the tumor. To this day, there are no biologic predictive markers for tumor response.

The purpose of this trial is to tailor the management according to the early tumoral response after short and intensive induction trichemotherapy. MRI volumetric tumor response will be used to distinguish between good responders and bad responders.

"Very good" responders will be randomized to either immediate surgery or radiochemotherapy followed by surgery (Standard arm: Cap 50). "Good or bad" responders will be randomized between two arms: intensive radiochemotherapy (Cap 60) or the standard arm (Cap 50).

This tailored management should result in a better oncologic prognosis with a lower rate of post therapeutic functional disorders.

Inclusion Criteria:

• Histologically confirmed rectal carcinoma

• Primary tumor evaluated by pelvic MR Imaging:

  i) iT3 ≥c tumors, with MRI showing a predictive CRM ≤ 2 mm or a EMS (Extra Mural Spread) ≥ 5 mm

ii) Resectable iT4 tumors (only randomized within the "poor responders" group)

iii) Any T tumors with MRI showing a predictive CRM ≤ 1 mm

• No detectable metastases: Thorax-abdomen-pelvic CT-scan
• Patient ≥ 18 years
• ECOG Performance Status 0-1-2
• Patient information and written informed consent form signed
• Patient who can receive radiotherapy and chemotherapy
• Negative pregnancy test in women of childbearing potential
• Patient covered by a Social Security system
• Hematology : Haemoglobin ≥ 9 g/dL, WBC ≥ 4000/mm3, neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L
• Hepatic function : total bilirubin ≤ 1.5 x ULN, AST and ALT ≤ 3 x ULN, Alkaline phosphatases ≤ 3 x ULN
• Renal function : creatinine ≤ 1.25 x ULN or creatinine clearance ≥ 60 ml/min

Exclusion Criteria:

• Indication for immediate surgery
• Primary tumor not measured at the MRI before inclusion
• Previous pelvic radiotherapy
• Contraindication to radiotherapy and/or chemotherapy
• Severe renal or liver impairment
• Cardiac and/or coronary disease which could contraindicate 5-Fu administration
• Active infectious disease
• Peripheral sensitive neuropathy
• History of prior cancer (except if it was cured more than 5 years ago, and if complete remission)
• Patient (male or female) of reproductive potential not using an effective contraceptive method during the whole treatment and up to 6 months after the completion of treatment
• Concurrent participation in any other clinical trial likely to interfere with the therapeutic schedule
• Fertile female patient not using adequate contraception, or breast-feeding woman