Preoperative Combined RadioChemo-Molecular Target Therapy With Capecitabine, Bevacizumab, and Radiotherapy

Preoperative Combined RadioChemo-MolecularTargetTherapy of the Locally Advanced Rectum Carcinoma (cT3NxM0) - a Phase II Pilot Study With Preoperative Application of Capecitabine, Bevacizumab and Radiotherapy (RTx)

• feasibility and tolerance of preoperative therapy with Bevacizumab in combination with Capecitabine and radiotherapy for patients with locally advanced, locally operable rectal carcinoma
• collection of response rate (T- and M-downstaging, pathological complete remission)

Combined RadioChemotherapy:

Therapy start: within 28 days after bioptical diagnosis

Radiotherapy: 5 x 5 days 1.8 Gy radiotherapy; cummulative dose 45 Gy

Chemotherapy: Capecitabin 825mg/m² bid, on each radiation day during the first 4 weeks RCTx

Molecular Targeted Therapy: Bevacizumab 5 mg/kg body weight; day 1, 15, 29 Operation due to TME adherence to a break of min. 42 to max. 56 days after the last application of bevacizumab

Inclusion Criteria:

• age: 18 - 80
• bioptical confirmed adenocarcinoma of the rectum in T3NxM0 status. The tumor has to be basically surgically complete resectable (->R0).
• no former chemotherapy, radiotherapy of pelvis or abdomen and/or tumor resection of rectum carcinoma
• WHO performance status 0-2
• adequate bone marrow reserve (granulocytes >= 3.000/µl, absolute neutrophil >= 0 1,5 x 10 9/l thrombocytes: >= 100.000/µl, haemoglobin >= 10g/dl)
• adequate hepatic function (Bilirubin: <= 1.5 x ULN, GOT und GPT <= 2.5 x ULN)
• adequate renal function (creatinin: <= 1.25 mg/dl, creatinin-clearance: > 50 ml/min (Cockcroft and Gault formula)), proteinuria: dipstick < 2+. In case of dipstick > 2+ protein has to be measured in 24h urine and does not exceed more than 1g/24h)
• ability of intake of pills
• women of childbearing potential: exclusion of pregnancy (negative urin or serum pregnancy test)
• willingness of women of childbearing potential and accordingly of potent men to use approved contraceptives (e.g. birth-control pill, loop, condom) during and at least 3 month after conclusion of the study
• life expectancy of at least 3 month
• INR and aPTT < 1.5 ULN
• signed Informed Consent before recruitment

Exclusion Criteria:

• failure of one inclusion criteria
• former radiotherapy of pelvis or abdomen
• former chemotherapy
• any other kind of malign tumor in the last 5 years
• any other kind of tumour in the last 5 years with exception of basal cell carcinoma of skin and cervix carcinoma in situ
• general contraindication or known hypersensitivity against Bevacizumab and/or Capecitabine
• non malign disease, if there is a contraindication with radiotherapy, or chemotherapy with Bevacizumab and Capecitabine, or a resection of rectum: uncontrolled hypertension (systolic > 150 mmHG and/or diastolic >100 mmHG) or clinical significant (e.g. active) cardiovascular disease: CVA (cardiovascular accident)/ cerebral apoplexy (< 6 months before recruitment), myocardial infarct (< 6 months before recruitment), instable angina pectoris, CHF with NYHA status II or higher, or treated serious arrhythmia, hepatic disease, significant neurologic or psychiatric disorders
• florid, serious infections at the time of recruitment
• peripheral neuropathy (NCI CTC >= Grade 1)
• legally limited contractual capability or evidence of neurological or psychiatric disease, if it will constrict the patients compliance in the opinion of the investigator
• evidence of lacking cooperation of the patient
• major intervention within 28 days before recruitment, open wounds
• serious injuries, unhealed wounds or fractures
• patients with spinal compressions or metastases in central nervous system
• evidence of bleeding diathesis or coagulation dysfunction
• actual intake of anticoagulant or thrombolytic agents, Aspirin > 325 mg/d or within 10 days before study start)
• actual or recent (within 10 days before recruitment) therapeutic therapy with fully-dosed anticoagulants. A prophylactic treatment is permitted.
• previous thromboembolic or hemorrhagic events within the last 6 months before recruitment
• previous abdominal fistulas, GI perforation or intra-abdominal abscess within the last 6 months
• treatment with other study medication within 28 days before recruitment
• patients with malabsorption syndrome or difficulties swallowing
• pregnant or breast feeding women