Prospective study in patients with colon or rectum cancer with liver metastasis of the efficacy and toxicity of standard therapy (chemotherapy + targeted therapy) combined with immunotherapy and internal radiotherapy targeting the liver

Prior treatment

• Severe chronic liver failure, which in the investigator's opinion would not allow SIRT to be received safely
• K+ < LLN, Mg²+ < LLN, Ca²+ < LLNAllergy to contrast agents that do not allow radioembolization to be performed
  • Uncontrolled hypertension (blood pressure > 140 mm Hg and/or diastolic blood pressure > 90 mm Hg)
  • Clinically significant cardiovascular disease, for example cerebrovascular accidents ≤ 6 months prior to the start of study treatment, myocardial infarction ≤ 6 months prior to the start of study treatment, unstable angina, congestive heart failure of NYHA (New York Heart Association Functional Classification) grade 2 or higher, or severe cardiac arrhythmia not controlled by drug therapy or which may interfere with study treatment
  • Significant vascular disease (e.g. aortic aneurysm requiring surgery or arterial thrombosis) within 6 months prior to initiation of study treatment
  • Venous thromboembolic disease within 3 months prior to initiation of study treatment
  • History of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to start of study treatment
  • Unhealing decaying wound, active ulcer, or untreated bone fracture
• Other malignancy in the 5 years prior to inclusion in the study, except for localized cancer in situ, basal or squamous cell skin cancer
• Confirmed peritoneal carcinomatosis (lesions detectable on CT-scan and/or MRI)
  • Active autoimmune disease or inflammatory bowel disease
  • Bone marrow allograft or solid organ transplant history
  • History of idiopathic pulmonary fibrosis, drug-induced pneumonitis or evidence of active pneumonitis on screening chest CT-scan and any severe chronic respiratory insufficiency that the investigator believes would not allow the SIRT to be received safely
  • Positive tests for HIV or other immunodeficiency syndromes

Other illness

• active infection still requiring intravenous antibiotics on the first scheduled day of protocol treatment

Lab values

• Active hepatitis B or hepatitis C. 1 - If patient has HBV, meets the following criteria as applicable to the infection type to be eligible: for patients with inactive/asymptomatic carrier, chronic, or active HBV: HBV DNA < 500 IU/mL (or 2500 copies/mL) at screening. Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at Screening should have been treated for > 2 weeks prior to enrollment and should continue treatment on study. 2 - For patients with HCV : to be eligible, patients with detectable HCV RNA should remain on continuous, effective antiviral therapy during the study
  • Active tuberculosis
  • Patient with contraindication to angiography and selective hepatic catheterization such as bleeding diathesis or coagulopathy with serious bleeding risk that is not correctable by usual therapy of hemostatic agents.
  • Patients on anticoagulant therapy different from low-molecular-weight heparin (LMWH) cannot be included (i.e. VKA and NOACs). Relaying these anticoagulants to a LMWH before inclusion is allowed. In addition, it must be possible to stop the LMWH 24 hours before invasive procedures according to the usual recommendations (before the work-up and before the SIRT).
  • Significant presence of ascites, cirrhosis, portal hypertension, main portal venous tumor involvement or thrombosis on clinical or radiological evaluation Previous radiotherapy in the upper abdominal region (liver or liver vessels in the radiation field)
  • If primary tumor is non-resected, it must be asymptomatic
  • Long-term immunosuppressant therapy (patients requiring corticosteroid therapy are eligible if they receive a dose equivalent to no more than 10 mg of prednisone equivalent dose per day, and corticosteroid administration is permitted by a route resulting in minimal systemic exposure (cutaneous, rectal, articular, ocular or inhalation) is authorized)
  • Patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with an immune-stimulatory anticancer agents
  • Patient with previous Johnson Stevens Syndrome (SJS) or Toxic Epidermal Necrosis (TEN)
  • Symptomatic or untreated central nervous system metastasis
  • Partial or complete DPD deficiency
  • Known hypersensitivity to any components of bevacizumab, Chinese Hamster Ovary cell products or other recombinant human or humanized antibodies and any other contraindications to the use of investigational medicinal products, in particular patients with peripheral sensory neuropathy with functional impairment (see SmPC of oxaliplatin) or in the case of recent or concomitant treatment with brivudine (see SmPC of capecitabine)
  • QT/QTc interval > 450 msec for male and > 470 msec for female at EKC

Age

• Medical history of other concomitant or previous malignant disease, except adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, or cancer in complete remission for ≥ 5 years
  • Proteinuria ≥ 2+ by urine dipstick unless a 24-hour urine protein < 1 g of protein is demonstrated
  • Lack of effective contraception in patients (male and/or female) at risk of reproduction, pregnant or breastfeeding women and women at risk of reproduction who have not had a pregnancy test. (Women of childbearing potential should agree to use a method of contraception during treatment of the trial and at least 4 months after discontinuation of oxaliplatin, 5 months after discontinuation of atezolizumab, and 6 months after discontinuation of bevacizumab. Men must agree to use a method of contraception during treatment and at least 6 months after discontinuation of oxaliplatin).
  • Persons deprived of freedom or under guardianship
  • Inability to undergo medical follow-up of the study for geographical, social or psychological reasons

• age over 18 years old
• adequate hematological function
• adequate hepatic function
• adequate renal function
• patient affiliated to a social security system information provided to patient and signature of the informed consent form by patient and the investigator
• histologically proven mismatch repair proficient metastatic colorectal cancer (pMMR and/ or MSS)
• liver-dominant disease with up to 6 extrahepatic lesions (only peritoneal lesions are not allowed) if asymptomatic and without organ dysfunction
• measurable disease according to RECIST 1.1
• patient with initially unresectable disease according to the local multidisciplinary team and eligible for radioembolization according to the radiologist's opinion
• tumor volume < 50% of total liver volume
• no prior oncologic treatment for metastatic disease. patients may have received adjuvant chemotherapy or (neo) adjuvant radiochemaotherapy to the pelvis but the last dose of chemotherapy / radiotherapy must be administred at least 6 months prior to entry into this study. analgesic radiotherapy of metastasis is permitted except on hepatic lesions and must be completed at least 14 days before inclusion
• WHO performance status
• estimated life expectancy >ou= 3