A multicentre, parallel group, randomized controlled Phase II clinical trial evaluating neoadjuvant Atezolizumab/Bevacizumab versus neoadjuvant SBRT in patients with biopsy proven solitary HCC with PVTT involving the portal vein branches. Both arms are considered experimental, and as such, a Simon two-stage design will be initially used within both arms. Only if both arms are deemed of interest for further study will a comparison between arms, using a pick-the-winner design, be conducted. Following the completion of neoadjuvant therapy, study participants will undergo a CT scan or MRI to assess tumour response to neoadjuvant therapy. Hepatic resection will be performed for those participants who meet the surgical resection criteria.
Surgical resection without adjuvant therapy is the standard of care for most patients with solitary hepatocellular carcinoma (HCC). The presence of portal vein tumour thrombus (PVTT) is associated with a poor prognosis, and as a result patients usually do not undergo surgery.1 One potential strategy to improve the outcome of patients with HCC and PVTT is to administer treatment to the tumour prior to surgery, i.e. "neoadjuvant" therapy. This strategy has been proven to be effective in other types of cancer, and results in tumour downstaging and potentially eliminates micro-metastatic disease In a recent randomized controlled trial (RCT) in patients with HCC and PVTT, the addition of radiation therapy (RT) to the tumour prior to hepatic surgery was compared with surgery alone.4 There was a statistically significant improvement in survival with RT. Systemic therapy with the tyrosine kinase inhibitor Sorafenib improved survival compared to placebo in patients with advanced HCC and PVTT.5 Another recent trial in patients with advanced HCC demonstrated improved survival with the combination of Atezolizumab, an immune checkpoint inhibitor (ICI), and Bevacizumab, an antibody to vascular endothelial growth factor compared to Sorafenib alone.6 Currently, there is no standard of care for the neoadjuvant treatment of solitary HCC. Radiotherapy has not been widely adopted despite recent evidence suggesting some benefit. It is conceivable that RT will downsize the tumour increasing the surgical resection rate and reducing the shedding of tumour cells. Stereotactic Body Radiation Therapy (SBRT) is a type of RT that provides high dose, focal radiation to tumours using highly precise imaging and treatment fields, with rapid dose fall-off thereby sparing normal tissue. Based on experience in other cancers, it would seem judicious that effective systemic therapy be considered for the neoadjuvant treatment of HCC to downsize the primary tumour and eradicate occult micro-metastases.2,3 We hypothesize that treating patients with HCC and PVTT with either 1) neoadjuvant systemic therapy, or 2) neoadjuvant SBRT may lead to improved hepatic resection rates. Complete hepatic resection is being considered as a surrogate for good long-term outcomes. The aim of our randomized Phase II trial is to select the treatment arm with the most favourable outcomes based on a trade-off between resection rate and toxicity for study in a future trial.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1
Neoadjuvant atezolizumab/bevacizumab or neoadjuvant SBRT prior to hepatectomy
Tom Baker Cancer Centre
Calgary, Alberta, Canada
Cross Cancer Institute
Edmonton, Alberta, Canada
Juravinski Cancer Centre
Hamilton, Ontario, Canada
Ottawa Regional Cancer Centre
Ottawa, Ontario, Canada
Princess Margaret Cancer Centre
Toronto, Ontario, Canada
8. Centre the recherche du Centre hospitalier de l'Université de Montréal - CHUM
Montreal, Quebec, Canada
McGill Cedars Cancer Centre
Montreal, Quebec, Canada
Hepatectomy
Proportion of patients who undergo hepatectomy in each arm (number of patients who undergo hepatectomy divided by the number of patients randomized to each arm).
Time frame: 17 Weeks
Response rate
Radiological and pathological response rate to neoadjuvant therapy.
Time frame: 2 years
Toxicity to SBRT
Toxicity rate related to neoadjuvant SBRT.
Time frame: 2 years
Postoperative complications
Postoperative complication rate and mortality
Time frame: 90 days post operatively
Survival Progression Free
Progression free survival (PFS).
Time frame: 2 years
Survival
Overall survival (OS).
Time frame: 2 years
Toxicity to Atezolizumab/Bevacizumab
Toxicity to Atezolizumab/Bevacizumab in the neoadjuvant setting
Time frame: 2 years
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