The treatment strategies for HCC with PVTT is still controversial, and differ substantially
between the west and the east. According to western guidelines, including those of the EASL,
BCLC, and AASLD, PVTT is regarded as a contra-indication to initial surgery or transarterial
At present, there is still no consensus on the diagnosis and treatment standards of HCC with
HVTT/IVCTT. European and American guidelines for liver cancer use The Barcelona Clinic Liver
Cancer (BCLC) staging as the standard and classify liver cancer with HVTT/IVCTT into the
advanced stage. Molecular targeted drugs such as sorafenib and lenvatinib are recommended to
the patients in this phase as first-line treatment drugs and methods. In this regard, experts
in China and Southeast Asian countries still have different opinions. They believe that
surgery, transarterial chemoembolization (TACE), radiotherapy, and combined treatment with
multiple treatment methods can achieve more satisfactory results.
HCC with VTT consists of heterogeneous populations with different disease behaviors and
prognoses. As a result of recent concept evolution and advances in surgical techniques and
perioperative management, emerging evidence shows that selected patients with PVTT may
benefit from more aggressive treatment modalities, which are recommended for by Chinese,
Japanese, South Korean, and Asia Pacific clinical practice guidelines. A national survey from
Japan showed median overall survival with liver resection treatment to be 1.77 years longer
than with nonresection therapies, which included TACE, radiotherapy, sorafenib, or
conservative treatment (2.87 years vs 1.10 years, respectively; p<0.001). After
propensity-score matching of patient baseline characteristics, median overall survival since
diagnosis in the liver resection group was 0.88 years longer than in the non-resection group.
In a large-scale, multicentre, propensity-score matched analysis from China, surgery was the
best treatment for patients with Cheng's type I and II PVTT with Child-Pugh A and selected B
liver function. Median overall survival after liver resection (745 of 1580 patients) was 15.9
months (95% CI 13.3-18.5 months) for Cheng's type I PVTT and 12.5 months (10.7-14.3 months)
for Cheng's type II PVTT. Thus, aggressive surgical resection in selected patients with HCC
with vascular invasion, as proposed by several tertiary health-care centers in the east,
seems to be reasonable.
Currently, there are no dedicated clinical trials to study the value of hepatic resection in
this population. Furthermore, cumulative evidence indicates that long-term overall survival
after hepatic resection alone remains unsatisfactory because of the high rate of tumor
recurrence and correspondingly low rate of disease-free survival. The combination of
perioperative therapies may be more efficacious to improve the prognosis in selected
population. More high-level evidence of novel multimodality treatment should be generated.
This trial will enroll HCC patients with PVTT CNLC Stage IIIa, who have no prior anti-cancer
treatment. Given the poor prognosis and limited treatment options for these patients, this
population is considered appropriate for trials of more aggressive and novel therapeutic
candidates in the initial treatment setting. The benefit risk profile for hepatic resection
combined with perioperative atezo/bev in this patient population is expected to be favorable.
This is a multicenter, open-label, two-arm, randomized study designed to evaluate the
efficacy and safety of surgical resection plus peri-operative atezo/bev compared with
continuous systemic atezo/bev in HCC patients with VTT and without EHS.
Initially eligible patients will be enrolled into induction phase, during which they will
receive 3 cycles of atezo/bev and 1 cycle of atezo alone as primary systemic therapy. Tumor
response assessment using computed tomography (CT) and/or magnetic resonance imaging (MRI)
will be conducted by the Independent-Review Facility (IRF) according to RECIST v1.1 after
cycle 2 and cycle 4.
Only those patients who are assessed as partial response (PR) or stable disease (SD) and
considered suitable for curative hepatic resection will be randomized in a 1:1 ratio to one
of the following two arms:
Arm A (experimental arm): hepatic resection with post-operative atezolizumab 1200mg and
bevacizumab 15mg/kg, both administered by IV infusion on Day 1 of each 21-day cycle
Arm B (control arm): atezolizumab 1200mg and bevacizumab 15mg/kg, both administered by
IV infusion on Day 1 of each 21-day cycle
Randomization will be performed after the second tumor assessment and stratified according to
the following stratification factors:
Tumor response: target lesion reduction (maximum diameter reduction ≥10% compared with
the entry baseline) vs non-reduction
Eastern Cooperative Oncology Group (ECOG) performance status: 0 vs 1 Those patients who
are assessed as disease progression (PD) or complete response (CR) and/or not suitable
for curative hepatic resection will be excluded from randomization and treated according
to local practice (Patients without PD may continue atezo/bev treatment at
In Arm A, hepatic resection surgery will be performed 0-2 weeks after the randomization.
Surgical approaches will be tailored to the individual patient according to local standards
with the goal of achieving R0 resection. The first administration of postoperative atezo/bev
treatment is recommended to start within 4-6 weeks after surgery, requiring full recovery
from the surgery prior to post-operative atezo/bev treatment, including:
Adverse events emerged from prior treatment, if any, should have been recovered to meet
the requirements of atezo/bev treatment according to investigator's judgement.
No significant medical events (e.g., gastrointestinal [GI] bleeding, cardiac events,
hepatorenal syndrome, biliary fistula, serious infection, etc.) during or after the
surgery procedure Treatment with atezo/bev will continue until loss of clinical benefit
(determined by the investigator), or unacceptable toxicity, withdrawal of ICF, death, or
the study is terminated by the Sponsor, whichever occurs first. For Arm A, whether to
continue atezo/bev treatment will be determined by the investigator at the end of the
12-month treatment period if none of the above occurs.
Tumor assessments will be performed in induction phase after cycle 2 and cycle 4
(randomization baseline), and in treatment period at regular intervals (Arm A will receive
tumor assessment at the first dose of postoperative treatment (±3 days）and every 9 weeks (±7
days）thereafter. Arm B every 9 weeks (±7 days）thereafter ). Additional scans will be
performed as clinically indicated. Following completion or discontinuation of the treatment,
information on recurrence or disease progression, survival and subsequent anti-cancer
therapies will be collected until death, loss to follow-up, withdrawal of ICF or study
termination by Sponsor, whichever occurs first. In the absence of disease recurrence or
progression, tumor assessments should continue regardless of whether patients start a new
anti-cancer therapy, until documented treatment failure events, withdrawal of ICF or study
termination. All patients will be followed for survival unless consent is withdrawn.
Patients who withdraw from the study will not be replaced. An IRF will be used to enable
centralized, independent reviews of images and other clinical data (e.g., histopathology,
tumor markers etc.) used for assessment of HCC response, recurrence and disease progression.
IRF reviews will be performed prior to the pre-specified efficacy analyses. IRF membership
and procedures will be detailed in an IRF Charter.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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