Trial Comparing PLA to HIGRT Therapy (PROVE-HCC)

Primary liver cancer is the world's third most common cause of cancer death. In the United
States, unlike other malignancies such as breast, prostate and lung cancer, the incidence of
hepatocellular carcinoma (HCC) is increasing. The present gold standard for HCC patients who
are medically fit is HCC resection or liver transplant. Surgery is a treatment option for
just one third of patients with HCC. For the patients who are not fit for surgery either due
to underlying liver disease with associated liver dysfunction or other co-morbidity, a number
of non-operative treatments are available for treatment including percutaneous tumor ablation
(PLA) or the emerging option of external beam radiotherapy techniques, such as
hypo-fractionated image guided radiation therapy (HIGRT) -also known as stereotactic body
radiotherapy (SBRT).

Percutaneous local ablation (PLA) selectively targets the tumor with an additional
intentional margin of 0.5-1cm of non-cancerous liver tissue and induces tumor cell death,
most often via coagulative necrosis. Local application of chemical agents or
microwave/radiofrequency waves does not induce systemic effects and is typically performed
under real-time ultrasound guidance using local anesthesia and conscious sedation.

Worldwide, RFA is the most commonly used ablation technique. In the US, MWA is quickly
becoming the preferred modality of PLA. MWA induces thermal injury through the delivery of
electromagnetic energy and the application of rapidly alternating microwave frequency current
leads to coagulative necrosis of tissue. Compared with RFA, MWA appears to be more effective
for lesions in close proximity to the portal or hepatic veins; heat sink is less of an issue
given increased speed with which therapy can be delivered. Additionally, tumor sizes >3cm
sometimes can be effectively treated with MWA. A recent meta-analysis comparing RFA to MWA
for primary HCC showed they had similar efficacy, although MWA appeared to have improved
local tumor control over RFA in the treatment larger tumors.

Advances in radiotherapy simulation, treatment planning and delivery integrated together
collectively termed HIGRT or SBRT, have facilitated safe dose escalation to HCC. A number of
small, single institutional prospective studies have evaluated the use of HIGRT for treatment
of HCC. These experiences suggest that HIGRT is well tolerated and yields excellent local
control rates, however, follow up is short and thus many institutions and consensus
guidelines favor ablation for early stage HCC patients who are not surgical candidates. The
benefits of HIGRT are that it is a non-invasive, outpatient procedure typically delivered in
3-10 fractions. Although no randomized studies have compared HIGRT with other local
therapies, in retrospective analysis outcomes appear comparable , warranting further
evaluation.

Health-related quality of life (QOL) for patients with HCC is important. QOL targets are
important post-treatment metrics; previous studies have shown that both pre-treatment QOL and
post-treatment QOL have been associated with overall survival in various cancers. While both
PLA and SBRT can ablate tumors, they do have known impacts on patients' QOL. QOL has recently
been reported as a clinically important target in patients treated with HIGRT for HCC.

Patients who are potentially eligible for study enrollment will be identified by their
treating physician. Ninety patients will be randomized with equal allocation to the two arms.
. Randomization will be stratified by whether the baseline QOL score is < 60 or ≥ 60, where
QOL is measured by the QLQ-C30 scale. The primary outcome is the change in QOL from baseline
to 1 month. The investigators anticipate that approximately 10% of the accrued patients will
withdraw before 1 month, leaving 80 evaluable patients to be used in the statistical
analyses.

The general linear model will be used to test for an arm effect (in patients receiving PLA vs
HIGRT) by regressing change across time in QOL on arm, controlling for the baseline value of
QOL and the Child Pugh score. To calculate the power of the arm effect (in patients receiving
PLA vs HIGRT) on change in QOL, the investigators first note that the standard deviation of a
normally distributed change score (SDC) depends upon the SD of the pre-score, the SD of the
post-score, and the Pearson correlation (ρ) between the two scores. If the SD's of the
pre-score and the post-score are assumed equal and the correlation between them is 0.50, then
SDC = SD. For purposes of the power calculation the investigators assume that SD=10 and ρ =
0.5; therefore SDC= 10. Assuming 40 evaluable patients per arm, the two-sample t-test
(1-sided alpha = 0.10) of an arm difference in change across time in QoL has power 0.82 when
the true arm difference in change score is 5 (i.e., 50% of SDC). An arm difference of 50% of
a standard deviation of an outcome variable is generally considered to be a "medium"-sized
effect. In order to have 80 evaluable patients, 90 patients will be accrued (assuming drop
out prior to the 1 month EOTRC QOL-C30 questionnaire).

Patients will be on study therapy for approximately 6 months. The end of study participation
will be at the completion of the 6 month survey, approximately 180 days post treatment (+/-
30 days). Thereafter patients will continue to be followed by the treating physician as per
standard of care for follow up care and long-term follow up information will continue to be
collected.

Inclusion Criteria:

- Patient has signed informed consent

- At least 1 solid liver lesion with arterial enhancement and delayed wash-out on
multi-phasic computerized tomography (CT) or magnetic resonance imaging (MRI)
characteristic of hepatocellular carcinoma.

- HCC diagnosed either by histology/pathology or Liver Imaging Reporting and Data System
(LIRADs 5 per the ACR's LIRADs criteria10)

- Patient is 18 years or older

- ECOG Performance status of 0-2

- Child Pugh score A or B

- Lesions less than or equal to 5cm in size

- Less than or equal to 3 lesions in the liver

- Lesion amenable to treatment with both PLA and HIGRT; for PLA treatment this requires
the lesion be visible via ultrasound and/or non-contrast CT

Exclusion Criteria:

- Child Pugh score C

- Fluctuating ascites

- Inability to complete baseline QOL forms

- Concurrent administration of systemic therapy for HCC

- Prior liver RT must be approved by the PI

- Positive serum pregnancy test