A total of 18 articles were used in the
assessment, which included 16 articles selected from searching domestic/foreign
databases according to predetermined protocol and two articles used to at the
time of new health technology assessment.
Safety
Of six studies that compared TARE and
TACE, two articles that reported on postoperative mortality within 30 days had
no cases of mortality within 30 days. Postoperative morbidity was reported in
five articles, but two RCTs and one prospective cohort study reported no
difference in incidence of grade 3 or higher toxicity between the two groups. One
non-RCT and prospective cohort study each reported that incidence of some
adverse effects, such as nausea/vomiting, fatigue, and pain, was significantly
lower in the TARE group.
Two RCTs that compared TARE and sorafenib
did not report on postoperative mortality within 30 days and reported on only postoperative
morbidity. Among a total of 408 patients in the TARE group, grade 3 or higher
radiation hepatitis and radiation pneumonia was found in 2 (1.5%) and 1 (<
1%) cases, respectively.
One RCT that compared TARE and hepatic
artery embolization (HAE) reported on postoperative morbidity. One (20%) case
of cholecystitis that required hospitalization occurred in the HAE group, and
as a result, the TARE group had a significantly shorter hospital stay (p=0.024).
Among three RCTs that compared
combination therapy with chemotherapy and TARE and chemotherapy alone, only one
article reported on postoperative mortality within 30 days, but postoperative
mortality within 30 days did not occur in both groups. Among three RCTs, one
article reported that four (1%) cases of radiation hepatitis was found among
507 patients in the TARE group. In that article, eight and three cases of
postoperative mortality were found in the TARE combination therapy and
chemotherapy only groups, respectively.
One RCT that compared combination therapy
with sorafenib and TARE and sorafenib alone therapy reported one incidence of
grade 3 or higher toxicity as postoperative morbidity, but there were no items
that showed significant differences between the two groups.
Effectiveness
Among the studies that compared with
TACE among patients with primary liver cancer, one non-RCT reported on 1-, 2-,
and 3-year survival rates; 59%, 40%, and 31% in the TARE group and 64%, 36%,
and 11% in the TACE group, respectively. Among the five articles that reported
on overall survival (OS) period, two RCTs and one non-RCT reported no difference
in OS between the two groups, whereas significantly longer survival period was
reported in the TACE group in one prospective cohort study and in the TARE
group in another prospective cohort study. With respect to ORR, one RCT
reported on response and progression rates based on best response, where ORR
and DCR was 30.8% and 77% in the TARE group and 13.3% and 73.3% in the TACE
group, respectively. In a meta-analysis of four non-RCTs, the results showed no
differences in ORR (p=0.11) and DCR (p=1.00) between the two groups. In one
RCT, there was a significant difference in time to progression to tumor with ≥
26 months (median values was not observed during the follow-up period) in the
TARE group and 6.8 months in the TACE group (p=0.0012), while one RCT and one
non-RCT reported no significant difference between the two groups. In one RCT
on QoL, there were significant differences in the initial physical function
scores between the two groups (p=0.04), but there were no differences in the
physical function and overall scores after 12 weeks.
There were two articles that reported
on comparison between TARE and sorafenib among patients with primary liver
cancer and both articles were from RCTs. In both articles, survival rate was a
hazard ratio (95% CI, p-value) of 1.12 (0.9-1.4, p=0.36) and 1.15 (0.94-1.41,
p=0.18), showing no significant difference between TARE and sorafenib groups. When
the OS and PFS periods presented in the two articles were quantitatively
synthesized, the results showed no heterogeneity. OS was significantly shorter
in the TARE group with 1.9 months (p=0.04), whereas there was no significant
difference in PFS (p=0.98). ORR was higher in the TARE group with 16.5~19%, as
compared to 1.7~12% in the sorafenib group (I2=86%, OR 3.03, 95% CI
1.91-4.80, p<0.0001), whereas there was no differences in DCR between the
two groups (41.8~68% vs. 42.7~78%; I2=0%, OR 0.90, 95% CI 0.64-1.27,
p=0.56). One article report time to progression to tumor with HR of 0.88 (95%
CI 0.7-1.1, p=0.29), showing no statistically significant difference between
the two groups. In one article that reported on QoL, the TARE group showed
significantly better overall QoL score and the difference between the two
groups increased over time, whereby QoL in the TARE group became better.
One prospective cohort study that
compared TARE and TACE in patients with metastatic liver cancer (neuroendocrine
tumor) reported on survival period, local treatment effect, and disease
progression. The median OS period was 17.7 months in the TARE group and 25
months in the TACE group, while the median PFS period was 14 months in the TARE
group and 18 months in the TACE group. ORR and DCR were presented at different
time points (3, 6, 12, 18, and 24 months), with the TARE group showing CR of
6.7~13.3%, PR of 33.3~93.3%, ORR of 46.6~100%, and DCR of 53.3~100% and the TACE
group showing CR of 0~10.7%, PR of 39.3~100%, ORR of 64.3~100%, and DCR of
67.9~100%.
One RCT that compared with HAE in
patients with metastatic liver cancer (neuroendocrine tumor) reported on local
treatment effect. There was a significant difference in ORR at 3 months with 0%
in the TARE group and 100% in the HAE group (p=0.0022), whereas there was no
significant difference in ORR at 6 months with 33.3% in the TARE group and 80%
in the HAE group (p=0.24).
Among three RCTs that compared
combination therapy with TARE and chemotherapy and chemotherapy alone in
patients with metastatic liver cancer (colorectal cancer), two studies reported
no difference in survival rate between the two groups (n=1,103, HR 1.04, 95% CI
0.90-1.19, p=0.61; n=44, HR 0.92, 95% CI 0.47-1.78, p=0.8), whereas one study
reported that survival rate was significantly higher in the combination therapy
(including TARE) group (n=21, HR 0.33, 95% CI 0.12-0.91, p=0.025). Three
studies reported median OS period of 10~29.4 months in the combination therapy
group and 7.3~23.3 months in the chemotherapy alone group. Meanwhile, one study
reported median PFS period of 11 months in the combination therapy group and
10.3 months in the chemotherapy alone group. All three studies reported on
local treatment effect and disease progression and meta-analysis results showed
significantly higher ORR in the combination therapy group (I2=64%,
OR 1.65, 95% CI 1.28-2.12, p<0.0001) and no significant difference in DCR between
the two groups (I2=84%, OR 1.26, 95% CI 0.89-1.78, p=0.19). Two
articles reported on time to progression to tumor, indicating that time to
progression to tumor was significantly longer in the combination therapy group
with one article reporting 5.5 months in the combination therapy group and 2.1
months in the standalone therapy group (HR 0.38, 95% CI 0.20-0.72, p=0.003) and
the other article reporting 18.6 months in the combination therapy group and
3.6 months in the standalone therapy group (p<0.0005). One article reported
on QoL, in which, measurement of QoL at baseline, 2-3, 6, 12, and 24 months
showed significantly lower QoL at 2-3 months in the TARE group (p=0.038) and no
significant differences in QoL between the two groups at all other time points.
Based on currently available
literature, the TARE subcommittee is presenting the following results in regard
to safety and effectiveness of TARE in patients with primary or metastatic liver
cancer.
In the comparison between TARE and TACE
in patients with primary liver cancer, the results were similar for safety
indicators postoperative mortality within 30 days and postoperative morbidity. The
overall results were also similar for effectiveness indicators survival rate,
survival period, ORR, DCR, time to progression to tumor, and QoL, but some
articles reported that ORR and DCR were higher and time to progression to tumor
was longer in the TARE group. Although the results of comparison between TARE
and TACE in patients with primary liver cancer showed differences in some effectiveness
indicators, the subcommittee determined that there were no major differences in
the overall safety and effectiveness.
In the comparison between TARE and sorafenib
in patients with primary liver cancer, the results were similar for safety
indicator postoperative morbidity and effectiveness indicators survival rate, DCR,
time to progression to tumor, and QoL. Among patients with primary liver cancer,
ORR and QoL were higher in the TARE group, while OS period was slightly longer
in the sorafenib group. The subcommittee determined that additional evidence
with consideration of appropriate selection of patient groups and heterogeneity
among articles is needed and that survival period and QoL need to be considered
when comparing and selecting TARE and sorafenib in patients with primary liver
cancer.
In the comparison between combination
therapy with TARE and sorafenib and sorafenib alone, the results were similar
for postoperative morbidity. However, the subcommittee determined that it would
be difficult to assess safety due to insufficient number articles and the low
level of evidence in the articles that compared combination therapy with TARE
and sorafenib to sorafenib alone.
In the comparison between TARE and TACE
in patients with metastatic liver cancer from neuroendocrine tumor, the results
were similar for safety indicators postoperative mortality within 30 days and postoperative
morbidity and effectiveness indicators survival rate, response rate, and disease
progression rate. However, because these results were reported in just one
article with low level of evidence, the subcommittee determined that assessment
would be difficult due to insufficient evidence from comparison between TARE
and TACE in patients with neuroendocrine tumor metastatic liver cancer.
In the comparison between combination
therapy with TARE and sorafenib and sorafenib alone in patients with neuroendocrine
tumor metastatic liver cancer, the results were similar for postoperative morbidity
and effectiveness indicator ORR. However, because the results were from a
single article with small sample size and did not sufficiently report effectiveness
results, the subcommittee determined that safety and effectiveness assessment
would be difficult based on comparison between combination therapy with TARE
and sorafenib and sorafenib alone in patients with neuroendocrine tumor
metastatic liver cancer.
In the comparison between combination
therapy with TARE and chemotherapy and chemotherapy alone in patients with
metastatic liver cancer from colorectal cancer, the results were similar for postoperative
mortality within 30 days and postoperative morbidity. Among effectiveness
indicators, ORR was superior, but there were no significant differences in
survival period, DCR, time to progression to tumor, and QoL. Accordingly, the subcommittee
determined that there is insufficient clinical evidence to support that
combination therapy with TARE and chemotherapy has superior effectiveness than
chemotherapy alone in patients with colorectal cancer metastatic liver cancer.
Based on the conclusions above and
current assessment results, the TARE subcommittee proposed the following. In
the comparisons of TARE and other treatment modalities in patients with primary
or metastatic liver cancer, the overall safety level was acceptable, but
evidence for effectiveness is currently insufficient.
The Health Technology Reassessment
Committee reviewed and determined that the findings of the subcommittee on TARE
are valid (September 20, 2019).