Discussion
We experienced a case of pathologically proven unresectable CHC treated
with Atez/Bev treatment after hepatic resection. Given the rarity and
heterogeneity of CHC, there is no established standard systemic
chemotherapy for unresectable CHC patients. We administered adjuvant
chemotherapy with TS-1, but CT showed multiple lymph node metastases at
13 months after surgical treatment. We first administered GEM/CDDP,
which is an established treatment for biliary tract malignant tumors,
but we did not continue this therapy due to the development of a severe
rash. Because no effective biliary tract regimen was available, we chose
lenvatinib treatment, which has demonstrated the efficacy and safety for
unresectable HCC and was recommended as the first-line treatment at that
time. Four months after the initiation of lenvatinib treatment, we
discontinued lenvatinib therapy due to grade 3 decreased appetite.
Because Atez/Bev became available in Japan after we had ceased
lenvatinib treatment, we started Atez/Bev treatment and achieved a
7.5-month PFS despite temporary bevacizumab interruption without severe
adverse events. To our knowledge, this is the first report of the
administration of Atez/Bev to CHC patients.
According to a previous study evaluating 68 CHC patients receiving
systemic therapies in a single institution 10, a
gemcitabine plus platinum-based regimen achieved an 8.0-month PFS and
11.5-month overall survival (OS), while gemcitabine plus fluorouracil
and sorafenib regimens achieved a 6.6- and 4.8-month PFS and 11.7- and
9.6-month OS, respectively. A multicenter retrospective analysis
reported from Japan showed that the median OS in patients receiving
fluorouracil plus cisplatin, GEM/CDDP, and sorafenib were 11.9, 10.2,
and 3.5 months, respectively 11. Sorafenib monotherapy
was shown to be an unfavorable factor influencing the OS in a
multivariate analysis 11. Another multicenter
retrospective study conducted in French hospitals showed that the median
PFS and OS were 9.0 and 16.2 months, respectively, in patients treated
with gemcitabine plus platinum-based chemotherapy 12.
In the present case, Atez/Bev resulted in a 7.5-month PFS, which was
comparable to the therapeutic efficacy of the gemcitabine plus
platinum-based regimen. Therefore, Atez/Bev might be a viable treatment
option for patients with unresectable CHC.
According to a randomized controlled trial (Imbrave150), Atez/Bev
treatment resulted in a 6.8-month median PFS in advanced HCC patients13. In real-world settings, the median PFS ranged from
5.0 to 6.5 months 14-16. Although both the HCC and
cholangiocarcinoma regions were negative for PD-L1 based on
immunohistochemical staining, the median PFS in the present case was
similar to that in Imbrave150 and these previous studies. Further
analysis will be conducted to investigate the importance of the PD-L1
expression in CHC patients. Another point of note is that we did not
administer bevacizumab from three to five cycles and in eight and nine
cycles due to bevacizumab-related adverse events. Bevacizumab enhanced
the efficacy of atezolizumab by supporting the maturation of dendritic
cells, infiltration of T cells into tumors, and recognition of cancer
cells 17. In addition, bevacizumab monotherapy has
shown therapeutic efficacy for HCC in clinical settings18,19. Recently, we reported that early bevacizumab
interruption was associated with a poor PFS and OS in patients receiving
Atez/Bev 20. Accordingly, Atez/Bev may show good
therapeutic efficacy for patients with CHC. A further study with a
larger number of cases is warranted to confirm these points.
CHC is a rare form of primary liver cancer, and the reported percentage
of CHC in primary liver cancer varies widely, from a rate of 1.0%
according to a nationwide survey reported by Kudo et al.21, to a rate of 3.6% reported by Jarnagin et al.22, to a high of 14.2% in the case series study
reported by Allen and Lisa 23. CHC is more common in
men 4 and individuals with cirrhosis or chronic liver
disease, notably hepatitis B infection or significant alcoholic
consumption 8,24, than in others. These clinical
features are similar to those of HCC and were compatible with the
present case in terms of chronic liver disease due to significant
alcohol consumption.
When CHC is diagnosed early and the tumor extent is locally limited,
surgical treatment may provide a long-term survival. A population-based
study showed that the median survival in patients undergoing surgical
treatment was 28 months, and prognostic factors were localized disease,
tumor size <5 cm diameter, and surgical treatment4. A single-institution study reported that the PFS
and OS in patients initially receiving surgical treatment was 10.4 and
25.7 months, respectively, whereas those in patients treated with
hepatic directed therapy and systemic therapy were 8.3 and 16.0 months
and 5.0 and 5.6 months, respectively 5. Another two
reports conducted the single-institution analysis of CHC patients
receiving surgical treatment, indicating that the 5-year OS rates were
improved beyond 30%, although the 1-year disease-free survival ranged
from 40% to 50% 7,8. In the present case, 13 months
have passed until the recurrence was observed after the initial surgical
treatment, and the patient was still alive at 28 months after initial
surgical treatment, which was presumed to be consistent with previous
studies. Another point of note is that the tumor recurrence rate after
surgical treatment was reported to be high. In the present case, we
prescribed TS-1 to prevent tumor recurrence after surgical treatment,
but multiple lymph metastases were observed. Further studies to explore
effective adjuvant chemotherapy should be conducted.
Several limitations associated with the present study warrant mention.
First, this was a single case report; a large number of CHC patients
will be needed to confirm the efficacy and safety of Atez/Bev treatment.
Second, while Atez/Bev has demonstrated efficacy and safety for HCC
patients, the efficacy of immune checkpoint inhibitors for biliary tract
malignant tumors remains uncertain. We were unable to determine which of
the two components (HCC or cholangiocarcinoma) was dominant based on the
changes in tumor markers due to the lack of elevation of any tumor
markers during the clinical course. Because recurrent lesions may not
always have the same component as primary hepatic resected lesions, a
pathological examination of the enlarged lymph nodes might be useful.
One reason why we did not perform a needle biopsy is that the amount of
obtained specimen was insufficient to evaluate the pathological
features, including which of the two components was dominant. In
addition, Atez/Bev is one of the most powerful HCC regimens and is
recommended as the new-first line treatment. Accordingly, treatment
options may not markedly differ depending on the findings of the
pathological examination at the metastasis site.
In conclusion, Atez/Bev exhibits
therapeutic efficacy for CHC patients. Further investigations with a
large number of cases are warranted to investigate the efficacy and
safety of Atez/Bev for unresectable CHC.