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.