Cholangiocarcinoma is classified into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma. The incidence of ICC in the US increased from 0.49 per 100,000 in 1995 to 1.49 per 100,000 in 2014, with an average annual increase rate of 5.49% [1]. In contrast, the incidence of ICC in China was reported to be approximately 6 per 100,000 [2, 3] and the mortality rate was about 1.86 per 100,000 [4]. Surgery is regarded as the only primary curative treatment for ICC. Nevertheless, more than two-thirds of patients are inappropriate for surgery at diagnosis, and more than 60% of patients relapse after surgery [5]. Therefore, the prognosis of advanced ICC is poor, and the five-year survival following resection ranges from 14 to 40% [6]. Surgery is not recommended for unresectable or metastatic ICC, while palliative therapy, such as transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), radiotherapy and chemotherapy are recommended. Gemcitabine+cisplatin (GC) and Gemcitabine+SI (GS) are widely used as the standard chemotherapy for unresectable or metastatic ICC. Meanwhile, GC and GS plans are also standard therapies for post-surgical ICC patients [7, 8]. Several prognostic factors, including curative resection (R0), the number of tumors (single or multiple), and the presence of vascular invasion and lymph node metastases are suggested as the most important independent predictors of survival [9].

Current therapeutic options for advanced or recurrent ICC are limited. Conventional chemotherapy, radiotherapy (RT) or radiochemotherapy do not show satisfactory responses [10–12]. In recent years, immunotherapy targeting PD-1/PD-L1 has achieved encouraging therapeutic effects in diverse cancers, and NCCN guidelines recommend pembrolizumab as a choice for advanced cholangiocarcinoma with dMMR or MSI-H [13–16]. Immunotherapy combined with targeted therapy or chemotherapy in ICC treatment has recently been investigated and exhibited promising therapeutic perspectives, although more evidence is still needed to confirm the efficacy [16–19]. Immunotherapy combined with radiotherapy, on the other hand, might be a potential alternative therapy for ICC [20–22]. However, no studies have been performed to investigate the therapeutic effectiveness of the combination in ICC, although it has shown promising therapeutic responses in melanoma, non-small cell lung cancer (NSCLC), neuroendocrine cervical carcinoma and refractory Hodgkin’s lymphoma [23–30]. It appears from these reports that radiotherapy administered before, after or concurrently with immunotherapy, all exhibited promising therapeutic response. The rationale behind the combined effect of radiotherapy with immunotherapy has been investigated. It was suggested that the effects of radiation in sensitizing the immunotherapy may result from the modification of the tumor microenvironment that can interfere with tumor resistance to immunotherapy. Ionizing radiation may enable the generation of a tumor-specific immune response. This includes a series biological process, including angiogenesis, vasculogenesis and fibroblasts, etc., mediated by a variety of inflammatory cells [31].

In the present report, we performed the first study investigating the responses of late-stage or recurrent ICC to the combined therapy of PD-1 blockade with SBRT in patients with low TMB, MSS, pMMR and negative PD-L1 expression. We found that the combination achieved satisfactory responses in ICC patients, which may expand its applications to patients who were previously regarded as not suitable for immunotherapy.

Advanced ICCs have a poor prognosis due to the low resection rate and high relapse rate. It is imperative to explore new effective treatment strategy of ICC. The newly updated NCCN guidelines recommended PD-1 blockade for ICC patients with dMMR or MSI-H. The recommendation was based on a series studies showing that cholangiocarcinoma patients can benefit from immunotherapy. One initial study including 4 patients with cholangiocarcinoma showed the efficacy of PD-1 blockade for dMMR cancers, in which one patient showed CR and others had stable disease, resulting in a disease control rate (DCR) of 100% [16]. Another study investigated the efficacy of nivolumab in 29 patients with advanced refractory biliary tract cancers. The DCR reached 55% as 5 patients achieved PR and 11 had stable disease (SD) [17]. The median PFS was 3.5 months (95% CI: 2.1–7.6) and the median OS had not been reached, and the 6-month OS was 76.3% for all 34 patients with median follow-up of 8 months [17]. The combination of immunotherapy (pembrolizumab) with targeted therapy (ramucirumab) was shown to be effective for advanced cholangiocarcinoma, and patients with PD-L1 positive expression exhibited improved overall survival compared with PD-L1 negative patients [18]. Furthermore, the combination of lenvatinib with pembrolizumab or nivolumab achieved an overall response rate (ORR) of 21.4% and DCR of 92.9% in 14 Stage IV ICC patients who had more than two lines of anticancer therapy, and high TMB was strongly associated with a better therapeutic response [19]. Combined therapy of PD-1 blockade with chemotherapy emerged very recently as a new option for advanced or recurrent ICC, and a few case reports showed promising results: patients with high TMB or high INDEL mutation frequency achieved marked response to the combined therapy [32, 33]. It appeared that ICC patients with high TMB, MSI-H, dMMR and/or PD-L1 positive expression can benefit from immunotherapy or its combination with targeted therapy or chemotherapy.

The combination of immunotherapy with radiotherapy has been shown to be an effective therapy in a few cancers (Table 1). The first study of the combined therapy reported a melanoma case in 2012, showing that the combination of ipilimumab with radiotherapy induced abscopal effect, which relieved both irradiated lesions and nonirradiated lesions [24]. Subsequent studies in melanoma expanded the sample size and investigated the performance of radiotherapy combined with nivolumab, pembrolizumab or ipilimumab [25–27]. One retrospective analysis compared the treatment response of combined radiotherapy/ipilimumab to that of ipilimumab alone in 101 patients with melanoma (Table 1). The median overall survival and the rate of complete response were significantly higher in the combined therapy than ipilimumab alone [25] (Table 1). There are many studies that investigated the efficacy of immunotherapy and radiotherapy combination in NSCLC. One meta-analysis focusing on metastatic NSCLC included 18 studies and concluded that the combination had a good safety profile and achieved high rates of local control and greater chances of obtaining abscopal responses than radiotherapy alone, with a relevant impact on PFS [28] (Table 1). The efficacy of the combination has also been studied in neuroendocrine cervical carcinoma and refractory Hodgkin’s lymphoma [29, 30]. Furthermore, one recent study reported the efficacy of the combined therapy of SBRT with pembrolizumab in 79 solid tumor patients covering 27 cancer types [34]. Multisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity, and achieved an overall ORR of 13.2% with median OS of 9.6 months, median PFS of 3.1 months and nonirradiated ORR of 26.9% (Table 1). Studies reviewed in Table 1 indicate that the combined radiotherapy with immunotherapy exhibited good therapeutic efficacy with low toxicity in a majority of cancer types.Tab1

Summary of representative studies on the combination of radiotherapy with immunotherapy in main cancer types investigated to date

Studies on the combination of immunotherapy with chemotherapy or targeted therapy showed that ICC patients with high TMB, dMMR, MSI or positive PD-L1 expression exhibited better response, while most studies on the combination of immunotherapy with radiotherapy in various cancers did not describe the status of TMB, MMR, MSS or PD-L1 expression. Our present study showed that late-stage or recurrent ICC patients can also benefit from the combination of immunotherapy with SBRT, even if they had low TMB, pMMR, MSS or negative PD-L1 expression. The combined therapy appeared to be effective regardless of the sequence of immunotherapy or SBRT. This suggests a huge potential advantage of immunotherapy combined with SBRT, since there are many cancer patients with low TMB, pMMR, MSS or negative PD-L1 expression, not only in ICC, but also in other cancers. This combination provides a new effective option for their therapy.

Strong abscopal effects were observed in all three patients in this study. Both irradiated and nonirradiated lesions responsed to the combination of radiotherapy and immunotherapy, and the responses in nonirradiated lesions, such as the lymph node metastases in patient A and C, were even better than the primary lesions. These observations suggest that the responses in these patients may be due to the combination of radiotherapy and immunotherapy. Since advanced ICC had limited sensitivity to conventional chemotherapy, radiochemotherapy, or immunotherapy alone [10–12], radiotherapy may sensitize immunotherapy and increase its efficacy. It was shown that radiotherapy enhanced the presentation of tumor-associated antigens, increased T-cell recognition and PD-L1 expression of tumor cells. The combination of radiotherapy with PD-1 blockade also increased endogenous T-cell infiltration of tumors and PD-L1 expression in tumor cells [35, 36]. It may be that the involvement of radiotherapy sensitized not only the local lesion, but also the abscopal metastatic lesion, which enhanced the efficacy of both radiotherapy and PD-1 blockade.

Our cases highlighted the therapeutic potential of the combination of radiotherapy with immunotherapy for late-stage or recurrent ICC patients with low TMB, pMMR, MSS and negative PD-L1 expression, and expanded immunotherapy to those patients who were previously regarded as unsuitable for PD-1 blockade. This therapeutic efficacy may be applied not only to ICC, but also to other refractory cancers. Abscopal effects were also confirmed in our study with the combination, which enhanced the efficacy of both radiotherapy and immunotherapy with well tolerance and acceptable toxicity. Our study provided a new option to maximize the benefit for late-stage or refractory cancer patients in therapies involving PD-1 blockade.