Stereotactic body radiotherapy (SBRT) for locally advanced intrahepatic and extrahepatic cholangiocarcinoma

Cholangiocarcinoma (CCC) is the second most common primary liver cancer after hepatocellular carcinoma and is divided anatomically into intrahepatic (IHCC) and extrahepatic cholangiocarcinoma (EHCC). EHCCs are subdivided into hilar/perihilar (pCC, also called Klatskin tumors), or distal (dCC). pCC is the most common type of cholangiocarcinoma, followed by dCC and intrahepatic forms [1]. The only potentially curative treatment option is surgical resection but 70% of the patients are deemed irresectable [2] and about half of the patients undergoing resection relapse within 1 year after resection [3]. The current standard of care for both locally advanced and metastatic patients with good performance status is combination chemotherapy with platinum and gemcitabine-containing protocols, which achieve a median overall survival of 11.7 and a median progression free survival of 8 months [4]. Currently primary treatment options for patients with unresectable or metastatic disease according to the National Comprehensive Cancer Network (NCCN) Guidelines version 1.2017 include: 1) clinical trial; 2) fluoropyrimidine-based or gemcitabine-based chemotherapy; or 3) best supportive care. In addition, fluoropyrimidine chemoradiation is included as an option for patients with unresectable disease. Locoregional therapies such as radiofrequency ablation (RFA) [5], trans-arterial chemoembolization (TACE) [6], drug-eluting bead trans-arterial chemoembolization (DEB-TACE) or TACE drug-eluting microspheres [7] and transarterial radioembolization (TARE) with yttrium-90 microspheres [8] have been shown to be safe and effective in a small retrospective series of patients with unresectable intrahepatic cholangiocarcinomas (NCCN version 1.2017, hepatobiliary cancers). Hepatic arterial infusion (HAI) chemotherapy also was used for the treatment of patients with advanced and unresectable intrahepatic cholangiocarcinoma [9]. Furthermore, liver transplantation was used in selected patients with locally advanced hilar cholangiocarcinomas [10] and the combination of photodynamic therapy (PDT) with biliary stenting was reported to be associated with prolonged OS in patients with unresectable cholangiocarcinoma in small randomized clinical trials [11].

The role of radiotherapy remains controversial due to lack of phase III randomised trials. However, several early phase studies have suggested that radiotherapy can prolong survival [12, 13], and there is evidence of a dose response relationship [12, 14]. This has prompted the investigation of SBRT as a method for dose-escalation. SBRT is an emerging treatment technique for cholangiocarcinoma where ablative doses can be applied with a steep dose gradient and thus sparing normal tissue. SBRT can lead to high local control rates with moderate toxicity in other primary or metastatic cancers of the liver [15, 16].

In this study, we evaluated the role of SBRT in the treatment of CCC in respect to toxicity as well as local control.

Our institution has previously reported outcomes on the role of SBRT [22, 23]. In this study, we present the results of SBRT in both IHCCC and EHCCC in one of the largest series reported for CCC and especially for EHCC (Table 4).

In the definitive and palliative setting, concurrent chemoradiation leads to a median OS of 2.2- 27 months and 3 y-years survival rates ranging from 6 to 73 months [24]. Local recurrence is the primary site of progression and dose escalation seems to be promising in terms of LC and OS. In a retrospective series using different fractionation regimes, Tao et al. could show that a BED greater than 80.5 Gy correlated with prolonged OS and LC (p = 0.017 and p = 0.04 respectively).These results, could not be reproduced in another retrospective study from Jung et al. [25] who treated patients using SBRT in 1-5 fraction. In his study a BED higher than 86 Gy did not correlate with better LC or survival (p = 0.4 and p = 0.1 respectively) which is in concordance with our findings. Furthermore, Jung et al. did not find any differences between patients treated for IHCCC (n = 33) vs EHCCC (n = 25) (p = 0.54) but they reported in 10% of the patients grade ≥ 3 complications such as duodenal and gastric ulceration and perforation as well as cholangitis and bile duct stenosis. Sandler et al. [26] reported 16% grade ≥ 3 toxicities in a retrospective analysis with 31 patients (IHCCC = 6, EHCCC = 25) treated with SBRT. Similar toxicities were also reported in a study of Kopek et al. [27] who treated 26 patients with Klatskin tumors. In this study, six patients developed a duodenal ulceration and 3 a duodenal stenosis (two of whom were among those with severe ulcers). They reported that the mean dose to 1 cm³ of duodenum (D 1 cm³) was significantly higher for patients developing grade ≥ 2 ulceration or stenosis at 37.4 Gy (83% of prescription dose) versus 25.3 Gy (p = 0.03) which corresponds to an EQD2₃ of 115 Gy and 57.8 Gy, respectively. Kopek and co-workers suggested a V_21Gy ≤ 1 cm³ as a dose constraint for the duodenum in 3 fractions which corresponds to an EQD2₃ of 42 Gy.

The increased toxicity in these studies is probably due to the large proportion of EHCCC included, because of the vicinity of these tumors with the duodenum. The above mentioned studies, together with the current one, are the largest reported series for EHCC (Table 4). In our series we had less late toxicities (3 cases of gastrointestinal bleeding), two of which could be explained due to other causes, such portal hypertension due to massive tumour progression and ascites and in the second case due to the manipulation after frequent biliary stenting. In both cases the institutional dose constraints were respected with a maximal EQD2₃ point dose significantly less than 65.8 Gy. We could show a favourable toxicity profile probably due to a moderate fractionation and the use of simultaneous integrated protection (SIP). This concept is being further evaluated in a prospective trial.

To date, the role of SBRT is not clearly established, but there is emerging evidence that SBRT could lead to an improved OS, LC and symptom control. Preliminary results on SBRT [22, 28, 29] have reported promising median OS rates ranging from 28.6–35.5 moths. These results could not be confirmed in subsequent analyses which included a higher number of patients [25, 26, 30]. Although all of these studies including the current one have several limitations such as the retrospective design and small sample size median OS rates of 10–17 months and LC rates at 1 year of 55–100% seem highly promising in patients with inoperable or recurrent cholangiocarcinoma. In patients who receive chemotherapy receipt of radiotherapy was associated with improved survival [31]. SBRT can be well integrated to systemic chemotherapy with minimal interruption delivering an effective local treatment. Furthermore, radiotherapy does not show relevant impairment of the quality of life [32, 33] with the only observed deficits being temporary worsening of appetite and fatigue. Patients with advanced CCC and higher bilirubin concentrations are not candidates for chemotherapy and the only alternative is best supportive care. In our study those patients had a median OS of 12 months, higher than the rest, probably also due to patient selection bias, yet with a certain profit from SBRT in comparison to best supportive care. Stereotactic body radiation therapy is well tolerated and warrants further evaluation.

Patients with cholangiocarcinoma, who are not candidates for surgical resection, have a dismal prognosis, and may benefit from locally ablative techniques such as SBRT. SBRT is a local treatment option with an acceptable toxicity profile, allowing its integration into multimodal treatment concepts. Prospective trials to validate these findings are underway.