Background
According to a recent statistics report in China, liver cancer remains one of the most common causes of cancer mortality due to its high aggressiveness and prevalence in East Asian populations [
1]. Liver cancer cells can spread throughout the body directly or indirectly through lymphatic and vascular pathways, resulting in simultaneous or heterochronic extrahepatic metastases (EHM). The development and deterioration of EHM have predicted a poor prognosis for liver cancer patients [
2]. Generally, AGM is the third most common EHM from liver cancer (followed by lung and bone), accounting for 6.9–19.1% of patients with EHM [
3]. Some patients with AGM may feel a sense of swelling distension, soreness in the kidney area, and back pain, which lead to a reduced quality of life (QoL) and even affect their survival.
Numerous therapies have been applied to treat AGM, but there is still no universally recognized treatment. With the advancement of systemic therapies such as immunotherapy and targeted therapy in recent years, more liver cancer patients with distant metastatic lesions may have a better chance of an improved OS. Currently, the best therapeutic option for progressive hepatocellular carcinoma is a combination of programmed death-ligand 1(PDL1) blockers and vascular endothelial growth factor(VEGF) antagonists, whereas chemotherapy remains the best alternative for intrahepatic cholangiocarcinoma [
4]. However, resistance to the drugs and heterogeneity in patient response limit their widespread use. Moreover, they have a limited effect on the local control rate of lesions compared with local therapy [
5]. Therefore, more aggressive local treatment options are proposed to reduce the growing tumor burden. Surgery is considered a curative option for isolated AGM, whereas contraindications such as the senior, poor cardiopulmonary function, and other co-morbidities may prevent it from conducting. Moreover, adrenalectomy is an invasive treatment for patients [
6]. Other loco-regional approaches, including transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA) are not suitable for large lesions, which may cause stenosis, fistulas, and bleed [
7]. Thus, there is an urgent need for a precise, reliable, and effective option.
The appropriate management of radiotherapy iseffective in relieving pain symptoms as well as improving survival in patients with AGMs from liver cancer [
8‐
11]. Radiotherapy techniques have been evolving, while stereotactic body radiation therapy (SBRT) can achieve better conformality, higher accuracy, and better dose distribution compared to conventional radiotherapy [
12]. SBRT could be well delivered with the advanced devices represented by the CyberKnife® system (Accuray Inc., Sunnyvale, CA, USA). The SBRT technique has been acknowledged as a non-invasive but curable treatment alternative. Distinguishing features of the CyberKnife® system include near real-time tracking via position information, the flexibility of robotic beam movement, and delivery capability [
13‐
15].
There are few reports on SBRT applied in AGM from liver cancer, which mainly have adopted conventional radiotherapy [
8‐
11]. In addition, previous studies of AGMs SBRT have focused on various solid tumors as primary tumors, and no report on the efficacy of SBRT in the treatment of AGMs from liver cancer. Therefore, the purpose of this retrospective two-center study is to evaluate the efficacy and safety of SBRT for AGMs from liver cancer.
Discussion
In this retrospective study, we reported the results of SBRT in the treatment of AGMs from liver cancer. Despite the fact that the majority of patients died of distant metastasis, SBRT could possibly provide survival benefits with high LC rates and low toxicity rates, particularly for the small lesions with GTV less than 34.5 ml. No severe adverse events (grade 4 or more) were reported. Despite the limited number of patients enrolled, this was the first two-center study to report CyberKnife in the treatment of AGMs from liver cancer.
The current first-line recommendations for metastatic liver cancer were multiple kinase inhibitors (sorafenib) and systemic anti-programmed cell death protein-1 inhibitors (nivolumab and pembrolizumab) for hepatocellular carcinoma [
5,
20,
21]. The ABC-02 trial reported gemcitabine in combination with cisplatin was currently regarded as the best choice for systemic treatment in palliative care for intrahepatic cholangiocarcinoma [
22]. Improvements in cancer diagnostic techniques and treatments have resulted in the emergence of a large number of advanced cancer patients, but in the good physical condition and claiming to reduce the tumor burden. Therefore, the treatment strategy relies on multidisciplinary medical practitioners to individualize the patient’s treatment to control systemic diseases. Compared to the common metastatic sites (e.g. bone, lung), adrenal metastases present with relatively few symptoms and few effective options available. Furthermore, an increasing number of liver cancer patients with AGMs were treated with definitive local therapies in a variety of ways.
Previous studies have shown that invasive and micro-invasive treatment of AGMs were associated with better outcomes, with survival ranging from 2 to 21.4 months and 9.3 to 24.9 months respectively after adrenalectomy and thermal ablation [
23‐
26]. However, serious complications after surgery such as pancreatic fistula, adrenal insufficiency, bleeding, and complications due to the technique may occur [
3]. In a study of 22 patients with single-sided AGMs who underwent percutaneous ultrasound (US)-guided radiofrequency ablation (RFA), Huang et al. [
7] found that local failure rates were 15.8%, 26.3%, and 26.3% at 3, 6, and 12 months respectively after the RFA procedures, with additional OS rates of 79.7%, 52.6%, and 32.9% at 6, 12, and 24 months, respectively. One patient, however, experienced a severe major complication (SIR C) known as myocardial transient ischemia. Lyu et al. [
27] analyzed 27 AGMs in hepatocellular carcinoma patients treated with CT-guided thermal ablation. The median follow-up was 19.3 months, and 40.7% of patients exhibited adrenal tumor progression after ablation. The median PFS and OS for the 27 patients were 6.9 months and 16.8 months, respectively. The OS rates at 6-, 12- and 24-month were 88.9%, 66.7%, and 33.3% respectively. In contrast, SBRT was a reliable option for patients who refused or were not suitable for adrenalectomy or micro-invasive treatment. The findings from our study with 24 AGMs from 23 liver cancer patients revealed that the mean LC, median PFS, and OS were 55.8 months, 4.5 months, and 18.6 months, respectively. The 1-year LC, PFS, and OS rates were 77.8%, 37.9%, and 88.8%, respectively. What’s more, patients with small lesions with GTV less than 34.5 ml were associated with better LC and OS. The outcomes were comparable to, if not better than, those of surgery or micro-invasive treatment. Importantly, the toxicities were tolerable, with no cases of grade 4 or higher toxicity reported.
Compared to the invasive and micro-invasive treatments described above, radiotherapy inactivated tumor tissue more gently without a surge of catecholamines, treatment-related hypertension, and adrenal dysfunction [
28]. A growing number of studies have focused on radiotherapy in the treatment of AGMs from hepatocellular carcinoma, with conventional radiotherapy being the most used [
8‐
11]. Yuan et al. investigated 81 patients with AGMs from hepatocellular carcinoma, 18 of whom received helical TomoTherapy while 63 patients received conventional radiotherapy. The 2-year OS rate was 35.0% with a median survival time of 15 months. One (1.2%) patient reported grade 3 leucopenia, while 7 (8.6%) patients reported grade 3 thrombocytopenia [
11]. In our study, a higher 2-year OS rate with a lower toxicity rate than those corresponding results reported in Yuan’s study. This is probably because SBRT has superior dose distribution compared to conventional radiotherapy, meanwhile, highly conformal and ablative radiation doses could be delivered by SBRT with a low incidence of toxicity. Notably, SBRT has emerged as an alternative to conventional radiotherapy in the management of pain control, which was similar to the conclusions reached in our study [
29]. Our study has demonstrated the efficacy and safety of SBRT as an alternative treatment for AGMs.
According to the previous studies on SBRT for AGMs [
30‐
36], the 1-year LC rate ranged from 73 to 97%. It has been shown that an elevated dose of BED
10 tends to be associated with better local tumor control. One study modeling the probability of LC about SBRT for AGM indicated that the 1-year LC rate was 95% when BED
10 was equivalent to 116.4 Gy [
37]. In addition, a meta-analysis of 39 studies revealed that when BED
10 were 60, 80, and 100 Gy, the corresponding 1-year LC rates were 70.5%, 84.8%, and 92.9%, respectively; the corresponding 2-year LC rates were 47.8%, 70.1%, and 85.6%, respectively [
38]. The median BED
10 in our study was 72 Gy (53.7-100.8 Gy) with both 1-and 2- year LC rates of 77.8%, which was similar to the findings from other published studies. However, patients with varying BED10 had comparable LC in our study. This is probably influenced by the limited number of patients enrolled as well as the relatively low overall BED
10 and the large volume of lesions. Different from our study, Ehret et al. analyzed 55 patients with AGMs from different primary tumors, with a median BED
10 of 80.4 Gy. 1-year and 2-year LC rates were 92.9% and 67.8%, respectively [
39], the favorable results might be attributed to the variable primary tumors, relatively small GTV, and high median BED
10. Voglhuber et al. [
40] analyzed 31 patients with 34 AGMs and concluded that PTV volume (PTV < 80 ml,
p = 0.033) was an indicator of LC, whereas GTV was an indicator of LC in our study.
SBRT for AGMs had mild and low frequent side effects owing to the highly accurate radiation delivery. 1.8% of patients reported grade 3 or higher toxicities while 0.2% of patients reported grade 4 toxicities according to the meta-analysis by Chen et al. [
38]. There was only one patient who reported grade 5 toxicity after receiving nivolumab with SBRT [
30,
32,
35,
36,
41‐
43], while in our study, only one patient recorded a grade 3 adverse reaction. Grade 1–2 toxicities including fatigue, nausea, poor appetite, abdominal pain, vomiting, hematochezia, and gastric distension were resolved spontaneously.
Our study had several limitations. Firstly, it was a retrospective study. Secondly, the limited number of patients enrolled could not be able to detect the rare event. Thirdly, the baseline of patients was heterogeneous, such as the variety of lesions by pathological histology. Additionally, the treatment of primary tumors was not thoroughly reviewed and future relevant studies are warranted.
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