According to the National Comprehensive Cancer Network guidelines, localized thermal treatment options such as RFA or microwave ablation for liver metastasis of GC are not considered the best supportive treatment option[24]. Systemic chemotherapy is currently the preferred treatment for patients with GCLM. There is no doubt that systemic chemotherapy can improve long-term survival and prolong PFS compared with BSC[25, 26]. TACE and hepatic arterial infusion chemotherapy have also been reported to be used for the treatment of GCLM, but only in small sample retrospective analysis and case reports[27–29]. At present, some scholars have proposed that patients with GCLM can be divided into three categories: potentially resectable tumor (category I), marginally resectable tumor (category II), and unresectable tumor (category III), this determination should be made by an MDT[6, 30]. There is also another group of scholars who were inspired by the evidence of substantially increased survival benefits observed in patients who received surgery for colorectal liver metastases and begun to further explore the role of surgery for GCLM[31].
Palliative gastrectomy is currently not recommended for patients with advanced GC (stage IV) unless perforation, bleeding, pyloric obstruction, etc occurs[4, 32]. However, when the metastatic lesions can be removed completely, expanded surgery may improve the patients’ prognosis. A retrospective study of 28 patients with GCLM with and without extrahepatic metastasis showed a 5-year survival rate of 32% after undergoing hepatectomy, with a median OS time of 49 months[9]. Another study involving 25 GC patients with synchronous liver metastasis showed that undergoing hepatectomy resulted in a 5-year recurrence-free survival rate of 11.1% and a 5-year OS of 29.4%[8]. It should also be noted that many patients lose the chance of surgery due to either the difficulty of surgical resection or the patients’ intolerance to surgery. Fortunately for such patients, RFA can be a viable treatment option for GCLM patients who are unable to undergo hepatectomy. Oki et al. reported that a total of 94 GCLM patients received either surgery or RFA or a combination of both and that the 5-year OS and 5-year recurrence-free survival rate was 42.3% and 27.7%, respectively[33]. Two observational studies compared the short- and long-term results of RFA with liver resection for GCLM patients. The results showed that there was no difference between the 3-year and 5-year survival rates of patients undergoing either RFA and surgery and that RFA had even fewer complications [10, 11].
Unfortunately, RFA has several limitations. RFA is not able to treat lesions located near the main biliary tract or gallbladder, major blood vessels, and just beneath the diaphragm[34]. PC is usually used to treat patients with GCLM who are unable to receive either RFA or surgery, but its long-term effects are disappointing. In recent years, HIFU has been increasingly used in the treatment of liver cancer[35, 36]. Due to its characteristics, some studies including our previous studies have shown that HIFU can be used as a potential treatment option for patients with liver cancer but are contraindicated for either RFA or surgery[18, 19]. In a previous study, we reported on 13 patients with colorectal liver metastases who were contraindicated for either resection or RFA and eventually received HIFU treatment. The 2-year PFS was 16.7%, and the median PFS was 9 months. Notably, the 2-year OS was 77.8%, and the median OS time was 25 months[18]. However, the long-term prognosis of patients with either GCLM or colorectal liver metastases who underwent primary lesion resection combined with hepatectomy is significantly different. The 5-year survival rate of GCLM is about 20%[10, 37], while that of colorectal liver metastases is as high as 50% after surgery[38, 39]. More importantly, few studies have evaluated the safety and efficacy of HIFU treatment for GCLM patients. Therefore, this is the first study to date that compares the long-term effects of HIFU, PC, and BSC in GCLM patients without extra-hepatic metastasis who were contraindicated for either hepatectomy or RFA. In order to increase the credibility of the study and to reduce the heterogeneity among the treatment groups, propensity matching analysis is used.
In this study, 40 patients with GCLM were included, and the baseline comparisons among the three groups were equivalent. Relevant studies have shown that the potential prognostic factors included but were not limited to age, the number of metastases, and size of metastases[7, 40, 41]. Among them, the number of lesions was the most significant prognostic factor. Multiple studies have shown that patients with a single metastasis have a better prognosis than patients with multiple metastases. Fortunately, the three groups in this study were similar in many aspects. In terms of tumor response, due to differences in treatment methods, the patients in the HIFU group were assessed using the mRECIST, while the patients in the PC and BSC groups were evaluated according to RECIST. The results of our study showed that more than half of the patients could achieve CR after HIFU treatment, while less than one-fifth of patients achieved CR in the PC group. In the BSC group, the tumor continued to progress. Similarly, the ORR was higher in the HIFU group than in the PC group. This suggests that HIFU treatment of metastatic lesions is potentially more beneficial compared with PC and BSC. In addition, no rapid tumor progression was observed during the follow-up of the three patients who did not achieve CR.
More importantly, survival analysis showed that patients treated with HIFU had the best OS and PFS, followed by PC, while the BSC group had the worst survival rate. The median survival time in the BSC group was about half a year, which is in line with previous studies[42, 43]. The median survival time of the patients who underwent PC was about twice as long as that of the BSC group, up to approximately 1 year. Picado et al. included 3000 patients with GCLM, and the results of this analysis showed that the median survival time of patients receiving PC was about 9.7 months. The median survival time after receiving palliative gastrectomy was 15.3 months, while the median survival time after receiving combined hepatectomy was 24.3 months[40]. Zhang et al.[32] reported that the median survival time for GCLM patients receiving BSC was only 2.8 months, compared with 9.4 months for those receiving systemic chemotherapy. Additionally, patients receiving multi-line chemotherapy had a longer median survival time compared to those receiving single-line chemotherapy (14.2 months versus 6.6 months). A phase II clinical trial showed that capecitabine combined with paclitaxel resulted in a median survival time of 10.1 months for GCLM patients[44]. Therefore, systemic chemotherapy rarely prolongs the median survival time of GCLM patients by more than 2 years.
Interestingly, our research showed that the median survival time of GCLM patients who underwent HIFU treatment was more than 2 years, which was twice that of the PC group, and the median PFS time was more than 1 year, which was 3 times that of the PC group.
HIFU due to its minimal invasiveness and safety characteristics is becoming more widely used in the treatment of liver cancer by inducing precise lesion coagulation necrosis without damaging the surrounding structures. Furthermore, HIFU treatment is reported to have the ability to enhance the patients’ tumor immune response [45]. A case of gastric leiomyosarcoma with liver metastases and multiple retroperitoneal lymphatic metastases was reported to be treated with HIFU combined with tetrahydropalmatine and oxaliplatin-based transarterial chemoembolization and the PFS was 4 months after treatment[46]. Park et al. reported in 2009 on 3 GCLM patients who received HIFU treatment, which was generally safe, but the efficacy in that study was indeterminate[47]. It has been reported that a 35-year female patient with metachronous GCLM achieved CR after receiving HIFU combined with chemotherapy[48]. A recent retrospective study showed that HIFU therapy for metastatic liver cancer yielded better long-term results[49]. The one-year survival rate was 48.0%, and the median OS time was 12 months. However, this study had several shortcomings. First, this study included patients with multiple malignant tumors associated with liver metastasis, including colorectal cancer, pancreatic cancer, GC, breast cancer, gallbladder cancer, etc. Second, several patients had extrahepatic metastasis. Therefore, the effect of HIFU on GCLM is not well reflected in this study. Our study preliminarily showed that HIFU treatment has a good long-term effect on patients with GCLM.
In terms of treatment-related AEs, HIFU therapy has been shown to be safe and is usually tolerated well by patients. No patient had grade 3 or above AEs, and other AEs were manageable. After symptomatic treatment, all AEs were alleviated. The AEs associated with HIFU treatment was not significantly worse than the AEs associated with PC.
To the best of our knowledge, this is the first research that specifically compared HIFU treatment with PC and BSC for patients with GCLM by coupled cases. This study evaluated the safety and efficacy of HIFU for patients with GCLM and determined that HIFU treatment can be considered to be a good alternative when surgery or RFA is contraindicated for patients with GCLM. Patients who received HIFU treatment has better long-term outcomes compared to the PC and BSC groups, with no significant increase in AEs.
The limitations of this study are as follows. First, this is a prospective observational study with a small sample size. Although the propensity matching analysis is carried out, the reliability of the conclusion is lacking due to the small sample size. Second, the patients received systemic chemotherapy after HIFU treatment, which may have increased the perceived efficacy of the HIFU treatment. As a result, the therapeutic effect of HIFU may be overestimated. Therefore, this study needs to be further verification by a large sample randomized controlled trial.