Background
According to global cancer statistics from 2020, hepatocellular carcinoma (HCC) has become the sixth most common cancer and the third- leading cause of cancer-related death in the world [
1]. In China, it is listed as the second-most common cancer and the fourth-most common cause of cancer-related death, with almost the same mortality and morbidity [
2]. At the first diagnosis, fewer than 30% of the patients are suitable for radical treatment because of the concealed onset of HCC, and for the rest of the patients, systematic antineoplastic monotherapy or combination therapy may transform it into a resectable tumor [
3]. Sorafenib, a tyrosine kinase inhibitor (TKI), has become one of the first-line treatments for HCC patients who are not suitable for local treatment [
4]. However, it has been reported that 40–56% of patients receive second-line treatment due to sorafenib resistance [
5]. In the RESORCE trial, a phase III trial demonstrated that regorafenib significantly improve the overall survival (OS) of HCC patients who progressed after sorafenib treatment, becoming the first TKI approved for second-line therapy [
6]. Regorafenib can block the activity of protein kinases associated with angiogenesis, tumor growth, and metastasis [
7,
8] and has previously been approved for the treatment of metastatic colorectal cancer and advanced gastrointestinal stromal tumors [
9,
10]. Recently, in a large real-world study in South Korea, similar results were obtained [
11]. In this study, we attempted retrospectively analyzed clinical data and follow-up results of patients with recurrent HCC treated with regorafenib to identify the factors affecting the prognosis of these patients.
Discussion
In this study, we reviewed patients with recurrent HCC in our hospital and evaluated the efficacy of regorafenib and prognostic factors after first-line systemic therapy failure. Unlike other study samples, these patients had undergone surgery and first-line drug treatment; they may have better liver function, PS scores and other indicators than other patients, and they may prefer more aggressive treatment strategies. Therefore, this study may record better results. The mOS was 15.9 months (
95%CI 11.7–20.1), the mTTP was 5.0 months (
95%CI 4.1–5.9), and the mOS since first-line systemic therapy was 26.3 months (
95%CI 20.3–32.3), which were all slightly better than 11.08 months, 3.2 months, and 26.0 months found in previous research [
14,
15]. These findings indicate the potential effectiveness of combined therapy. Eighty-seven patients (93.5%) had at least one adverse event, of which 10 (10.8%) had grade 3–4 adverse events, and the type and incidence were similar to those in Lee's study (15.8%) [
11]. The ORR and DCR of the patients enrolled in the group were 14.0 and 62.4%, respectively, which were similar to 11 and 65% of the RESORCE trial. Overall, this study indicated that regorafenib showed tolerable safety and valuable effectiveness.
At present, Child–Pugh classification and ECOG PS have been recognized as important factors affecting the prognosis of patients [
16,
17]. In this study, we found that the patients with high ECOG PS scores had more adverse events (χ
2 = 7.836,
P = 0.005) and earlier drug withdrawal (χ
2 = 17.201,
P < 0.001). In addition, the number of patients with BCLC stage C after LT was significantly higher than that of non-LT patients (94.1 and 63.2%,
P = 0.013), but there was no difference in OS (
P = 0.731) or adverse events (
P = 0.272). Combined with the findings of Iavarone et al. [
18], we believe that regorafenib is safe and effective in patients with recurrent HCC after LT.
Inflammatory cell infiltration is related to tumorigenesis and development [
19]. Lymphocytes are involved in inhibiting the proliferation and migration of tumor cells and inducing cytotoxic cell death. In contrast, neutrophils determine the development and invasiveness of tumors [
20]. Therefore, a higher NLR may reflect a poorer prognosis. However, no optimal cutoff value has been reported for the NLR. Bruix et al. [
16] used the median NLR as the dividing line in a study of prognostic factors of sorafenib, and a meta-analysis of more than 3000 patients with HCC [
21] revealed that the threshold NLR value ranged from 1.9 to 5, and NLR > 3 was a better predictor of OS than NLR between 2 and 2.9. In this study, we found that this value is an important predictor of OS (22.8 months/12.7 months,
P = 0.002) when taking NLR = 2.5 as the cutoff value, which may be due to the dissimilar sample of patients assessed.
The purpose of combined therapy is to resect the tumor and reduce the tumor burden. Sixty patients (64.5%) received combined therapy under multidisciplinary treatment (MDT), of which 15 patients received a combination of more than two regimens, and the incidence of adverse events did not increase with the increase in treatment (P = 0.766). HCC has a high degree of heterogeneity, and increasing treatment models and timely multidisciplinary discussions will help to improve the treatment accuracy and compliance of each patient.
A recent study showed [
22] that regorafenib could enhance antitumor immunity by reversing the M2 polarization of tumor-associated macrophages, which provides a theoretical basis for the combination of regorafenib and ICIs in the treatment of HCC. The mOS of 26 patients who received combined treatment with ICIs (including multiple combinations) was significantly longer than that of those without combined therapy (20.5 months/11.6 months,
P = 0.020). Three patients achieved PR, and the DCR was 61.5%. It was suggested that there was a potential synergistic effect between ICIs and standard regimens with immunomodulatory effects. However, the TTP and OS of the other 19 patients who received TACE treatment did not show significant advantages (
P = 0.324,
P = 0.431). In the recent TACTICS study [
23], the newly established specific end point of TACE was used to define the "time to untreatable progression (TTUP)", that is, "no TACE progression or TACE failure". Finally, it was found that the median PFS of the “TACE + sorafenib” group was significantly longer than that of the simple TACE group (25.2 months vs. 13.5 months,
P = 0.006), and the median TTUP was also significantly prolonged (26.7 months vs. 20.6 months,
P = 0.02) with controllable toxicity.
Conversed therapy is an important way to improve the survival of patients with advanced HCC [
24]. A total of 107 patients with advanced HCC treated with lenvatinib were followed up, of which 16 (15.0%) underwent surgery and 9 (9.4%) received R0 resection; these patients had a longer OS (
P = 0.002) [
25]. In addition, there are a number of case reports describing that patients benefit significantly from TKI drugs for the conversion of advanced HCC [
26‐
29]. In this study, one patient received combination treatment with regorafenib and ICIs; this patient was found to have abdominal metastasis 3 months after HCC resection, and then, the abdominal tumor was resected. The OS was 26.3 months. Another patient was also found to have abdominal and colon metastasis. After the administration of sorafenib, the metastatic focus was resected and then treated with regorafenib combined with ICI adjuvant therapy, and a 19.8-month OS was obtained. By the end of follow-up, the 2 patients were found to have achieved PR and CR. In this study, 18 patients (19.1%) achieved downstaging of tumors, 6 patients underwent reresection after regorafenib (5 in R0) and 12 in RFA, and more than half of them survived until the end of follow-up. The 75% OS was 15.4 months, and the average OS reached 27.3 months.
In the subgroup analysis of the study, the prognosis of patients with recurrent HCC treated with conversion therapy seemed to be better than that of patients treated with ICIs or TACE. Systematic treatment degrades the tumor stage of some patients with strict screening, which represents a bridge to successful surgery or RFA therapy. Some patients could still be evaluated for PR or even CR after two or even multiple operations, which provided us with the hope of cure for patients with recurrent HCC. However, due to the unique biological behavior of HCC and the low sensitivity to TKIs and ICIs, the surgical conversion rate of advanced HCC is not ideal, and how to choose suitable patients and the opportunity for operation need to be studied in follow-up work.
When we observed the patient's disease progression, we did not immediately withdraw regorafenib, but combined with other treatments. However, combination therapy will dilute the efficacy of regorafenib, and as a retrospective study, we cannot determine how much of it accounts for. In the real world, combination therapy strategies are very common, but the timing, methods and side effects of combination therapy are waiting to be studied. Therefore, one of the conclusions of our study is that the combination therapy discussed by MDT, including regorafenib, can be more effective than regorafenib alone, and the side effects can be controlled.
Different from the RESORCE test, we take exposure time of regorafenib ≥ 56 days as one of the inclusion criteria, which may cause selection bias. However, during the research, we found that the first imaging reexamination of the patients was 8 weeks after treatment with regorafenib, which was an important basis for us to evaluate the curative effect; we also found that this standard can effectively exclude patients with poor compliance and premature death due to rapid tumor progression. In a sense, the standard can reject certain bias.
Nevertheless, there are several limitations in this research. First, this study was based on a retrospective analysis of limited data from a single institution. The size of the participants was small, and selection bias and a lack of data were inevitable. The conclusions need to be verified in a multicenter large-sample prospective study. Second, almost all the patients were infected with HBV, which was consistent with the characteristics of the Chinese HCC population, but for HCC patients with HCV infection, alcoholic hepatitis, nonalcoholic hepatitis and other causes, more follow-up data are needed to confirm our conclusions. Third, the treatment plan for postoperative recurrence in this study was based on the latest clinical guidelines at that time, combined with the tumor characteristics and clinical information of the patients, but in the end, it was limited by the patients' preference for less invasive procedures and economic conditions, and there may be bias. The above factors may reduce the quality of the conclusions obtained in this study. In the next step, a larger, multicenter real-world study with longer follow-up is needed to improve the level of evidence of the conclusions of this study, to provide a basis for the formulation of individual and accurate treatment plans and to improve the prognosis of patients with HCC.
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