In this dose-escalating study of patients with unresectable HCC, two DLT cases (grade 3 leukopenia) were observed in the apatinib 500 mg group. Therefore, in combination with IMRT, apatinib 250mg daily was considered as the recommended dosage in the phase 2 study.
Hypertension was a commonly observed AE in previous studies of apatinib treatment, and the incidence of hypertension was 40% in the treatment of metastatic gastric cancer [14] and 73% in HCC [21]. Considering that hypertension typically occurs early after apatinib treatment and can be well controlled by antihypertensive agents, well-controlled hypertension was not defined as DLT in this study [19]. Four cases in our study were found to have grade 3 hypertension in the first week of treatment with apatinib, and all cases of hypertension were controlled to grade 0 or 1 through single or combined antihypertensive drugs.
In 2017, Lu et al. [16] demonstrated the efficacy and safety of TACE and apatinib for the treatment of HCC. Twenty patients were allocated to the combined treatment group, in which the apatinib dose was 250–500 mg. The common AEs in the combined treatment group included fever, abdominal pain, nausea, diarrhoea, bone marrow suppression, proteinuria, hand-foot syndrome, and hypertension. Severe AEs occurred in three patients, including hand-foot syndrome, diarrhoea, and upper gastrointestinal haemorrhage. In our study of apatinib and IMRT in the treatment of HCC, AEs of grade 1–2 were common, such as fatigue, hypertension, dizziness, bone marrow suppression, and hyperbilirubinemia. Because of the history of hepatitis or cirrhosis, although grade 1–2 toxicities were all reversible, treatment-associated toxicities should be taken seriously. In the subsequent course of apatinib treatment, one case of liver decompensation occurred within 6.6 months, and the patient died of hepatic encephalopathy. Another patient developed upper gastrointestinal haemorrhage within 5.3 months, but the bleeding was controlled by symptomatic treatment. Given the complications of liver cirrhosis, the occurrence of severe AEs and decompensation-related deaths should be considered in HCC treatment. We thought it important in locally advanced HCC to ensure the safety of radiation therapy and to ensure the tolerance in long-term targeted therapy.
The outcome of systemic treatment alone for HCC was unsatisfactory. In the standard first-line treatment, lenvatinib and sorafenib showed similar survival, and the median survival time was 13.6 months and 12.3 months, respectively [22]. According to the mRECIST evaluation criteria, the ORR and mPFS were respectively 40.6% and 7.3 months in lenvatinib group, and were respectively 12.4% and 3.6 months in sorafenib group. Systemic therapy combined with effective locoregional therapy is a promising approach in locally advanced HCC. In a previous study, apatinib was shown to be effective in combination with TACE, with the best ORR and mPFS of 60% and 12.5 months, respectively [16]. Similarly, in this study, apatinib combined with IMRT for the treatment of locally advanced HCC also showed an encouraging outcome. The best ORR was 67%. The mPFS was 17.0 months, and the mOS was 16.7 months. In a previous study of our team, 63 patients with HCC and macrovascular invasion, underwent IMRT plus TACE combined with or without sorafenib from 2015–2018 [8]. In the failure pattern analysis, intrahepatic metastasis out of the radiation field was the most common failure in the locoregional treatment group, with an incidence of 57.1%. However, in the locoregional treatment plus sorafenib group, intrahepatic metastasis decreased to 28.6%. Thus, locoregional treatment combined with systemic treatment may be an effective treatment option for locally advanced HCC.
In summary, our findings showed that apatinib 250 mg daily may be a safe dosage when combined with IMRT for the treatment of unresectable HCC. The antitumor activity of the combination treatment was encouraging. However, due to the small sample size, the efficacy reported in this phase 1 study should be interpreted with caution. The safety and efficacy of apatinib combined with IMRT for unresectable HCC should be investigated in future studies.