All-treatment array of hepatocellular carcinoma from initial diagnosis to death: observation of cumulative treatments

Hepatocellular carcinoma (HCC) is the sixth most frequent tumor worldwide, and the second most common cause of cancer-related death (Ferlay et al. 2015). Surgical resection, liver transplantation, and loco-regional treatments including radiofrequency ablation (RFA) are recommended as curative treatments for HCC (Korean Liver Cancer Study Group (KLCSG), National Cancer Center, Korea (NCC) 2015; Bruix and Sherman 2011; European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer 2012). However, only one-third of HCC patients are possible candidates for these curative treatments (European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer 2012) and the remaining 60–70% of patients receive non-curative treatments such as transarterial chemoembolization (TACE) or sorafenib as initial therapy (Bruix and Sherman 2011; European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer 2012). Globally, TACE is the most frequently used initial treatment for unresectable HCC (Ikai et al. 2005; Park et al. 2015; Takayasu et al. 2006). Unfortunately, the outcome for patients with HCC treated with either curative or palliative modalities is not satisfactory. Such poor prognosis of HCC is partly due to tumor characteristics, which are referred to as frequent remaining, progressing, or recurring tumors (RPRT) after treatment (Kim et al. 2014).

All guidelines and most treatment outcome studies have been established based only on the initial treatment modality (Korean Liver Cancer Study Group (KLCSG), National Cancer Center, Korea (NCC) 2015; Bruix and Sherman 2011; European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer 2012; Kudo et al. 2011). However, HCC frequently recurs with a 5-year recurrence rate of 70% even after curative liver resection (Llovet 2005). Therefore, in clinical practice most patients with HCC require subsequent treatments for RPRT. Appropriate subsequent treatment is just as important as initial treatment for improving patient survival in HCC. Unfortunately, there are no prospective studies on the best sequencing of treatment options for RPRT and even no longitudinal cohort study based on overall real-practice scenarios in patients with HCC. We, for the first time, investigated the patterns of all treatments provided to patients and outcomes of RPRTs in an HCC cohort from initial diagnosis to death at a single referral institution in South Korea.

By evaluating the results of cumulative treatments in the real-world management, healthcare providers can recognize the limited effects of single treatment and the meaning of initial treatment-based survival outcome in patients with HCC, and could improve the design of clinical trials and therapeutic strategies.

This study clearly demonstrates that most patients with HCC receive multiple treatments from diagnosis to death and the treatment array is very heterogeneous. After the first report of a second treatment in a global observation study (Park et al. 2015), information on the treatment patterns in patients with HCC remained poorly understood. In this cohort, 80.4% of patients received second or further treatments to control RPRTs; the mTF was 3.0 (range 1–20) during a median follow-up of 20.4 months (Table 2). This cohort study was performed at a referral center (Kwak et al. 2014), and so, there were a large number of patients with BCLC stage C, who had less frequent treatments and shorter survival time than patients with BCLC stage 0–B. The patients who received more treatment sessions showed a tendency toward longer survival (data not shown); however, this study was observational and so the frequency of treatments seems to only suggest that the patients had a medical condition that could be treated. However, patients with BCLC stage 0 had the longest survival period, but the mTF was the smallest and mTI was the longest (Tables 1, 2, 3). As stage progressed, the survival period decreased and the treatment frequency increased; patients with BCLC stage B had the highest number of treatments. However, patients with stage C had the shortest survival period and fewer treatments. This suggests that as the stage progresses, tumor progression may be accelerated due to changes in tumor biology; additional treatments may have limited effect due to deterioration of liver function and/or performance status after treatment and to the absence of appropriately effective modalities. Cheng et al. assumed that small HCCs may have either Gompertzian type of growth, in which the initial exponential growth decreases as tumor size increases, or rapid exponential growth (Cheng et al. 2002). This study seems to support a rapid exponential growth. Both tumoral and extratumoral factors determine the growth rate and biological aggressiveness of HCC (Trevisani et al. 2008). The ill-defined type HCC, recognized to have a poor prognosis (Demirjian et al. 2011), was associated with the shortest survival time and the fewest number of treatments; in multivariate analysis, tumor type appeared to be the most potent, but no statistical significance was found (Table 2).

Analysis of the treatment interval also supports the assumption concerning accelerated tumor progression. That is, as stage progresses, the treatment interval becomes significantly shorter (Table 3). As the BCLC stage progressed from 0 to C, the mTI decreased from 21.7 to 8.0 weeks. Because this cohort was collected from a single institution and treatment followed the Korean guidelines (Korean Liver Cancer Study Group (KLCSG), National Cancer Center, Korea (NCC) 2015), most patients were followed-up relatively regularly; the follow-up period was 1–2 months after the initial treatment, 2–4 months without RPRT, and 6 months after complete remission for 2 years. The difference in the treatment interval associated with the initial treatment method seems to be due to differences in disease stage at initial treatment (Table 3).

Subsequent treatment array was very heterogeneous, and this observational study could not suggest a certain pattern of subsequent treatment; a descriptive array was observed (Figs. 2, 3, 4, 5, 6). Widely heterogeneous RPRTs and the lack of evidence-based guidelines for subsequent treatment are causes for these various treatments arrays. In general, second and subsequent treatments are suggested to be based on initial treatment guidelines (Bruix and Sherman 2011; European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer 2012), but this lacks solid evidence. Prospective controlled studies are needed to guide subsequent treatment. Recently, a prognostic prediction model for second treatment outcome has been proposed (Choi et al. 2016) and will be useful for further study.

Similar to results from a global observational study (Park et al. 2015), TACE was the most common initial treatment (n = 1089, 64.6%) in our population, followed by surgical resection (n = 367, 21.8%). TACE is also the most commonly used second therapy for RPRTs after initial treatment of all methods; the proportion of TACE as second treatment was 66, 69, and 62.5% after initial resection, TACE, and RFA/PEI, respectively. The mTF with TACE was 3 (range 1–19) (Table 4). In this cohort, all TACE was performed on demand. Repeated administration of TACE may mean TACE failure or refractoriness, and other alternative treatments such as sorafenib may be necessary. Recently, there have been studies and reviews of TACE failure/refractoriness (Cheng et al. 2014; Kim et al. 2012; Kudo et al. 2014b; Yamanaka et al. 2012), but there is still no global consensus on the definition of TACE failure/refractoriness. In the Western world, a second TACE treatment is not recommended if there is a decrease in hepatic function after the first TACE (Hucke et al. 2014). However, in Asia including Korea or Japan, where TACE is performed with a superselection technique, significant deterioration of hepatic function after TACE is rare (Chung et al. 2011; Kudo et al. 2014a; Takayasu et al. 2006). Therefore, TACE could be applied repeatedly for the treatment of RPRTs if there is no stage progression. Some patients may be treated with TACE even if stage progression occurs (Chung et al. 2011).

In this cohort, RFA cases were relatively rare because National Insurance reimbursement was not feasible at that time. Recently, the number of cases of RFA as the initial treatment has been rapidly increasing after an insurance policy change. Transplantation as an initial treatment is also relatively rare in this cohort. In Korea, liver transplantation may not be acceptable to patients as an initial treatment because most cases are living-donor transplantation, which is provided by the family (Chen et al. 2013; Lee et al. 2016). After systemic chemotherapy including sorafenib, most patients have experienced RPRT and most have several subsequent treatments with other cytotoxic chemotherapy agents or TACE; about 40 and 20% of patients received a second and a third treatment, respectively (Fig. 6a; Table 4). In the recent cohort under construction, changes in the era of sorafenib are noted concerning systemic chemotherapy. Now that regorafenib has succeeded as a second-line treatment after sorafenib (Bruix et al. 2017), a major change in the subsequent treatment pattern is expected.

Although this study has certain limitations in that it is a practice-based observational study with wide heterogeneity of RPRTs, our findings provide the novel insight that the outcome of HCC is a result of cumulative multiple treatments. Our results provide a key cornerstone to discuss what the primary goal of treatment in HCC should be. The Panel of Experts in HCC-Design Clinical Trials recommend that the primary endpoint for phase 3 studies that assess primary HCC treatment is survival and clinical trials of locoregional therapies should report a time-to-local recurrence endpoint (Llovet et al. 2008). As seen in this study, time-to-local recurrence, or recurrence-free survival rather than overall survival seems to be more meaningful in the efficacy evaluation of local treatment, if we recognize that in real-world clinical practice, multiple subsequent treatments are provided after the initial local treatment. Even in patients managed with initial systemic chemotherapy, a part of patients received multiple subsequent treatments. It is time to actively consider prospective studies evaluating sequential and/or combination treatment of HCC.