Long-term Results of Palliative Stereotactic Radiotherapy of Barcelona Clinic Liver Cancer Stage C Hepatitis B–Related Hepatocellular Carcinoma

Hong Kong J Radiol 2021 Jun;24(2):81-6

 

 

Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong

 

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Hepatocellular carcinoma (HCC) is the fifth most common cancer in Hong Kong and sixth most common cancer worldwide. Eighty-nine percent of HCC cases are hepatitis B virus (HBV)–related. There were more than 1834 new cases in 2017. It was the third most common cause of cancer deaths in males in 2017.[1]

 

In the past, radiotherapy (RT) was seldom used in the management of HCC because of the high risk of liver toxicity. Recent studies have shown that stereotactic body radiotherapy (SBRT) in HCC has high control rates with low liver toxicities.[2] The Barcelona Clinic Liver Cancer staging system (BCLC) does not include radiotherapy as a treatment option. According to the BCLC treatment algorithm, stage C locally advanced HCC is treated with sorafenib.[3] With the advances in radiotherapy planning and delivery,[4] SBRT has been shown to be a safe and effective treatment for unresectable HCC.[5] [6] [7] The National Comprehensive Cancer Network Guidelines for HCC recommends RT as a locoregional therapy option.[8]

 

To the best of our knowledge, there is limited literature evaluating the role of SBRT in BCLC stage C HBV-related HCC. In our previous paper,[7] we reported radiotherapy details, short-term response, safety, and toxicity of palliative SBRT in 36 patients with HBV-related HCC. In the present study, we investigated the long-term efficacy of palliative SBRT for HBV-related HCC, as well as prognostic factors.

 

The data of consecutive patients with HBV-related BCLC stage C HCC, Child’s grade A to B8 without distant metastases treated with SBRT from 2008 to 2010 were retrieved retrospectively from hospital records in 2015. Eligibility criteria are described in our previous paper studying the impact of SBRT on liver function, with stages other than BCLC stage C excluded.[7]

 

Patients were prescribed 4 Gy per fraction to the planning target volume for five to 10 fractions.[7]

 

The data were analysed using SPSS (Windows version 23.0; IBM Corp., Armonk [NY], United States). Kaplan–Meier testing was used for univariate overall survival (OS) analysis with p < 0.05 considered significant. Cox regression was used for those variables that were significant in the univariate OS analysis.

 

Between January 2008 and December 2010, 32 consecutive patients with BCLC stage C unresectable HCC underwent SBRT at our institution (Table 1). These patients had large unresectable tumours, with median gross tumour volume (GTV) 509.5 cm³ (range, 2.2-3088 cm³). The tumour size was >10 cm in 15 (46.9%) patients and >15 cm in five (15.6%) patients. The median age was 58.5 years (range, 36-90 years). The majority (25 [78.1%]) of patients had a Karnofsky Performance status ≥80. In 2015, 30 patients were dead. Of the surviving two patients, one patient was alive for 5.9 years since treatment and censored on 12 October 2015 when data were collected. The other patient was lost to follow-up and censored on 26 March 2010, 1.5 years after treatment.

 

Table 1. Patient characteristics.

 

All 32 patients received 4 Gy per fraction with a median total prescription dose of 32 Gy (range, 20-40 Gy). Prior treatments included surgical resection or radiofrequency ablation in eight (25%) patients, and transarterial chemoembolisation (TACE) in 23 (71.9%) patients. Sorafenib was administered to six (18.8%) patients before SBRT and five (15.6%) patients after SBRT. No patient received steroid therapy. Details of the radiotherapy can be found in our previous study.[7]

 

The most common presenting symptoms were right upper quadrant pain and distension. After 3 to 4 weeks of radiotherapy, up to 90% of patients had significant pain relief.

 

Weight loss was defined as a decrease in body weight of ≥10% within the 3 months before treatment. In total, 12 (37.5%) of the 32 cases had increased body weight 1 month after radiotherapy; univariate and multivariate analysis showed that this was significantly associated with longer survival (p < 0.001 and p < 0.001) [Tables 2 and 3]. In all, 11 (34.4%) patients had unchanged body weight after radiotherapy and nine (28.1%) patients experienced weight loss. Univariate and multivariate analysis showed that patients with weight loss were observed to have shorter survival (p < 0.001 and p < 0.001) [Tables 2 and 3].

 

Table 2. Univariate analysis of variables associated with overall survival.

 

Table 3. Multivariate analysis of variables associated with overall survival.

 

Only 31 patients were evaluated for change of alpha-fetoprotein (AFP) levels after radiotherapy because of missing data for one patient. In total, 24 of 31 patients (77.4%) had elevated AFP level (>20 μg/L) at the time of treatment planning. Seven (22.6%) patients had reduction of AFP level that persisted for ≥3 months after radiotherapy. Seven (22.6%) patients had increased AFP level after radiotherapy, and 17 patients had decreased or static AFP level within 3 months after radiotherapy. In the seven patients with reduction of AFP level, median survival was 640 days (range, 398-2190 days). Univariate and multivariate analysis showed that reduced AFP level was significantly associated with longer survival (p = 0.041 and p = 0.018) [Tables 2 and 3]. In the seven patients with increased AFP levels after radiotherapy, median survival was 210 days (range, 101-1277 days).

 

The median survival of all 32 patients was 13.3 months (95% confidence interval [CI]=11.4 -15.2) The 1-year and 3-year survival was 62.5% (95% CI=53.9%-71.1%) and 14.1% (95% CI=7.74%-20.5%), respectively. Figure 1 shows the Kaplan–Meier curves illustrating factors affecting the OS. Figure 2 shows Kaplan–Meier curves illustrating OS of patients with HCC after SBRT.

 

Figure 1. Kaplan–Meier curves illustrate the overall survival of hepatocellular carcinoma: (a) with (green curve) or without (blue curve) change in Child–Pugh class; (b) with (green curve) or without (blue curve) persistent pain after radiotherapy; (c) decrease (blue curve), no change (green curve), or increase (yellow curve) in body weight (BW); and (d) alpha-fetoprotein (AFP) level decreased >3 months after radiotherapy (blue curve), decreased <3 months after radiotherapy or remained static (yellow curve), or increased after radiotherapy (green curve).

 

Figure 2. Kaplan–Meier curve illustrating the overall survival of hepatocellular carcinoma after stereotactic body radiotherapy.

 

In Hong Kong, HBV-related HCC is clinically different to hepatitis C–related HCC in Western populations. It is relatively larger in size and some of the tumours are encapsulated. In terms of efficacy, we previously demonstrated the response to and efficacy of moderate doses of hypofractionated SBRT for patients with unresectable HCC.[7] Most patients had significant pain relief after radiotherapy. In the present study, we investigated the long-term efficacy of palliative SBRT for HBV-related HCC.

 

With a median follow-up of 13.4 months, no patients developed progressive disease within 3 months after radiotherapy. The tumour response rate by mRECIST criteria was 69%. The median survival was 13.3 months. Que et al[5] published the treatment results of SBRT in patients with BCLC stage C HCC. Their series found the overall RECIST response rate was 81.5% (complete response, 36.2%; partial response, 45.3%), with a stable disease rate of 14.4%. Their median dose was 40 Gy in three to five fractions (range, 39-40 Gy). In the current study, the tumour size was much larger and the equivalent doses delivered in 2-Gy fractions (EQD2) Gy10 were lower than those in Que et al’s study (37.3 Gy10 vs 60 Gy10)[5] [Table 4]. Thus, the higher response rate in Que et al’s study may have been due to the smaller size of tumours as well as the higher radiation dose.[5]

 

Table 4. Efficacy of stereotactic body radiotherapy in patients with Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma.

 

The 1-year OS was 62.5%, and 3-year OS was 14.1%. The 1-year and 3-year OS rates in Que et al’s series were 56% and 28%, respectively.[5] The survival rates are comparable. Que et al’s response rate was much higher than that in our study.[5] Again, it may be due to the tumour size, which was much smaller than that in our study cases, or higher radiation dose. In univariate analysis, the present study showed that change in Child–Pugh class, pain at presentation, change in body weight, and change in AFP were significantly related to OS. TACE before RT was not significant but there was a trend to improve OS. In multivariate analysis, only change in body weight and decrease in AFP were significantly associated with OS.

 

This is the first study to show that patients with large unresectable HCCs can benefit from a small palliative dose. We found a significant survival benefit. It is worthwhile to administer palliative radiotherapy to large HBV-related liver tumours. An individualised dose prescription is safe up to a ceiling dose of 40 Gy in 10 fractions in accordance with dose constraints to uninvolved liver (V30 <40% and mean dose <28 Gy) and uninvolved liver volume >700 cm³ in a relatively large liver tumour (median GTV 509.5 cm³; range 2.2-3088 cm³).

 

Palliative SBRT with individualised dose up to 40 Gy in 10 fractions can be delivered safely to large unresectable HBV-related HCCs. The median survival rate of patients with BCLC stage C HCC in this study was 13.3 months. AFP reduction at ≥3 months and body weight gain after radiotherapy were positive prognostic factors. More prospective studies are warranted to confirm these results.