There are differences between China and the Western world regarding hepatocellular carcinoma in the following ways:
This retrospective study included thirty-three patients with recurrent or residual HCC from the Radiotherapy Department of Ruikang Hospital of the Guangxi Traditional Chinese Medicine University who were treated with SBRT between June 2008 and July 2015. All patient medical records were carefully reviewed. Inclusion criteria were as follows:
The median age of 33 patients was 55 years (range: 42–75), and 75.8% were male. All patients had either recurrent (
Patient characteristics.
Characteristics | Total |
---|---|
Gender ( |
|
Male | 25 (75.8) |
Female | 8 (24.2) |
Age (years) | 55 (42–75) |
Reason for uncontrolled disease ( |
|
Recurrent | 12 (36.4) |
Residual | 21 (63.6) |
AFP before CyberKnife (ng/mL) | |
>400 | 5 (15.2) |
>200, <400 | 8 (24.2) |
>50, <200 | 13 (39.4) |
>4, <50 | 7 (21.2) |
Clinical staging |
|
I | 4 (12.1) |
II | 15 (45.5) |
III | 14 (42.4) |
The livers of all patients were implanted with 3-4 fiducials (99.9% pure gold particles) one week before the CT location scan. Fiducials localize to the tumour, within 2 cm, and no three gold fiducials can be coplanar. The tumour area was identified and outlined using a plain CT scan image as the basis to fuse CT/MR/DSA enhanced images. A plan was designed with 4D-CT treatment simulation using the CyberKnife® Robotic Radiosurgery System: X-sight Fiducials Tracking System (Accuray Incorporated, Sunnyvale, CA, USA). Target and critical structures (spinal cord, lung, heart, oesophagus, remaining healthy liver, stomach, intestine, and kidneys) were contoured. The GTV (gross target volume) was defined as a tumour visible on the CT/MR scan. The GTV was expanded by 3–5 mm to form the PTV (plan target volume). All patients were treated with a total dose of 39–45 Gy/3–5 fractions. The mean target volume was 128 cm3 (range: 36–236 cm3). Plans were devised so that the prescribed dose was the isodose line encompassing >96% of the PTV. No more than 3% of the PTV was to receive <94% of the prescribed dose. Patients were treated with the Accuray CyberKnife (1310 Chesapeake Terrace, Sunnyvale, CA 94089, USA). Dose constraints are shown in Table
Dose constraints for critical structures (treatment in 3–5 fractions).
Critical structures | Dose constraints |
---|---|
Spinal cord |
|
| |
Lungs (right + left) |
|
|
|
Heart |
|
| |
Oesophagus |
|
Remaining healthy liver |
|
|
|
Stomach |
|
Intestines |
|
Kidneys |
|
An index AFP level was recorded before TACE and before SBRT. AFP levels were also recorded at 3 months and 6 months after SBRT or at 1 month before death for those with a survival time less than 6 months.
Toxicity induced by SBRT was scored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Radiation-induced liver disease (RILD) was defined as an anicteric elevation in alkaline phosphatase of at least 2-fold the upper normal level (classic RILD) or elevated transaminases of at least 5-fold (nonclassic RILD), without progressive disease (PD) and the development of nonmalignant ascites [
Survival rates were calculated from the date of SBRT. Kaplan-Meier survival analysis was used to estimate overall survival (OS). SPSS® software version 17.0 (IBM Corp., Armonk, NY) was used for statistical analyses.
6 months after treatment, all patients underwent CT/MR examination. According to mRECIST criteria, there were 63 lesions in 33 patients. The degree of change was as follows: CR: 7 (18. 9%), PR: 33 (56. 9%), and PD: 14 (24. 2%). Objective response rate (CR + PR) was 84.8% (28/33) at 6 months.
The overall survival rates at 6, 12, 18, and 24 months were 87.9%, 75.8%, 57.6%, and 45.5%, respectively. Median overall survival was 19 months. The Kaplan-Meier curve for overall survival is presented in Figure
The Kaplan-Meier curve for overall survival.
The AFP index values of all patients were more than 400 ng/mL before TACE treatment. Those decreased at various rates after TACE. In the recurrent disease group, the AFP index of 4 patients fell to normal levels after TACE (chemiluminescence method: normal range is 0–4 ng/mL). However, the levels rose again after 3 months. The remaining patients had no reduction to normal levels. In the residual disease group, no patients had their AFP index decline to the normal range after TACE. At 3 months, AFP decreased by more than 75% in 51.5% of patients (17/33). Overall survival was significantly different (
Kaplan-Meier survival curve for overall survival stratified by significant difference (
8 patients (24.2%) had grade 1-2 transient fatigue, and 11 patients (33.3%) had grade 1-2 gastrointestinal reactions within 1 month. The symptoms were relieved or had disappeared after symptomatic and supportive treatment. No grade 3 or higher acute toxicities attributable to SBRT were found at 1 month (Table
Toxicity after SBRT at 1, 3, and 6 months.
Toxicity (grade) | 1 month | 3 months | 6 months | |||
---|---|---|---|---|---|---|
1, 2 | 3, 4 | 1, 2 | 3, 4 | 1, 2 | 3, 4 | |
Transient fatigue | 8 | 0 | 5 | 0 | 2 | 0 |
Gastrointestinal reactions | 11 | 0 | 6 | 0 | 2 | 0 |
Anemia | 3 | 0 | 2 | 0 | 2 | 1 |
Liver failure | 0 | 0 | 0 | 2 | 1 | 1 |
Gastrointestinal hemorrhage | 0 | 0 | 0 | 0 | 0 | 1 |
Tumour tissues could not be completely eliminated through TACE. Previous studies reported that approximately only 22%–50% of the tumour tissue was totally destroyed as determined by pathology examination. The rate of recurrence and metastasis correlated with tumour size, type, scope, biological characteristics, collateral circulation, liver function, embolization, lipiodol dosage, and deposition [
There is no uniform suggestion for the treatment of residual cancer or recurrence of liver cancer. Surgery, TACE/TAE, radiation therapy, radiofrequency ablation, freezing, microwave, alcohol, and other methods have been reported in the literature [
In our study, the overall survival rate was 87.9% (29/33), 75.8% (25/33), 57.6% (19/33), and 45.5% (15/33) at 6, 12, 18, and 24 months, respectively. Median overall survival was 19 months. Therefore, SBRT combined with TAE/TACE may be an effective complementary treatment approach.
Detection of serum alpha-fetoprotein (AFP) is used in clinical follow-up for high-risk population screening and cancer patients. Although 30% ~ 40% of patients have negative AFP detection in HCC of China [
Expanding the boundary outside the target area directly affects the control of tumours in radiotherapy. How far can liver cancer be confined to the liver in a subclinical tumour? A study on the range of foreign invasion of subclinical foci provided the basis for us to determine the imaging needs for the targeted tumour to evaluate the extent of expansion. After research, the tumour boundary was expanded 4 mm to include most of the area of invasion. If the tumour diameter was <5 cm, then 95% of tumour lesions could be treated by a 2 mm expansion [
In this study, 8 patients (24.2%) had grade 1-2 transient fatigue, and 11 patients (33.3%) had grade 1-2 gastrointestinal reactions within 1 month. The symptoms were relieved or eliminated after symptomatic and supportive treatment. No grade 3 or higher acute toxicities attributable to SBRT were found at 1 month. 2 patients experienced liver failure toxicity at 3 months, and 1 patient was relieved after treatment. 1 patient with enlargement of the spleen experienced gastrointestinal haemorrhage at 6 months. 3 patients experienced anemia at 1 month and one of them with long-term gastrointestinal reactions turned worse at 6 months. Most toxicities could be related to tolerance, which could be recovered after acceptance of treatment. In this study, patients with less adverse reactions may be associated with patients who have only selected Child-Pugh A class.
The liver has poor radiation tolerance. The occurrence of subacute radiation hepatitis is a standard for measurement. The total liver irradiation TD5/5 (minimum tolerance dose) is 25 Gy, and the whole liver irradiation level TD50/5 (maximum tolerated dose) is 40 Gy [
The major strengths of SBRT compared with conventional fractionated RT are as follows:
AFP was significantly elevated at the time of initial treatment. For patients receiving radiotherapy for recurrence of hepatocellular carcinoma, a 75% decline in AFP levels at 3 months may be a predictor of survival prognosis.
This study has several limitations. First, this was a retrospective single-center study. In this study, the short observation time, the small number of cases, and single-center study may affect the accuracy of the statistical test. Further prospective studies are needed to investigate the true effect of this novel treatment.
SBRT is a promising noninvasive and palliative treatment with acceptable toxicity for recurrent or residual HCC after TACE. And a >75% decline in AFP levels at 3 months may be a predictor of survival prognosis.
The original anonymous dataset is available on request from the corresponding author at 35123948@qq.com.
Ethical approval was obtained from the Medical Ethics Committee of Ruikang Hospital, Guangxi, China. Experiments reported in this manuscript did not involve human samples and hence institutional review is not applicable.
All study participants or their legal guardians provided informed written consent about personal and medical data collection prior to study enrolment.
All the authors have no conflicts of interest related to the manuscript.
Erhua Yao and Jinghong Chen are equal contributors.
This study was supported by the Foundation of Guangxi Traditional Chinese Medical University China, no. RKZ201009.