Abstract
Background: This study aimed to assess the need to consider microscopic invasion in terms of treatment planning in stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma and elucidate the appropriate clinical target volume (CTV) margin. Patients and Methods: A total of 121 patients (with 146 liver tumors) who underwent SBRT between July 2007 and August 2016 were analyzed, regarding overall survival and local control (LC). Results: The 2- and 5-year LC rates were 91.5% and 89.8%, respectively. Planning target volume (PTV) margin <8 mm was associated with poor LC. Of the 77 patients with PTV margin of <8 mm, age <75 years was associated with poor LC, while alpha-fetoprotein (AFP) ≤20 ng/ml was associated with good LC. Conclusion: In patients with high AFP levels, there is a possibility of microscopic invasion around the tumor, suggesting that LC may be improved by adding an additional clinical target volume margin to the gross tumor volume.
- Stereotactic body radiation therapy
- intensity-modulated radiotherapy
- stereotactic ablative radiation therapy
- hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common primary hepatic tumor, developing in approximately 90% of patients with advanced cirrhosis (1). As local treatment for HCC, surgical resection and radiofrequency ablation (RFA) therapy have been established; however, these interventions are often complicated by certain factors, such as the liver reserve capacity, localization of the tumor, and degree of progression (2, 3). Promising results have been achieved using stereotactic body radiation therapy (SBRT), which allows for administration of high radiation doses to the primary tumor, while sparing the normal liver tissue (4-10). Therefore, the use of radical radiotherapy for unresectable HCC has increased dramatically in recent years (11-20). In addition, the excellent outcomes observed after liver SBRT have recently been reported to be comparable with those of RFA treatment (21).
Consequently, as the prescribed radiation doses are escalated, and particularly the high fractional doses associated with SBRT, it is becoming increasingly important to improve the accuracy of the target volume definition. In addition, due to the more accurate organ specification provided by image-guided radiation therapy (IGRT), the planning target volume (PTV) margin can now be optimized, with a minimization of patient set-up uncertainties.
Advanced radiation therapy techniques, including IGRT, tumor-tracking, and respiratory gating, may allow for a reduced PTV margin for SBRT. Furthermore, modern imaging techniques enable a more precise delineation of the gross tumor volume (GTV). However, none of the available imaging techniques can currently robustly identify the clinical target volume (CTV). Furthermore, there is a potential danger associated with IGRT techniques in terms of creating a false sense of confidence regarding margin reduction around the CTV (22). In addition, under normal circumstances, a CTV margin would not be added to the GTV when using SBRT (23). However, it remains poorly understood whether a CTV margin is actually necessary.
With this in mind, the purpose of the present study was to elucidate the optimal CTV margin from clinical data of patients receiving SBRT for HCC.
Patients and Methods
Patient selection. The present study was conducted according to the principles of the Declaration of Helsinki. The Institutional Review Board of Miyakojima IGRT Clinic (Osaka, Japan) approved the data collection and analysis (approval no. 9), with written informed consent for radiotherapy being obtained from all patients. The HCC diagnosis was established based on the results of imaging studies using computed tomography (CT) or magnetic resonance imaging (MRI), since pathological confirmation was not feasible for SBRT candidates. The exclusion criteria were as follows: (i) patients with insufficient blood collection data before SBRT; (ii) patients whose follow-up was discontinued within 12 months after SBRT; and (iii) patients who had manually reduced PTV margins to protect the gastrointestinal tract. As a result, a total of 146 liver tumors from 121 patients who received SBRT at Miyakojima IGRT Clinic between July 2007 and August 2016 were analyzed. The patient characteristics are shown in Table I. Between July 2007 and April 2013, we treated 69 tumors using a PTV that was created by adding an 8-mm uniform expansion to the internal target volume (ITV) in all directions. However, based on the clinical results and an evaluation of tumor position reproducibility by IGRT techniques, from May 2013 onward, for 77 tumors, the PTV margin was generated by adding a 4- or 6-mm uniform expansion to the ITV (4-mm or 6-mm expansion for tumors near and far from the vertebral bodies, respectively).
SBRT technique. SBRT for HCC treatment was performed as previously described (24). Briefly, CT scans for treatment planning were obtained using a 4 slice BrightSpeed Excel™ (GE Healthcare Bio Sciences Corp., Pittsburgh, PA, USA) scanner between July 2007 and June 2014, and a 64 slice SOMATOM Definition AS Open RT Pro edition (Siemens Healthcare, Munich, Germany) scanner from July 2014 onward. MRI images for treatment planning were obtained using a SIGNA EXCITE HDx 1.5-T (GE Healthcare Bio Sciences Corp.) MRI scanner. Contrast enhanced, 4 dimensional CT scans and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid based contrast-enhanced MRI images were used to determine the GTV. The CTV margin was not added to the GTV at our Institution. The ITV was defined as the superposition of all CTVs from the different respiratory phase data of the 4-dimensional CT. The PTV was created by adding a 4-, 6-, or 8 mm margin in all directions to the ITV. The prescribed radiation doses were documented at the reference point using conformal beams in 38 tumors, or were prescribed to deliver the tumor dose to 95% of the PTV using intensity-modulated radiation therapy in 108 tumors. There was no statistically difference in a dose–volume histogram within the target volume, even with any irradiation technique. We administered a prescription dose equivalent to a biological effective dose10 of approximately 80 Gy. Fractioned regimens were scheduled to spare organs at risks, including the normal liver tissue. SBRT was performed using a 6 MV linear accelerator (Novalis, BrainLAB AG, Munich, Germany).
Follow-up. Local control (LC) was defined as the absence of local failure. The LC and overall survival (OS) times were defined as the intervals between the start of SBRT and the date of diagnosis of local failure or the date of death, respectively. Local failures were identified by experienced physicians using CT and MRI, and defined as any regrowth of the target tumor or the appearance of tumor staining in the target tumor on contrast enhanced images. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 3.0 (25).
Statistical analysis. Quantitative variables are described as the median and range, and qualitative variables as percentages. The OS and LC were calculated using the Kaplan–Meier method, and statistical differences were evaluated using the log rank test. Cox proportional hazards models were used to evaluate the factors affecting the LC and OS. The results are reported as the hazard ratio (HR) and corresponding 95% confidence interval (CI). Variables with p-values of less than 0.20 in the univariate analyses were analyzed in the multivariate models. Multivariate analyses were performed by Cox regression. All statistical analyses were performed using JMP software version 12.2.0 (SAS Institute, Cary, NC, USA). p-Values of less than 0.05 were considered statistically significant.
Results
Patient eligibility and tumor characteristics. Of the 121 eligible patients, 11 patients received SBRT for two different lesions simultaneously, 11 patients received SBRT for two different lesions that occurred sequentially, and one patient received SBRT for three different lesions that occurred sequentially. The median follow-up duration after SBRT for all patients was 21 months (range=2-70 months).
Local control. Considering all lesions, the LC rates were 91.5% and 89.8% at 2 and 5 years, respectively (Figure 1a). Multivariate analysis showed that a PTV margin <8 mm (HR=13.04, 95% CI=1.18-143.70 p=0.036) was associated with poor LC (Table II). The 2-year LC rates were 97.8% and 88.5% in the 8-mm and <8-mm margin groups, respectively (p=0.034) (Figure 1b).
Survival. For patients overall, the OS rates were 66.8% and 43.7% at 2 and 5 years, respectively (Figure 2a). Multivariate analysis showed that a performance status of 0 was associated with good OS (HR=0.474 95% CI=0.246-0.914 p=0.026), while a previous history of undergoing transarterial chemoembolization was associated with poor OS (HR=2.520, 95% CI=1.202-5.283 p=0.014) (Table III). The 2-year OS rates were 73.7% and 57.0% in the groups with performance status 0 and ≥1, respectively (p=0.052) (Figure 2b). The 2-year OS rates were 76.2% and 59.0% for patients with and without a history of transarterial chemoembolization, respectively (p=0.037) (Figure 2c).
Toxicity. In terms of toxicity, two patients (1.5%) experienced cholangiectasis, one of which was grade 3. Two patients (1.5%) experienced grade 1 radiation pneumonitis, with both treated sites being segment 7 of the liver. One patient (0.7%) experienced radiation mucositis. One patient (0.7%) experienced a grade 1 rib fracture, with this patient having been irradiated for a nearby lesion from the initial treatment. Finally, 34 patients (25.2%) experienced ascites, three (2.2%) experienced jaundice, and two (1.5%) experienced pleural effusion. Hematological toxicities were not observed in patients who exhibited hematological abnormalities prior to radiotherapy, with no apparent changes from baseline.
Patient and treatment characteristics (121 patients and 146 tumors).
Local control rates from the time of stereotactic body radiotherapy treatment in all patients (n=146) (a) and according to planning target volume margin (b).
PTV margin. We further analyzed 77 patients who were treated using PTV margins of <8 mm. As a result, multivariate analysis showed that age <75 years was associated with poor LC (HR=15.06, 95% CI=1.20-189.80 p=0.036), while alpha-fetoprotein (AFP) ≤20 ng/ml was associated with good LC (HR=0.125, 0.021-0.758 p=0.024) (Table IV). Among these patients, the 2-year LC rates were 96.0% and 80.3% in those aged ≥75 years and <75 years, respectively (p=0.013) (Figure 3a). The 2-year LC rates were 97.8% and 69.2% in the groups with AFP ≤20 ng/ml and >20 ng/ml, respectively (p=0.007) (Figure 3b).
Discussion
As local therapy, surgical resection and RFA are well-established treatments for HCC. Several factors can make these interventions more challenging, including poor liver function, ill-defined anatomical barriers and vessels from ultrasound, and tumors with portal infiltration. Modern radiotherapy techniques, including SBRT, have recently attracted increasing attention for various malignancies, including as treatment with curative intent. Moreover, SBRT has recently been reported to be equally effective as RFA for HCC (21).
In contrast to these results, the recurrence of HCC tumors after SBRT is hard to predict since there are multiple, complex factors associated with recurrence and disease progression. Accordingly, in the present study, there were many variables significantly related to LC in the univariate analysis for all patients; however, the PTV margin was the only independent factor in the multivariate analysis. This result implies that reducing the PTV margin results in a higher risk of recurrence. Engels et al. reported that patients with prostate cancer who underwent radiotherapy with a reduced PTV margin, positioned with implanted markers, had poorer treatment outcomes than those without the implanted markers (5-year freedom from biochemical failure rate: 58% vs. 91%, p=0.02). This result shows the potential danger associated with image guidance techniques creating a false sense of confidence regarding margin reduction around the CTV (22). Recurrence is another important treatment outcome that must be considered when reducing the PTV margin. Therefore, we examined a subgroup of 77 patients whose PTV margins were <8 mm. As a result, age and AFP levels were the only independent factors associated with LC in the multivariate analysis.
While modern imaging techniques can enable precise delineation of the GTV, none can robustly detect the microscopic extent of HCC. Moreover, although the CTV is defined as the volume that includes both gross and microscopic extensions of the malignancy, the CTVs used in SBRT are frequently equal to the GTV (23). At present, the necessity for a CTV margin remains under debate.
The extent of microscopic disease from liver tumors and the implications for radiotherapy are limited and remain unknown. In addition to direct invasion, HCC is also associated with a high risk of daughter nodules around the tumor tis sue, which can result in locoregional recurrence (26). Wang et al. reported a potential margin of microscopic disease beyond the gross tumor of 8.0 mm; however, 94.7% of patients with HCC had microscopic extensions ≤3.5 mm, with a median of 1 mm (27). In another report by the same group, 149 resected HCC specimens were found to have a mean diameter of 5.8 cm (range=1.0-22.0 cm), with microinvasion not observed in 47.0% of patients (28). Moreover, microinvasion distances ≤2 mm were found in 94.5% of patients with AFP levels <400 μg/l. AFP is an important predictor of prognosis and recurrence (29-32). Many authors have reported AFP to be an independent predictor of poor prognosis, even in patients receiving curative resection (33-36). These findings were supported by the outcome data in our study, in which a high prevalence of microscopic extension was noted in patients with high AFP values.
Factors associated with local control of 146 tumors.
Factors associated with overall survival in 121 patients
Factors associated with local control in 77 patients treated using a planning target volume (PTV) margin <8 mm.
Overall survival from the time of the first stereotactic body radiotherapy treatment in all patients (n=121) (a), and according to performance status (PS) (b), and history of previous transarterial chemoembolization (TACE) (c).
Local control rates in 77 patients treated with a planning target volume margin <8 mm. The local control rates were calculated from the time of the first stereotactic body radiotherapy treatment according to age (a) and alpha-fetoprotein (AFP) level (b).
This study has some limitations. Firstly, this was a retrospective, single-institution study and not a randomized trial. Therefore, the patients were not controlled with respect to variable prognostic factors. Nevertheless, all patients met the inclusion criteria of prospective studies and received consistent SBRT treatment, which allows for selection bias to be controlled to a considerable degree. In addition, we analyzed a relatively large number of patients with a reliable follow-up period. Moreover, to the best of our knowledge, this is the first report of the possible requirements for CTV margins derived from clinical data after SBRT treatment for HCC. A second limitation is that the biological characteristics of tumor microinvasion were unclear due to insufficient pathological examination in the present study. A future comparison study between clinical and histological data, using surgically resected specimens, may validate our findings.
In conclusion, in this study, we analyzed the clinical outcomes of patients receiving SBRT for HCC, focusing on the irradiation volume rather than the magnitude of the dose. As a result, it was revealed that the risk of recurrence was increased by reducing the PTV margin and was associated with elevated AFP level. In patients with high AFP levels, there is a possibility of microscopic invasion around the tumor, suggesting that the LC may be improved by adding an additional CTV margin to the GTV.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number JP17H04119. The Authors would like to thank Editage (www.editage.jp) for English language editing.
Footnotes
Ethics approval and consent to participate
The study design was approved by the Medical Corporation SHINMEIKAI Ethics review board in June 2016 (Approval No. 9) and retrospectively registered.
Conflicts of Interest
The Authors declare that they have no competing interests in regard to this study.
- Received October 26, 2017.
- Revision received November 12, 2017.
- Accepted November 16, 2017.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
