Introduction
Hepatocellular carcinoma (HCC) primarily affects patients with chronic liver disease. Patients with chronic hepatitis or cirrhosis secondary to viral hepatitis B or C and alcoholism are at the highest risk of developing HCC. Clinical practice guidelines[
1,
2] recommend surgical resection, transplantation or percutaneous ablation to treat solitary HCC in patients with adequate liver function.
Stereotactic ablative body radiotherapy (SABR) is an emerging treatment modality that enables delivery of ablative doses to tumors with acceptable toxicity. Several single institution phase I and phase II trials of SABR for liver tumors have reported promising results and high local control rates of over 90%[
3‐
6]. Additional multi-institutional prospective studies could establish this as an alternative treatment for patients who are ineligible for other local treatments for solitary HCC. However, there are wide variations in dose and fractionation due to different prescription policies and treatment methods across SABR series that have been published to date[
3,
4,
7‐
9].
We assessed inter-institutional variations in SABR planning to treat HCC and run a benchmark in preparation for a multi-institutional prospective study.
Discussion
SABR is expected to be a treatment option indicated for HCC patients who are ineligible for surgery or radiofrequency ablation. However, various dose prescription and treatment planning strategies are currently used by different groups[
3,
4,
7‐
9] and an optimal dose has not been determined.
For trials involving advanced radiation therapy techniques, the minimum acceptable degree of protocol compliance must be described to mitigate unacceptable variation between institutions[
11]. This study revealed many differences in planning and treatment protocols at several institutions (Table
1). In conducting a clinical trial of SABR, treatment planning can vary based on multiple factors, such as planning CT, target volume delineation, beam arrangement, dose calculation algorithms and prescription point[
12]. It is difficult to unify the method to acquire planning CT because treatment modalities vary among institutions. In regard to measures to account for respiratory movement, it is important to set up some criteria with acceptable range in preparing for a protocol. Calculation algorithms have influence on dose distribution when some beams pass through materials with air density, therefore newer generation calculation algorithms such as superposition or comparable algorithm may be preferable. Variations in target delineation have been reported by several investigators[
13,
14]. Delineation of HCC can also be affected by scanning protocol of triphasic CT, with or without use of MRI. In this study, identical target volumes were intentionally delineated prior to data distribution to eliminate variation and enable direct comparison of DVH parameters used in different planning methods.
In the practice plan, PTV dose distribution varied among institutions due to differences in prescription dose and prescription point. A uniform prescription dose of 40 Gy in five fractions administered as D95 were required in protocol plan 1. As a result, there was a significant gap between institution A and the other three institutions (Figure
2d-f) due to different prescription methods because institution A prescribed at the 70% isodose level relative to the global maximum dose, while the other three institutions prescribed at the isocenter.
There are two different concepts regarding dose within the target in SABR. One maintains dose homogeneity within the target, which is generally prescribed at the isocenter. The concept has been widely utilized in Japan. In the other concept, dose is prescribed at the PTV margin and does not maintain dose homogeneity[
15]. In the latter concept, there is another variation in prescription method which provides more flexibility and is more treatment planning system and technique independent. In a randomized phase III trial of Radiosurgery Or Surgery for operable Early stage (stage 1A) non-small cell Lung cancer (ROSEL) study, the dose prescription was based on D95 of the PTV receiving at least the nominal fraction dose, and D99 of the PTV receiving a minimum of 90% of the fraction dose. The dose maximum within the PTV should preferably be between 110% and 140% of the prescribed dose. The location of the treatment plan normalization point can be left to the institutions preference[
16].
In conventional radiotherapy, International Commission on Radiation Units and Measurements (ICRU) Report 50[
17] recommends a uniform dose to the target volume within −5% to +7% of the prescribed dose with a radiation dose at the reference point, which is generally the isocenter. In contrast, dose heterogeneity within the target is acceptable in SABR for targets that do not involve functional normal tissue, as outlined in best practice guidelines by the American Association of Physicists in Medicine (AAPM) Task Group 101[
18]. By ignoring dose homogeneity within the PTV, tight conformity with steep and isotropic dose fall-off and high dose delivery to the target volume can be achieved in addition to a simultaneous reduction in the normal tissue dose[
19]. In this study, institution A prescribed the dose at a 70% isodose line. Accordingly, protocol plan 2 required dosing to the 70% isodose line of the global maximum dose within 95% of the PTV. As a result, GTV and PTV doses were increased in protocol plan 2, while the normal liver dose decreased compared with protocol plan 1.
Improvements in DVH were primarily attributed to prescribing the dose at the 70% isodose line. Widder et al.[
20] reported that dose prescription in SABR for lung cancer at isodose levels between 50% and 70% of the dose at the isocenter resulted in a lower dose to surrounding tissues and lungs compared with an 80% isodose level. Although there are no reports on optimal isodose levels for SABR to treat HCC, prescription to the 70% isodose level rather than an isocenter improved dose distribution in the current study.
Differences in DVH parameters between institutions, particularly in the V20 and MLD in the practice plan and protocol plan 1, were grouped according to static and dynamic beam arrangements. Institutions A and B, which used a dynamic conformal arc, had lower V20 and MLD values than institutions C and D, which used non-coplanar static beams. Although a greater number of beams generally results in better conformity and dose distribution gradients, six to eight non-coplanar static beams sufficiently fulfilled the planning requirement in protocol plan 2. Prescription at the 70% isodose line successfully reduced the dose to surrounding normal tissues regardless of different beam arrangements.
In addition to improving planning quality, the current study shared treatment strategies at various institutions. After data collection, researchers from the institutions discussed their treatment planning policies and compared study results. With respect to dose distribution at each institution (Figure
4), institution C selected beam directions that increased non-irradiated normal liver volume as much as possible, while institutions A and B were not as concerned about low doses to the normal liver. Institution D indicated that avoiding as much of the gastrointestinal tract as possible rather than dose reduction in the normal liver was important. Multi-leaf collimator margin size also varied among institutions, from uniform margins around the PTV (generally 5 to 10 mm) to variable margins in three-dimensional directions, due to different dose prescription policies. This information, which was discussed in person, can favorably influence researchers toward improved treatment planning. This study uncovered possible variations in SABR planning among participating institutions and would help to prepare for a comprehensive protocol as well as to define credentialing and evaluation criteria beforehand. In multi-center clinical trials, maintaining protocol treatment quality by minimizing these variations is a challenge. Therefore, this type of study prior to establishing a protocol is in agreement with the goals of quality assurance (QA) programs that attempt to minimize variations. According to a meta-analysis and a systematic review, radiation therapy protocol deviations are associated with increased risk of treatment failure and overall mortality[
21,
22]. Well-organized QA programs will result in improved reliability of clinical trials and quality of practice[
23].
As limitations, the current study only compared treatment planning methods directly related to SABR and did not consider other factors that could affect treatment, such as methods of planning CT acquisition, contouring of at-risk targets and organs, patient fixation and respiratory gating. Calculation algorithms were not a key focus, which could influence dose distribution under specific conditions. The impact of variations in calculation algorithms based on dose distribution should be further evaluated.
Competing interests
AT received grant from Varian Research Collaboration Program. SI received fees from Elekta K.K. for consultancy for the company.
The other authors declare that they have no competing interests.
Authors’ contributions
TE analyzed data, drafted and revised the manuscript. AT, NS, SI, TK, YM, YM, YI revised the manuscript critically. YO prepared patient data sets for this planning study, collected and analyzed data. AT, YO, TK, SO, TN, YM, MN, YM, SY performed treatment planning. All the authors participated in this study design and discussion all along this study, read and approved the final manuscript.