Knowledge-based IMRT planning for individual liver cancer patients using a novel specific model

Liver cancer is the fifth most common type of cancer and the third leading cause of cancer-related death worldwide. Consequently, liver cancer is an issue that needs to be urgently addressed [1]. Intensity-modulated radiotherapy (IMRT), based on computerized treatment plan optimization, permits the delivery of higher therapeutic doses to the target volume, while reducing the impact on adjacent normal tissue [2]. However, each step in the clinical workflow, from contouring to delivery, contains variability and uncertainties that ultimately translate into inconsistencies and inefficiency [3, 4].

A variety of solutions were studied, to reduce the variability present the back and forth between plan creation and approval [5‐10]. Among these methods, knowledge-based planning is the most commonly used. It can predict achievable planning target volume (PTV) and DVHs for organs-at-risk (OARs) for prospective patients, utilizing models built using a library consisting of previous plans [11‐19]. Chanyavanich et al. [18] used an algorithm based on mutual information to identify similar patients, and then generate new plans for the target cases. Zhu et al. [20] developed an evaluation tool for quantification, that generates DVHs based on organ volumes, as well as distance-to-target histograms (DTH), using a machine learning approach. Wu et al. [16] predicted DVHs of target cases by establishing the overlap volume histogram (OVH). Based on that, Varian developed the Geometry-based Expected Dose (GED) algorithm and build a commercially available knowledge-based planning solution (RapidPlan, Varian Medical Systems, Palo Alto, CA), which semi-automates the treatment planning process. It uses a library of previous plans to build a model that can achieve OAR DVHs prediction range for a new patient, and subsequently guides the volumetric modulated arc therapy (VMAT) or IMRT optimization process using the Eclipse treatment planning system, along the inferior boundary of the DVH-prediction range. Previous work suggested that RapidPlan achieved clinically acceptable plans for different treatment sites [21‐27]. To verify whether a model is suboptimal, Hussein et al. [24] suggested that there should be an insignificant effect on resulting plan quality when removing dosimetric outliers from the model training set. Similarly, Delaney et al. [28] found that statistical outliers removed from or added to models (5-10 outliers) had only a marginal impact on plan results. In a study by Tol et al. [27], a model created using 30 plans generated plans that were similar to those in a model based on 60 plans, when their plans were selected arbitrarily from all of 90 plans.

In this study, two models were developed, one general model and one specific model. All the studies mentioned above are based on the general model, which suits a wide variety of patient cases. However, the prediction ability of specific models tailored for specific patient cases, with specific anatomical features, has not been investigated. The aim of this study was (1) to evaluate the accuracy of RapidPlan prediction capability in IMRT (Eclipse, Varian) plans for individual liver cancer patients by using model libraries consisting of different total number of plans, with different similarity; and (2) to investigate the prediction capability of the general model vs. our specific model.

All knowledge-based plans were deemed to conform with the liver IMRT clinical protocol used at our institution, regarding dose-volume constraints. Table 5 and Fig. 1 summarize the RapidPlan results for the evaluation group, averaged over all patients, whereas Fig. 2 shows results for individual patients.

The comparison of RP-plans to M-plans revealed that RP-plans significantly improved V_95% of PTV (RPG-plans vs. RPS-plans vs. M-plans: 98.4% vs. 98.4% vs. 97.9%). The D_98%, D_2%, HI and CI values of PTV were improved, although most differences were not significant. For the OAR, RP-plans had significantly more sparing of the right kidney (Dmean: RPG-plans vs. RPS-plans vs. M-plans, 3.9 Gy vs. 3.8 Gy vs. 4.5 Gy). For the normal liver, RPG-plans delivered similar doses, while RPS-plans delivered higher doses than those delivered by M-plans (Dmean: RPG-plans vs. RPS-plans vs. M-plans, 10.8 Gy vs. 11.1 Gy vs. 10.8 Gy). No difference was found between RP-plans and M-plans in the maximum dose to the spinal cord.

With respect to RapidPlan models, there are different. For the PTV coverage, the V_95%, D_98%, D_2%, and HI values were very similar, but RPS-plans had better CI values (1.117 vs. 1.102, p <  0.05). For OAR doses paring, RPS-plans delivered a lower dose than the maximizing point doses to spinal cord (19.0 Gy vs. 20.7 Gy). Regarding the dose sparing for the right kidney, RPS-plans were better than RPG-plans, especially with V_20Gy (4.5% vs. 5.6%, p <  0.05), although others were very similar. Figure 1 shows the advantages of RPS-plans in the DVH curves for the right kidney and spinal cord. For normal liver, RPS-plans delivered a higher dose (Dmean: 10.8 Gy vs. 11.1 Gy, p <  0.05; V_20Gy: 20.1% vs. 22.6%, p <  0.05), although all RPS-plans were deemed conform with the liver IMRT clinical protocol. However, for certain individual patients, such as patient 11 (Fig. 2), RPG-plans are better for normal liver sparing.

Fogliata et al. [21] tested RapidPlan for the optimization of RapidArc plans, and generated clinically acceptable plans for hepatocellular cancer radiotherapy. This shows that the model is reliable when no special selection criteria are applied to generate the training, i.e. including all cases, for which the only requirement is to be clinically acceptable. However, liver cancer has high variability in tumor size and position, and the general model (Model-G) may have limited accuracy for special patients. Thus, a specific model (Model-S) was established in this study, using plans with specific anatomical features for individual patients. For Model-G, Jol et al. [27] demonstrated that 30 plans were sufficient for building a general model. However, in this study, Model-G consisted of 60 patients, to ensure the variety of the data, whereas Model-S consisted of 30 patients, to guarantee high similarity in the geometry of the region of interest. The scope of the minimum reasonable sample size will be addressed in further studies. Nevertheless, Jim et al. [27] observed that more OAR outliers did not necessarily translate into a worse OAR dose. Hussein et al. [24] showed that there were insignificant effects on resulting plan quality when removing dosimetric outliers from the model training set.

In this study, we evaluated the prediction capability of two models (Model-G & Model-S) in knowledge-based IMRT planning for individual liver cancer patients. Pooled results show that, generally, RapidPlan can improve planning quality and efficiency for liver IMRT, and the prediction ability of the two models with different configurations have a remarkable difference. RP-plans significantly improved the target coverage and the sparing of the right kidney compared to the M-plans. The advantages of some RP-plans compared to the M-plans may be due to challenges in performing an interactive planning of plans that contain many OARs optimally and consistently in a limited number of iterations. Comparison of the two models revealed that Model-S improved the CI and delivered lower dose to the right kidney (V_20Gy) and spinal cord, while Model-G delivered lower dose to normal liver tissue. This indicates that the RP-plans are sensitive to the configuration of the model library and the anatomical characteristics of the patient that knowledge-based planning is performed on. The degree of similarity of the cases that make up the model library has a significant effect on the predictive capability of the model.

The selection criteria for establishing the specific model in this study was that the distance from PTV to the right kidney should measure less than 3 cm. We expected to better protect the right kidney, while improving the target coverage, and the experimental results show that Model-S achieved substantial gains compared to Model-G. The pooled data (Table 5 and Fig. 2) shows that RPS-plans slightly improved the right kidney sparing. However, for certain individual patients, RPS-plans had a significant advantage when compared to RPG-plans. For example, in patient 3 (Fig. 1), high variability in right kidney sparing was obtained, RPS-plans decreased V_10Gy, V_15Gy, V_20Gy and Dmean to the right kidney compared to RPG-plans. In patient 11 (Fig. 2), RPG-plans are better for normal liver sparing. From an anatomical point of view, the reason may be that the PTV was small (24 cm3), and located in the inferior segment of the left side of the liver. In addition, it is encouraging that RPS-plans significantly reduced the maximum dose of the spinal cord compared to RPG-plans. This may be due to the fact that the spinal cord has a relatively fixed geometry, adjacent to the kidneys. Therefore, the specific model has great potential in clinical applications for individual patients and we will focus on this.

Some of the findings indicate the different tradeoffs in knowledge-based planning results. According to the pooled results of dosimetry, Model-G is better than the Model-S for normal liver sparing. The following factors may contribute to this: (1) the large size of the liver, only considering the cases with short distance between PTV and the right kidney may not meet the requirements for livers located far away from right kidney; (2) Model-G consisted of more cases, which increases geometric heterogeneity. It is conceivable that further improvements could be made and/or some complex tradeoffs should be addressed. Therefore, some parameters may be adjusted during the optimization process. It is worth noting that a review of plans used for RapidPlan models is still required.

This study shows that RapidPlan can create high quality plans and significantly improve the planning efficiency of IMRT for individual liver cancer patients. Furthermore, these findings demonstrate that the specific model can result in more sparing of OAR, while increasing the conformity index of PTV for liver cancer. Although more systematic studies are needed before a broad clinical application of the proposed methodology, this specific model might be considered as a way to improve the planning quality. Further studies are needed to determine the optimal composition of model libraries, including the relationship between model composition and dosimetry of subsequent plans.