Complex Target Volume Delineation and Treatment Planning in Radiotherapy for Malignant Pleural Mesothelioma (MPM)

Introduction: Radiotherapy alone or combined with surgery and/or chemotherapy is being investigated in the treatment of malignant pleural mesothelioma (MPM). This study aimed to simulate a Volumetric Modulated Arc Therapy (VMAT) treatment of a patient with MPM. Materials and Methods: CT images from a patient with intact lungs were imported via DICOM into the Pinnacle 3 treatment planning (TP) system (TPS) and used as a model for MPM to delineate organs at risk (OAR) and both clinical and planning target volumes (CTV and PTV) with a margin of 5 mm. Elekta Synergy with 6 MV photons and 80 leafs MLCi2 was employed. VMAT plans were generated using two coplanar arcs with gantry rotation angles of 178˚ - 182˚, the collimator angles of each arc were set to 90˚, Octavius ® 4D 729 was employed for quality assurance while the calculated and measured doses were compared using VeriSoft. Results: A TP was achieved. The Gamma volume analysis with criteria of 3 mm distance to agreement and 3% dose difference yielded the gamma passing rate = 99.9%. The reference isodose was 42.75 Gy with the coverage constraints for the PTV D95 and V95 = 95.0% of 45 Gy. The remaining dosimetric parameters met the recommendations from the clinically acceptable guidelines for the radiotherapy of MPM. Conclusion: Using well-defined TV and VMAT, a consistent TP compared to similar ones from publications was achieved. We obtained a high agreement between the 3D dose reconstructed and the dose calculated. in for Malignant Pleural Mesothelioma (MPM).


Introduction
Malignant pleural mesothelioma (MPM) is a rare locally invasive (malignant), asbestos-related cancer [1] [2] that arises from the pleural surfaces, which encapsulate the lung and thoracic cavity. But, non-asbestos-related mesothelioma has been reported [3]. The typical growth pattern is along the pleural surface; but, infiltration of the lung and/or mediastinal and chest wall structures can occur in a more advanced stage while distant metastases outside the chest can result also [4]. Video thoracoscopy is the standard procedure for confirming the disease and obtaining sufficient tissue for the diagnosis; and the complete and detailed staging is mandatory for MPM categorization and for therapeutic decision making [5].
Technically, the radiotherapy treatment of MPM with intact lungs (i.e. no surgery) is very challenging not only due to the large size and the complex shape of the target volume (TV), but also because of the difficulty to distinguish the tumor from non-malignant radiographic abnormalities in addition to the need to spare organs at risk (OAR) within and in the vicinity including the ipsilateral lung to protect from ionizing radiation [7].
The accuracy of the set-up, tumor delineation, treatment plan generation and the treatment delivery itself are all conditioned by the ability to deliver a precise lethal dose of radiation to the tumor while minimizing dose to surrounding healthy structures. Thus, one of the most challenging aspects in this scenario is the accurate localization and delineation of the OAR and TV followed by the accurate development of a treatment planning (TP) prior to the actual radiation treatment delivery. Volumetric modulated arc therapy (VMAT) is a promising new treatment method which compared with conventional radiotherapy, has the potential to allow more effective sparing of normal tissues and OAR while providing conformal high-dose irradiation for improved target coverage and dose delivery [8]. However, there are limited reports available on VMAT.
The purpose of this study based on a simulation of a patient with MPM and intact lungs, was to manually delineate TV and OAR, then to plan an irradiation of TV around an OAR as the whole involved lung pleural space. A Volumetric Modulated Arc Therapy (VMAT) TP on a Pinnacle 3 treatment planning system (TPS) was used.

Tumor Board Indication-Imaging for Target Volume Delineation
The chain of procedures in a modern radiation treatment process that must be followed to guarantee the safety of the patients by making sure they are pro-A. I. Bogmis et al.
tected from overexposure to ionizing radiation is the following (Figure 1). Figure 1. Sequential process of planning and delivery of radiotherapy as applied at AMETHYST Radiotherapy Center, Otopeni, Romania.

Materials
The Volumetric modulated arc therapy (VMAT) system used at AMETHYST

Target Volume Delineation
For the treatment of MPM with radiotherapy, there is no published delineation guideline, thus, in this work, we followed target volume delineation (TVD) tips and instructions from the Target Volume Delineation Guidelines in Malignant Pleural Mesothelioma [9]. We delineated both lungs following the atlas for the delineation of OAR in thoracic RT proposed by the Radiation Therapy Oncology Group (RTOG) [10] [11] by using the pulmonary window. Thus, lungs considered as two distinct organs were delineated separately as right and left, and then both were combined as a single organ prior to the dose volume histogram (DVH) evaluation step. The chest wall and ribs were delineated by expanding 2 cm lateral, anterior, and posterior to the ipsilateral lung and excluding the lung itself starting 3 cm superior to the PTV and ending 3 cm inferior to it. The CTV included in the PTV was defined inside the chest wall and ribs contouring. That delineation (chest wall and ribs) includes intercostal muscles and nerves but excludes the vertebral bodies, sternum, skin, and other muscles. In addition to the CTV and PTV, both breasts and the OAR located inside the chest cavity: the heart, the esophagus, the spinal cord and of course the lungs were also contoured.

Radiation Therapy Planning
Organs at risk (OAR) and two target volumes (TV): clinical target volume (CTV) and planning target volume (PTV) were delineated manually on the TPS with a margin of 5 mm following instructions from the target volume delineation (TVD) Guidelines in MPM [9]. Using the inverse planning method, VMAT plans were generated employing two coplanar arcs with gantry rotation angles of 178˚ -182˚ on the TPS. The collimator angles of each arc were set to 90˚.

Plan Evaluation and Volume Analysis -Quality Assurance
The complexity associated with MPM treatment planning is due to the presence of radiosensitive structures with different dose prescriptions. The treatment plan evaluation was made by analyzing the dose distribution over the transverse section and by evaluating the dose volume histogram (DVH) which displays the radiation doses received by all structures/regions of interest (ROI) (PTV, CTV, OAR). Octavius ® 4D phantom with a 2D-array 729 detector was used for the quality assurance (QA). The Volume Analysis displays the analysis of the Octavius ® 4D measurements. The Gamma 3D method was used to calculate the 3%/3mm passing rates. To evaluate the deviation between the TP developed and the measured beam, the 3D Gamma Index method available in VeriSoft was employed. The Volumetric Gamma analysis provides a useful statistical overview of the 3D gamma calculation.

Dose Prescription
The prescribed dose was 45 Gy in the PTV for 25 fractions resulting to 1.8 Gy per fraction. The ipsilateral involved lung should be spared optimally.

Dose Constraints of Organs at Risk
For the treatment of malignant pleural mesothelioma for a patient with intact A. I. Bogmis et al.
lungs, the target volume for radiotherapy (RT) of one lung includes the entire visceral and parietal pleura which form a circumferential envelope around the lung, extend along fissures between lobes of the lung, and are attached to ipsilateral, pericardial, and diaphragmatic surfaces leading to a tumoricidal dose of RT for gross disease to be >60 Gy, while the normal tissue tolerance of the adjacent organs is much lower [12]. Table 1 presents the whole organ tolerances for these structures.

Results
Some of the CT images slices imported via DICOM and showing our manual delineation, the treatment plan developed and the dose distribution are presented in the three planes. The result of the treatment planning verification is also presented.
A. I. Bogmis et al.

Results (2): Treatment Planning and Dose Distribution
The planning goal was to deliver the prescription dose (4500 cGy) to 95% of the PTV (95% × 4500 cGy = 4275.0 cGy which is the reference isodose while meeting the normal tissue constraints. The dose distribution is presented separately in the mediastinal window and in the lung (pulmonary) window for both target volumes (the PTV and CTV) for the clarity purpose. Figure 3(a), Figure 3(b) and Figure 4(a), Figure 4(b) show the result of the treatment planning developed and the dose distribution.

Results (3): Plan Evaluation and Volume
Analysis-Quality Assurance Figure 5 shows the dose volume histograms (DVH) obtained.
In the volume analysis of our result ( Figure 6), we obtained the rate for gamma pass = 99.9%. By evaluating the dose distribution and the dose-volume histograms, it can be seen that VMAT plan offers a good coverage of the TV with avoidance of OAR. The reference isodose was 42.75 Gy with the coverage constraints for the PTV D95 and V95 = 95.0% of the prescribed dose (45 Gy).

Measured and Calculated Dose Distributions-Their Comparison
The measured doses (Figure 7(a)) in Octavius ® 4D with a 2D-array 729 detector and the calculated Pinnacle 3 doses (Figure 7(b)) compared using VeriSoft (Figure 8(b)) are presented together with the corresponding dose profiles (Figure 8(a)) created using Octavius ® 4D. Although the dose distribution is presented in the three plans (transverse, sagittal, coronal), only the transverse section or view was employed because it relates most easily to the treatment plan isodose displayed on the transversal CT slices of the patient. This is because when the 3D dose reconstruction grid is set in the VeriSoft, the plane coordinates matches measurement and calculation dose distribution, but, this advantage vanishes if the coronal and sagittal view in which it is not an easy task to control the exact pixel positions in the calculated dose matrix exported from the TPS are used.
The analysis of the measured dose distribution (Figure 7(a)), calculated dose distribution (Figure 7(b)) and combined doses distributions (Figure 8

Discussion
We have compared our results (Figure 9) with others from different publications to show how consistent was the TP developed and the protection of the involved lung realized (Table 2).
A. I. Bogmis et al. This study used only one patient as a model for malignant pleural mesothelioma (MPM). It was a 58-year old female patient with an ovarian cancer and intact lungs. The choice for that particular patient was based on the fact that MPM and ovarian/peritoneal serous carcinoma have a lot of features in common. They are two of the most common tumours affecting the serosal cavities, they share a common histogenesis, they are difficult to differentiate morphologically, and they co-express many of the diagnostic markers used by cytopathologists in effusion diagnosis [18]. Therefore, we believed that the said patient was a perfect candidate to use as a model to simulate the VMAT treatment of a patient A. I. Bogmis et al. Figure 9. The ROI statistics of our results extracted from the Plan Evaluation section in Figure 5.  (1) No surgery, i.e. MPM model for a case of a patient with intact lungs. (2) Surgery: Radiotherapy adjuvant treatment after pleuropneumonectomy [14].
with MPM and intact lungs while using in clinical conditions the same VMAT system employed in the treatment of the ovarian cancer of our model. The clinical and sociodemographic characteristics of that patient were not relevant to be mentioned in this study.
The choice to use VMAT in this work in addition was motivated by its multiple advantages. VMAT can achieve highly conformal dose distributions with improved target volume coverage and sparing of normal tissues compared with conventional radiotherapy techniques [19]. VMAT allows for dynamic modulation of the speed of gantry rotation, the position and movement speed of multileaf collimators (MLC) and the rate of dose delivery. It can deliver a treatment that would require 7 -9 Intensity modulated radiation therapy (IMRT) fields in one or two arcs, reducing treatment delivery time [20]. However, there are also disadvantages associated with VMAT. VMAT requires more extensive quality

Conclusions
In this work, we were concerned with the delineation of complex target volume for malignant pleural mesothelioma (MPM) in radiotherapy using a model for MPM and the development of a treatment planning for Volumetric-Modulated Arc Therapy (VMAT) with associated quality assurance employing Octavius ® 4D phantom. Using a well-defined TV and an adequate irradiation technique as VMAT, a consistent TP with the protection of the involved lung parenchyma was achieved.
By evaluating the dose distribution and the dose-volume histogram, it can be seen that VMAT plan offers a good coverage of the target volume with avoidance of organs at risk. The coverage of PTV was more than 95% of prescribed dose for 95% of the volume. The Volumetric Gamma analysis provides a useful statistical overview of the 3D gamma calculation. In the volume analysis of our The Octavius ® 4D phantom with its detector array is well equipped for the verification of the dose distribution for VMAT plans in the three transverse, sagittal and coronal planes.
Our results compared to similar ones from the literature show that the treatment planning we developed is consistent.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.