Summary

METHODS
Three plans were generated: VMAT_M was generated with Monaco Treatment Planning System (TPS), VMAT_E with an Eclipse TPS, and HT plans were generated using a Hi-Art Tomotherapy system. The prescribed dose was 54 Gy delivered in three fractions. The planning target volume (PTV) doses and organs at risk (OAR) doses were compared between three plans.

RESULTS
All plans met the criteria for PTV coverage. Maximum PTV doses were significantly higher in VMATM plan, and minimum PTV doses were significantly lower in VMAT_E plan. The dose conformity and homogeneity indices of PTV were better in VMAT_E plan. Only mean bowel maximum dose was significantly higher in HT plan compared to VMAT_M plan only. The liver D_mean were significantly higher in PTV larger than 50 cm³. Liver D_mean in PTV >50 cm³ was significantly less in VMATM plan compared to HT (p=0.04) and VMATE plans (p=0.04).

CONCLUSION
All three plans met the criteria for PTV coverage with no significant difference in OARs doses. VMAT_E plan yielded better homogeneity and conformity in PTV compared to VMAT_M and HT, and healthy liver tissue was better spared especially in larger tumors (>50 cm^³) with VMAT_E plans.

Introduction

Over the past two decades, the role of RT in the management of LM has evolving with the increase in RT delivery techniques. Stereotactic body RT (SBRT), also known by stereotactic ablative body radiation, is a high precision RT technique that allows higher radiation doses to the target with a steep dose gradient. In other words, higher radiation doses could be delivered safely to the liver without causing functional compromise with new RT technics.[11] There are strong evidences that SBRT could be an effective treatment option for patients with LM that are unresectable or not amenable to RFA or TACE.[12,13] The local control rate is satisfactory with reports of being 90% or higher in selected patients, and with acceptable toxicity rates.[12,14]

Various technics have been used for hepatic SBRT, and the planning modalities for each RT technic may vary. Furthermore, the precise doses to the target volumes and dose constraints for both liver and organs at risk (OARs) have not yet been standardized. Although it has been previously demonstrated that volumetric arc therapy (VMAT) is advantageous for SBRT delivery in various cancer types,[15-17] it remains to be determined which rotational volumetric IMRT is advantageous for LM treatment.

We aim to compare VMAT to HT, both rotational techniques with different forms of implementation and requiring dedicated helical tomotherapy (HT) versus general purpose (VMAT) machines. The dosimetric data for target volumes and OARs were assessed; also target volume homogeneity and conformity were analyzed.

Methods

Simulation, Delineation, and Image Registration
Patients underwent 1.25 mm multi-slice contrast enhanced planning computed tomography (CT) from tracheal bifurcation to the lower border of the kidneys for simulation (Optima 580, (GE Healthcare, Waukesha, WI, USA). Patients were positioned supine with arms above the head and immobilized using a Body- FIX® bluebag with vacuum wrap (Elekta, Stockholm, Sweden). An abdominal compress was also used to minimize the target volume motion.

Magnetic resonance imaging and 18-Fluorodeoxyglucose positron emission tomography CT were fused with planning CTs to help clinicians localize the target volume precisely, where appropriate. Gross tumor volume (GTV) included the visible tumor in imaging; however, no clinical tumor volume was defined. Planning tumor volume (PTV) was expanded with a 7 mm in all directions except for 12 mm craniocaudal margin.[12,18,19] No fiducial markers were implanted before treatment planning.

Treatment Planning
Three different plans were generated with same CT images including the same GTV, PTV, and OARS. The prescribed dose was 54 Gy delivered in three fractions, and the dose was prescribed to 90% isodose line. Treatment was delivered every other day. First VMAT plan (VMATM) was calculated with the Monaco Treatment Planning System (TPS) version 5.10 (Elekta Ltd, Crawley, UK) using the Monte Carlo photon algorithm and a sliding window multileaf collimator (MLC) delivery technique. All treatment plans were performed for delivery with an Axesse® linear accelerator (Elekta AB, Stockholm, Sweden). VMAT plans consisted of double or triple 358° arcs.

Second VMAT plan (VMATE) was generated with an Eclipse version 13.7 (Varian Medical Systems, Palo Alto, CA, USA) with using Acuros algorithm with 6MV energy (MLC; Varian RapidArc, Varian Medical Systems, Palo Alto, California, USA). Similar to VMATM plan, VMATE plans also consisted of double or triple arcs that included 179° as the starting angle, and 359° as the end angle. All VMAT plans were generated in the same manner, including same arc numbers and angles to provide adequate target coverage and dose constraints.

The HT plans were generated using a Hi-Art Tomotherapy system (TomoTherapy Inc., Madison, WI, USA), a helical fan-beam IMRT using 6-MV photon with inverse planning software. The HT plans were made for the TomoEdge™ Dynamic Jaws system of the Tomo- HDA™ series. A collimator aperture of 2.5 cm, pitch of 0.287, and modulation factor of 2.5 were used, which has been previously defined.[20,21] Dose calculations were performed using the fine-dose calculation grid (1 mm in the craniocaudal direction over a 256×256 matrix in the axial plane from the original CT scan).

Dose Constraints
The OARs, including kidneys, liver, bowel, and spinal cord, were contoured by the same physician. The dose volume histograms generated from three different TPSs were analyzed, and comparison was made between plans. We adopted the constraint that at least 700 cm³ of healthy liver (entire liver volume minus cumulative GTV) should receive <15 Gy in three fractions. Other dose constraints of OARs included: total kidney volumes V35 <15 Gy (volume receiving 15Gy should be less than 35%), maximum dose (D1cm³) of spinal cord <18 Gy, D1cc for duodenum <21 Gy, D1cm³ for small bowel <21 Gy, D1cm³ for esophagus< 21 Gy, D1cm³ for stomach <21 Gy, D1cm³ for heart <30 Gy, and D30 cm³ for the ribs <30 Gy.

Plan Evaluation
For all patients, cumulative dose-volume histograms and dosimetric parameters were calculated and compared for the PTV and OARs. Target volume coverage was compared in terms of the minimal (D_min), maximal (D_max), and mean doses (D_mean). Dxx was defined as the minimum dose in the most irradiated XX cm³ tissue volume. D₂ and D₉₈, the minimal doses to 2% and 98% of the target volume, respectively, were used as surrogates for the maximum and minimum doses. Target homogeneity and conformity indices (HI and CI, respectively) were compared. The HI was calculated as HI=([D2-D98]/D50), where a greater HI value indicated poorer uniformity of dose distribution.[22] The CI was calculated as V_T,ref/V_T×V_T,ref/V_ref, where VT,ref was the volume of the target covered by the reference isodose line, V_T was PTV, and V_ref was the volume of tissue covered by the reference isodose line. The reference isodose was selected as 95% of the prescribed dose. The value of CI varied between 0 and 1, with a value closer to 1 indicating better conformity of the dose to PTV.[23]

Statistical Analysis
Statistical analysis was performed using SPSS software v. 21.0 (SPSS Inc., Chicago, IL). The Wilcoxon's matched-pairs test was used to determine statistical differences between volumes and doses in VMAT_M, VMAT_E, and HT plans. The dose-volume parameters of PTV and OARs for each planning system were measured and compared to each other. The mean liver doses (D_mean) and doses of 700 cc healthy liver (D_700cc) according to PTV subgroups (<50 cm³ vs. >50 cm³) was compared according plans. The Mann-Whitney U-test was used to compare volumes or dose values in independent patient groups. All p-values reported were two-sided, and p<0.05 was considered significant.

Results

Table 1: Dose volume histogram parameters for planning target volume according to radiotherapy techniques

Fig 1: Representative axial computed tomography slices showing 90% of prescribed dose distributions for (a) VMATM, (b) HT, and (c) VMATE plans, and 50% of prescribed dose distributions for (d) VMAT_M, (e) HT, and (f) VMAT_E plans.
VMAT: Volumetric arc therapy; VMAT_M: VMAT with Monaco treatment planning system; VMAT_E: VMAT with Eclipse treatment planning system; HT: Helical tomotherapy.

The HI was significantly higher in VMAT_M plan (1.05±0.02) compared to HT plan (1.03±0.01; p<0.001) and VMAT_E (1.01±0.01; p<0.001) plans, similarly the HI was significantly higher in HT plan compared to VMAT_E plan (p<0.001). VMAT_E plans achieved superior CI compared to VMAT_M plan (p=0.003) and HT (p=0.001) plans. The mean monitor units (MU) in VMAT_E plan were significantly higher than those measured in VMAT_M plan (5145±391 vs. 3874±1421; p=0.02).

OAR Doses
A comparison of the dosimetric parameters of OARs for each of the plan types is listed in Table 2. The Dmean, V20 and V30 of both kidneys did not differ significantly for VMATM, HT, and VMATE plans. Maximum bowel dose was significantly higher in HT plan compared to VMAT_M plan only (2.00±1.65 Gy vs. 1.21±1.06 Gy; p=0.03), but there was no significant difference in bowel doses between VMAT_M and VMAT_E plans, and HT and VMAT_E plans. Spinal cord mean maximum doses did not differ significantly between techniques.

Table 2: The dosimetric parameters of organs at risk for three different radiotherapy plans

Liver Dosimetry
The dosimetric parameters for liver volumes are summarized in Table 3. Although liver D_mean doses did not differ significantly between VMAT plans and HT plan (Fig. 2a), maximum doses were significantly higher in VMAT_M plan (57.4±1.7 Gy) compared to HT plan (55.7±0.4 Gy; p<0.001) and VMAT_E plan (54.5±0.3 Gy; p<0.001). The mean liver D_700cc for VMAT1, HT, and VMAT plans was 5.6±4.0 Gy, 6.5±4.6 Gy and 6.5±4.9 Gy, respectively, and no significant difference was observed between plans (Fig. 1b). The liver doses from V10-V40 were significantly higher in VMATE plan compared to VMAT_M and HT plans (Fig. 3). The liver dose volume parameters of VMAT_M and HT plans were similar except for V10 values, which significantly lower in VMAT_M plan.

Table 3: The dosimetric parameters for liver volumes for three different radiotherapy plans

Fig 2: Box plot graph demonstrating (a) mean liver doses and (b) mean doses of 700 cm³ of healthy liver for VMAT and HT plans.
VMAT: Volumetric arc therapy; HT: Helical tomotherapy; VMAT_M: VMAT with Monaco treatment planning system; VMAT_E: VMAT with Eclipse treatment planning system; Gy: Gray.

Fig 3: The mean dosimetric indices for the healthy liver volume receiving 10-40 Gy with the three techniques.
VMAT: Volumetric arc therapy; VMAT_M: VMAT with Monaco treatment planning system; VMAT_E: VMAT with Eclipse treatment planning system; HT: Helical tomotherapy; Gy: Gray.

The liver D_mean according to tumor volume is presented in Figure 4a. The D_mean of liver was significantly higher in PTV larger than 50 cm³ compared to PTV <50 cm³ in VMAT_M plan (11.54±1.49 Gy vs. 7.42±2.27 Gy; p<0.001), VMAT_E plan (12.18±1.90 Gy vs. 7.51±2.25 Gy; p<0.001), and HT plan 12.03±2.01 vs. 7.11±2.19 Gy; p<0.001) (Fig. 5a). Liver D_mean in PTV >50 cm³ was significantly less in VMAT_M plan compared to HT (p=0.04) and VMAT_E plans (p=0.04).

Fig 4: (a) Mean liver doses and (b) mean doses of 700 cm³ of healthy liver according to tumor volume in three techniques.
VMAT: Volumetric arc therapy; VMAT_M: VMAT with Monaco treatment planning system; VMAT_E: VMAT with Eclipse treatment planning system; HT: Helical tomotherapy; Gy: Gray.

Fig 5: Box-plot graphs demonstrating the (a) mean liver doses and (b) mean doses of 700 cm³ of healthy liver according to planning tumor volume <50 cc and >50 cc.
PTV: Planning target volume; VMAT: Volumetric arc therapy; VMAT_M: VMAT with Monaco treatment planning system; VMAT_E: VMAT with Eclipse treatment planning system; HT: Helical tomotherapy; Gy: Gray.

There were no significant difference in mean liver D_700cc between PTV <50 cm³ and PTV >50 cm³ in VMAT_M (4.52±2.63 Gy vs. 7.41±5.24 Gy; p=0.21) and HT plans (5.59±3.49 Gy vs. 7.93±5.95 Gy; p=0.37) (Fig. 5b). However, mean liver D700cc was significantly higher in larger PTV compared to small PTV in VMATE plan only (9.64±5.89 Gy vs. 4.51±2.93 Gy; p=0.03). The liver D_700cc was significantly higher in PTV >50 cm³ with VMAT_E plan compared to HT plan (p=0.001) and VMAT_M plan (p=0.03).

Discussion

The SBRT is gaining importance as a non-invasive and effective treatment method for patients with LM. Although surgery still remains the treatment of choice in LM, most patients cannot undergo surgery because of comorbidity, poor performance status, or tumor related factors such as size, location, and relationship with vascular structures.[5,6] SBRT offers non-invasive, effective, and safe local treatment in patients with LM. The feasibility of SBRT for LM was demonstrated by numerous studies with 1-and 2-year local control rates ranging from 70% to 100% and 60% to 90%, respectively.[9] Toxicity profile of SBRT compared to other invasive/minimally invasive local therapies is quite better. The reported Grade III or higher toxicity rates were 1-10%, and the incidence of radiation induced liver disease (RILD) ranged between 1% and 5%.[12,14,19]

The feasibility and efficiency of VMAT in SBRT for liver tumors were shown in various dosimetric and clinical studies.[16,19,24] Recently, Qui et al.[24] demonstrated an acceptable target volume coverage with VMAT technique in nine patients with liver tumors. The authors pointed that out that the main advantages of VMAT plans were substantial decrease in beam on time and lower MU. Thomas et al.[25] demonstrated that inversely optimized IMRT plans were dosimetrically superior to conventional IMRT plans with shorter delivery times. Paik et al.[16] analyzed the dosimetric comparison of VMAT and robotic radiosurgery in 29 liver tumors. They reported better conformity in robotic radiosurgery plans while VMAT plans had also good dosimetric distribution, better sparing healthy liver, and shorter beam on time. Our study supported the feasibility of VMAT plans in liver SBRT with acceptable OARs doses and good homogeneity even in large tumors.

HT based SBRT was investigated by Baisden et al.[26] in a phase I study. They hypothesized that the maximum tolerable dose delivered to a lesion by HT based SBRT could be predicted based on the PTV and liver volume. The authors found that HT was capable of performing SBRT for liver lesions with adequate target dose while sparing normal tissues. Furthermore, Engels et al.[15] conducted a phase II study of HT in the multidisciplinary treatment of oligometastatic colorectal cancer. They treated a total of 53 metastasis of lung, liver, and lymph nodes. They reported the actuarial 1-year local control, progression-free survival, and overall survival were 54%, 14%, and 78%, respectively, with only 4% Grade III toxicity. Lee et al.[27] analyzed SBRT with HT for patients with hepatic oligometastasis. 54 hepatic lesions were treated, and 1-and 2-year local control rates were 59.9 and 49.0%, respectively, without any Grade 3 or higher toxicity. Our dosimetric study also supported that HT was a feasible technique for liver SBRT compared to with modern VMAT techniques.

Historically, the most common toxicity with liver SBRT had been reported as RILD. In most of the recent studies, the rates of RILD were reported <1%. [28] The generally-accepted dose constraint for the healthy liver was 700 cm³ <15 Gy, for minimizing the risk of RILD.[17,29] Although, in the current study, the dose constraints for both OARs and healthy liver were acquired, our dosimetric analysis indicated that liver doses increased with the increased tumor size in VMAT_E plan. However, VMAT_M was advantageous in achieving lower liver mean doses and better sparing healthy liver in larger tumors.

Our study had certain limitations. First, due to its retrospective nature, we only compared the dosimetric parameters of two different VMAT techniques and HT in the management of LM in a limited cohort of patients. Second, considering the fact that a comparison of dosimetric parameters does not indicate a comparison of clinical effectiveness, our results should be interpreted carefully in the absence of clinical studies. Finally, long follow-up periods are essential for better analyzing the tolerance and/or toxicity profile of OARs. Nevertheless, this study is important as it is the first dosimetric study comparing two modern VMAT techniques and HT technique in the treatment planning for LM.

Conclusion

Peer-review: Externally peer-reviewed.

Conflict of Interest: All authors declared no conflict of interest.

Ethics Committee Approval: The study was approved by the Baskent University Faculty of Medicine Ethics Committee (no: KA18/148, date: 30/04/2018).

Financial Support: None declared.

Authorship contributions: Concept - E.O., O.C.G., C.Ö.; Design - E.O., O.C.G., C.Ö.; Supervision - E.O., O.C.G., C.Ö.; Funding - None; Materials - E.O., O.C.G., C.Ö.; Data collection and/or processing - E.O., O.C.G., C.Ö.; Data analysis and/or interpretation - E.O., O.C.G., C.Ö.; Literature search - O.C.G.; Writing - E.O., O.C.G.; Critical review - E.O., O.C.G., C.Ö.

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