Introduction

More than 30% of patients with non-small cell lung cancer (NSCLC) are diagnosed at a locally advanced stage [1]. Definitive radiotherapy (RT) combined with chemotherapy remains the standard treatment for these patients, with a 5-year overall survival (OS) of 20%–30% [2, 3]. Intensity-modulated radiation therapy (IMRT) has been routinely used in the RT of patients with locally advanced NSCLC (LA-NSCLC) in the past two decades and has been confirmed to be superior to 3D-CRT in terms of retaining local control and reducing pulmonary toxicity [4]. In recent years, volumetric modulated arc therapy (VMAT), a newly advanced RT technique, has been adopted for LA-NSCLC RT. VMAT notably decreases the treatment delivery time compared with IMRT [5] because it allows beam-on when the gantry position, multi-leaf collimator (MLC) moves, and dose rate simultaneously varies [6].

However, one concern is the low irradiation dose to normal tissues using the VMAT technique, especially for LA-NSCLC patients with a large tumor size. Previous studies have demonstrated that VMAT plans can achieve higher degrees of conformity and homogeneity in the target dose than fixed-field IMRT [7-9]. Jiang et al. [7] and Zhang et al.[10] found that VMAT plans achieved a lower 20 Gy/30 Gy dose volume (V₂₀/V₃₀) and mean lung dose (MLD) in both lungs and contralateral lungs, but a higher 5 Gy/10 Gy dose volume (V₅/V₁₀) compared to IMRT plans. Despite the great advantage of the VMAT technique, VMAT plans result in higher lung V₅ and V₁₀ compared to traditional IMRT plans [7, 10], which might increase the risk of symptomatic radiation pneumonitis [11, 12]. Radiation pneumonitis (RP), caused by thoracic RT, is the main dose-limiting complication in LA-NSCLC. Ren et al. indicated that lung V₅ and MLD were independent predictors of RP grade ≥ 3 [13]. Another study reported that lung V₁₀ was an independent factor for predicting symptomatic RP among lung cancer patients who underwent VMAT as RT[14]. Several reports recommend keeping V₅ of the total lung below 60%–65% in RT plans of LA-NSCLC patients with concurrent chemotherapy [15, 16]. Thus, normal lung tissue sparing has raised great interest in VMAT planning design, especially in the low-dose range (5 Gy–10 Gy) of normal lung tissue.

The virtual block method has been used in helical tomotherapy (HT) planning (Accuray, Sunnyvale, CA) to reduce the lung dose. Makoto et al. [17] made plans with a virtual block structure in HT for 15 patients with cervical esophageal carcinoma and found that V₅, V₁₀, and V₂₀ of the lungs and MLD dose were significantly reduced in B-plans. Hong et al. [18] optimized beam angles in tomotherapy by applying directional/complete block functions for ten patients with stage IIIB NSCLC and found that the plan with virtual block had superior normal lung sparing compared to Linac-based static IMRT plans. However, to the best of our knowledge, this virtual block method has not been implemented in VMAT plans. In addition, the block currently used by Makoto[17] in HT was generated considering only the beamlet direction and the lungs, but omitting the changes in tumor targets between different computed tomography (CT) slices. Concurrently, tomotherapy provides the directional/complete block function: 1) The directional block function closes the beamlet and limits the entrance direction of beamlets when the blocked structure is proximal to the targets and 2) the complete block function blocks the beamlets from entering and exiting a certain blocked structure volume [19].

Currently, commercial treatment planning system (TPS) manually restrict the angle of the beam passing through the lungs in VMAT planning to reduce the low-irradiation-dose volume to the lungs. For example, Eclipse (Varian Medical Systems, Palo Alto, CA) [20, 21] could restrict the beam angle using arc avoidance sectors for predefined fixed arcs, whereas Pinnacle (Philips Radiation Oncology Systems, Fitchburg, WI) [22] adopted several partial arcs instead of the full arc. This method ignores the location and shape of targets that vary between different slices and does not block the beamlets precisely. Thus, we invented a new virtual block method to block the beamlets by closing the MLC at prerequisite arc angles and first introduced the block as an optimization objective in the VMAT optimization process. This new virtual block with proper optimization objectives in the VMAT planning system could provide a function like that of the directional/complete block in the HT planning system.

In the present work, we have exploited a new virtual block contouring method and optimization parameter to generate VMAT plans, taking tumor location and shape, normal lung, and beamlet direction into account. We also report the feasibility and efficacy of block objects in reducing the lung dose when making VMAT plans for LA-NSCLC.

Experimental Section

2.5

Virtual block method

The virtual block method was introduced to decrease the low-dose exposure of the lung in the VMAT plans, which blocked the beamlets by closing the MLC at certain angles. The principle of closing the MLC depends on the thickness of the beamlets passing through the lungs, especially in the lateral direction, to spare the exposure of the OARs. A partial ring virtual block was determined to only avoid entrance radiation beamlets and was contoured with the scripting tool provided by Pinnacle.

This type of block has several advantages. First, the PTV shape with large variances between the slices was considered. Unlike the previous method, which shielded beamlets by reducing the beam angles, this new virtual block was determined by the following principles: (1) the proximity of the MLC depended on the thickness of the beamlets passing through the lungs; (2) avoiding only entrance radiation beamlets; (3) maintaining a minimum distance of 8 cm away from the PTV in the left and right directions, which avoided beam interference; (4) adding the maximum dose constraint for the virtual block in VMAT optimization; and (5) the virtual block could be contoured automatically.

The contouring algorithm and process are illustrated in Fig. 1 as follows: (1) a supporting structure, denoted as PTV-extend, was created by adding an 8-cm margin to the PTV in the left-right direction and a 20-cm margin in the anterior-posterior direction. The PTV-extension is represented by the solid dark blue line in Figures 1a–3a. The expansion direction is indicated by the light blue arrow in Figures 1a–3a, and these expansion distances were based on our clinical experience. (2) A supporting structure, called Outline, was the external sketch of the patient’s body and only in the body where PTV was presented. (3) Thereafter, a structure was created by contracting Outline with 1 cm. This structure is denoted as a ring-outline and is shown as a hollow bright yellow line in Figure 1b–3b. (4) Finally, a partial ring was generated by removing the ring outline part in the PTV-extension. This partial ring is named the ring block (hereafter, “block”). A ring block is present in the hollow bright yellow area in Figs. 1c–3c.

Fig. 1Full-screen View

(Color online) Schematic diagram of axial view of the virtual ring block from three representative slices. (1-3a) PTV-extend, (1-3b) ring outline, (1-3c) and ring block.

Fig. 2Full-screen View

(Color online) Transverse sections of the representative N-plans (left four panel) and B-plans (right four panel) of one patient with isodose lines. The dose distributions show planning target volume (PGTV and PTV) prescribed to 60.20 Gy (red line) and 50.40 Gy (purple line). The yellow, orange, green, bronze, pink, lavender, and indigo blue lines represent the dose curve of 66 Gy, 45 Gy, 40 Gy, 30 Gy, 20 Gy, 10 Gy, and 5 Gy, respectively.

Fig. 3Full-screen View

(Color online) The DVH comparison between N-plan (solid lines) and B-plans (dashed lines) for one patient include the following selected ROIs: PTV (green), PGTV (red), total lungs (dark green), left lung (violet), right lung (dark blue), esophagus (yellow green), heart (brown), trachea (sky blue), and spinal cord (beige).

Results and Discussion

Totally, 34 plans were designed according to the protocol. Figure 2 shows the transverse sections of both the N-plan (a1-d1 panel of Fig. 2) and B-plan (a2-d2 panel of Fig. 2) with irradiation dose curves for one patient. As displayed in the left and right panels of Fig. 2, V₅ and V₁₀ of the total lungs in B-plan were apparently smaller than those in the N-plan. The conformity of the 95% isodose line of the PGTV (60.2 Gy) and PTV (50.4 Gy) in the B-plan was as good as that in the N-plan. A few hot spots (66 Gy) were observed in the B-plan, whereas invisible hot spots were observed in the N-plan.

Representative VMAT plans for a patient with dose-volume histograms (DVHs) of targets and OARs from both the N-plans (solid line) and B-plans (dashed line) are shown in Fig. 3. PGTV and PTV achieved 95% of the prescribed doses in both plans. N-plan produced a steeper DVH of PGTV than B-plan in the 102%–107% range of the prescribed dose, yet the area of PGTV receiving 110% of the prescription dose was quite small. Regarding the selected OARs, the normalized percentage volume of the total lung in the B-plan was smaller than that in the N-plan at doses below 20 Gy. A similar numerical trend was observed in the DVH of the right lung. The V_20Gy of the heart in the B-plan was notably lower than that in the N-plan. Interestingly, the tracheal area receiving a < 50 Gy dose in the B-plan was less than that in the N-plan. Although the near‐maximum-absorbed dose of the cord was comparable between the block and N-plans, the percentage volume of the cord receiving doses of 10–30 Gy in the B-plan was higher than that in the N-plan. The volume of the left lung receiving a dose of 20–30 Gy in the B plan was slightly higher than that in the N plan.

3.3

Pulmonary dose

As listed in Table 4 and presented in Fig. 4, some dosimetric metrics of the total lungs has significantly statistically reduced as following: (1) V₅ decreased from 63.3% ± 7.36% in N-plans to 59.26% ± 7.84% in B-plans (P<0.001), with a median numeric decreased proportion of 5.1% (0.1%– 18.8%); (2) V₁₀ decreased from 44.41% ± 7.49% in N-plans to 40.68% ± 6.58% in B-plans (P<0.001), with a median numeric decreased proportion of 8.0% (4.0%–15.1%); (3) D_mean was 13.68 ± 1.86 Gy in N-plans and 13.28 ± 1.78 Gy in B-plans (P = 0.001), with a median numeric decreased proportion of 2.3% (-0.8%–6.2%). (4) NTCP was significantly lower for B-plans compared to N-plans (mean: 1.60 ± 1.39 vs. 1.76 ± 1.6, P = 0.015). Similar dosimetric metrics were observed in the right lung: significant reductions in V₅ (60.41% ± 10.31% vs. 53.46% ± 11.58%, P < 0.001) and V₁₀ (34.69% ± 11.65% vs. 28.38% ± 10.25%, P < 0.001) were observed for B-plans, with a median decrease of 10.1% (0.4%–36.7%) and 18.4% (7.0%–44.2%), respectively. Other dosimetric parameters, including V₂₀/V₃₀/V₄₀ /V₅₀ of the total lungs and right lung V₂₀, were equivalent between the B-plans and N-plans.

Fig. 4Full-screen View

Box-plots of dosimetric parameters for non-block vs B-plans. (A) Mean lung dose, (B) total lung V₅, (C) total lung V₁₀, (D) right lung V₅, (E) right lung V₅, (F) heart Dmean, (G) heart V₄₀, (H) NT V₅, and (I) NT V₁₀.

Discussion

In recent years, the VMAT technique has been applied for the treatment of LA-NSCLC. Although several retrospective studies have confirmed the efficacy and safety of VMAT plans [37, 38], there are still concerns about pulmonary toxicity caused by increased low-dose volumes. Therefore, for the first time, we used a virtual block method in VMAT planning for LA-NSCLC cases. The N-plan used all beamlets of the set gantry angles in the optimization process. In contrast, the B-plan prevents some of the beamlets from crossing the predefined block. The results indicated that B-plans were effective in reducing lung and heart doses.

According to our implementation experience, this virtual block has six advantages compared to previous methods: (1) Partial arcs over 180° are utilized in most LA-NSCLC VMAT cases. This ring block stands in the most direction before the beamlets pass through the lung, which is mentioned in the form of a block by Hong et al. [18]; (2) this ring block considered a constant distance of 8 cm from the target. The 8-cm distance is sufficient to avoid destroying the targets’ conformity. Because the prescription dose to targets is high up to 60 Gy, the constraint to the ring block is as low as 5 Gy, a 1.5-cm distance between the block and targets used by Hong et al. [18] may not be sufficiently large; (3) this ring block could be easily implemented in a clinical routine in three steps, as shown in Fig. 1. The contouring of this ring block could be programmed by the Pinnacle scripting tool and performed automatically. Other commercially available TPS, such as Eclipse, Monaco (Elekta AB, Stockholm, Sweden), and RayStation (RaySearch Laboratories, Sweden) have their own programming modules and can accomplish the ring-block contouring process automatically. (4) Although Eclipse has arc avoidance sectors and other TPSs, such as the Pinnacle, use more than two partial arcs to limit the low-dose area to the lungs, this method of handling the beamlet entrance, which ignores the location and shape of targets, varies slices by slices, and does not precisely block the beamlets. (5) Most TPSs, such as RayStation 10A, Pinnacle, Eclipse, Monaco, and RayStation, could specify avoidance for entrance and/or exit dose through specific contours, but the contours should be manually defined and drafted by planners. Nevertheless, manual contours were time-consuming and varied among different planners. This new virtual block was invented based on the principle of overcoming these problems and was easily implemented in VMAT plans for planners. (6) It should be noted that all LA-NSCLC cases were selected for this study because of the large tumor size and the unmet constraint of total lung V₅, V₁₀, and mean dose (D_mean). Although an expected value on DVHs of the lungs could also be achieved by putting a very low total lung V₅/V₁₀ during the optimization in some LA-NSCLC cases, PTV coverage was sacrificed, and the prescription isodose line missed PTV in some slices. Sometimes, PTV dose coverage is critical. The optimization process will preferentially achieve a lower V₅/V₁₀ if it is not guided. The virtual block method considers the relative locations of the total lungs and tumor, which could avoid this problem and close the beamlets properly.

Radiation pneumonitis (RP) is one of the most common side effects of thoracic RT in patients with LA-NSCLC. This complication has a considerable impact on patient morbidity and can even lead to death. As demonstrated earlier, RP risk is strongly correlated with the irradiation dose delivered to the lungs, Ren et al. [13] and Wu et. al [14] indicated that lung V₅/V₁₀ and MLD were independent factors for predicting symptomatic RP in patients with lung cancer. The incidence rate of grade ≥3 RP was reported to be 2% in patients with V₅ values ≤70%, but 21% in those with values > 70% (P=0.17)[16]. Shi et al. reported that severe acute RP could be reduced from 29.2% to 5.7% if the lung V₁₀ was controlled to less than 50% [39]. As for the MLD, Barriger et al. reported that the grade ≥2 RP could be reduced from 19% to 2.2% if the MLD was controlled to be less than 18 Gy [40]. The present study demonstrated that B-plans achieved notable reductions in total lung V₅/V₁₀ and MLD with median decreased proportions of 5.1%, 8.0%, and 2.3%, respectively, which promoted the protection of normal lungs. Several studies have suggested that V₅ should optimally be less than 60%–65% for patients treated with concurrent chemoradiotherapy [15, 16]. In recent years, V₅ has gained considerable attention for the evaluation of the quality of radiation plans. Our study observed sharp reductions in both total lung V₅ and contralateral lung V₅ in the B-plans, which improved the safety of VMAT planning in NSCLC. However, similar V₂₀/V₃₀/V₄₀/V₅₀ values of the total lung were observed between the B-plans and N-plans. This indicated that the advantages of the virtual block mainly relied on the decrease in low-dose exposure, instead of high/inter-median dose exposure.

Previous studies have reported that the doses to the heart are highly related to the cardiac events of LA-NSCLC. Thus, it is associated with the OS of LA-NSCLC. There is increasing recognition of the importance of sparing the heart in patients with LA-NSCLC owing to the increase in long-term survivors. The Pacific trial revealed a significant improvement in LA-NSCLC patients with consolidation immunotherapy, with a median OS of 47.5 months[41, 42]. According to a pooled analysis of six prospective trials, the 2-year competing risk-adjusted cardiac event rates for stage III NSCLC patients with a heart D_mean<10 Gy/ 10–20 Gy/ ≥20 Gy were 4%, 7%, and 21%, respectively [43]. Chun et al.[44] performed a second analysis of the RTOG 0617 trial and found higher V₄₀ of the heart which resulted in worse OS among stage III NSCLC patients, with a hazard risk of 1.012. In our study, notable reductions in heart D_mean/V₄₀ were observed for B-plans, which decreased proportions by 3.29%/1.1%. The B-plans displayed effective performance in heart protection.

We applied a SIB-based dose-reduction protocol in LA-NSCLC patients in this study, and the dose prescriptions was 50.4 Gy to PTV, with a simultaneously 60.2 Gy to PGTV in a total fraction of 28. This dose protocol was confirmed to be effective and well-tolerated in our previous studies [45, 46]. All radiation plans with or without virtual blocks were made by senior medical physicists working over 5 years [24] to exclude the influence of various technical levels. Two types of plans achieved ≥ 95% prescription dose coverage for PGTV/PTV. The B-plans showed better quality than the N-plans did. Although B-plans obtained a higher HI in PGTV and PTV-PGTV than N-plans, the plans were still acceptable for clinical use. Furthermore, the high-dose region of targets can be reduced in several ways, such as (1) increasing the weight of the maximum dose and uniform dose to targets in objective settings of the optimization parameters; (2) the addition of appropriately angled small-weighted conformal fields; and (3) multiple arcs using an appropriately set.

It should be noted that the ring block could also be used in other tumor entities such as esophageal carcinoma and hepatocellular carcinoma. RP is also a general complication of esophageal cancer RT, which is associated with low-dose irradiation of the lung volume [17]. Hepatic radiation toxicity has been at the center of interest for hepatocellular carcinoma, and radiation delivery to targets is limited by the tolerance of the surrounding normal liver parenchyma [47]. Ring-block is potentially a good solution to restrict the low-dose volume of the lungs in esophageal carcinoma and normal liver tissue in hepatocellular carcinoma.

This study has several limitations. First, because the B-plans were made, which were not used in clinical practice, verification of treatment-related toxicities was not performed. Second, the tumor locations of all enrolled patients with lung cancer in the study were retained. It should be noted that the role of the B-plan in patients with right lung tumors remains unclear. In addition, the homogeneity of the target volume for B-plans was slightly worse than that of N-plans, and the D_0.1cc of the esophagus was higher in B-plans than in N-plans. This implies that the block types should be further optimized. Third, the contouring of this virtual block method was based on our clinical experience; thus, further research is required to prove this theoretically.

Conclusion

To reduce the risk of RP, we created a novel virtual block that can be applied in VMAT planning for patients with LA-NSCLC. The VMAT plan with the virtual block method could significantly reduce V₅, V₁₀, MLD of the lung, and V₃₀ and D_mean of the heart, with the same conformity of targets as the VMAT plan with the virtual block method. In addition, the homogeneity of the target volume for the VMAT plan with the virtual block method was slightly worse than that for the VMAT plan with the virtual block method. Advantageous profiles obtained by VMAT planning for LA-NSCLC can be achieved using our novel virtual block. The use of a ring block at a distance of 8 cm from the targets with proper weight in the optimization parameter is recommended based on our analysis. This block is conveniently implemented routinely clinical scenarios and can promote the application of VMAT plans in LA-NSCLC patients.