If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Dosimetric effect of intensity-modulated radiation therapy for postoperative non-small cell lung cancer with and without air cavity in the planning target volume
Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, ChinaShcool of Physics and Technology, University of Wuhan, Wuhan, China
To evaluate the dosimetric effect of intensity-modulated radiation therapy (IMRT) for postoperative non-small cell lung cancer (NSCLC), with and without the air cavity in the planning target volume (PTV). Two kinds of IMRT plans were made for 21 postoperative NSCLC patients. In Plan-0: PTV included the tracheal air cavity, and in Plan-1: the air cavity was subtracted from the PTV. For PTV, the dosimetric parameters, including Dmean, D98, D95, D2, D0.2, conformity index (CI), and homogeneity index (HI) were evaluated. For organs at risk (OARs), the evaluation indexes, included the V5, V20 and the mean lung dose (MLD) of total lung, the V30, V40, and the mean heart dose (MHD) of heart, the spinal cord Dmax, and the V35 and the mean esophageal dose (MED) of esophagus. The number of segments and MUs were also recorded. Additionally, the correlation between the Plan-1 dosimetric change value relative to Plan-0, the size of air cavity, and the volume proportion of the cavity in the PTV was also analyzed. The Dmean of PTV, D2, D0.2, HI and CI in Plan-1 decreased compared with those in Plan-0. For OARs, the V30, MHD, and MED also decreased. The CI change value of Plan-1 relative to Plan-0 had a significantly negative correlation with the size and the volume proportion of air cavity, and the MED change value also had a significantly negative correlation with the air cavity size. The IMRT plans for patients with postoperative NSCLC can achieve a better target dose distribution and offer an improved sparing of the heart and esophagus by removing the PTV air cavity, while reducing the target conformity. The change value of CI and MED had a significantly negative correlation with the air cavity size.
Clinically, the preferred treatment for lung cancer is surgery, however, surgery alone cannot effectively treat advanced lung cancer that has large lesions and local metastasis. Radiotherapy is another major method for the treatment of malignant tumors, and more than 70% of patients require radiotherapy.
The combination of surgery and radiotherapy is an important and effective method for the treatment of lung cancer patients. Several reports have shown that postoperative radiotherapy for patients with N2 non-small cell lung cancer (NSCLC) can optimize local control and improve survival.
Adjuvant radiation therapy in locally advanced non-small cell lung cancer: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline.
Intensity-modulated radiation therapy (IMRT) is one of the main radiotherapeutic techniques that can improve the target dose, while sparing the organs at risk (OARs).
However, when treating lung cancer with IMRT, normal tissues are covered by low-dose areas that have large volumes and that are prone to unexpected hot spots, and that result in an increased risk of secondary cancer.
This is specifically observed with planning target volume (PTV) that is within a certain volume of air cavity, due to the electron disequilibrium region on the air-tissue interface, where the disturbance of electron flux is easy to occur, and which results in the distortion of the dose distribution and its insufficient reach of the target.
These air cavities present a challenge to inverse-planning software due to its attempt in pushing the dose into the air to achieve sufficient PTV coverage. This unnecessary attempt in dose accumulation may lead to increased hot spots within the rest of the PTV and its surrounding soft tissues.
In recent years, most of the studies on the impact of the air cavity on the planned dosimetry of IMRT have focused on the parts that have relatively large air cavity volumes, such as the nasopharynx, mouth, and larynx. Liu et al.
found that the radiation dose of the primary tumor and brain stem of OARs could be increased by the air cavity in the IMRT of nasopharyngeal carcinoma. While studying oral cancer, Lian et al.
compared three different methods that included the air cavity into the PTV radiotherapy plan and found that the air cavity effect could easily increase the skin and optic nerve radiation doses. Asher et al.
Dosimetric comparison of intensity-modulated radiation therapy for early-stage glottic cancers with and without the air cavity in the planning target volume.
found that removing the air cavity from the PTV for early stage glottic cancers could lead to a more homogeneous IMRT plan. The above studies showed that the air cavity effect may influence the dose distribution in the PTV. However, it is unclear whether there is a correlation between the dosimetric parameters, the size of the air cavity, and the volume proportion of the cavity in the PTV. Meanwhile, we did not encounter relevant literature reports on the influence of the PTV tracheal air cavity on the dose distribution in the IMRT plan for NSCLC.
For NSCLC patients who need postoperative adjuvant radiotherapy, the main irradiation areas are mainly the hilar and mediastinum regions. When radiation oncologists delineate the target, the tracheal air cavity can easily be included as part of the PTV, which may affect the PTV dose distribution.
In this study, the IMRT dosimetric effect for postoperative NSCLC, with and without the air cavity in the PTV, was studied. Based on the two kinds of PTV (with or without air cavity), two-group plans for 21 patients with postoperative NSCLC were made. By comparing the dose-volume histograms (DVHs), conformity index (CI), and homogeneity index (HI), the number of segments, and Mus, that were generated by the two plans, the effects of the air cavity in the PTV of NSCLC on the dose distribution within the target and on the dose exposure of the surrounding OARs, were evaluated. Additionally, the correlation between the change value of the two plans evaluation indexes, the air cavity size, and the cavity volume proportion in the PTV, was also studied. It is hoped that the results provide a reference for radiation oncologists to decide whether the air cavity should be included when delineating PTV for postoperative NSCLC patients.
2. Materials and methods
2.1 Patient selection
A total of 21 NSCLC patients, who were treated in our center between January and July 2020, were included in this retrospective study. All patients received postoperative radiotherapy. Each patient received 50.4 Gy in 1.8 Gy per fraction. The patient characteristics are listed in Table 1.
All patients were in the supine position and fixed with thermoplastic membrane or vacuum mold according to the requirements of the therapeutic position. SOMATOM Definition AS (Siemens Healthcare GmbH) CT scans were performed under free breathing conditions. The CT Images were taken at a 3 mm thickness throughout the upper edge of the second cervical vertebra to the lower edge of the second lumbar vertebra (Department specification
). All CT images were transmitted via the network to the Philips Pinnacle 9.10 treatment planning system (TPS) (Philips Healthy, Fitchburg, WI) for the treatment planning.
2.3 Contouring
The clinical target volume (CTV) of postoperative NSCLC patients was delineated on the CT images by a radiation oncologist and uniformly expanded 5-8 mm to form PTV. Some details might have been manually modified by the radiation oncologist. To remove the air cavity from the PTV, the tracheal air area in the PTV was first manually delineated, and then the original PTV was used to subtract the delineated air cavity to form the PTV-1 structure (Fig. 1B). To facilitate the distinction, the original PTV was renamed as PTV-0 (Fig. 1A). The OARs, including the total lung, heart, spinal cord, and esophagus, were manually delineated by the radiation oncologist, or using semi-automatic tools. All structures had been reviewed and approved by at least one experienced radiation oncologist before treatment planning.
Fig. 1A CT cross-sectional view of a patient before and after removal of the air cavity in PTV. The orange region is PTV structure: (A) PTV-0 structure within air cavity; (B) PTV-1 structure without air cavity. (Color version of figure is available online.)
Static IMRT plans were made for all patients using 5 to 7 coplanar beams with 6 MV on Pinnacle 9.10 TPS. The beams’ angle was designed according to the patient current clinical situation. Edge linear accelerator (Varian Medical Systems, Palo Alto, CA) was selected. The optimization algorithm used the direct machine parameter optimization (DMPO) and the dose calculation employed the collapsed cone concentration (CCC) algorithm. The dose rate of all plans was 600 MU/min, and the grid resolution of the dose calculation was 3 mm.
In the design of the plan, 95% of the PTV received 100% of the prescribed dose. One percent of the PTV not to exceed 110% of the prescribed dose and 1% of the PTV not less than 95% of the prescribed dose. The OARs’ dose constraint was based on our center clinical standard, which details are listed in Table 2. To reduce the required planning time, improve the plan overall quality, and reduce the differences between the plan designers, the auto-planning module that was built in the pinnacle 9.10 TPS, was used to generate plans. Using the same beam setting and optimization objectives for OARs, two treatment plans were independently generated for each patient according to two PTVs: Plan-0 was optimized using the PTV-0 and Plan-1 with the PTV-1.
Table 2OARs’ dose constraint
OARs
Parameter
Constraint
Total lung
V5
≤ 45%
V20
≤ 20%
MLD
≤ 13Gy
Heart
V30
≤ 40%
V40
≤ 30%
MHD
≤ 26Gy
Spinal cord
Dmax
< 45Gy
Esophagus
V35
< 50%
MED
< 34Gy
MED, mean esophagus dose; MHD, mean heart dose; MLD, mean lung dose; Vx, the volume of the organ receiving ≥ x Gy.
In this study, the dosimetric differences between Plan-0 and Plan-1 were compared, and DVHs were used to evaluate the doses in the target, total lung, heart, spinal cord, and esophagus. The target was evaluated by Dmean, D98, D2, D0.2, conformity index (CI), and by the homogeneity index (HI). As for the OARs, the evaluation index included V5, V20 and MLD of total lung, V30, V40 and MHD of heart, Dmax of spinal cord, V35 and MED of esophageal. The number of segments and MUs of the two plans were evaluated. Additionally, the correlation between ΔN (ΔN meant the change value of the evaluation indexes, ΔN = the value of the evaluation index in plan-1 - the value of the same evaluation index in plan-0) in the two plans and the air cavity size was studied. Meanwhile, the correlation between ΔN and the volume proportion of the PTV air cavity (Vair/VPTV) was also explored.
where VT,ref is the PTV volume receiving a dose equal or greater than the prescribed dose, VT is the PTV volume, and Vref is the volume receiving a dose equal to or greater than the prescribed dose. CI varied from 0 to 1, and the higher the CI, the better the PTV conformity.
According to the report of ICRU 83, HI was defined as:
(2)
where D2, D50 and D98 correspond to radiation doses delivered to 2%, 50%, and 98% of the PTV, respectively. The lower the HI, the better the target homogeneity.
2.6 Statistical analysis
SPSS 22.0 (SPSS Inc., Armonk, NY) was used to conduct the statistical analysis, and the measurement data were expressed by the mean ± standard deviation. Meanwhile, a paired-samples t-test was used to analyze the dosimetric relations between the groups, and the Pearson correlation analysis was adopted to analyze the correlation between the dosimetric change value of Plan-1 relative to Plan-0, the air cavity size, and the volume proportion of the cavity in the PTV. If p < 0.05, it was considered statistically significant. r is the correlation coefficient, ranging from -1 to 1. The closer |r| was to 1, the stronger the correlation would be.
3. Results
3.1 PTV dosimetric effect with and without air cavity on the target
Table 3 describes the dosimetric comparison of the two PTVs in Plan-1 with the PTV-0 in Plan-0, respectively. We found that Dmean, D2 and D0.2 of PTV-1 in Plan-1 were lower than those of PTV-0 in Plan-0, and that the difference was statistically significant (p < 0.05). Similar results occurred for PTV-0 in Plan-1 and PTV-0 in Plan-0. There was no significant difference in D98 between the two plans (p > 0.05). D95 was manually normalized to the prescribed dose, therefore there was no significant difference in D95 between the two plans (p > 0.05). The homogeneity of both PTVs in Plan-1 was better than that of PTV in Plan-0, and their differences were both statistically significant (0.09 ± 0.01 vs 0.10 ± 0.02, p < 0.05; 0.09 ± 0.02 vs 0.10 ± 0.02, p < 0.05). The difference was that the conformity of PTV-1 in Plan-1 was significantly poorer than that of PTV-0 in Plan-0 (0.67 ± 0.05 vs 0.72 ± 0.06, p < 0.05), while the difference between the conformity of PTV-0 in Plan-1 and that of PTV-0 in Plan-0 was not statistically significant (0.72 ± 0.06 vs 0.72 ± 0.06, p > 0.05). In Plan-1, the dosimetric parameters for the two PTVs were approximately equal except the CI, therefore removing the PTV air cavity did not affect the original PTV (PTV-0) coverage dose.
Fig. 2, Fig. 3 show the isodose lines of a certain CT cross-section and DVHs of a patient in the two plans, respectively. As shown in Fig. 2, the hot spots (red outline) were decreased and the high-dose volume (purple outline) was effectively controlled after the removal of the air cavity in the patient's PTV, which was beneficial in decreasing the target dose and in making it closer to the prescribed dose. As shown in Fig. 3, the dose drop gradient of PTV-1 curve in Plan-1 was larger than that of PTV-0 in Plan-0 on the standard of 100% prescribed dose that covered 95% of PTV, indicating that the homogeneity of dose distribution was improved after removing the air cavity from PTV.
Fig. 2The comparison of dose distribution in Plan-0 (A) and Plan-1 (B) for a patient. The orange region is PTV. The red curve is 55.44Gy (prescribed dose ×110%) isodose line, indicating there are hot spots. The pink curve is 53.93Gy (prescribed dose ×107%) isodose line, indicating a high-dose volume. The green curve is 50.40 Gy (prescribed dose) isodose line; The blue curve is 47.88Gy (prescribed dose ×95%) isodose line. (Color version of figure is available online.)
Fig. 3The PTV curve in the DVHs of the same patient in the two plans. The solid line represents PTV-0 in Plan-0, and the dashed line represents PTV-1 in Plan-1. (B) and (C) are the enlarged images of the red box area in (A). (Color version of figure is available online.)
3.2 PTV dosimetric effect with and without air cavity on OARs
Table 4 shows the OARs’ dose distribution in the two plans. V5, V20, and MLD of the total lung were not statistically different between Plan-0 and Plan-1 (p > 0.05). In comparison, removing the air cavity from the PTV could reduce V30 and MHD of the heart (p < 0.05), while there was no statistical difference in the V40 (p > 0.05). Although removing the PTV air cavity would increase the Dmax of the spinal cord, the increased degree was small, and the difference was not statistically significant (p = 0.767). The MED of the esophagus was 24.52 ± 4.93 Gy in Plan-0, while it was 24.40 ± 4.85 Gy in Plan-1, indicating that removing the PTV air cavity could reduce MED. In this case, the difference was statistically significant (p = 0.019).
Table 4Comparison of dose distributions of OARs between Plan-0 and Plan-1
The number of segments was 23.19 ± 5.90 in Plan-0, while it was 23.19 ± 6.24 in Plan-1, and the difference was not statistically significant (p = 1). The MUs in Plan-0 (385.62 ± 64.77) was slightly higher than that in Plan-1 (380.67 ± 64.66), and there was no statistical difference (p = 0.294).
3.4 The correlation between ΔN, the air cavity size and the Vair/VPTV
The PTV median volume in 21 patients was 211.48 cm3 (94.07 to 358.03 cm3), and the median volume of the PTV air cavity was 14.55 cm3 (4.24 to 21.72 cm3). The median volume proportion of the PTV air cavity was 6.44% (3.47% to 10.40%). Table 5 shows the correlation data between the change value of evaluation indexes (ΔN) in the two plans, the air cavity size, and the cavity volume proportion (Vair/VPTV). There was a strong negative correlation between the CI change value and the air cavity size (r = -0.564, p = 0.008), and a negative correlation between the MED change value and the air cavity size (r = -0.470, p = 0.031). Meanwhile, the correlation between other evaluation indexes and the air cavity size was weak, and there was no statistical significance (p > 0.05). The Vair/VPTV had a significantly negative correlation with the CI change value (r = -0.648, p = 0.001). The correlation between the change value of the remaining evaluation indexes and the Vair/VPTV was relatively weak, and there was no statistical significance (|r| < 0.4, p > 0.05). The three scatter plots in Fig. 4 describe their correlation.
Table 5The correlation between ΔN, the air cavity size and the Vair/VPTV
Fig. 4Scatter plot of the correlation between ΔN, the air cavity size, and the Vair/VPTV. Statistical differences were observed. (A) the CI change value and air cavity size, (B) the CI change value and Vair/VPTV, (C) the MED change value and air cavity size. The straight line is fitted by scattered points.
The tissue structures in the human body are complex, and during radiotherapy, the incident photon beam will encounter soft tissue, bone, air cavity and other tissues. These structures that have different densities in the transport path, while the interface between tissues that have large differences in density, will have an electron disequilibrium phenomenon, that seriously affects radiation energy deposition in the medium.
When IMRT is applied to postoperative NSCLC, the electron disequilibrium between the air-tissue interface tends to produce low-dose regions due to the existence of the PTV air cavity. When optimizing the PTV of the IMRT plan that is generated by the inverse-planning software, the air cavity poses a challenge to the inverse optimization process when optimized as a part of the PTV. On the one hand, it is difficult for the inverse-planning software to generate an IMRT plan with a homogeneous dose in the PTV, including the air cavity, due to the large differences in density or CT value between the air cavity and the surrounding tissues. On the other hand, to make up for the insufficient dose in the air cavity and achieve enough PTV coverage, the inverse-planning software may increase the overall dose of the target. However, this behavior is likely to cause a target overdose that results in unacceptable hot spots (see Fig. 2A), and that produce serious consequences if they fall on the important surrounding soft tissues, such as the great vessels. Therefore, in the IMRT plan for postoperative NSCLC, it may reduce hot spots to make the target dose closer to the prescribed dose, and which may lead to a more homogeneous plan by removing the PTV air cavity.
This study aimed to evaluate the PTV dosimetric effect with and without air cavity in IMRT for postoperative NSCLC. First, the PTV air cavity is not a tumor, and thus, removing the PTV air cavity will not affect the tumor control. The PTV without the air cavity can better reflect the patients’ true target. It was found that, when the same coverage of PTV (i.e., 100% prescribed dose covering 95% of PTV) was maintained, removing the PTV air cavity could obtain a plan which target dose was closer to the prescribed dose, with fewer hot spots, more homogeneous dose distribution and did not affect the coverage dose of the original PTV. This result is consistent with the conclusion drawn by Asher et al.
Dosimetric comparison of intensity-modulated radiation therapy for early-stage glottic cancers with and without the air cavity in the planning target volume.
who studied the influence of air cavity effect on the IMRT plan for laryngeal cancer.
After removing the air cavity, the target of plan-1 had a poorer conformity (lower CI) compared with the original plan-0. This was mainly caused by the dose within the air cavity. Due to the high dose of the target around the air cavity, it was difficult to completely drop the dose below the prescribed dose in the small air cavity (an example is shown in Fig. 2B), which led to an increased difference between the dose coverage and the shape of the target, and ultimately resulted in an decreased conformity. The CI decrease in the PTV, without the air cavity, could also be objectively explained by Equation (1). After removal of the air cavity, the PTV denominator volume (VT) decreased, and the intersection of the prescribed dose line and the PTV volume (VT.ref) decreased by a similar magnitude. Due to the quadratic relationship, the numerator widely decreased more widely, leading to a decrease in CI. After removing the air cavity, the PTV complex shape was also an important reason for the CI decrease. Mosleh Shirazi et al.
found that the more complex the PTV shape was, the less conformal the target would be. After removing the air cavity, the CI decrease might also be related to the decrease in the PTV volume. Brennan et al.
reported that there was a certain correlation between the PTV volume for NSCLC and the target conformity (r = 0.287, p = 0.023). In other words, the decrease in PTV volume implied a less conformal plan, though the correlation between the two was relatively weak.
The comparison of the OARs’ dose distribution in the two plans is shown in Table 4. After removal of the air cavity, the V30 and MHD of the heart statistically decreased. The V40 also decreased, but was not statistically significant. Although the change in the heart dose distribution was very small, it also showed that removing the air cavity from the PTV had the potential to reduce the heart radiation dose and to relatively decrease the patients’ radiation-associated myocarditis. In this study, the MED decrease suggests that the air cavity removal from the PTV can further decrease the risk of radiation-associated esophagitis. Since the PTV outer boundary, before and after the removal of the air cavity was almost unchanged, the beam setting also remained unchanged, and the irradiation area was mainly the mediastinum area. Therefore, air cavity removal had little impact on the total lung dose distribution, and there was no statistical difference in V5, V20 and MLD between the two plans. After air cavity removal, the spinal cord Dmax slightly increased, but was not statistically significant.
There was no statistical difference in the number of segments and MUs between the two plans. The number of segments and MUs correlated with the complexity of the plan,
Therefore, the results of this study indicate that the utilization ratio of MUs was similar in the two plans, and that the total complexity of the plan remains unchanged. Moreover, the consistency of the planned dose with the delivered dose was equivalent.
When studying the correlation between the change value of the evaluation indexes (ΔN) in the two plans, the air cavity size, and the cavity volume proportion (Vair/VPTV), we found that the CI change value had a significantly negative correlation with the air cavity size (r = -0.564, p = 0.008) and the Vair/VPTV (r = -0.648, p = 0.001) (Table 5 and Fig. 4A and B). This indicated that the CI change value would decrease with the increase of the air cavity size or the Vair/VPTV. Since the CI change value was mostly negative, the decrease in the value reflected the increase in the decrease of the CI amplitude in Plan-1, which made the Plan-1 conformity worse. The correlation degree between the CI change value and the Vair/VPTV (|r| = 0.648) was higher than that between the CI change value and the air cavity size (|r| = 0.564), indicating that the influence of the Vair/VPTV on the CI was greater than that of the air cavity size. Moreover, it could be seen that the increase in the air cavity size would result in the decrease in the MED change value, and therefore, a larger decrease in MED, which was statistically significant (r = -0.47, p = 0.031) (Table 5 and Fig. 4C). However, the correlation between the Vair/VPTV and the MED change value was weak, as reflected by the absence of statistical significance (|r| = -0.29, p = 0.203). This indicated that MED was easily affected by the air cavity size than the Vair/VPTV. The remaining evaluation indexes had no significant correlation with the air cavity size or the Vair/VPTV.
In this study, it was proved that PTV, without air cavity, had certain dosimetric advantages in the dose distribution of the target and OARs dose reduction when IMRT was used in postoperative NSCLC. There may be some differences between the different dose algorithms that were applied to this study, but the trend in dose variation associated with the cavity effect should similar. The study limitation of this study is due to its small sample size and its retrospective approach. Besides, another disadvantage is the manual delineation of the air cavity structure that increases the radiation oncologist workload. However, with the continuous technological development, it is believed that TPS will develop the ability to automatically describe the air cavity structure.
5. Conclusions
For the postoperative NSCLC treatment with IMRT, it is possible to make the target dose closer to the prescribed dose and generate fewer hot spots and a more homogeneous dose distribution by removing the PTV air cavity. The heart V30, MHD and the esophagus MED were reduced, and a larger air cavity size would lead to a lower MED and poorer conformity. Therefore, it is suggested that, when delineating PTV, radiation oncologists should decide whether to remove the PTV air cavity based on the results of this study and individual needs of postoperative NSCLC patients.
Authors’ Contributions
WG was involved in conceptualization, data curation, data analysis, investigation, methodology, and writing; YD was involved in conceptualization, data curation, data analysis, and methodology; HW was involved in conceptualization, data analysis and methodology; YS, HC, AF, HG, YH, YY and XF were involved in methodology, resources, supervision; HQ was involved in writing – review and editing. ZX was involved in conceptualization, data analysis, methodology, project administration, supervision, and writing – review/editing.
Acknowledgments
This study was supported by grants from the Interdisciplinary Program of Shanghai Jiao Tong University (No. YG2019ZDB07).
References
Bray F
Ferlay J
Soerjomataram I
et al.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
Adjuvant radiation therapy in locally advanced non-small cell lung cancer: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline.
Dosimetric comparison of intensity-modulated radiation therapy for early-stage glottic cancers with and without the air cavity in the planning target volume.
Significant difference.
00075-3&id=gr1.jpg){kind=link}
00075-3&id=gr2.jpg){kind=link}
00075-3&id=gr3.jpg){kind=link}
00075-3&id=gr4.jpg){kind=link}