Study of the dose-volume parameters variation in tumor target volumes and organs at risk during nasopharyngeal carcinoma radiotherapy applying deformation registration

Introduction

Nasopharyngeal carcinoma (NPC) occurs mostly in Southeast Asia and southern China (1,2). Due to the particularity of its anatomical location, NPC is surrounded by many important tissues and organs. The vast majority of NPC are more sensitive to radioactivity, and consequently radiotherapy or radiotherapy-based comprehensive treatment has now become the main method for radical treatment of patients with NPC (3). For patients with early NPC after radical radiotherapy, the 5-year survival rate can reach 80%.

There are many important organs at risk (OARs) around the target volume of NPC, such as the parotid glands, brain stem, spinal cord, eyeballs, optic nerves and lens. The exposure doses by these OARs were closely related to the quality of life of patients after treatment. The key to improving the effect of radiotherapy is to ensure the dose of the target volume and to minimize the dose of normal tissues and OARs. Therefore, it is of great significance to accurately predict the dose of the target volume and OARs during the radiotherapy process for patients with NPC.

Intensity-modulated radiotherapy (IMRT) is a routine clinical radiotherapy technique for NPC. It has a steep dose gradient distribution, which can reduce the exposure dose of OARs around the tumor while ensuring that the tumor target volume can be irradiated with a sufficient dose (4). However, some studies have shown that the volume and location of tumor target volume and OARs are different during the IMRT for NPC (5-7). In particular, the volume of the parotid glands was significantly reduced during IMRT for NPC (8). Differences in the volume of the parotid glands may lead to inadequate coverage of a radiation dose over the tumor target volume or excessive dosage of OARs, which deviates from the original plan. Deformed registration provides a feasible method for accurately accumulating radiation doses to target volume and OARs in NPC patients during radiotherapy. The purpose of deformed registration technology is to accumulate the dose through point-to-point registration, and then track the dose of the target volume and OARs during IMRT for NPC.

In the course of radiotherapy for NPC, the volume reduction in tumor target and OARs may not be synchronized with the changes in their dose volume indices. This study used registration technology to accumulate the dose of two plans of IMRT for NPC by rigid and deformed methods, and to thereby analyze the difference in the dose-volume index of the tumor target volume and OARs. This study provided an approach to evaluate the dose volume of IMRT for the NPC objective.

Methods

Patient characteristics

Eighteen NPC patients (13 males and 5 females) who received simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) from July 2010 to May 2018 were selected. The clinical stage was divided into 10 cases at the T₂ stage and 8 cases at the T₃ stage according to the AJCC 2010 staging standard T stage.

CT scanning and planning design

All patients underwent scanning and simulation on a Philips large-aperture CT, taking the supine position; fixing the head, neck, and shoulder with a thermoplastic mask; and scanning from the top of the head to the lower 3 cm of the clavicle with a layer thickness of 3 mm. The scanned CT image was transmitted to the Eclipse 13.5 planning system and the SIB-IMRT technique was used. The radiologist outlined the target volume, as well as OARs such as the parotid gland, brain stem, spinal cord, eyeballs, optic nerves, and lens. The dosage limitation conditions for OARs are a 50% parotid volume dose less than 30 Gy, brainstem dose less than 54 Gy, spinal cord dose less than 45 Gy, optic nerve dose less than 54 Gy, eyeball dose less than 50 Gy, lens dose less than 8 Gy, etc. Plan₁ was the IMRT plan on simulation CT before radiotherapy and Plan₂ was the IMRT plan on repeated simulation CT at the middle and late stages of radiotherapy. The prescribed dose was 66–70 Gy.

Image registration

The patient’s two radiotherapy plans were imported into the velocity image registration software based on B-spline algorithm, and the repeated simulated CT₂ was registered into the first simulated CT₁ to obtain the transformed registration image CT₃. The dose distribution of Plan₂ and the dose distribution of Plan₁ were separately subjected to rigidity and deformation registration to obtain Plan_rig and Plan_def.

Statistical indicators

The volume of the gross tumor volume (GTV) and bilateral parotid glands; average dose (D_mean), 95% volume dose (D₉₅) and 99% volume dose (D₉₉) of GTV; and plan gross tumor volume (PGTV) were measured and recorded. Indicators of various OARs include the bilateral parotid D_mean, 50% volume dose (D₅₀) and 30 Gy surrounded volume (V₃₀); maximum point dose (D_max) and 5% volume dose (D₅) of the brain stem; D_max of the bilateral eyeballs, optic nerves and lens; and Dice Similarity Coefficient (DSC) of the GTV, PGTV, parotid gland, brainstem, eyeballs, optic nerves and lens after deformation registration and rigid registration. (DSC=2|A∩B|/(|A|+|B|). The volume of the target volume and OARs in CT₁ and CT₂ were A and B respectively.)

Statistical methods

The data are expressed in the form (x¯±s). A paired t-test was performed using SPSS 19.0 statistical software. P<0.05 indicates that the difference is statistically significant.

Results

Change in the volume of the GTV and parotid gland

Compared with the initial simulated CT₁, the volumes of the GTV, left parotid gland and right parotid gland in the repeated simulated CT₂ decreased by 20.83% (P<0.001), 36.83% (P<0.001) and 37.47% (P<0.001), respectively. After deformation registration, the volume of the GTV decreased by 3.15% (P<0.001) compared with the initial positioning of the GTV, the left parotid volume decreased by 6.56% (P<0.001), and the right parotid volume decreased by 5.89% (P<0.001) (Table 1).

Dosimetric comparison in the target volume

There was no significant change in the dose indices of the GTV and PGTV between Plan₂ and Plan₁ (P>0.05). Compared with Plan₁, the D_mean of the GTV in Plan_def and Plan_rig decreased by 0.42% and 0.62%, respectively (Table 2), and the difference was statistically significant (P<0.05). The D_mean of the PGTV in Plan_def and Plan_rig decreased by 1.08% and 1.49%, respectively; the D₉₅ of the PGTV in Plan_def and Plan_rig decreased by 2.77% and 5.49%, respectively; the D₉₉ of the PGTV in Plan_def and Plan_rig decreased by 4.29% and 7.39% (Table 2); and these differences were statistically significant (P<0.05).

DSC comparison between rigid registration and deformation registration

The DSC of the target volume and the OARs after rigid registration and deformation registration, respectively, is shown in Table 3. The DSC of the target volume and the OARs after deformation registration was greater than the DSC of the rigid registration target volume and the OARs. The DSC difference between the left and right parotid deformation registration and rigid registration was significant (P<0.05).

Dosimetric comparison in the OARs

The dose distribution of each OAR in Plan₁, Plan₂, Plan_def and Plan_rig is shown in Table 4. Compared with Plan₁, the V₃₀ of the left parotid gland in Plan₂ decreased by 33.5%, the D_mean of the right parotid gland decreased by 31.45%, the V₃₀ decreased by 60.13%, and the D₅₀ decreased by 28.35%. The difference was statistically significant (P<0.05). The D_mean of the left and right parotid glands in Plan_def decreased by 1.98% and 2.3%, respectively, compared with Plan₁, and the difference was statistically significant (P<0.05). The changes in V₃₀ and D₅₀ of the left and right parotid glands between Plan_def and Plan₁ were not significant (P>0.05). The D_mean of the left and right parotid in Plan_rig decreased by 4.21% and 4.93% compared with Plan₁, V₃₀ decreased by 7.68% and 10.35%, and D₅₀ decreased by 3.37% and 3.46%, and this difference was statistically significant (P<0.05).

Compared with Plan₁, D_max and D₅ of the brainstem in Plan₂ were reduced by 17.04% and 27.3%, respectively. The D_max of the left eyeball, right eyeball, left lens, right lens, left optic nerve and right optic nerve were decreased by 36.43%, 28.48%, 24.95%, 24.29%, 44.69% and 41.1%, respectively. The difference was statistically significant (P<0.05). Compared with Plan₁, D₅ of the brainstem in Plan_def was reduced by 3.3%. The D_max of the left eyeball, right eyeball, left optic nerve and right optic nerve were decreased by 6.13%, 3.44%, 5.67% and 5.19%, respectively. The difference was statistically significant (P<0.05).

Compared with Plan_rig, the D_mean, V₃₀ and D₅₀ of the left parotid gland in Plan_def increased by 2.26%, 4.36% and 2.1%, respectively, and the difference was statistically significant (P<0.05). The difference in D_mean, V₃₀ and D₅₀ in the right parotid gland was not significant. The D_max of the OARs, such as the brainstem, eyeballs, lens and optic nerves, were all decreased.

Discussion

In the process of IMRT, although IMRT is more effective than conventional radiotherapy in increasing the target dose, the radiation exposure of normal tissues and OARs is relatively low (9,10). However, for NPC, factors such as changes in the patient weight, volume of tumors and OARs may have a certain impact on dose assessment. Anatomical changes may result in an insufficient target dose and excessive exposure of OARs. The difference between the actual dose received by the patient and the radiotherapy plan designed by simulation CT was 15% (11). Lu et al. (12) compared the repeated simulated CT with the initial simulated CT in 12 patients with NPC and found that the volume of the PGTV was reduced by an average of 16.4%±27.3%. In this study, the tumor target volume of repeated simulated CT was reduced by 20.83% on average compared with that of the initial simulated CT, and the difference between the Plan deformation, Plan₂ and Plan₁ dose evaluation showed that the D_mean, D₉₅ and D₉₉ of the GTV were not significant. Cheng et al. (13) and Wang et al. (14) showed that in the course of radiotherapy for NPC, the volume of the tumor target was smaller than that before radiotherapy, but the target dose index did not decrease. In this study, it was found that the volume of the target gradually decreased during IMRT for NPC, and this conclusion is consistent with most studies (12-14). The dose index of the target volume was basically the same in the four plans. Therefore, the dose index of target volume in the initial plan can accurately evaluate the efficacy of radiotherapy.

The parotid gland is sensitive to radiation, and the volume of the parotid gland changes significantly during radiotherapy for NPC. Fung et al. (15) transmitted the original plan dose distribution of NPC radiotherapy to the new CT to form a synthetic plan compared with the original plan dosimetry, the dose of the OARs increased, and the D_mean of the left and right parotid glands significantly increased. In this study, we found that the volume of the parotid gland changed significantly compared with the initial location CT, and the left and right parotid glands were reduced by 36.83% and 37.47%, respectively. Compared with Plan₁, the V₃₀ of the left parotid gland in Plan₂ decreased by 36.15%; the D_mean, V₃₀ and D₅₀ of the right parotid gland decreased by 30.07%, 36.2% and 25%, respectively. The dose-volume evaluation of Plan_def and Plan₁ showed that the D_mean of the left and right parotid glands decreased by 1.98% and 2.3%, respectively, and the V₃₀ and D₅₀ of the left and right parotid glands were not statistically significant. These studies have shown that the parotid gland volume shrinks as the dose is absorbed during radiotherapy, and the proportion of shrinkage is not synchronized with the shrinkage of the tumor target volume. In this study, it was found that the dose-volume index of parotid glands in Plan₁ and Plan₂ was significantly different. The dose-volume index of Plan₁ and Plan₂ may not accurately predict the radiation damage of parotid glands during radiotherapy. However, deformation accumulation is an objective method to eliminate the effect of volume shape change, and the difference in the dose-volume index between the Plan₁ and Plan_def were less than 5%. Therefore, it can be considered that the use of the initial planned dose-volume index can accurately predict the radiation damage of the parotid gland during IMRT for NPC.

Compared with the initial simulated CT, repeated simulated CT was deformed to different degrees, and therefore, the dose distribution of the two plans cannot be accumulated directly. Image registration method is needed to deform and accumulate the dose. Janssens et al. (16) used the Demons algorithm based on the image grayscale and the Morphons algorithm based on the edge and line to achieve the deformation registration. In this study, deformation registration and rigid registration based on the B-spline algorithm were adopted. The DSC of the target volume and OARs in the deformation registration were larger than that in the rigid registration, especially with respect to the parotid glands (P<0.05), which shows that deformation registration was superior to rigid registration.

The volume changes in the brain stem, eyeballs, optic nerves, and lens during IMRT for NPC were very small. Compared with Plan₁, Plan₂ showed a significant difference (P<0.05) in the dose index of these OARs, which was attributed to the shrinking of the GTV volume, and the variation in the dose-volume index in Plan_def compared with Plan₁ were very small.

Conclusions

In summary, during IMRT for NPC, the volume of the tumor target volume and parotid gland were significantly reduced. However, there was no significant difference between the dose-volume index of the tumor target and OARs in the first planning and the dose-volume index accumulated by deformation registration. Therefore, the dose-volume index of the initial plan can be used to evaluate the curative effect of NPC patients in the whole radiotherapy process and to predict the radiation damage.

Acknowledgments

Funding: This research was supported by the Key Research and Development Program of Guangxi Province (No. AB17195005) and the Key Research and Development Program of Shandong Province (No. 2018GSF118006).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2019.11.06). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This retrospective study was approved by the Institutional Review Board (IRB) and the Ethics Committee of the Shandong Cancer Hospital, and the number/ID of the approval 201806033. Individual informed consent was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Zeng L, Sun XM, Chen CY, et al. Comparative study on prophylactic irradiation to the whole neck and to the upper neck for patients with neck lymph node negative nasopharyngeal carcinoma. Head Neck 2014;36:687-93. [Crossref] [PubMed]
2. Zhang L, Chen QY, Liu H, et al. Emerging treatment options for nasopharyngeal carcinoma. Drug Des Devel Ther 2013;7:37-52. [PubMed]
3. Wei WI, Sham JST. Nasopharyngeal carcinoma. Lancet 2005;365:2041-54. [Crossref] [PubMed]
4. Lai SZ, Li WF, Chen L, et al. How does intensity-modulated radiotherapy versus conventional two-dimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys 2011;80:661-8. [Crossref] [PubMed]
5. Zhao L, Wan Q, Zhou Y, et al. The role of replanning in fractionated intensity modulated radiotherapy for nasopharyngeal carcinoma. Radiother Oncol 2011;98:23-7. [Crossref] [PubMed]
6. Wang RH, Zhang SX, Zhou LH, et al. Volume and dosimetric variations during two-phase adaptive intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma. Biomed Mater Eng 2014;24:1217-25. [Crossref] [PubMed]
7. Orlandi E, Tomatis S, Potepan P, et al. Critical analysis of locoregional failures following intensity-modulated radiotherapy for nasopharyngeal carcinoma. Future Oncol 2013;9:103-14. [Crossref] [PubMed]
8. Zhou N, Chu C, Dou X, et al. Early evaluation of radiation-induced parotid damage in patients with nasopharyngeal carcinoma by T2 mapping and mDIXON Quant imaging: initial findings. Radiat Oncol 2018;13:22. [Crossref] [PubMed]
9. Deng S, Liu X, Lu H, et al. Three-Phase Adaptive Radiation Therapy for Patients with Nasopharyngeal Carcinoma Undergoing Intensity-Modulated Radiation Therapy: Dosimetric Analysis. Technol Cancer Res Treat 2017;16:910-6. [Crossref] [PubMed]
10. Zhang Y, Lin C, Wu J, et al. A longitudinal evaluation of early anatomical changes of parotid gland in intensity modulated radiotherapy of nasopharyngeal carcinoma patients with parapharyngeal space involvement. J Med Radiat Sci 2017;64:188-94. [Crossref] [PubMed]
11. Lee C, Langen KM, Lu W, et al. Assessment of Parotid Gland Dose Changes During Head and Neck Cancer Radiotherapy Using Daily Megavoltage Computed Tomography and Deformable Image Registration. Int J Radiat Oncol Biol Phys 2008;71:1563-71. [Crossref] [PubMed]
12. Lu J, Ma Y, Chen J, et al. Assessment of anatomical and dosimetric changes by a deformable registration method during the course of intensity-modulated radiotherapy for nasopharyngeal carcinoma. J Radiat Res 2014;55:97-104. [Crossref] [PubMed]
13. Cheng HC, Wu VW, Ngan RK, et al. A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients. Radiother Oncol 2012;104:317-23. [Crossref] [PubMed]
14. Fung WW, Teo PM, Wu VW. Developing an adaptive radiation therapy strategy for nasopharyngeal carcinoma. J Radiat Res 2014;55:293-304. [Crossref] [PubMed]
15. Fung WW, Wu VW, Teo PM. Dosimetric evaluation of a three-phase adaptive radiotherapy for nasopharyngeal carcinoma using helical tomotherapy. Med Dosim 2012;37:92-7. [Crossref] [PubMed]
16. Janssens G, Xivry JOD, Fekkes S, et al. Evaluation of nonrigid registration models for interfraction dose accumulation in radiotherapy. Med Phys 2009;36:4268-76. [Crossref] [PubMed]