Tailoring PTV expansion to improve the dosimetry of post modified radical mastectomy intensity‐modulated radiotherapy for left‐sided breast cancer patients by using 4D CT combined with cone beam CT

Abstract Purpose Our study aimed to improve the dosimetry of post modified radical mastectomy intensity‐modulated radiotherapy (PMRM‐IMRT) for left‐sided breast cancer patients by tailoring and minimizing PTV expansion three‐dimensionally utilizing 4D CT combined with on‐board cone beam CT (CBCT). Methods We enrolled a total of 10 consecutive left‐sided breast cancer patients to undergo PMRM‐IMRT. We measured the intra‐fractional CTV displacement attributed to respiratory movement by defining 9 points on the left chest wall and quantifying their displacement by using the 4D CT, and measured the inter‐fractional CTV displacement resulting from the integrated effect of respiratory movement, thoracic deformation and set up errors by using CBCT. We created 3 different PMRM‐IMRT plans for each of the patients using PTVt (tailored PTV expansion three‐dimensionally), PTV0.5 and PTV0.7 (isotropic 0.5‐ cm and isotropic 0.7‐ cm expanding margin of CTV), respectively. We performed paired samples t test to establish a hierarchy in terms of plan quality and dosimetric benefits. P < 0.05 was considered statistically significant. Results The inter‐fractional CTV displacement (2.6 ± 2.2 mm vertically, 2.8 ± 2.3 mm longitudinally, and 1.7 ± 1.2 mm laterally) measured by CBCT was much larger than the intra‐fractional one (0.5 ± 0.5 mm vertically, 0.5 ± 1.0 mm longitudinally, and 0.3 ± 0.3 mm laterally, respectively) measured by 4D CT. Intensity‐modulated radiotherapy with tailored PTV expansion based on inter‐fractional CTV displacement had dosimetrical advantages over those with PTV0.5 or those with PTV0.7 owing to its perfect PTV dose coverage and better OARs sparing(especially of heart and left lung). Conclusion The CTV displacement in PMRM‐IMRT predominantly arises from inter‐fraction rather than from intra‐fraction during natural respiration and differs in 3 coordinate axes either inter‐fractionally or intra‐fractionally. Tailoring and minimizing PTV expansion three‐dimensionally significantly improves the dosimetry of PMRM‐IMRT for left‐sided breast cancer patients.


Conclusion:
The CTV displacement in PMRM-IMRT predominantly arises from inter-fraction rather than from intra-fraction during natural respiration and differs in 3 coordinate axes either inter-fractionally or intra-fractionally. Tailoring and minimizing PTV expansion three-dimensionally significantly improves the dosimetry of PMRM-IMRT for left-sided breast cancer patients.

| INTRODUCTION
Our previous study had demonstrated that intensity-modulated radiation therapy has dosimetrical advantages over three-dimensional conformal radiotherapy with field-in-field technique (3DCRT-FinF) and 2partial arc volumetric modulated arc therapy (2P-VMAT) for left-sided breast cancer patients after modified radical mastectomy, and suggested that individually quantifying and minimizing CTV displacement might improve target dose coverage and heart and left lung sparing. 1 Given the heart irradiation leading to the subsequent increasing risk of life-threatening major cardiac events, including myocardial infarction, coronary revascularization, or death from ischemic cardiac disease, [2][3][4][5][6][7] and the nature of lack of a threshold value, their long-term, dosage-related effect as well as the additive nature of the risk with preexisting cardiac diseases, 8 heart radiation exposure should be used as an a priori limitation parameter to evaluate which of the radiotherapy plans for left-sided breast cancer after modified radical mastectomy is more advantageous if PTV dose coverage and other OARs sparing are acceptable. 1 Our study aimed to verify the dosimetry improvement of post modified radical mastectomy intensity-modulated radiotherapy (PMRM-IMRT) for the patients by tailoring and minimizing PTV expansion three-dimensionally utilizing four-dimensional computed tomography (4D CT) simulation combined with onboard cone beam CT (CBCT) verification under natural respiration.

| MATERIALS AND METHODS
We enrolled a total of 10 left-sided breast cancer patients undergoing IMRT after modified radical mastectomy in this study. Based on the contouring atlas published by the Radiation Therapy Oncology Group (RTOG), 9 we delineated CTV including left chest wall and ipsilateral lymph node drainage area. A prescribed dose of 50 Gy/5w/ 25f was delivered to PTV. Each patient had 4D CT simulation before radiotherapy and three times of on-board cone beam CT verification inter-fractionally during the treatment. The intra-fractional CTV displacement attributed to respiratory movement was measured by the 4D CT. The inter-fractional CTV displacement resulting from the integrated effect of respiratory movement, thoracic disformation and setup errors was measured by the on-board cone beam CT.
The study was performed in accordance with the Declaration of Helsinki, and was approved by the Ethics Committee of the Cancer Hospital of Shantou University Medical College. Informed consent form was obtained from each patient.

2.C | Plan comparison and statistical analysis
We created three different PMRM-IMRT plans for each of the patients using the PTV t (tailored PTV expansion three-dimensionally), PTV 0.5 and PTV 0.7 (isotropic 0.5-cm and isotropic 0.7-cm expanding margin of CTV), respectively. All PMRM-IMRT plans used two opposed tangential beams, and two anterior beams with a 10-degree angle from the tangential ones, and a supraclavicular beam. The dose calculations were employed with a grid of 2.5 mm using the Anisotropic Analytical Algorithm (AAA). All plans were created with a prescribed dose of 50 Gy covering 95% of the PTV.
Clinical target volume (CTV) and OARs including heart, ipsilateral lung, spinal cord, and contralateral breast were contoured as previously 1 using the Eclipse treatment planning system (Eclipse represents better homogeneity. A lower CI value, ranging from 0 to 1, represents worse conformity. D mean is an average dose delivering to an organ. V (xGy) represents the percentage of an organ's volume receiving (x) Gy or higher. D 2% represented the dose corresponding to 2% PTV volume as shown in the dose volume histogram (DVH) and could be deemed as the maximum dose, whereas D 98% could be deemed as the minimum dose. D 50% represented the reference dose (or prescription dose) for PTV. D mean , V 5 Gy , V 10 Gy , and V 20 Gy were calculated for the heart and the left lung. We performed paired samples t test between any two of the three plans, to establish a hierarchy in terms of plan quality and dosimetric benefits. P < 0.05 were considered statistically significant. The SPSS 19.0 software (IBM, Chicago, IL) was used for statistical data management and analysis. P < 0.05 was considered statistically significant.

| RESULTS
The intra-fractional CTV displacement in PMRM-IMRT for left-sided breast cancer patients measured by 4D CT during natural respiration.
The overall intra-fractional CTV displacement attributed to respiratory movement measured by 4D CT simulation differed in three directions, with 0.5 ± 0.5 mm vertically, 0.5 ± 1.0 mm longitudinally, and 0.3 ± 0.3 mm laterally, respectively. As exhibited in Table 1, the result indicated that the lower and lateral part of the chest wall tends to have a larger range of displacement than the upper and middle one during natural breathing. Either the displacement in y direction or in z direction was larger than in x direction during natural respiration ( Table 1).
The inter-fractional CTV displacement in PMRM-IMRT for leftsided breast cancer patients measured by CBCT during natural breathing.
The inter-fractional CTV displacement in PMRM-IMRT was much larger than the intra-fractional one during natural breathing. The inter-fractional CTV displacement resulting from the mixed effect of respiratory movement, thoracic disformation and setup errors, measured by on-board cone beam CT were 2.6 ± 2.2 mm vertically, 2.8 ± 2.3 mm longitudinally, and 1.7 ± 1.2 mm laterally, respectively ( Table 2). The CTV displacement predominantly arises from interfraction rather than from intra-fraction during natural breathing, and differs in three directions either inter-fractionally or intra-fractionally.
Dosimetrical advantage of PMRM-IMRT using PTV t over those using PTV 0.5 or those using PTV 0.7 for left-sided breast cancer patients under natural respiration.  X, Y, and Z values indicated the inter-or intra-fractional CTV displacement in x (laterally), in y (longitudinally) and in z coordinate axis (vertically), respectively. Data presented as mean ± standard deviation (Mean ± SD) (mm). The values in the last three columns were the CTV coverage rates under the corresponding status when using CTV expanding values with 2, 3, and 4 mm, respectively. Abbreviations: PMRM-IMRT = post modified radical mastectomy intensity-modulated radiotherapy. CBCT = cone beam computed tomography. sparing compared with those using PTV 0.7 (all P < 0.01) (Figures 1, 2 and Table 3).

| DISCUSSION
Increasing PTV expansion in post modified radical mastectomy intensity-modulated radiotherapy (PMRM-IMRT) for left-sided breast cancer incredibly leads to the increasing radiation exposure of heart and left lung, which leads to the increasing risk of the long-term radiation injury correspondingly. 2,5,8,10,11 Considering setup and respiration motion uncertainties, either an isotropic 0.7-cm or an 0.5-cm expanding margin of CTV was referred to as an "approximate value" in published study 12  In our study, we measured the intra-fractional CTV displacement 13,14 attributed to respiratory movement by defining nine points on the left chest wall and quantifying their displacement by using the 4D CT. We than measured the inter-fractional CTV displacement resulting from the integrated effect of respiratory movement, thoracic disformation and setup errors by using the on-board cone beam CT. Interestingly, we found that the CTV displacement in post modified radical mastectomy intensity-modulated radiotherapy predominantly arises from inter-fraction rather than from intra-fraction during natural breathing, and differs in three directions either interfractionally or intra-fractionally. Tailoring and minimizing PTV expansion three-dimensionally based on inter-fractional CTV displacement T A B L E 3 Dosimetric comparison of PMRM-IMRT for left-sided breast cancer patients using PTV t with those using PTV 0.5 or those using PTV 0 . 7 . These data represent statistically significant data (p < 0.05), and bold is used to make it more obvious. Abbreviations: PMRM-IMRT = post modified radical mastectomy intensity-modulated radiotherapy. PTV t = tailored PTV expansion three-dimensionally. PTV 0.5 = PTV generated from isotropic 0.5-cm expanding margin of CTV. PTV 0.7 = PTV generated from isotropic 0.7-cm expanding margin of CTV. Data presented as mean ± standard deviation. D mean = mean dose (Gy

| CONCLUSION
Our study exhibits that the CTV displacement in post modified radical mastectomy intensity-modulated radiotherapy for left-sided breast cancer patients predominantly results from inter-fraction rather than from intra-fraction during natural breathing, and differs in three dimensions either inter-fractionally or intra-fractionally. The

ETHICAL DECLARATIONS
The study was performed in accordance with the Declaration of Hel-

CONFLI CT OF INTEREST
No conflict of interest.