Medical Dosimetry ] (2014) ]]]–]]]
Medical Dosimetry journal homepage: www.meddos.org
Postoperative radiotherapy following mastectomy for patients with left-sided breast cancer: A comparative dosimetric study Jiahao Wang ,* Xiadong Li ,† Qinghua Deng ,† Bing Xia, Ph.D.,* Shixiu Wu ,* Jian Liu ,# and Shenglin Ma † Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, China; †Department of Radiation Oncology, Hangzhou First People's Hospital, Hangzhou, China; and #Department of Breast Surgery, Hangzhou First People's Hospital, Hangzhou, China
*
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 June 2014 Received in revised form 25 October 2014 Accepted 11 November 2014
The purposes of this article were to compare the biophysical dosimetry for postmastectomy left-sided breast cancer using 4 different radiotherapy (RT) techniques. In total, 30 patients with left-sided breast cancer were randomly selected for this treatment planning study. They were planned using 4 RT techniques, including the following: (1) 3-dimensional conventional tangential fields (TFs), (2) tangential intensity-modulated therapy (T-IMRT), (3) 4 fields IMRT (4F-IMRT), and (4) single arc volumetricmodulated arc therapy (S-VMAT). The planning target volume (PTV) dose was prescribed 50 Gy, the comparison of target dose distribution, conformity index, homogeneity index, dose to organs at risk (OARs), tumor control probability (TCP), normal tissue complication probability (NTCP), and number of monitor units (MUs) between 4 plans were investigated for their biophysical dosimetric difference. The target conformity and homogeneity of S-VMAT were better than the other 3 kinds of plans, but increased the volume of OARs receiving low dose (V5). TCP of PTV and NTCP of the left lung showed no statistically significant difference in 4 plans. 4F-IMRT plan was superior in terms of target coverage and protection of OARs and demonstrated significant advantages in decreasing the NTCP of heart by 0.07, 0.03, and 0.05 compared with TFs, T-IMRT, and S-VMAT plan. Compared with other 3 plans, TFs reduced the average number of MUs. Of the 4 techniques studied, this analysis supports 4F-IMRT as the most appropriate balance of target coverage and normal tissue sparing. & 2014 American Association of Medical Dosimetrists.
Keywords: Postmastectomy radiotherapy Breast cancer Target coverage Normal tissue sparing
Introduction Radiotherapy (RT) is one of the main treatments for patients after mastectomy. Postmastectomy RT (PMRT) can effectively reduce the recurrence rate in local area, improve the tumorspecific survival rate, and disease-free survival rate; however, the total survival rate is insignificant.1 Cardiovascular injury has been implicated as the reason that, although adjuvant RT improved breast cancer–specific survival, no improvement in overall survival was demonstrated in meta-analyses that included randomized RT trials.2 Especially, anthracycline-based chemotherapy, trastuzumab, and both in combination were being used increasingly in the adjuvant therapy of patients with invasive breast cancer. These agents alone or in combination with RT may cause later cardiac morbidity.
Reprint requests to: Shenglin Ma, Department of Radiation Oncology, Hangzhou First People's Hospital, Huan Sha Road 261, Hangzhou 310000, China. E-mail: [email protected] http://dx.doi.org/10.1016/j.meddos.2014.11.004 0958-3947/Copyright Ó 2014 American Association of Medical Dosimetrists
There have been various RT techniques proposed to patients with breast conservation surgery (BCS), Teh et al.3 reported that the conventional opposed tangential fields (TFs) technique (3-dimensional–conformal RT [3DCRT]) delivers too much radiation to a large volume of the ipsilateral lung and heart in breastconserving therapy. Meanwhile, tangential intensity-modulated therapy (T-IMRT) was reported by Rongsriyam et al.4 having better target dose homogeneity and conformity and sparing normal tissue, such as the heart and the ipsilateral lung for patients undergoing adjuvant RT after BCS. However, Yin et al.5 showed another significant result that intensity-modulated arc RT performed better in target conformity and can reduce high-dose volume in the heart and the left lung in treatment of BCS. Some reports6,7 also suggested that different planning target volume (PTV) size may lead to different results in using various irradiating techniques in RT with breast cancer. If the PTV includes only the breast, such as treatment of BCS, then the technique typically consists of 2 TFs placed medially and laterally to the
J. Wang et al. / Medical Dosimetry ] (2014) ]]]–]]]
2
breast. This field arrangement attempts to minimize the amount of underlying normal tissue irradiated. However, if the PTV also includes chest wall (CW), anterior supraclavicular area (SA) and internal mammary node (IMN), then simple TFs usually do not offer the best solution. Then volumetric-modulated arc therapy (VMAT) as a new RT technology has dynamic parameters, including variations of dose rate, gantry rotation speed, leaf motion speed, and gantry position. However, for the target of PMRT that is located on the chest and next to the lung and the heart, whether these dynamic parameters could produce ascendant results should also be reconsidered. The purpose of this planning study was to evaluate and compare 4 RT (TF, T-IMRT, 4 fields IMRT [4F-IMRT], and single arc VMAT [S-VMAT]) techniques in the treatment of patients with left-sided breast cancer following mastectomy.
Methods and Materials Clinical data selection Treatment planning was performed retrospectively on 30 patients with leftsided breast cancer previously treated from February 2013 to July 2013 in Hangzhou Cancer Hospital, Hangzhou City, Zhejiang Province, P.R. China. The ages of patients ranged from 44 to 63 years with the median age being 56 years. The stage of disease was T4a-4cN3M0, and all patients received a course of chemotherapy before RT. Written informed consents were obtained from all patients or their families. All procedures of this study were approved by the Ethical Committee of Hangzhou Cancer Hospital.
Target and normal tissue delineation The PTV included CW, SA, and IMNs. It was created by adding a 7-mm expansion in all directions around the clinical target volume, and another 8 mm was added on the surface of the CW skin for the purpose of compensation of movement. All 30 cases were delineated by the same senior radiation oncologist based on the computed tomography (CT) image. The contours of all the involved organs at risk (OARs), including the contralateral breast, heart, coronary artery (CA), and left and right lung were outlined by the treating physician. All targets and OARs were outlined slice by slice in the CT image in the treatment planning system (TPS) and then the 3D contour was reconstructed automatically.
Treatment plan All plans were completed in 3D Oncentra TPS (Nucletron BV, Veenendal, Netherlands). The TPS determined homogeneous media and density in the body based on the CT density calibration curve and calculated the dose with collapse cone convolution, which took into account the calibration of the homogeneous medium. The Elekta Axesse linear accelerator with 6-MV photon energy was used. The PTV was prescribed 50 Gy given in 25 fractions within 5 weeks, and the optimization constraint is that ensuring 95% isodose line encompasses 95% of PTV (V95% Z 47.5 Gy). The detailed method was as follows: The TF plan used 2 opposite half beam, which included whole PTV and avoided direct exposure to the contralateral breast. The arrangement of gantry angle was 3001 and 1201. The T-IMRT plan was created with same angle of the conventional TF plan. 4F-IMRT plan added the other opposite half beam based on the T-IMRT plan and the gantry angle was 3001, 3201, 1201, and 1401. S-VMAT, in which arc direction is such that beam enters the breast before exiting through the lung, may increase the dose volume of the lung and contralateral breast. The VMAT plan used a single arc field in which starting angle Table 1 The optimization objective applied in IMRT and VMAT planning Structure
Planning aim (weight)
PTV
V53 Gy r 1% (70), V50 Gy Z 95% (80), and V49 Gy Z 98% (80) V5 Gy r 45% (10), V20 Gy r 25% (10), and V30 Gy r 18% (10) Dmax r 5 Gy (8) V20 Gy r 18% (10) and V10 Gy r 22% (10) V10 Gy r 27% (12), V20 Gy r 18% (12), and V30 Gy r 8% (12)
Left lung Contralateral breast Heart CA
and ending angle were respectively the same as the 4F-IMRT beam angle, and the degree of the subfield interval of 41 was used. For the IMRT and VMAT plans, the optimization objective listed in Table 1 was used. Collapsed cone (graphics processing unit) algorithm optimization was applied to optimize plans. The minimum field size and monitor unit (MU) of subfield were restricted to 2 cm2 and 2 MU. The different treatment techniques have been applied to the patients' data set without any clinical application. This activity does not require an ethical approval according to our institution's rules. Biophysical dosimetric evaluation The biophysical dosimetric evaluation metrics were chosen for each structure, and the same metrics were used to evaluate all plans. Dose-volume histograms (DVHs) were calculated for all involved structures, including the target volume, left lung, heart, CA, and contralateral breast. For each target volume, the mean dose, D2% and D98% (dose corresponding to 2% and 98% target volume); V95%, and V110% (volume of the target received 95% and 110% prescription dose); conformal index (CI)8; and homogeneity index (HI)9 were tabulated and reviewed. For the normal tissues, metrics included the mean dose for each structure. For the left lung, the values for the percentage of left lung that received 5 Gy (V5), 20 Gy (V20), and 30 Gy (V30) were chosen; for the heart and CA, values for the percentage of heart and CA that received 5, 10, 20, and 30 Gy (V5, V10, V20, and V30, respectively) were both chosen; and for the contralateral breast, values for the percentage of contralateral breast that received 5 and 10 Gy were obtained. Other metrics included tumor control probability (TCP) for PTV and normal tissue complication probability (NTCP) for the left lung and the heart. The CI, HI, TCP and NTCP are described later. The CI and HI were defined to describe the quality of target as follows: CI ¼
VT:ref V T:ref VT Vref
where VT represents target volume, VT.ref represents the target volume wrapped by reference isodose curve face, and Vref represents all the volume wrapped by reference isodose curve face. A higher CI value, ranging from 0 to 1, represents better conformity. HI ¼
D2% D98% Dmean
where D2% represents the dose corresponding to 2% target volume as shown in DVH and can be deemed as the maximum dose; D98% represents the dose corresponding to 98% target volume as shown in DVH, and can be deemed as the minimum dose. LQ-Poisson model was used to calculate the TCP for PTV10: n o 2 TCPPTV ¼ exp N0 exp n αd þ βd where N0 is the number of tumor cells about clone source. α is the probability of cell injury by a single ionizing particle strike to DNA, and β is the probability of cell injury by double ionizing particles strike to DNA. α/β Ratio was 3 for PTV. These tumor-specific parameters were cited from a study by Webb.11 The NTCP-Lyman model was used to calculate the NTCP of the left lung as follows12,13: Z t 1 x2 dx EXP NTCP left lung ¼ pffiffiffiffiffiffi 2 2π ∞ t¼
D max D 50 ðvÞ m D 50 ðvÞ
D50 ðvÞ ¼ D50 ðv
¼ 1Þ
Vn
where m is the slope of 50% complication probability in the curve of dose effect (m ¼ 0.18), and D50 (v) is the tolerance dose for 50% complication probability. The tissue-special parameters were based on the Lyman model (AAPM No.166).14 The NTCP-RSM (relative seriality [RS]) model was accepted as the most suitable biological model to calculate the NTCP for the heart.15 This model is based on Poisson statistics, and it accounts for the architecture of the organ through the parameter of RS. The RS is derived from the ratio of serial subunits to all subunits in the organ. ( NTCP
Heart
¼
N
1 ∏
i ¼ 1
ΔV i 1 pðDi Þs
)1=s
p ðDi Þ ¼ 2expðe U γ U ð1 Di =D50 ÞÞ The 50% dose response and the maximal relative slope, γ, were used to describe the dose-response curve. ∏ Is related to the parameter m of the probit formula, where N is the number of calculation subvolumes in the dose calculation volume, Di is the dose in the subvolume considered, and △Vi ¼ Vi/V where Vi is the volume of each subvolume in the DVH and V is the total volume of the organ. p (D) Is the Poisson dose-response relationship. The tissue-special parameters were based on the RS model.15
J. Wang et al. / Medical Dosimetry ] (2014) ]]]–]]] Statistical analysis
3
Table 3 OAR sparing and MU comparison
The results difference between any 2 of the 4 plans were compared and analyzed with analysis of variance test. When an overall significant difference was observed, the post hoc Turkey test was used to determine which pairwise comparisons differed. All statistical analyses were conducted with SPSS 19.0 software. The differences were considered statistically significant when p o 0.05.
Results Average target coverage of the different treatment schemes is summarized in Table 2. The mean dose of PTV was similar for all the treatment schemes. TF was inferior in target coverage, as indicated by the volume covered by 95% (p o 0.001) and 110% (p ¼ 0.012) of the prescription dose. The S-VMAT plan was superior in terms of CI (p ¼ 0.027) and HI (p ¼ 0.006). The OARs sparing and MU comparison are summarized in Table 3. T-IMRT showed the lowest low dose volume (V5) for the left lung (p ¼ 0.042). 4F-IMRT plan was superior regarding the NTCP of heart (p ¼ 0.003) and showed lowest dose of CA irradiated by 5 to 30 Gy (p o 0.05). Meanwhile, V5 to V10 and mean dose of contralateral breast in 4F-IMRT plan were also the lowest values compared with the other 3 plans (p o 0.05). TF plan reduced the average number of MU by 38.6%, 55%, and 51.4%, respectively, when compared with T-IMRT, 4F-IMRT, and S-VMAT (p o 0.05). In analysis of variance comparison with each other plan, the TCP of 3 plans is not statistically significant (Fig.).
Variable
TF
T-IMRT
4F-IMRT
S-VMAT
p
All plans (mean ⫾ standard deviation) Left lung V5 V20 V30 Dmean (Gy) NTCP
45.3 28.6 17.7 11.7 0.05
⫾ ⫾ ⫾ ⫾ ⫾
3.7 1.2 2.1 2.5 0.2
41.2 26.3 15.3 9.1 0.04
⫾ ⫾ ⫾ ⫾ ⫾
3.5 2.1 2.6 2.1 0.1
44.3 24.1 14.2 9.3 0.03
⫾ ⫾ ⫾ ⫾ ⫾
5.2 4.2 1.7 1.5 0.2
48.9 22.6 12.5 10.8 0.05
⫾ ⫾ ⫾ ⫾ ⫾
4.1 3.5 3.1 3.6 0.1
0.042 0.014 0.012 0.008 0.67
Heart V5 V10 V20 V30 Dmean (Gy) NTCP
24.6 17.2 11.7 6.8 8.7 0.14
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2.8 1.9 1.8 1.5 2.1 0.2
22.3 16.1 10.5 5.4 5.7 0.1
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
1.5 1.8 1.4 2.1 2.5 0.3
15.6 12.3 7.3 4.2 3.5 0.07
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2.3 2.1 3.2 1.0 1.6 0.2
25.5 17.6 9.7 4.4 7.4 0.12
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2.6 1.5 2.4 2.9 1.4 0.4
0.009 0.024 0.013 0.068 0.023 0.003
CA V5 V10 V20 V30 Dmean (Gy)
57.8 40.6 27.8 18.6 16.6
⫾ ⫾ ⫾ ⫾ ⫾
22.6 20.2 18.5 7.2 3.7
53.5 39.1 25.3 17.4 12.4
⫾ ⫾ ⫾ ⫾ ⫾
21.5 22.8 15.6 7.3 4.3
45.3 26.8 20.6 10.4 8.5
⫾ ⫾ ⫾ ⫾ ⫾
18.7 24.1 20.3 8.4 3.5
67.7 38.2 24.5 15.7 15.4
⫾ ⫾ ⫾ ⫾ ⫾
23.4 19.3 23.5 9.2 2.6
0.009 0.027 0.024 0.017 0.005
Contralateral breast V5 V10 Dmean (Gy) MU
1.8 1.3 1.9 253
⫾ ⫾ ⫾ ⫾
2.6 1.2 1.7 26
1.8 1.2 1.7 412
⫾ ⫾ ⫾ ⫾
3.2 2.1 2.1 37
0.7 0.0 0.5 562
⫾ ⫾ ⫾ ⫾
1.3 0.0 1.5 31
2.1 1.4 2.1 521
⫾ ⫾ ⫾ ⫾
2.4 1.5 2.2 28
0.045 0.022 0.026 0.038
Discussion The present report compared 4 PMRT techniques using DVHs, TCP, and NTCP metrics to assess the dose to the PTV and the risks of pneumonitis and cardiovascular disease. Using these biophysical index, the S-VMAT plan generated the greatest CI and HI in 4 technical studies; however, this approach also increased in the percentage of all the OARs that received low dose. The use of 4FIMRT showed the best V95% requirement and resulted in the least percentage of the heart, CA and contralateral breast that received 5 to 20 Gy, 5 to 30 Gy, and 5 to 10 Gy, respectively. TF and T-IMRT plans cannot meet the requirement of target coverage and increased in the percentage of OARs that received high dose. However, TF as the non–IMRT can significantly reduce the mean number of MU. Rongsriyam et al.4 draw a conclusion that T-IMRT should be the best treatment for breast cancer after conserving surgery. However, The PTV included the CW, SA, and ipsilateral upper IMNs in this study was obviously more complex than the BCS. With respect to the physical parameters of PTV, T-IMRT plan had no advantages on target coverage, which showed worse V95% and higher V110% and inferior CI and HI. These data demonstrate that the use of standard tangents IMRT plan cannot meet the requirement of complex target dose. Table 2 PTV coverage comparison PTV
TF
T-IMRT
4F-IMRT
S-VMAT
p
All plans (mean ⫾ standard deviation) CI HI V95% V110% D2% (Gy) D98% (Gy) Dmean (Gy) TCP
0.42 0.35 91.4 5.6 58.6 43.1 53.2 0.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.03 0.51 ⫾ 0.08 0.68 ⫾ 0.07 0.87 ⫾ 0.04 0.027 0.02 0.23 ⫾ 0.04 0.17 ⫾ 0.02 0.10 ⫾ 0.01 0.006 1.28 93.53 ⫾ 1.14 97.35 ⫾ 1.97 96.23 ⫾ 1.23 o 0.001 1.3 3.6 ⫾ 1.6 2.5 ⫾ 1.5 2.3 ⫾ 1.4 0.012 1.4 55.8 ⫾ 0.7 53.5 ⫾ 1.3 52.4 ⫾ 0.3 0.023 1.6 44.7 ⫾ 1.5 45.6 ⫾ 1.3 47.3 ⫾ 0.4 0.022 0.4 52.9 ⫾ 0.3 52.4 ⫾ 0.5 52.1 ⫾ 0.6 0.65 0.3 0.91 ⫾ 0.2 0.92 ⫾ 0.1 0.91 ⫾ 0.1 0.71
The present study provided estimates of NTCPs for pneumonitis and cardiovascular disease for PMRT techniques. NTCP models are important tools for estimating complication risks. 4F-IMRT plan achieved a relatively lower left lung NTCP (0.03 ⫾ 0.2) than the other 3 plans did, but no statistically significant differences were observed (p ¼ 0.67). Marks et al.16 reported that only 0.5% of patients treated with partially wide tangent fields had persistent pneumonitis symptoms. Therefore, although pneumonitis is a risk that should be considered with patients, 3DCRT and IMRT could both effectively avoid the risk even if treatment of complex target in PMRT. Cho et al.17 compared 3 techniques in the treatment of the left breast and upper internal mammary lymph node chain, and they showed that the lowest NTCP value of heart was found in the oblique electron and the IMRT techniques (both were 0.6), which were compared with 3DCRT. The results were similar in our study that the IMRT (4F-IMRT and T-IMRT) plans were better than 3DCRT (TF) plan for heart protection. However, the calculated heart NTCP values using the IMRT techniques in our study were smaller than reported by Cho, and 4F-IMRT plan resulted in a significantly smallest mean cardiac NTCP (0.07 ⫾ 0.2) compared with the other methods (0.14 ⫾ 0.2, 0.1 ⫾ 0.3, and 0.12 ⫾ 0.4). These results predict that 4F-IMRT will perform low rate of heart disease. Although these values were small, the NTCP model parameters used to estimate them have relative uncertainties so the absolute values should be interpreted with caution. As better prospective dosimetric and outcome data become available, the accuracy of these models should improve. In any case, it is important to minimize cardiac exposure to radiation whenever possible and 4F-IMRT provides this handing method. Some studies analyzed the irradiated dose of heart, but they did not specify the dosimetric parameters of CA when comparing the dose difference of treatment plans for the left-side breast cancer after mastectomy. Tan et al.18 suggested that coronary heart disease after postoperative RT for breast cancer was one of the radiation-related complications and Mert et al.19 indicated the
4
J. Wang et al. / Medical Dosimetry ] (2014) ]]]–]]]
Fig. Dose distribution of 4 plans in isocentral slice. (Color version of figure is available online.)
most serious radiation-induced complication of the heart is CA injury. The dose volume (V5 to V30) of CA in our research showed lowest in 4F-IMRT compared with other plans. Various studied have shown that the incidence of second cancer risk would increase with the increasing of the irradiated dose of the contralateral breast.20,21 Although S-VMAT plan was desired with the same dose constraint for contralateral breast as
the other plans, the V5 to V10 of contralateral breast were significant higher compared with the other 3 plans. Conclusions Four techniques used in the delivery of PMRT were compared for target coverage and normal tissue sparing. Of the techniques
J. Wang et al. / Medical Dosimetry ] (2014) ]]]–]]]
studied, our analysis supports the use of 4F-IMRT as the most appropriate compromise for both target coverage and normal tissue toxicity. The final selection of RT technique should be based on the estimated risk reduction in locoregional recurrence and its potential effect on survival, and the technical expertise available to implement complex treatment plans. References 1. Rutqvist, L.E.; Rose, C.; Cavallin-Stahl, E. A systematic overview of radiation therapy effects in breast cancer. Acta Oncol. 42:532–45; 2003. 2. Early Breast Cancer Trialists' Collaborative Group Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 355:1757–70; 2000. 3. Teh, B.S.; Lu, H.H.; Sobremonte, S.; et al. The potential use of intensity modulated radiotherapy (IMRT) in women with pectus excavatum desiring breast-conserving therapy. Breast J. 7:233–9; 2001. 4. Rongsriyam, K.; Rojpornpradit, P.; Lertbutsayanul, C.; et al. Dosimetric study of inverse planned intensity modulated, forward-planned intensity modulated and conventional tangential techniques in breast conserving radiotherapy. J. Med. Assoc. Thai. 91:1571–82; 2008. 5. Yin, Y.; Chen, J.H.; Sun, T.; et al. Dosimetric research on intensity-modulated arc radiotherapy planning for left breast cancer after breast-preservation surgery. Med. Dosim. 37:287–92; 2012. 6. Huang, X.B.; Jiang, G.L.; Chen, J.Y. Dosimetrical optimization study of intensity modulated radiotherapy for intact breast. China Oncol. 18:832–7; 2008. 7. Bechham, W.A.; Popsecu, C.C.; Patenaude, W. Is multibeam IMRT better than standard treatment for patients with left-sided breast cancer? Int. J. Radiat. Oncol. Biol. Phys. 69:918–24; 2009. 8. Van't Riet, A.; Mak, A.C.; Moerland, M.A.; et al. A conformation number to quantify the degree of conformity in brachytherapy and external beam irradiation: application to the prostate. Int. J. Radiat. Oncol. Biol. Phys. 37:731–6; 1997.
5
9. ICRU Prescribing, recording, and reporting photon-beam intensity-modulated radiation therapy (IMRT). Absorbed-dose and dose–volume prescribing and reporting. ICRU report 83. J. ICRU; 201010(1): [Oxford University Press, Oxford]. 10. Cho, B.C.; Schwarz, M.; Mijnheer, B.J.; et al. Simplified intensity-modulated radiotherapy using pre-defined segments to reduce cardiac complications in left-sided breast cancer. Radiother. Oncol. 70:231–41; 2004. 11. Webb, S. Optimum parameters in a model for tumor control probability including inter patient heterogeneity. Phys. Med. Biol. 39:1895–914; 1994. 12. Lyman, J.T.; Wolbarst, A.B. Optimization of radiation therapy: a method of assessing complication probabilities from dose-volume histograms. Int. J. Radiat. Oncol. Biol. Phys. 13:103–9; 1987. 13. Burman, C.; Kutcher, G.J.; Emami, B.; et al. Fitting of normal tissue tolerance data to an analytic function. Int. J. Radiat. Oncol. Biol. Phys. 21:123–35; 1991. 14. Li, X.A.; Alber, M.; Deasy, J.O.; et al. The use and QA of biologically related models for treatment planning. American Association of Physicists in Medicine (AAPM Report No.166). 15. Gagliardi, G.; Lax, I.; Ottolenghi, A.; et al. Long-term cardiac mortality after radiotherapy of breast cancer-application of the relative seriality mode. Br. J. Radiol. 69:839–46; 1996. 16. Marks, L.B.; Clough, R.; Fan, M.; et al. Radiation (RT)-induced pneumonitis following tangential breast/chest wall irradiation. Int. J. Radiat. Oncol. Biol. Phys. 48:294; 2000. 17. Cho, B.C.J.; Coen, W.; Hurkmans; et al. Intensity modulated versus non-intensity modulated radiotherapy in the treatment of the left breast and upper internal mammary lymph node chain: a comparative planning study. Radiother. Oncol. 62:127–36; 2002. 18. Tan, W.; Wang, X.; Qiu, D.; et al. Dosimetric comparison of intensity-modulated radiotherapy plans, with or without anterior myocardial territory and left ventricle as organs at risk, in early-stage left-sided breast cancer patients. Int. J. Radiat. Oncol. Biol. Phys. 80:1544–51; 2011. 19. Mert, M.; Arat-Ozkan, A.; Ozkan, A. Radiation-induced coronary artery disease. Z. Kardiol. 92:682–5; 2003. 20. Hong, L.; Hunt, M.; Chui, C.; et al. Intensity-modulated tangential beam irradiation of the intact breast. Int. J. Radiat. Oncol. Biol. Phys. 44:1155–64; 1999. 21. Wallgren, A. Late effects of radiotherapy in the treatment of breast cancer. Acta Oncol. 31:237–42; 1992.
Medical Dosimetry journal homepage: www.meddos.org
Postoperative radiotherapy following mastectomy for patients with left-sided breast cancer: A comparative dosimetric study Jiahao Wang ,* Xiadong Li ,† Qinghua Deng ,† Bing Xia, Ph.D.,* Shixiu Wu ,* Jian Liu ,# and Shenglin Ma † Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, China; †Department of Radiation Oncology, Hangzhou First People's Hospital, Hangzhou, China; and #Department of Breast Surgery, Hangzhou First People's Hospital, Hangzhou, China
*
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 June 2014 Received in revised form 25 October 2014 Accepted 11 November 2014
The purposes of this article were to compare the biophysical dosimetry for postmastectomy left-sided breast cancer using 4 different radiotherapy (RT) techniques. In total, 30 patients with left-sided breast cancer were randomly selected for this treatment planning study. They were planned using 4 RT techniques, including the following: (1) 3-dimensional conventional tangential fields (TFs), (2) tangential intensity-modulated therapy (T-IMRT), (3) 4 fields IMRT (4F-IMRT), and (4) single arc volumetricmodulated arc therapy (S-VMAT). The planning target volume (PTV) dose was prescribed 50 Gy, the comparison of target dose distribution, conformity index, homogeneity index, dose to organs at risk (OARs), tumor control probability (TCP), normal tissue complication probability (NTCP), and number of monitor units (MUs) between 4 plans were investigated for their biophysical dosimetric difference. The target conformity and homogeneity of S-VMAT were better than the other 3 kinds of plans, but increased the volume of OARs receiving low dose (V5). TCP of PTV and NTCP of the left lung showed no statistically significant difference in 4 plans. 4F-IMRT plan was superior in terms of target coverage and protection of OARs and demonstrated significant advantages in decreasing the NTCP of heart by 0.07, 0.03, and 0.05 compared with TFs, T-IMRT, and S-VMAT plan. Compared with other 3 plans, TFs reduced the average number of MUs. Of the 4 techniques studied, this analysis supports 4F-IMRT as the most appropriate balance of target coverage and normal tissue sparing. & 2014 American Association of Medical Dosimetrists.
Keywords: Postmastectomy radiotherapy Breast cancer Target coverage Normal tissue sparing
Introduction Radiotherapy (RT) is one of the main treatments for patients after mastectomy. Postmastectomy RT (PMRT) can effectively reduce the recurrence rate in local area, improve the tumorspecific survival rate, and disease-free survival rate; however, the total survival rate is insignificant.1 Cardiovascular injury has been implicated as the reason that, although adjuvant RT improved breast cancer–specific survival, no improvement in overall survival was demonstrated in meta-analyses that included randomized RT trials.2 Especially, anthracycline-based chemotherapy, trastuzumab, and both in combination were being used increasingly in the adjuvant therapy of patients with invasive breast cancer. These agents alone or in combination with RT may cause later cardiac morbidity.
Reprint requests to: Shenglin Ma, Department of Radiation Oncology, Hangzhou First People's Hospital, Huan Sha Road 261, Hangzhou 310000, China. E-mail: [email protected] http://dx.doi.org/10.1016/j.meddos.2014.11.004 0958-3947/Copyright Ó 2014 American Association of Medical Dosimetrists
There have been various RT techniques proposed to patients with breast conservation surgery (BCS), Teh et al.3 reported that the conventional opposed tangential fields (TFs) technique (3-dimensional–conformal RT [3DCRT]) delivers too much radiation to a large volume of the ipsilateral lung and heart in breastconserving therapy. Meanwhile, tangential intensity-modulated therapy (T-IMRT) was reported by Rongsriyam et al.4 having better target dose homogeneity and conformity and sparing normal tissue, such as the heart and the ipsilateral lung for patients undergoing adjuvant RT after BCS. However, Yin et al.5 showed another significant result that intensity-modulated arc RT performed better in target conformity and can reduce high-dose volume in the heart and the left lung in treatment of BCS. Some reports6,7 also suggested that different planning target volume (PTV) size may lead to different results in using various irradiating techniques in RT with breast cancer. If the PTV includes only the breast, such as treatment of BCS, then the technique typically consists of 2 TFs placed medially and laterally to the
J. Wang et al. / Medical Dosimetry ] (2014) ]]]–]]]
2
breast. This field arrangement attempts to minimize the amount of underlying normal tissue irradiated. However, if the PTV also includes chest wall (CW), anterior supraclavicular area (SA) and internal mammary node (IMN), then simple TFs usually do not offer the best solution. Then volumetric-modulated arc therapy (VMAT) as a new RT technology has dynamic parameters, including variations of dose rate, gantry rotation speed, leaf motion speed, and gantry position. However, for the target of PMRT that is located on the chest and next to the lung and the heart, whether these dynamic parameters could produce ascendant results should also be reconsidered. The purpose of this planning study was to evaluate and compare 4 RT (TF, T-IMRT, 4 fields IMRT [4F-IMRT], and single arc VMAT [S-VMAT]) techniques in the treatment of patients with left-sided breast cancer following mastectomy.
Methods and Materials Clinical data selection Treatment planning was performed retrospectively on 30 patients with leftsided breast cancer previously treated from February 2013 to July 2013 in Hangzhou Cancer Hospital, Hangzhou City, Zhejiang Province, P.R. China. The ages of patients ranged from 44 to 63 years with the median age being 56 years. The stage of disease was T4a-4cN3M0, and all patients received a course of chemotherapy before RT. Written informed consents were obtained from all patients or their families. All procedures of this study were approved by the Ethical Committee of Hangzhou Cancer Hospital.
Target and normal tissue delineation The PTV included CW, SA, and IMNs. It was created by adding a 7-mm expansion in all directions around the clinical target volume, and another 8 mm was added on the surface of the CW skin for the purpose of compensation of movement. All 30 cases were delineated by the same senior radiation oncologist based on the computed tomography (CT) image. The contours of all the involved organs at risk (OARs), including the contralateral breast, heart, coronary artery (CA), and left and right lung were outlined by the treating physician. All targets and OARs were outlined slice by slice in the CT image in the treatment planning system (TPS) and then the 3D contour was reconstructed automatically.
Treatment plan All plans were completed in 3D Oncentra TPS (Nucletron BV, Veenendal, Netherlands). The TPS determined homogeneous media and density in the body based on the CT density calibration curve and calculated the dose with collapse cone convolution, which took into account the calibration of the homogeneous medium. The Elekta Axesse linear accelerator with 6-MV photon energy was used. The PTV was prescribed 50 Gy given in 25 fractions within 5 weeks, and the optimization constraint is that ensuring 95% isodose line encompasses 95% of PTV (V95% Z 47.5 Gy). The detailed method was as follows: The TF plan used 2 opposite half beam, which included whole PTV and avoided direct exposure to the contralateral breast. The arrangement of gantry angle was 3001 and 1201. The T-IMRT plan was created with same angle of the conventional TF plan. 4F-IMRT plan added the other opposite half beam based on the T-IMRT plan and the gantry angle was 3001, 3201, 1201, and 1401. S-VMAT, in which arc direction is such that beam enters the breast before exiting through the lung, may increase the dose volume of the lung and contralateral breast. The VMAT plan used a single arc field in which starting angle Table 1 The optimization objective applied in IMRT and VMAT planning Structure
Planning aim (weight)
PTV
V53 Gy r 1% (70), V50 Gy Z 95% (80), and V49 Gy Z 98% (80) V5 Gy r 45% (10), V20 Gy r 25% (10), and V30 Gy r 18% (10) Dmax r 5 Gy (8) V20 Gy r 18% (10) and V10 Gy r 22% (10) V10 Gy r 27% (12), V20 Gy r 18% (12), and V30 Gy r 8% (12)
Left lung Contralateral breast Heart CA
and ending angle were respectively the same as the 4F-IMRT beam angle, and the degree of the subfield interval of 41 was used. For the IMRT and VMAT plans, the optimization objective listed in Table 1 was used. Collapsed cone (graphics processing unit) algorithm optimization was applied to optimize plans. The minimum field size and monitor unit (MU) of subfield were restricted to 2 cm2 and 2 MU. The different treatment techniques have been applied to the patients' data set without any clinical application. This activity does not require an ethical approval according to our institution's rules. Biophysical dosimetric evaluation The biophysical dosimetric evaluation metrics were chosen for each structure, and the same metrics were used to evaluate all plans. Dose-volume histograms (DVHs) were calculated for all involved structures, including the target volume, left lung, heart, CA, and contralateral breast. For each target volume, the mean dose, D2% and D98% (dose corresponding to 2% and 98% target volume); V95%, and V110% (volume of the target received 95% and 110% prescription dose); conformal index (CI)8; and homogeneity index (HI)9 were tabulated and reviewed. For the normal tissues, metrics included the mean dose for each structure. For the left lung, the values for the percentage of left lung that received 5 Gy (V5), 20 Gy (V20), and 30 Gy (V30) were chosen; for the heart and CA, values for the percentage of heart and CA that received 5, 10, 20, and 30 Gy (V5, V10, V20, and V30, respectively) were both chosen; and for the contralateral breast, values for the percentage of contralateral breast that received 5 and 10 Gy were obtained. Other metrics included tumor control probability (TCP) for PTV and normal tissue complication probability (NTCP) for the left lung and the heart. The CI, HI, TCP and NTCP are described later. The CI and HI were defined to describe the quality of target as follows: CI ¼
VT:ref V T:ref VT Vref
where VT represents target volume, VT.ref represents the target volume wrapped by reference isodose curve face, and Vref represents all the volume wrapped by reference isodose curve face. A higher CI value, ranging from 0 to 1, represents better conformity. HI ¼
D2% D98% Dmean
where D2% represents the dose corresponding to 2% target volume as shown in DVH and can be deemed as the maximum dose; D98% represents the dose corresponding to 98% target volume as shown in DVH, and can be deemed as the minimum dose. LQ-Poisson model was used to calculate the TCP for PTV10: n o 2 TCPPTV ¼ exp N0 exp n αd þ βd where N0 is the number of tumor cells about clone source. α is the probability of cell injury by a single ionizing particle strike to DNA, and β is the probability of cell injury by double ionizing particles strike to DNA. α/β Ratio was 3 for PTV. These tumor-specific parameters were cited from a study by Webb.11 The NTCP-Lyman model was used to calculate the NTCP of the left lung as follows12,13: Z t 1 x2 dx EXP NTCP left lung ¼ pffiffiffiffiffiffi 2 2π ∞ t¼
D max D 50 ðvÞ m D 50 ðvÞ
D50 ðvÞ ¼ D50 ðv
¼ 1Þ
Vn
where m is the slope of 50% complication probability in the curve of dose effect (m ¼ 0.18), and D50 (v) is the tolerance dose for 50% complication probability. The tissue-special parameters were based on the Lyman model (AAPM No.166).14 The NTCP-RSM (relative seriality [RS]) model was accepted as the most suitable biological model to calculate the NTCP for the heart.15 This model is based on Poisson statistics, and it accounts for the architecture of the organ through the parameter of RS. The RS is derived from the ratio of serial subunits to all subunits in the organ. ( NTCP
Heart
¼
N
1 ∏
i ¼ 1
ΔV i 1 pðDi Þs
)1=s
p ðDi Þ ¼ 2expðe U γ U ð1 Di =D50 ÞÞ The 50% dose response and the maximal relative slope, γ, were used to describe the dose-response curve. ∏ Is related to the parameter m of the probit formula, where N is the number of calculation subvolumes in the dose calculation volume, Di is the dose in the subvolume considered, and △Vi ¼ Vi/V where Vi is the volume of each subvolume in the DVH and V is the total volume of the organ. p (D) Is the Poisson dose-response relationship. The tissue-special parameters were based on the RS model.15
J. Wang et al. / Medical Dosimetry ] (2014) ]]]–]]] Statistical analysis
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Table 3 OAR sparing and MU comparison
The results difference between any 2 of the 4 plans were compared and analyzed with analysis of variance test. When an overall significant difference was observed, the post hoc Turkey test was used to determine which pairwise comparisons differed. All statistical analyses were conducted with SPSS 19.0 software. The differences were considered statistically significant when p o 0.05.
Results Average target coverage of the different treatment schemes is summarized in Table 2. The mean dose of PTV was similar for all the treatment schemes. TF was inferior in target coverage, as indicated by the volume covered by 95% (p o 0.001) and 110% (p ¼ 0.012) of the prescription dose. The S-VMAT plan was superior in terms of CI (p ¼ 0.027) and HI (p ¼ 0.006). The OARs sparing and MU comparison are summarized in Table 3. T-IMRT showed the lowest low dose volume (V5) for the left lung (p ¼ 0.042). 4F-IMRT plan was superior regarding the NTCP of heart (p ¼ 0.003) and showed lowest dose of CA irradiated by 5 to 30 Gy (p o 0.05). Meanwhile, V5 to V10 and mean dose of contralateral breast in 4F-IMRT plan were also the lowest values compared with the other 3 plans (p o 0.05). TF plan reduced the average number of MU by 38.6%, 55%, and 51.4%, respectively, when compared with T-IMRT, 4F-IMRT, and S-VMAT (p o 0.05). In analysis of variance comparison with each other plan, the TCP of 3 plans is not statistically significant (Fig.).
Variable
TF
T-IMRT
4F-IMRT
S-VMAT
p
All plans (mean ⫾ standard deviation) Left lung V5 V20 V30 Dmean (Gy) NTCP
45.3 28.6 17.7 11.7 0.05
⫾ ⫾ ⫾ ⫾ ⫾
3.7 1.2 2.1 2.5 0.2
41.2 26.3 15.3 9.1 0.04
⫾ ⫾ ⫾ ⫾ ⫾
3.5 2.1 2.6 2.1 0.1
44.3 24.1 14.2 9.3 0.03
⫾ ⫾ ⫾ ⫾ ⫾
5.2 4.2 1.7 1.5 0.2
48.9 22.6 12.5 10.8 0.05
⫾ ⫾ ⫾ ⫾ ⫾
4.1 3.5 3.1 3.6 0.1
0.042 0.014 0.012 0.008 0.67
Heart V5 V10 V20 V30 Dmean (Gy) NTCP
24.6 17.2 11.7 6.8 8.7 0.14
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2.8 1.9 1.8 1.5 2.1 0.2
22.3 16.1 10.5 5.4 5.7 0.1
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
1.5 1.8 1.4 2.1 2.5 0.3
15.6 12.3 7.3 4.2 3.5 0.07
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2.3 2.1 3.2 1.0 1.6 0.2
25.5 17.6 9.7 4.4 7.4 0.12
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2.6 1.5 2.4 2.9 1.4 0.4
0.009 0.024 0.013 0.068 0.023 0.003
CA V5 V10 V20 V30 Dmean (Gy)
57.8 40.6 27.8 18.6 16.6
⫾ ⫾ ⫾ ⫾ ⫾
22.6 20.2 18.5 7.2 3.7
53.5 39.1 25.3 17.4 12.4
⫾ ⫾ ⫾ ⫾ ⫾
21.5 22.8 15.6 7.3 4.3
45.3 26.8 20.6 10.4 8.5
⫾ ⫾ ⫾ ⫾ ⫾
18.7 24.1 20.3 8.4 3.5
67.7 38.2 24.5 15.7 15.4
⫾ ⫾ ⫾ ⫾ ⫾
23.4 19.3 23.5 9.2 2.6
0.009 0.027 0.024 0.017 0.005
Contralateral breast V5 V10 Dmean (Gy) MU
1.8 1.3 1.9 253
⫾ ⫾ ⫾ ⫾
2.6 1.2 1.7 26
1.8 1.2 1.7 412
⫾ ⫾ ⫾ ⫾
3.2 2.1 2.1 37
0.7 0.0 0.5 562
⫾ ⫾ ⫾ ⫾
1.3 0.0 1.5 31
2.1 1.4 2.1 521
⫾ ⫾ ⫾ ⫾
2.4 1.5 2.2 28
0.045 0.022 0.026 0.038
Discussion The present report compared 4 PMRT techniques using DVHs, TCP, and NTCP metrics to assess the dose to the PTV and the risks of pneumonitis and cardiovascular disease. Using these biophysical index, the S-VMAT plan generated the greatest CI and HI in 4 technical studies; however, this approach also increased in the percentage of all the OARs that received low dose. The use of 4FIMRT showed the best V95% requirement and resulted in the least percentage of the heart, CA and contralateral breast that received 5 to 20 Gy, 5 to 30 Gy, and 5 to 10 Gy, respectively. TF and T-IMRT plans cannot meet the requirement of target coverage and increased in the percentage of OARs that received high dose. However, TF as the non–IMRT can significantly reduce the mean number of MU. Rongsriyam et al.4 draw a conclusion that T-IMRT should be the best treatment for breast cancer after conserving surgery. However, The PTV included the CW, SA, and ipsilateral upper IMNs in this study was obviously more complex than the BCS. With respect to the physical parameters of PTV, T-IMRT plan had no advantages on target coverage, which showed worse V95% and higher V110% and inferior CI and HI. These data demonstrate that the use of standard tangents IMRT plan cannot meet the requirement of complex target dose. Table 2 PTV coverage comparison PTV
TF
T-IMRT
4F-IMRT
S-VMAT
p
All plans (mean ⫾ standard deviation) CI HI V95% V110% D2% (Gy) D98% (Gy) Dmean (Gy) TCP
0.42 0.35 91.4 5.6 58.6 43.1 53.2 0.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.03 0.51 ⫾ 0.08 0.68 ⫾ 0.07 0.87 ⫾ 0.04 0.027 0.02 0.23 ⫾ 0.04 0.17 ⫾ 0.02 0.10 ⫾ 0.01 0.006 1.28 93.53 ⫾ 1.14 97.35 ⫾ 1.97 96.23 ⫾ 1.23 o 0.001 1.3 3.6 ⫾ 1.6 2.5 ⫾ 1.5 2.3 ⫾ 1.4 0.012 1.4 55.8 ⫾ 0.7 53.5 ⫾ 1.3 52.4 ⫾ 0.3 0.023 1.6 44.7 ⫾ 1.5 45.6 ⫾ 1.3 47.3 ⫾ 0.4 0.022 0.4 52.9 ⫾ 0.3 52.4 ⫾ 0.5 52.1 ⫾ 0.6 0.65 0.3 0.91 ⫾ 0.2 0.92 ⫾ 0.1 0.91 ⫾ 0.1 0.71
The present study provided estimates of NTCPs for pneumonitis and cardiovascular disease for PMRT techniques. NTCP models are important tools for estimating complication risks. 4F-IMRT plan achieved a relatively lower left lung NTCP (0.03 ⫾ 0.2) than the other 3 plans did, but no statistically significant differences were observed (p ¼ 0.67). Marks et al.16 reported that only 0.5% of patients treated with partially wide tangent fields had persistent pneumonitis symptoms. Therefore, although pneumonitis is a risk that should be considered with patients, 3DCRT and IMRT could both effectively avoid the risk even if treatment of complex target in PMRT. Cho et al.17 compared 3 techniques in the treatment of the left breast and upper internal mammary lymph node chain, and they showed that the lowest NTCP value of heart was found in the oblique electron and the IMRT techniques (both were 0.6), which were compared with 3DCRT. The results were similar in our study that the IMRT (4F-IMRT and T-IMRT) plans were better than 3DCRT (TF) plan for heart protection. However, the calculated heart NTCP values using the IMRT techniques in our study were smaller than reported by Cho, and 4F-IMRT plan resulted in a significantly smallest mean cardiac NTCP (0.07 ⫾ 0.2) compared with the other methods (0.14 ⫾ 0.2, 0.1 ⫾ 0.3, and 0.12 ⫾ 0.4). These results predict that 4F-IMRT will perform low rate of heart disease. Although these values were small, the NTCP model parameters used to estimate them have relative uncertainties so the absolute values should be interpreted with caution. As better prospective dosimetric and outcome data become available, the accuracy of these models should improve. In any case, it is important to minimize cardiac exposure to radiation whenever possible and 4F-IMRT provides this handing method. Some studies analyzed the irradiated dose of heart, but they did not specify the dosimetric parameters of CA when comparing the dose difference of treatment plans for the left-side breast cancer after mastectomy. Tan et al.18 suggested that coronary heart disease after postoperative RT for breast cancer was one of the radiation-related complications and Mert et al.19 indicated the
4
J. Wang et al. / Medical Dosimetry ] (2014) ]]]–]]]
Fig. Dose distribution of 4 plans in isocentral slice. (Color version of figure is available online.)
most serious radiation-induced complication of the heart is CA injury. The dose volume (V5 to V30) of CA in our research showed lowest in 4F-IMRT compared with other plans. Various studied have shown that the incidence of second cancer risk would increase with the increasing of the irradiated dose of the contralateral breast.20,21 Although S-VMAT plan was desired with the same dose constraint for contralateral breast as
the other plans, the V5 to V10 of contralateral breast were significant higher compared with the other 3 plans. Conclusions Four techniques used in the delivery of PMRT were compared for target coverage and normal tissue sparing. Of the techniques
J. Wang et al. / Medical Dosimetry ] (2014) ]]]–]]]
studied, our analysis supports the use of 4F-IMRT as the most appropriate compromise for both target coverage and normal tissue toxicity. The final selection of RT technique should be based on the estimated risk reduction in locoregional recurrence and its potential effect on survival, and the technical expertise available to implement complex treatment plans. References 1. Rutqvist, L.E.; Rose, C.; Cavallin-Stahl, E. A systematic overview of radiation therapy effects in breast cancer. Acta Oncol. 42:532–45; 2003. 2. Early Breast Cancer Trialists' Collaborative Group Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 355:1757–70; 2000. 3. Teh, B.S.; Lu, H.H.; Sobremonte, S.; et al. The potential use of intensity modulated radiotherapy (IMRT) in women with pectus excavatum desiring breast-conserving therapy. Breast J. 7:233–9; 2001. 4. Rongsriyam, K.; Rojpornpradit, P.; Lertbutsayanul, C.; et al. Dosimetric study of inverse planned intensity modulated, forward-planned intensity modulated and conventional tangential techniques in breast conserving radiotherapy. J. Med. Assoc. Thai. 91:1571–82; 2008. 5. Yin, Y.; Chen, J.H.; Sun, T.; et al. Dosimetric research on intensity-modulated arc radiotherapy planning for left breast cancer after breast-preservation surgery. Med. Dosim. 37:287–92; 2012. 6. Huang, X.B.; Jiang, G.L.; Chen, J.Y. Dosimetrical optimization study of intensity modulated radiotherapy for intact breast. China Oncol. 18:832–7; 2008. 7. Bechham, W.A.; Popsecu, C.C.; Patenaude, W. Is multibeam IMRT better than standard treatment for patients with left-sided breast cancer? Int. J. Radiat. Oncol. Biol. Phys. 69:918–24; 2009. 8. Van't Riet, A.; Mak, A.C.; Moerland, M.A.; et al. A conformation number to quantify the degree of conformity in brachytherapy and external beam irradiation: application to the prostate. Int. J. Radiat. Oncol. Biol. Phys. 37:731–6; 1997.
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9. ICRU Prescribing, recording, and reporting photon-beam intensity-modulated radiation therapy (IMRT). Absorbed-dose and dose–volume prescribing and reporting. ICRU report 83. J. ICRU; 201010(1): [Oxford University Press, Oxford]. 10. Cho, B.C.; Schwarz, M.; Mijnheer, B.J.; et al. Simplified intensity-modulated radiotherapy using pre-defined segments to reduce cardiac complications in left-sided breast cancer. Radiother. Oncol. 70:231–41; 2004. 11. Webb, S. Optimum parameters in a model for tumor control probability including inter patient heterogeneity. Phys. Med. Biol. 39:1895–914; 1994. 12. Lyman, J.T.; Wolbarst, A.B. Optimization of radiation therapy: a method of assessing complication probabilities from dose-volume histograms. Int. J. Radiat. Oncol. Biol. Phys. 13:103–9; 1987. 13. Burman, C.; Kutcher, G.J.; Emami, B.; et al. Fitting of normal tissue tolerance data to an analytic function. Int. J. Radiat. Oncol. Biol. Phys. 21:123–35; 1991. 14. Li, X.A.; Alber, M.; Deasy, J.O.; et al. The use and QA of biologically related models for treatment planning. American Association of Physicists in Medicine (AAPM Report No.166). 15. Gagliardi, G.; Lax, I.; Ottolenghi, A.; et al. Long-term cardiac mortality after radiotherapy of breast cancer-application of the relative seriality mode. Br. J. Radiol. 69:839–46; 1996. 16. Marks, L.B.; Clough, R.; Fan, M.; et al. Radiation (RT)-induced pneumonitis following tangential breast/chest wall irradiation. Int. J. Radiat. Oncol. Biol. Phys. 48:294; 2000. 17. Cho, B.C.J.; Coen, W.; Hurkmans; et al. Intensity modulated versus non-intensity modulated radiotherapy in the treatment of the left breast and upper internal mammary lymph node chain: a comparative planning study. Radiother. Oncol. 62:127–36; 2002. 18. Tan, W.; Wang, X.; Qiu, D.; et al. Dosimetric comparison of intensity-modulated radiotherapy plans, with or without anterior myocardial territory and left ventricle as organs at risk, in early-stage left-sided breast cancer patients. Int. J. Radiat. Oncol. Biol. Phys. 80:1544–51; 2011. 19. Mert, M.; Arat-Ozkan, A.; Ozkan, A. Radiation-induced coronary artery disease. Z. Kardiol. 92:682–5; 2003. 20. Hong, L.; Hunt, M.; Chui, C.; et al. Intensity-modulated tangential beam irradiation of the intact breast. Int. J. Radiat. Oncol. Biol. Phys. 44:1155–64; 1999. 21. Wallgren, A. Late effects of radiotherapy in the treatment of breast cancer. Acta Oncol. 31:237–42; 1992.
