research article Doses in organs at risk during head and neck radiotherapy using IMRT and 3D-CRT Magdalena Peszynska-Piorun1, Julian Malicki2 3 4, Wojciech Golusinski56 1 Medical Physics Department, Mikolaj Kopernik Memorial Regional Specialized Hospital, Lodz, Poland 2 Medical Physics Department, Greater Poland Cancer Centre, Poznan, Poland 3 Electroradiology Department, University of Medical Sciences, Poznan, Poland 4 Medical Physics Department, Adam Mickiewicz University, Poznan, Poland 5 Head and Neck Surgery Department, Greater Poland Cancer Centre, Poznan, Poland 6 Maxillofacial Surgery Department, University of Medical Sciences, Poznan, Poland Radiol Oncol 2012; 46(4): 328-336. Received 17 June 2012 Accepted 17 September 2012 Correspondence to: Dr Magdalena Peszynska-Piorun, Medical Physics Department, Nikolaj Kopernik Memorial Regional Specialized Hospital, Lodz, Poland. Phone: +48664196245; E-mail: m-peszynska@o2.pl Disclosure: No potential conflicts of interest were disclosed. Background. Treatment planning for head and neck (H&N) cancer is complex due to the number of organs at risk (OAR) located near the planning treatment volume (PTV). Distant OAR must also be taken into consideration. Intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) are both common H&N treatment techniques with very different planning approaches. Although IMRT allows a better dose conformity in PTV, there is much less evidence as to which technique less dose to OAR is delivered. Therefore, the aim of the study was to compare IMRT to 3D-CRT treatment in terms of dose distribution to OAR in H&N cancer. Patients and methods. This was a prospective study of a series of 25 patients diagnosed with stage cT3-4N0-2 laryngeal cancer. All patients underwent total laryngectomy and bilateral selective neck dissections. In all cases, patients were treated with IMRT, although a 3D-CRT treatment plan was also developed for the comparative analysis. To compare doses to specific OAR, we developed a new comparative index based on sub-volumes. Results. In general, IMRT appears to deliver comparable or greater doses to OAR, although the only significant differences were found in the cerebellum, in which 3D-CRT was found to better spare the organ. Conclusions. Organs located outside of the IMRT beam (i.e., distant organs) are generally thought to be well-spared. However, the results of this study show that, in the case of the cerebellum, this was not true. This finding suggests that larger studies should be performed to understand the effects of IMRT on distant tissues. Anthropomorphic phantom studies could also confirm these results. Key words: radiotherapy; IMRT; 3D-CRT; head and neck cancer Introduction The global incidence of head and neck cancer is about 650000 cases per year, which represents about 6% cancer incidence (skin cancer excluded). Radiotherapy plays an important role in the treatment of head & neck (H&N) cancers.12 However, patients, who undergo irradiation, require a comprehensive pre-treatment evaluation.3 In recent decades, the treatment for H&N cancer has moved from two-dimensional radiotherapy to three-dimensional conformal radiotherapy (3D-CRT) and recently also to intensity-modulated radiotherapy (IMRT). Both 3D-CRT and IMRT represent a significant advance over the conventional radiotherapy because they increase dose delivery accuracy while sparing surrounding normal tissues and organs at risk (OAR). The dose-modulating ability of IMRT gives a theoretical advantage over 3D-CRT, which recently has been also supported in the clinical trial.45 IMRT is still a relatively new technique and although its superiority over 3D-CRT in term of tu- mor dose coverage is clear, there is still some concerns about doses in OAR.5-8 Nevertheless, IMRT has become the primary treatment technique in H&N cancers due to its better dose conformity, demonstrated very well in the treatment of lesions with complex anatomy which are adjacent to vital structures such as the spinal cord or brain stem.79-11 However, this improved the conformity to the target which may have an undesirable drawback as the large number of fields used in IMRT can potentially lead to higher doses outside the planning treatment volume (PTV).9,12,13 IMRT also requires more complex quality assurance procedures.214-17 Few studies have compared IMRT to 3D-CRT in H&N radiotherapy to evaluate doses to OARs located outside of the PTV.1819 The present study was aimed to compare differences in calculated dose distributions to OAR for IMRT vs. 3D-CRT in a series of 25 patients with H&N cancer. In the article we focused on organs that had not been previously analyzed i.e.: thyroid gland, mandible, brain stem, brain and the cerebellum. Patients and methods This was a prospective study of a series of 25 patients diagnosed with stage cT3-4N0-2 laryngeal cancer. All patients underwent total laryngectomy and bilateral selective neck dissections. In all cases, patients were treated with IMRT, although a 3D-CRT treatment plan was also developed for the comparative analysis. The IMRT treatment plan had prescription of 54 Gy delivered in fractions of 1.8 Gy (30 fractions) for the PTV1 with a simultaneous integrated boost (SIB) of 60 Gy at 2 Gy/fraction to the PTV2. A set of 6 non-coplanar 6 MV photon beams was used for 15 patients that entered the study first and a set of 7 non-coplanar 6 MV photon beams for 10 patients who followed the first group. Originally, 6-field IMRT plan was considered as a standard setup. Afterwards, as a result of a thorough comparison of the 7-field and the 6-field technique, the latter one was used. The gantry angles used for the 6-field technique were as follows: 35° (col-limator 0°, table 0°), 110° (collimator 10°, table 15°), 180° (collimator 0°, 0°), 250° (collimator 350°, table 345°), 325° (collimator 0°, table 0°), 340° (col-limator 0°, table 0°). Respectively, for the 7-field technique gantry angles were: 0° (collimator 0°, table 0°), 40° (collimator 0°, table 0°), 110° (collimator 108.9°, table 10°) , 150° (collimator 5°, table 0°), 210° (collimator 352.7°, table 0°), 250° (collimator 265°, table 350°), 320° (collimator 90°, table 0°). The 3D-CRT treatment plans included two separate phases, one for the primary treatment and the second plan for the boost. Fifty Gy (2 Gy/fraction) were prescribed to the PTV1. The second phase was a boost of 10 Gy at 2 Gy/fraction to the PTV2, for a total of 30 fractions (the same as for IMRT). Both plans were mainly based on 6 MV photons, except for fields with small weights (only in phase 1), in which case 15 MV photons were used. The first phase called for 10 to 12 fields with extra 2-3 fields was used for the boost phase. All fields were coplanar, in some cases opposed: (90° and 270°, 0° and 180° but also 60°, 300°, 100°, 260°). In 2-4 fields the collimator angle was ± 18° (first phase) and ± 5° (second phase). Many field wedges (mostly 45°) had to be used due to contouring irregularity inherent in H&N treatments. In some cases, the irradiated regions could not be completely covered by a homogenous dose and wedged fields, so half-beams were also used. Treatment plans for both techniques were calculated and optimized using the Eclipse Treatment Planning System (Varian, Medical System, Palo Alto, CA, USA) with AAA algorithm. The IMRT used a dynamic sliding window technique. The CT images acquired included the whole head and the neck to the level of T3-T4 (thoracic vertebra). The clinical target volume (CTV), PTV1, PTV2/boost and OAR volumes were delineated by the same radiation oncologist for all patients and techniques. The following OARs were chosen for the dose comparison: thyroid gland, mandible, brain stem, cerebellum, brain. For 3D-CRT doses in all structures were optimized manually while for IMRT the automated optimization was performed for the following structures: PTVs, CTVs, salivary glands, spinal cord and the area above the PTV, which often overlapped with the mandible and the back side of the head/occipital bone and the neck at shallow depth under the skin, to spare the hair. Treatment planning was performed in accordance with the International Commission on Radiation Units and Measurements (ICRU) reports on H&N cancer and IMRT (#50, #62 and #83)101420-23, which recommend a homogenous dose distribution (range, 95% - 107% of the prescribed dose) to the PTV. Values for the constraints used in the process of dose optimization have been as follows: dose fractionation 1.8-2.0 Gy. Following: Brain, D(33%) <60 Gy, D(66%)<50 Gy, D(100%)<45 Gy with priority from 40 to 80; Brain stem, Dmax=54 Gy with priority circa 80, Spinal cord, Dmax=48 Gy ® ® FIGURE 1. Dose volume histogram for the IMRT (A) and 3D-CRT (B) plans. The organs at risk are: cerebellum (c), brain stem (b), mandible (d), thyroid gland (e) and brain (a). with priority circa 110, Salivary gland, Dmean<30 Gy, Mandible which is a part of area above the PTV, Dmax<70 Gy with priority circa 90.2425 For particular patients, additional constraints have been used, i.e. for salivary glands D(70%)<5 Gy, D(50%)<18 Gy, D(30%)<25 Gy, D(15%)< 35Gy with priority from 50 to 90. Function "normal tissue objective" with priority 100 was used to the further lower dose in all OARs. The modification of constraints and priorities is a part of treatment planning. It makes the optimization process slightly subjective which, however, is inevitable as a patient anatomy differs from one to another, and parameters have to be modified in order to obtain the uniform dose in PTV and the low dose in the optimized OARs Standard parameters produced by the treatment planning software (TPS) were not sufficient to an effectively and quantitatively assess the differences between IMRT and 3D-CRT plans. Doses were very inhomogeneous and often low in OARs, making it difficult to identify small deviations. To more precisely evaluate a dose distribution to the OARs, we realized that we needed more detailed information aside from the standard maximum, minimum, and mean values. Doses at 0% volume, 30% volume, 60% volume, 90% volume (notation D(0%), D(30%), D(60%), D(90%)) are considered to be representative in normal tissue complication probability (NTCP) models.2126 For this reason, we evaluated doses for each OAR in 4 sub-volumes (0%, 30%, 60%, 90% of the relative volume) and wherever more complex information was desired we evaluated doses in 10 sub-volumes (with each sub-volume representing from 0% to 90% of the volume, with a step of 10% of a relative volume). For each of the sub-volumes, maximal doses were read from the cumulative histogram for both IMRT and 3D-CRT, and then the differences and mean values for all sub-volumes were calculated. In this paper, we present all 10 sub-volume doses in the cerebellum and brain. For other organs evaluated, we present doses only for 4 sub-volumes (90%, 60%, 30%, 0%). Statistical analysis and ethical consideration After calculating the dose received by the various sub-volumes according to the treatment technique (IMRT or 3D-CRT), we used the Shapiro-Wilk test to assess the distribution of the data, which was found to be non-Gaussian. Therefore, the nonparametric U Mann-Whitney rank sum test was applied, with a significance level of 0.05. We used the software programs Statistica 8.0 and Origin 8.0 (OriginLab, Northampton) to perform the statistical analysis. The prospective study was carried out according to the Declaration of Helsinki. Results As discussed above, the primary analysis for this study was based on an index of sub-volumes for the OARs. However, prior to evaluating these sub-volumes, we calculated the dose-volume histogram (DVH) for all 25 patients and OARs evaluated in this study. The histograms for both IMRT and 3D-CRT presented similar trends for the dosevolume dependence of the OAR, although it was not possible to detect significant differences. As a result, we concluded that conventional histograms were not sufficient to perform a dose distribution comparison. The histogram of a patient in Figure 1 was taken to demonstrate the similarity between the two techniques. Table 1 shows the doses received by the OARs for all patients. The only positive values are found for the cerebellum while the other OAR' show a range of positive and negative values (-10 Gy to +14.5 Gy), TABLE 1. The authors' index of the mean dose difference (DIMRT - D3dcrt) for the organs at risk and sub-volumes evaluated for this series of 25 patients. The index value was the mean dose difference (DIMRT - D3dcrt) for the doses in 10 sub-volumes for cerebellum and brain and of 4 sub-volumes for thyroid gland, brain stem, and mandible. A positive value indicated that the mean dose for intensity-modulated radiotherapy (IMRT) was greater than the mean three-dimensional conformal radiotherapy (3D-CRT) dose. Patient Cerebellum Thyroid gland Brain stem Mandible Brain Number Dose [Gy] Dose [Gy] Dose [Gy] Dose [Gy] Dose [Gy] 1 5.75 3.09 -2.82 1.92 -0.66 2 9.82 11.83 1.15 -9.68 0.70 3 13.13 0.01 2.43 -2.06 1.16 4 12.08 8.28 6.69 1.04 2.45 5 12.81 -1.70 2.28 0.32 1.80 6 8.58 3.53 0.67 5.03 6.59 7 6.43 1.51 2.30 -10.11 1.92 8 9.06 1.88 1.49 4.09 1.59 9 8.58 3.53 0.67 5.53 2.08 10 6.74 0.48 3.49 5.59 0.74 11 7.25 2.49 -3.83 1.52 1.03 12 5.54 -0.93 0.27 5.65 0.71 13 10.05 -1.55 2.22 7.13 0.39 14 5.02 2.98 1.03 -4.18 0.86 15 8.89 -1.26 -3.64 1.22 0.73 16 8.85 0.75 0.59 0.93 2.05 17 10.72 1.83 -1.83 11.97 1.57 18 8.53 -0.57 -1.20 7.09 1.57 19 5.43 -1.34 -1.22 7.74 0.20 20 14.50 -0.25 2.59 3.26 1.70 21 1.60 0.98 -0.97 3.28 -0.65 22 8.84 -1.98 1.66 8.66 1.74 23 11.61 1.79 -0.39 -1.71 2.20 24 6.91 -2.17 2.57 6.17 0.88 25 8.33 2.16 -1.07 6.54 0.54 with less dispersion for the brain stem. The brain shows a consistent trend with minimal deviation between techniques, with many values near 0. Dose differences between the two treatment techniques can be more clearly seen in the sub-volumes. In Figure 2, dose plots for chosen OARs are shown for all 25 patients. Dose differences (IMRTdose -3D-CRTdose) for cerebellum (a), mandible (b), thyroid gland (c), brain stem (d) and brain (e) are shown. Figures 3 to 7 show the mean dose, maximal and minimal doses, and standard deviation in sub-volumes for the study group, for each OAR at IMRT and 3D-CRT. Table 2 shows the mean radiation doses to the cerebellum for the group (25 patients) by the treatment technique (IMRT, 3D-CRT). The differential dose is also shown. IMRT = intensity-modulated radiotherapy; 3D-CRT = three-dimensional conformal radiotherapy The statistical analysis for the mandible showed significant differences in doses for 3 sub-volumes (90%, 60% and 0%; P= 0.04, 0.00 and 0.001, respectively). The upper-tailed Mann Whitney test showed that doses in sub-volume of 90% (p=0.02) and sub-volume of 60% (p=0.0006) were greater for IMRT than for 3D-CRT. The lower-tailed Mann Whitney test showed that maximal doses (which correspond to the dose at 0% of the volume) were lower for IMRT (p=0.00003) than for 3D-CRT. The only sub-volume for which no significant difference was detected was for 30% (p= 0.91) (Figure 3). In the thyroid gland, we found significant differences for 90% of volume (p= 0.01) and 0% (p=0.01), Cerebellum 35 0 30 1 25 S 20 I 15 I 10 ui ž 5 --*— V90% V60% -o-- V30% .4- ■ vo% Mandible • A r \ -•«■•'I:«. ' Vvf' f-ö or: ".-/.^J i ° >)f, „ : j: * i ..i.v^-i-i Д^* /-ж;/:„ ti' •' ® 0 2 4 6 8 101214161820222426 Patient no. > O ® u C £ £ Ђ ф И O Q 35 30 25 20 15 10 5 0 -5 -10 -15 --*-- V90% ■■*■■ V60% - - o- - V30% --.--vo% -i..........it ..... • o ; tj ,: f >' js » : * : т ir ■•■•^■/nifyv!" ..... «vi ; i .....p «• Л* ■ ^Шјда..... nV ■■ ^HK : ■/9 ■ T*-;.....:>Г'Т ■ T— ■ :..... 0 2 4 6 8 101214161820222426 Patient no. Thyroid gland but no significant differences in sub-volume of 60% (p=0.09) or 30% (p=0.66). At the p-level of 0.005 for the upper-tailed test, the IMRT doses in sub-volume of 90% were significantly higher than those of 3D-CRT while the lower-tailed test revealed that maximum doses were lower with IMRT than 3D-CRT (Figure 4). The dose differences in the brain stem were not statistically significant (90% of volume, p=0.06; 30%, p=0.07; 0%, p=0.55) except for 60% of volume (p=0.034) (Figure 5). >2П 0 15 8 10 c c ® 5 1 0 T -5 Q) 0 -10 Q -15 ® ( E train stem ■ ■»■ ■ V90% * V60% -----o- V30% -vo% T ir 1 ■ ! Mi if < : > : b : ..... I ■ ■ a L~l.iU..... ) 2 i 6 i 101214161 Patient no. B20 22 24 26 FIGURE 2. Dose differences (IMRT dose - 3D-CRT dose) for the organs at risk: cerebellum (A), mandible (B), thyroid gland (C), brain stem (D) and brain (E). For low dose areas of the brain (i.e., sub-volumes ranging from 40% to 90%), no significant differences were found (40%, p=0.11; 50%, p=0.40; 60%, p=0.85; 70%, p=0.60; 80%, p=0.35; 90%, p=0.94). The only significant differences found were in the smaller volumes (0% to 30%) that received higher doses overall. For these sub-volumes, IMRT delivered higher doses than 3D-CTR, with a mean difference of 5-8 Gy. For 0% of volume (IMRT- 48.76 Gy; 3D-CRT- 41.20 Gy), p=0.0001; for 10% (IMRT- 6.18 Gy; 3D-CRT- 2.99 Gy), p=0.00; for 20% (IMRT- 2.96 Gy; 3D-CRT-1.82 Gy), p=0.0005; for 30% (IMRT-2.09 Gy; 3D-CRT- 1.38 Gy), p=0.01. The IMRT techniques delivered higher doses to these volumes, with a higher maximum dose (30%, p=0.003; 20%, p=0.0003; 10%, p=0.0005; 0%, p=0.0001). Discussion Of all the organs at risk evaluated, the cerebellum was the only OAR in our study with a positive CD a> u E