Summary

METHODS
Using 12 image sets, VMAT with double arcs and IMRT with 7 fields were planned. The femoral heads, rectum, bladder, iliac bone marrow, and bowels were contoured as organs at risk (OARs). Planned treatment volume (PTV) was prescribed to be 45 gray (Gy). Target and OAR parameters, conformity, and homogeneity indices were evaluated. P value under 0.05 was considered statistically significant.

RESULTS
Objectives for target volumes were achieved. No significant differences were found in conformity index, maximum dose (Dmax), or integral dose. Homogeneity index was better with IMRT (1.06 vs. 1.07; p<0.01). Dose received by 2% volume of PTV (D2%), D5%, the volume receiving 107% of prescribed dose (V107%), and V105% were lower with IMRT (p<0.05). PTV D98%, percent volume receiving ≥45 Gy (V45 Gy), and clinical target volume V45 Gy were higher with VMAT (p<0.05). Regarding OARs, only rectum V40 Gy, rectum PTV V40 Gy, and dose volume parameter D2cc were lower with VMAT (p<0.05). VMAT was superior with respect to monitor units and beam-on time per fraction: 465 vs. 1689 and 166 vs. 338 seconds, respectively (p<0.001).

CONCLUSION
Static IMRT is superior to VMAT regarding homogeneity, Dmax and OAR sparing, except for the rectum and the bladder. However, it is a marginal benefit with small differences. VMAT remains an attractive solution due to low number of monitor units needed and shorter treatment duration, which allows more time for patient imaging and positioning.

Introduction

Today, treatment of endometrial cancer in the postoperative setting is widely done with 3DCRT. Free contouring atlases for the delineation of OARs and target volumes are available online.[4?6] IMRT is reported to be even superior to 3DCRT regarding acute gastrointestinal and hematological toxicities.[7,8] A study performed with 36 mixed gynecologic cases showed less chronic gastrointestinal toxicity and complication rates with IMRT, and RTOG 0418 is the first published multicenter phase II study proving the feasibility of IMRT for this group of patients in routine practice.[9,10]

Volumetric Modulated Arc Therapy (VMAT) is an advanced form of IMRT where irradiation continues while the gantry is rotating around the patient. Studies including various gynecological malignancies showed dosimetric superiority of VMAT to static IMRT regarding OARs.[11,12] However the number of published studies and endometrial cancer cases included are limited. Moreover, the methods used and parameters evaluated do not match our standard clinical practice. Therefore we needed to compare static IMRT technique with double-arc VMAT on previously treated cases having only endometrial cancer in postoperative setting.

Methods

Treatment planning
CT images were transferred to Varian Eclipse software (version 8.6.15 - Varian Medical Systems, Palo Alto, CA - US). Contouring of the Clinical Target Volume (CTV) and organs at risk (OARs) were done by the same physician in accordance with RTOG atlases.[5,6] OARs included: rectum, iliac crests, small bowel, femoral heads and bladder. In addition to OARs, OAR minus Planning Treatment Volume (PTV) structures were also created. Iliac crests were delineated for assessment of dose to iliac bone marrow (BM) where contouring was done including the whole bony structure. Following dose constrains were used for planning: rectum V40 Gy <50%, Dmax <50 Gy; BM V10 Gy <90%, V20 Gy <75 Gy; small bowel V45 Gy ≤200 cc, Dmax <50 Gy; femoral heads Dmax <50 Gy, V40 Gy <40%, V45 Gy <25%; bladder V40 Gy <50%, Dmax <50 Gy.

PTV was automatically created with 1 cm margin added to CTV. Dose prescription to PTV was set as 45 Gy in 25 fractions. No more than 0.03 cc in a confluent volume was allowed to receive more than 110% of prescribed dose. There was an exception in the vaginal cuff region where we set the upper limit to 115%. No more than 0.03 cc of PTV was allowed to receive less than 93% of the target dose. 6 MV photon energy was used. All static IMRT plans were made with 7 field arrangement and VMAT plans with double-arc.

For the standardization of integral dose calculation, external body contours were restricted to 3.5 cm above and below the PTV volume. PTV was subtracted from this cropped body contour. The resulting volume was used for integral dose calculation.

Planning optimization and dose calculations were done with Eclipse software (version 8.6.15). For both techniques, multi-leaf collimators (MLC) were used in dynamic mode. MLCs consist of 120 leaves which are 0.5 cm thick at the isocenter for the central 20 cm, and 1 cm in the outer 2x10 cm (maximum leaf speed 2.5 cm/s and leaf transmission of 1.6%; maximum gantry speed of 5.54°/s).

IMRT
For the IMRT plans; 7 gantry angles were chosen (30°, 80°, 130°, 180°, 230°, 280°, 330°) using sliding window technique. Isocenter was the center of the PTV volume. Maximum dose rate was 300 MU/min. Dose constrains were defined for PTV, OARs and OAR-PTV volumes in accordance of priority, where rectum had the maximum priority among OARs. Body-PTV volume had also dose constrains in order to limit any hot spots. Anisotropic Analytical Algorithm (AAA) photon dose calculation algorithm was used for all plans. [13-15] The dose calculation grid was set to 2.5 mm.

VMAT
Same photon energy, isocenter point and dose constrains as for the IMRT were used for VMAT plans to achieve the optimal solution. Progressive Resolution Optimization (PRO) algorithm used for the optimization process calculates in 177 control points with 2° intervals. After the optimization dose calculation grid was set to 2.5 mm and AAA was used.

Two arcs with 181°-179° clockwise and 179°-181° counterclockwise rotations were used with maximum dose rate of 600 MU/min. To minimize the "tongue and groove" effect 45° collimator angle was used.

Evaluation and statistical analysis
Evaluation of plans was done over standard dose-volume histograms (DVHs) and with examination of all slices. Homogeneity and conformity indices were calculated with the formulas proposed by RTOG: Homogeneity Index (HI)=[maximum isodose in the target]/ [reference isodose], Conformity Index (CI)=[volume of reference isodose]/[target volume].[16] Normal distribution pattern of each parameter was measured with Saphiro-Wilk Test. Two-tailed paired Student"s t Test was used for normally distributed data, and twotailed non-parametric paired tests for the remaining (Wilcoxon Signed-Rank and Sign Test for symmetric and asymmetric distributed data, respectively). All statistical analysis were performed using JMP 9.0 (SAS Institute Inc. North Carolina, US). Two-sided p values under 0.05 were considered as statistically significant.

Results

Target Coverage, Dose Distributions, MU and Beam-on-time (Tables 1, 2) Between IMRT and VMAT, there was no significant difference in mean CI, Dmax (global maximum dose), integral dose and PTV V95% (volume receiving 95% of the prescribed dose) or CTVmin (minimum point dose CTV receives). Mean HI, PTV D2% (highest dose covering 2% of PTV), PTV D5%, PTV D98%, PTV V107%, PTV V105%, PTV V45 Gy (percent of volume receiving at least 45 Gy) and CTV V45 Gy were significantly lower with IMRT. MU and beam-on-time per fraction were markedly lower with VMAT technique. It shall be also noted that each IMRT field setup required additional time (not measured).

Table 1: MU/fx, beam on time/fx, integral dose and global dose distribution

Table 2: Dosimetric comparison of target volume parameters

Organs at Risk (Table 3) (Only results with p<0.05 are presented in Table 3) Small bowel: Slight but statistically significant mean differences were observed in small bowels Dmax, D2%, D2cc and in favor (lower) of IMRT. D2cc and V45 Gy of "small bowel - PTV structures" were also lower with IMRT.

Iliac BM: Dmax, D2%, D2cc of BM and D2cc, V45 Gy of BM-PTV were significantly lower with IMRT

Bladder: No significance found in mean difference of parameters regarding bladder.

Rectum: Results related with the parameters of rectum were against the general trend. Only rectum Dmax was lower with IMRT. On the contrary; rectum V40 Gy, rectum-PTV V40 Gy and D2cc were lower with VMAT, all reaching statistical significance.

Femoral heads: D2cc, D2% and V45 Gy of only left femoral heads were significantly lower with IMRT. However there was also a trend towards statistical significance (p=0.079) in D2cc and D2% of the right side.

Table 3: Dosimetric comparison of OAR parameters (only significant values)

Discussion

VMAT techniques were developed after implementation of IMRT. Over the past ten years they were compared to IMRT and 3DCRT, Wong et al., compared VMAT, IMRT and 3DCRT.[11,12] The study included 5 post-operative endometrial cancer cases, some of them treated with para-aortic volumes as well. The arc technique consisted of 30-300° and 60-330° gantry arrangements and the IMRT was delivered with 8 fields. There were no significant difference between IMRT and VMAT. Both of them were superior to 3DCRT regarding the small bowel and iliac BM doses. Unlike that, we used 7-field IMRT setup and did not restrict the angular arrangement of VMAT. With the use of static IMRT we observed significant reduction in doses to small bowel (Dmax: 48.35 vs. 49.09 Gy, D2%: 46.27 vs. 46.94 Gy, D2cc: 47.5 vs. 48.22 Gy, V45: 180.97 vs. 219.31 cc) and iliac BM (D2%: 46.93 vs. 47.45 Gy, V10 Gy: 95% vs. 99%) compared to VMAT. In our study, formula defined by RTOG was used for HI calculation (maximum isodose volume/reference isodose volume) and HI was better with static IMRT over VMAT (1.06 and 1.07, respectively). Wong et al., used a different formula (dose difference between D5% and D95% of PTV) and their results were in favor of IMRT against VMAT as well (7.5% dose difference vs. 11%, respectively).[11]

Cozzi et al., compared single-arc VMAT and IMRT in 8 cases with cervix cancer who were treated with chemo-radiation.[12] The prescription was 50.4 Gy in 28 fractions to PTV. Results were in favor of static IMRT both for CI and the doses to OAR. They reported significant reduction in V40 Gy of small bowel and "small bowel-PTV" with VMAT in contrast to our study which resulted with better Dmax, D2%, D2cc of small bowel and D2cc, V45 Gy of "small bowel-PTV" with IMRT (Table 3). We could not find any difference in parameters of bladder whereas Cozzi et al., reported reduction in D2% of "bladder-PTV", V40 Gy of bladder and "bladder- PTV" with VMAT.[12] Both studies showed reduction in V40 Gy of rectum, V40 Gy and D2cc of "rectum-PTV" with VMAT (51% vs. 59%, 12% vs. 21% and 40.66 Gy vs. 42.22 Gy respectively in our study). Although there is a decrease in dose to femoral heads in our study, it does not have any clinical importance.

For the parameters of PTV, Cozzi et al., reported no difference in D98% and V95% between two techniques but a superiority of VMAT for in D2%.[12] In our study parameters representing maximal doses like D2%, D5%, V107% and V105% were lower with IMRT. On the other hand, with higher D98%, PTV V45 Gy, CTV V45 Gy and CTVmin, VMAT was capable of delivering better dose coverage (Table 2). We think that the main underlying reason for this distinction is the difference of PTV and anatomy between cervical and post-operative endometrial cancers. Additionally, it should be noted that Cozzi et al., did not define the pelvic BM as OAR and used another formula than RTOG for the calculation of CI and HI.

Yang et al., also compared 3DCRT, IMRT and a conformal double-arc technique on 10 cases with postoperative endometrial cancer.[22] They made plans with an optimization for 50 Gy to ≥95% of the PTV. Regarding OAR parameters, arc plans had better results than 3DCRT and worse results than IMRT plans. But the arc technique used in this study was a rotational conformal modality with neither inverse planning nor intensity modulation. Mean MU for 3DCRT, arc and IMRT was reported as 240, 451 and 877 MU, respectively. Our results for MU/fraction and "beam on time" (IMRT/VMAT: 1688.58/465.5 MU and 337.72/166.42 seconds) are in concordance with the results of Cozzi et al., showing a marked advantage of VMAT.[12] Risk of secondary malignancy due to higher MU of IMRT versus slightly higher toxicity risk with VMAT (except for rectum) is an issue open to discussion.

A recent dosimetric study by Sharfo et al., compared different IMRT and VMAT strategies on 10 cervix cancer patients using automated in-house planning software.[23] The planning goal was to achieve highly conformal plans while sparing the OARs with a higher priority for the small bowel. The treatment delivery time was shorter with VMAT, but with IMRT superior plan quality was observed. Although performed on cervix and not on endometrial cancer patients, for us the results of this original work have profound importance, since they depend on an unbiased fully automated software solution where modern techniques were compared. In their conclusions, the authors also emphasized the importance of the trade-off between the plan quality and treatment delivery.

Two articles were published comparing 3DCRT, static field IMRT and helical tomotherapy using planning CT data of 10 endometrial cancer patients.[24,25] An interval from 95% to 110% was used for target coverage optimization. Lian et al., reported the results of extended-field radiotherapy for stage IIIC patients.[24] Target coverage was identical in both IMRT and tomotherapy plans. No difference in integral dose between tomotherapy and IMRT was shown. Yang et al., reported statistically insignificant differences in conformity among IMRT and tomotherapy plans.[25] Tomotherapy had 3.3% higher integral dose to normal tissue than static field IMRT (p<0.01).

In the present study, we could reach most of our dosimetric targets. Regarding the parameters of OAR, the objectives for bladder and femoral heads were achieved. Both techniques failed to keep V10 Gy of BM under 90%, but the V20 Gy target was easily reached. However it is important to emphasize for this group of patients that no hematologic toxicity is observed in our clinical routine. It was an unrealistic objective trying to keep V40 Gy of rectum under 35% because of the large intersection of PTV and rectum. For the same reason, it prohibited achieving dosimetric goals for small bowel except for the maximum dose constrain. We think that the main reason behind this problem is our choice of +1 cm margin around CTV to create PTV. This relatively large margin could be reduced with daily instead of weekly Cone Beam CT (CBCT). The choice between a smaller PTV margin with high body kV X-ray exposure due to daily CBCT versus a larger margin with lower exposure due to less frequent CBCT is beyond the scope of this study.[26]

Even there is statistically significant difference between two techniques, one may find it as clinically unimportant. Thus, we did not observe any difference in toxicity profile during or after the treatment with IMRT or VMAT for post-operative endometrial cancer patients in our clinic so far. Acute toxicity is limited with genitourinary and gastrointestinal toxicity never higher than RTOG grade 2. Because of shorter treatment times compared to static IMRT, VMAT allows more time for patient set-up, daily image guidance and provides better patient comfort. Shorter treatment times also restrict intrafractional organ movement.[27]

As limitations, our study contains 12 pairs of plans for matched comparison, and although unique for endometrial cancer, the findings we present are not surprising based on previously published data on cancers of uterine cervix and anal canal. We also want to emphasize that statistical correction of p value due to multiple hypothesis testing was performed neither in any of the previously published studies nor in our study. If we were to interpret our results with a strongly conservative Bonferroni correction, results with p>0.0008 should be discarded. This would leave only the differences in MU/fraction, beam on time and BM-PTV D2% parameters as statistically significant.

Conclusion

Disclosure Statement
The authors declare no conflicts of interest.

References

1) Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61(2):69-90.

2) Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, et al. SEER Cancer Statistics Review, 1975-2007. National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2007/. Accessed Jun 14, 2017.

3) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Uterine Neoplasms Version 2. 2015. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/uterine.pdf. Accessed Jun 14, 2017.

4) Gay HA, Barthold HJ, O"Meara E, Bosch WR, El Naqa I, Al-Lozi R, et al. Pelvic normal tissue contouring guidelines for radiation therapy: a Radiation Therapy Oncology Group consensus panel atlas. Int J Radiat Oncol Biol Phys 2012;83(3):e353-62.

5) Small W, Mundt AJ. Consensus guidelines for the delineation of the intensity modulated pelvic radiotherapy ctv in the postoperative treatment of endometrial and cervical cancer. Available at: http://www.rtog.org/CoreLab/ContouringAtlases/GYN.aspx. Accessed Jun 14, 2017.

6) Gay HA, Barthold J, O"Meara E, Bosch WR, El Naqa I, Al-Lozi R, et al. Female RTOG Normal Pelvis Atlas. Available at: https://www.rtog.org/CoreLab/ContouringAtlases/ FemaleRTOGNormalPelvisAtlas.aspx. Accessed Jun 14, 2017.

7) Mundt AJ, Lujan AE, Rotmensch J, Waggoner SE, Yamada SD, Fleming G, et al. Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys 2002;52(5):1330-7.

8) Lujan AE, Mundt AJ, Yamada SD, Rotmensch J, Roeske JC. Intensity-modulated radiotherapy as a means of reducing dose to bone marrow in gynecologic patients receiving whole pelvic radiotherapy. Int J Radiat Oncol Biol Phys 2003;57(2):516-21.

9) Mundt AJ, Mell LK, Roeske JC. Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy. Int J Radiat Oncol Biol Phys 2003;56(5):1354-60.

10) Jhingran A, Winter K, Portelance L, Miller B, Salehpour M, Gaur R, et al. A phase II study of intensity modulated radiation therapy to the pelvis for postoperative patients with endometrial carcinoma: radiation therapy oncology group trial 0418. Int J Radiat Oncol Biol Phys 2012;84(1):e23-8.

11) Wong E, D"Souza DP, Chen JZ, Lock M, Rodrigues G, Coad T, et al. Intensity-modulated arc therapy for treatment of high-risk endometrial malignancies. Int J Radiat Oncol Biol Phys 2005;61(3):830-41.

12) Cozzi L, Dinshaw KA, Shrivastava SK, Mahantshetty U, Engineer R, Deshpande DD, et al. A treatment planning study comparing volumetric arc modulation with RapidArc and fixed field IMRT for cervix uteri radiotherapy. Radiother Oncol 2008;89(2):180-91.

13) Bragg CM, Wingate K, Conway J. Clinical implications of the anisotropic analytical algorithm for IMRT treatment planning and verification. Radiother Oncol 2008;86(2):276-84.

14) Fogliata A, Vanetti E, Albers D, Brink C, Clivio A, Knöös T, et al. On the dosimetric behaviour of photon dose calculation algorithms in the presence of simple geometric heterogeneities: comparison with Monte Carlo calculations. Phys Med Biol 2007;52(5):1363-85.

15) Knöös T, Wieslander E, Cozzi L, Brink C, Fogliata A, Albers D, et al. Comparison of dose calculation algorithms for treatment planning in external photon beam therapy for clinical situations. Phys Med Biol 2006;51(22):5785-807.

16) Feuvret L, Noël G, Mazeron JJ, Bey P. Conformity index: a review. Int J Radiat Oncol Biol Phys 2006;64(2):333-42.

17) Roeske JC, Lujan A, Rotmensch J, Waggoner SE, Yamada D, Mundt AJ. Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies. Int J Radiat Oncol Biol Phys 2000;48(5):1613-21.

18) Ahamad A, D"Souza W, Salehpour M, Iyer R, Tucker SL, Jhingran A, et al. Intensity-modulated radiation therapy after hysterectomy: comparison with conventional treatment and sensitivity of the normal-tissuesparing effect to margin size. Int J Radiat Oncol Biol Phys 2005;62(4):1117-24.

19) Georg P, Georg D, Hillbrand M, Kirisits C, Pötter R. Factors influencing bowel sparing in intensity modulated whole pelvic radiotherapy for gynaecological malignancies. Radiother Oncol 2006;80(1):19-26.

20) Iğdem S, Ercan T, Alço G, Zengin F, Ozgüleş R, Geceer G, et al. Dosimetric comparison of intensity modulated pelvic radiotherapy with 3D conformal radiotherapy in patients with gynecologic malignancies. Eur J Gynaecol Oncol 2009;30(5):547-51.

21) Yang B, Zhu L, Cheng H, Li Q, Zhang Y, Zhao Y. Dosimetric comparison of intensity modulated radiotherapy and three-dimensional conformal radiotherapy in patients with gynecologic malignancies: a systematic review and meta-analysis. Radiat Oncol 2012;7:197.

22) Yang R, Jiang W, Wang J. A novel conformal arc technique for postoperative whole pelvic radiotherapy for endometrial cancer. Int J Gynecol Cancer 2009;19(9):1574-9.

23) Sharfo AW, Voet PW, Breedveld S, Mens JW, Hoogeman MS, Heijmen BJ. Comparison of VMAT and IMRT strategies for cervical cancer patients using automated planning. Radiother Oncol 2015;114(3):395-401.

24) Lian J, Mackenzie M, Joseph K, Pervez N, Dundas G, Urtasun R, et al. Assessment of extended-field radiotherapy for stage IIIC endometrial cancer using three-dimensional conformal radiotherapy, intensitymodulated radiotherapy, and helical tomotherapy. Int J Radiat Oncol Biol Phys 2008;70(3):935-43.

25) Yang R, Xu S, Jiang W, Xie C, Wang J. Integral dose in three-dimensional conformal radiotherapy, intensitymodulated radiotherapy and helical tomotherapy. Clin Oncol (R Coll Radiol) 2009;21(9):706-12.

26) Alaei P, Spezi E. Imaging dose from cone beam computed tomography in radiation therapy. Phys Med 2015;31(7):647-58.

27) Jhingran A, Salehpour M, Sam M, Levy L, Eifel PJ. Vaginal motion and bladder and rectal volumes during pelvic intensity-modulated radiation therapy after hysterectomy. Int J Radiat Oncol Biol Phys 2012;82(1):256-62.