ONCOLOGY LETTERS 13: , 2017

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1 ONCOLOGY LETTERS 13: , 2017 Dosimetric comprison of intensity-modulted rdition therpy nd volumetric-modulted rc therpy plns for the tretment of gliom using flttening filter-free nd flttening filter modes DANDAN XU *, FEI JIA *, GUOWEN LI nd HONGFEI LI Deprtment of Rdition Oncology, The First Affilited Hospitl of Zhengzhou University, Zhengzhou, Henn , P.R. Chin Received September 29, 2015; Accepted Februry 23, 2017 DOI: /ol Abstrct. In the present study, the dose verifiction between 6X nd 6X flttening filter free (FFF) in intensity modulted rdition therpy (IMRT) nd volumetric modulted rc therpy (VMAT) ws compred, nd the dvntges nd disdvntges of different rdiotherpy plns were evluted. All four plns chieved comprble heterogeneity nd conformity indices. For frontl tumor, VMAT demonstrted more improved spring of the brinstem compred with the IMRT (P=0.045); while in the model of FFF, the Dmx of eye lens ws significntly reduced by 16 21% (P<0.001). The orgns t risk (OARs) in the temporl lobe tumor were spred well in the IMRT pln. With the removl of FF, the low dose volume for both tumor loctions ws significntly reduced (P<0.05). By contrst, there ws no significnt difference in monitor units (MUs) with FFF, but the MUs were significntly reduced in the VMAT pln (P<0.001). Regrding the protection of OARs, FFF ppered to be superior compred with FF. For the frontl gliom, the VMAT pln hd more dvntges, nd for temporl lobe tumor, dynmic IMRT ws more pproprite. The VMAT pln reduces the low dose volume of norml brin tissues nd the MUs. While the removl of FF my increse the dose rte, the shortened tretment delivery time my improve the ccurcy of tretment due to intr frctionl ptient motion. Introduction Gliom is type of tumor tht origintes from glil cells of the neuroderm (1). At present, postopertive rdiotherpy is the stndrd tretment for high grde gliom. Rndomized Correspondence to: Dr Guowen Li, Deprtment of Rdition Oncology, The First Affilited Hospitl of Zhengzhou University, 1 Jinshe Rod, Zhengzhou, Henn , P.R. Chin E mil: ligouwen8@126.com * Contributed eqully Key words: gliom, flttening filter free, intensity modulted rdition therpy, volumetric modulted rc therpy, dosimetry controlled trils hve demonstrted tht postopertive rdiotherpy prolongs the medin survivl time of ptients from 3 6 months to 9 12 months (1). For gliom, intensity modulted rdition therpy (IMRT) hs been reveled to provide more conforml dose distribution compred with conventionl rdiotherpy, with improved spring of djcent tissues (2 4). Volumetric modulted rc therpy (VMAT) is novel form of IMRT optimiztion tht regultes the rdition dose with enhnced degrees of freedom, by continuously modulting the multi lef collimtor (MLC) field shpe, gntry rottion speed nd dose rte. VMAT enbles for dditionl flexibility in dose delivery nd could further improve dose conformity nd spring of vitl tissues. Compred with IMRT, the potentil dvntges of VMAT include lrge reduction in tretment time nd concomitnt reduction in the number of monitor units (MUs) required to deliver given frction size (5 9). It hs been demonstrted tht the removl of the flttening filter results in chnges to the dose rte (10 13). Cliniclly, the MUs nd dose rte increse with the use of flttening filter free (FFF) bems nd the tretment delivery time is reduced compred with IMRT (10 13). A totl of 21 ptients with tumors locted within the frontl lobe re (11 ptients) nd temporl lobe re (10 ptients), who hd been treted for tumor with rdiotherpy t The First Affilited Hospitl of Zhengzhou University (Zhengzhou, Chin) between 2013 nd 2014 were retrospectively selected. All ptients hd pthologicl dignosis of gliom. For ech ptient, four tretment plns, including 6X dynmic (d) IMRT, 6FFF dimrt, 6X VMAT nd 6FFF VMAT pln were generted. The dose prescription ws set to 60 Gy delivered over 30 frctions. The dose distributions for the plnning trget volume, orgns t risk (OARs) nd norml tissue were compred. The MUs were lso evluted. The dose distribution of trget (Dmx, Dmin, Dmen, dose conformity nd heterogeneity index), OARs (Dmx) nd norml tissue (Dmen, V20Gy, V10Gy nd V5Gy) were compred mong the four plns. Mterils nd methods Ptients. A totl of 21 ptients with gliom were selected from The First Affilited Hospitl of Zhengzhou University

2 3452 XU et l: DOSIMETRIC ANALYSIS IN GLIOMA between September 2013 nd August 2014 to be included in the present study. According to the World Helth Orgniztion clssifiction, the clinicl stges were s follows: Astrocytom (stge II, n=5); oligodendrogliom (stge II, n=5); nplstic strocytom (stge III, n=3); nplstic oligodendrogliom (stge III, n=3); nd glioblstom (stge IV, n=5) (8). The exclusion criteri included ny ptient with bnorml function of hert, lung, liver nd kidney (Krnofsky performnce sttus <80). The medin ge ws 43 yers (rnge, yers), with 14 mles nd 7 mles. For ll ptients, the loction of gliom ws in the frontl lobe re (11 ptients) or temporl lobe re (10 ptients). For frontl lobe gliom, the lrgest bem field of plnning trget volume (PTV) ws 11.5x13.5 cm 2 (rnge, 8x x13.5 cm 2 ) nd medin PTV ws cm 3 (rnge, cm 3 ). For temporl lobe gliom, the lrgest bem field of PTV ws 11.5x9 cm 2 (rnge, 6.5x7 11.5x9 cm 2 ) nd the medin PTV ws cm 3 (rnge, cm 3 ). Definition nd contour of trgets. The trget volume ws delineted ccording to the no. 50 nd 62 reports of the Interntionl Commission on Rdition Units nd Mesurements (8). For low grde gliom, the gross tumor volume (GTV) ws defined s the bnorml signl intensity re of T2 weighted fluid ttenuted inversion recovery on mgnetic resonnce imging (MRI) scn, while mrgin of 2.0 cm ws dded to the GTV to produce the clinicl trget volume (CTV). For high grde gliom, the GTV ws defined s the residul tumor nd/or cvity of T1 on the MRI scn, nd the CTV ws defined s the GTV plus mrgin of 3.0 cm. The CTV ws expnded by 5 mm to produce the PTV. Tretment plnning. The tretment plns were generted using Eclipse 3D TPS softwre (version 10; Vrin Medicl Systems, Plo Alto, CA, USA). dimrt nd VMAT plns were produced using 6 MV photons, nd the dose prescription ws set to 60 Gy in 30 frctions. The dose constrints to the OARs were determined using Rdition Therpy Oncology Group protocol (6). The dimrt plns consisted of six coplnr fields t gntry ngles of 220. The VMAT plns consisted of single rc, strting t gntry ngle of 179 nd rotting counter clockwise through 358 to stop t gntry ngle of 181, nd nother rc in the opposite direction. The two plns dopted the sme pproch during optimiztion. The upper limits of the dose rte for the 6X nd FFF bems were 600 nd 1,200 MU/min, respectively. Dosimetric comprison. The dose volume histogrm included the Dmx, Dmen nd Dmin of CTV; nd the Dmx, Dmen nd Dmin of PTV. Conformity index ws clculted s follows: (PTV ref /V PTV ) x (PTV ref /V ref ) (14). Heterogeneity index (HI) ws clculted s follows: D 5 /D 95. To quntify the dose distribution on OARs nd norml tissue (NT) t different dose levels, the percentge volume of the OARs nd NT receiving dose of 20, 10 nd 5 Gy (V20, V10 nd V5, respectively) were evluted nd compred. Sttisticl nlysis. Sttisticl significnce ws evluted using two tiled Student's t test. P<0.05 ws considered to indicte sttisticlly significnt difference. Anlyses were performed using SPSS softwre (version 19.0; SPSS, Inc., Chicgo, IL, USA). Results Frontl lobe gliom PTV coverge. In the sme model, the Dmx nd Dmen of CTV nd PTV in dimrt were incresed compred with tht in the VMAT plns (Tble I). In the 6X, the Dmx nd Dmen of CTV ws 2.27 nd 0.49%, respectively, nd of PTV ws 2.62 nd 0.64%, respectively. In model of 6FFF, the corresponding vlues were 1.58, 0.54, 1.75 nd 0.59%, respectively. In the flttening filter (FF), the HI ws more improved compred with the VMAT plns. Trditionlly, the FF in the X ry bem pth of liner ccelertor produces n lmost uniform fluence over collimted field. Bsed on these functions, the removl of the FF results in n increse in the dose rte nd decrese in rdition lek. Thus, in the FFF model, the dose distribution to single field will be different from tht of n FF bem (Fig. 1). The off xis response to dose distribution in the control group ws similr in the 6X nd FFF model (Fig. 1A), while the off xis responses in the experimentl groups were significntly lrger in the 6X model compred with the FFF model (Fig. 1B nd C). Integrl dose to the OARs nd NT. Compred with dimrt, the VMAT pln significntly decresed the men Dmx of the brinstem to 36% in the 6X (P=0.008), while the sme index ws 30% in the 6FFF model (P=0.045). In 6FFF dimrt, the men Dmx decresed to 21% in the ipsilterl eye lens nd 17% in the contrlterl eye lens. Compred with 6X VMAT, 6FFF VMAT reduced the men Dmx of the ipsilterl nd contrlterl eye lens to 16 nd 10%, respectively (Tble II). Regrding the Dmen of NT, the 6X dimrt ws incresed compred with 6FFF dimrt, nd the 6X dimrt ws significntly incresed compred with 6X VMAT (P=0.013). No significnt differences were identified in other groups. For the men of low dose of volume in NTs (V20Gy nd V10Gy), the 6X dimrt ws incresed compred with 6X VMAT, nd compred with 6FFF VMAT, the 6FFF dimrt ws significntly incresed (P<0.05). Among the four groups, there were significnt differences in the men of MUs. Compred with 6X dimrt, the group of 6X VMAT decresed the men of MUs from 543.9±29.78 to 414.7± The number of MUs for 6FFF VMAT decresed by 19% compred with for 6FFF dimrt (Tble III). Temporl lobe gliom PTV coverge. Under two different models, the men of PTV's Dmin in dimrt ws reduced compred with the VMAT pln. The verge vlue ws 5,066.49±118.4 cgy nd 5,333.67±88.79 cgy in 6X, while 5,113.98± cgy nd 5,316.28±95.28 cgy in 6FFF. Regrding the HI, the 6FFF dimrt ws incresed compred with 6FFF VMAT. The men vlue ws 1.050± nd 1.041± No sttisticl differences were identified in other prmeters. Integrl dose to the OARs nd NT. In comprison to dimrt, 6X VMAT significntly incresed the verge vlue of Dmx

3 ONCOLOGY LETTERS 13: , Tble I. Comprison of dosimetric prmeters of PTV, CTV, HI nd CI. CTV, cgy Dmx 6,474.44± ,442.74± ,330.69± ,344.22±19.85 <0.001 Dmen 6,152.70± ,164.70± ,122.73±7.68 6,131.68± Dmin 5,782.30± ,854.56± ,920.35± ,900.39± PTV, cgy Dmx 6,532.77± ,506.39± ,365.63± ,394.85±20.01 <0.001 Dmen 6,150.95±9.85 6,154.30±8.93 6,111.22±6.00 6,118.94±6.07 <0.001 Dmin 5,020.95± ,089.82± ,515.19± ,458.32± HI 1.051± ± ± ± <0.001 CI 0.916± ± ± ± with those in 6X VMAT or 6FFF VMAT. PTV, plnning trget volume; CTV, clinicl trget volume; HI, heterogeneity index; CI, conformity index; dimrt, dynmic intensity modulted rdition therpy; FFF, flttering filter free; VMAT, volumetric modulted rc therpy. Figure 1. The off xis curve of 6X nd FFF in different depths. (A) The off xis response to dose distribution in the control group ws similr in the 6X nd FFF model. (B nd C) The off xis responses in the experimentl groups were significntly lrger in the 6X model compred with the FFF model. FFF, flttening filter free.

4 3454 XU et l: DOSIMETRIC ANALYSIS IN GLIOMA Tble II. Comprison of dosimetric prmeters of orgns t risk nd norml tissue. Brinstem Dmx, cgy 1,838.13± ,711.94± ,174.82± ,188.24± Pituitry Dmx, cgy ± ± ± ± Lens ips Dmx, cgy ± ± ± ±54.61 <0.001 Lens cont Dmx, cgy ± ± ± ± ON ips Dmx, cgy 1,046.32± ,071.75± ,709.34± ,761.39± ON cont Dmx, cgy ± ± ± ± Chism Dmx, cgy 1,219.61± ,209.86± ,421.86± ,418.78± TL cont Dmx, cgy 1,719.79± ,697.98± ,706.99± ,486.35± Brin Dmen, cgy ± ± ± ± V20Gy, cm ± ± ± ±92.94 <0.001 V10Gy, cm 3 1,048.81± ,024.69± ,076.32± ,064.28± <0.001 V5Gy, cm 3 1,503.2± ,480.34± ,490.86± ,477.09± MU 543.9± ± ± ± with those in 6X VMAT or 6FFF VMAT. Ips, ipsilterl; cont, contrlterl; ON, optic nerve; TL, temporl lobe; MU, monitor units; dimrt, dynmic intensity modulted rdition therpy; FFF, flttering filter free; VMAT, volumetric modulted rc therpy. Tble III. Comprison of dosimetric prmeters of PTV, CTV, HI nd CI. CTV, cgy Dmx 6,451.92± ,433.79± ,389.89± ,418.67± Dmen 6,164.94±9.62 6,177.13± ,054.71± ,163.13± Dmin 5,760.52± ,784.79± ,797.90± ,785.88± PTV, cgy Dmx 6,489.08± ,456.15± ,417.40± ,439.05± Dmen 6,155.03±8.01 6,160.96±8.73 6,131.84±6.45 6,145.86± Dmin 5,066.49± ,113.98± ,333.67± ,316.28±95.28 <0.001 HI 1.05± ± ± ± CI 0.912± ± ± ± with those in 6X VMAT or 6FFF VMAT. PTV, plnning trget volume; CTV, clinicl trget volume; HI, heterogeneity index; CI, conformity index; dimrt, dynmic intensity modulted rdition therpy; FFF, flttering filter free; VMAT, volumetric modulted rc therpy. nd Dmen of the pituitry glnd by 21% (P=0.012), while in the 6FFF VMAT, the vlue incresed by 19% (P=0.030). No sttisticl differences were identified in the other groups. Regrding the bilterl lens, the men of Dmx ws significntly reduced in 6FFF dimrt compred with 6X (P<0.05). There ws reduction in the men of Dmx of the ipsilterl lens in 6X dimrt (304.93±47.99 cgy) compred with 6FFF dimrt (283.45±43.96 cgy), with simultneous decrese in the vlue of the contrlterl lens from ±48.68 to ±47.72 cgy. The dt reveled tht the men Dmx of the ipsilterl optic nerve ws significntly reduced in 6FFF dimrt compred with tht of 6FFF VMAT (P<0.05). All vlues for the chism were compred in pirs, nd the men of Dmx of dimrt ws identified to be significntly decresed compred with VMAT in 6X nd 6FFF (P<0.05). While compred with dimrt, the pln of 6X VMAT reduced the vlue of Dmx on the contrlterl temporl lobe by 19%, nd in the 6FFF model by 20%. In the helthy brin tissue, the Dmen in 6X dimrt ws incresed compred with 6FFF dimrt, nd the 6X dimrt ws significntly incresed compred with 6X VMAT (P<0.001). No other sttisticl differences were identified. For the low dose volume of NTs, the men of V20Gy ws incresed

5 ONCOLOGY LETTERS 13: , Tble IV. Comprison of dosimetric prmeters of orgns t risk nd norml tissue. Brinstem Dmx, cgy 2,619.63± ,617.22± ,333.51± ,370.47± Pituitry Dmx, cgy 1,605.23± ,667.76± ,950.39± ,976.34± Lens ips Dmx, cgy ± ± ± ± Lens cont Dmx, cgy ± ± ± ± ON ips Dmx, cgy 1,223.89± ,225.89± ,805.86± ,835.06± ON cont Dmx, cgy ± ± ± ± Chism Dmx, cgy 1,601.55± ,594.55± ,112.10± ,129.90± TL cont Dmx, cgy 1,708.14± ,688.19± ,386.26± ,346.53± Brin Dmen, cgy ± ± ± ±57.63 <0.001 V20Gy, cm 3 1,013.02± ± ,044.68± ± V10Gy, cm 3 1,524.98± ,494.73± ,507.08± ,487.40± V5Gy, cm ± ± ± ±22.56 <0.001 MU ± ± ± ±57.63 <0.001 with those in 6X VMAT or 6FFF VMAT. Ips, ipsilterl; cont, contrlterl; ON, optic nerve; TL, temporl lobe; MU, monitor units; dimrt, dynmic intensity modulted rdition therpy; FFF, flttering filter free; VMAT, volumetric modulted rc therpy. in 6X dimrt compred with 6X VMAT, nd 6FFF dimrt ws significntly incresed compred with 6FFF VMAT (P<0.05). For V10Gy in dimrt, the model of 6FFF reduced the men vlue from 1,013.02± to ± compred with 6X. While in VMAT the 6FFF model reduced the men vlue from 1,044.68± to ± Compred with 6X dimrt, the 6X VMAT reduced the men vlue of MUs from ± to 450.0± The men of MUs in 6FFF VMAT ws 469.2±22.56, which ws reduced by ~20% compred with in 6FFF dimrt (583.8±28.66) (Tble IV). Discussion Previous studies hve suggested tht the clinicl ppliction of FFF in prostte cncer or nsophrynx crcinom improves the protection of the rectum nd bldder (15,16). Considering the decresed dose to OARs nd NT, FFF hs n dvntge over FF. The men MUs were greter in the 6FFF model compred with 6X, which my be due to the softness of the rys. If the dose of the rys to deeper tissue is reduced, the MUs should be incresed to rech the sme depth. During the process of VMAT the prmeters, including the dose rte, the gntry rottion speed nd the site of MLC chnge dynmiclly. Two types of products re currently in clinicl use, Vrin RpidArc nd Elekt VMAT. As the ppliction develops, the VMAT pln my become equl or superior to IMRT nd tomotherpy. Compred with IMRT, the VMAT pln my increse the scttering of NTs, reduce the MUs nd reduce the tretment durtion (17,18). In the current study, for frontl lobe gliom, the Dmx nd Dmen of PTV in VMAT were incresed compred with dimrt, but no significnt differences were identified in the OARs nd NTs. For temporl lobe gliom, the protection of OARs, including pituitry glnd, optic nerve nd chism were more improved in the dimrt pln compred with VMAT. The reson for this is primrily due to the sptil ssocition between the loction of the gliom nd OARs. In n identicl ry model, the differences in dose distribution to OARs between the two plns were not demonstrted to be sttisticlly significnt, s frontl lobe gliom is fr from the lens nd optic nerve. However, temporl lobe gliom is close to the OARs, nd in certin ptients, the tumor hd invded the edge of chism. The rottory speed of the mchine is constnt t 4.8 /s in the process of VMAT; the dose of djcent field shpe my be overlid becuse of the speed of MLC, the positioning ccurcy nd the lekge ry, nd s result the Dmx of the pituitry glnd nd chism in VAMT ws incresed compred with dimrt. In the pst few yers, the VMAT pln hs been grdully pplied in clinicl tretment. The FFF model provides brod rnge of dose rtes, nd will be useful in the optimiztion of VMAT. However, simultneously, the specilty of high dose rte in the FFF model complictes the regultion of the qulity. In the future, s the speed of MLC increses, the high dose rte of FFF will be tken full dvntge of. The VMAT pln should be reconsidered s the tretment durtion my be reduced with use of the FFF bem or nother technicl innovtion. References 1. Wlker MD, Green SB, Byr DP, Alexnder E Jr, Btzdorf U, Brooks WH, Hunt WE, McCrty CS, Mhley MS Jr, Meley J Jr, et l: Rndomized comprison of rdiotherpy nd nitrosoures for the mlignnt gliom fter surgery. N Eng J Med 303: , Chn MF, Schupk K, Brmn C, Chui CS nd Ling CC: Comprison of intensity modulted rdiotherpy with three dimensionl conforml therpy plnning for glioblstom muhiforme. Med Dosim 28: , 2003.

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