Sanja Ognjenovic A PROJECT. submitted to. Oregon State University. University Honors College

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1 Volumetric-modulated arc radiotherapy for pancreatic malignancies: Dosimetric comparison with helical TomoTherapy By Sanja Ognjenovic A PROJECT submitted to Oregon State University University Honors College in partial fulfillment of the requirements for the degree of Honors Baccalaureate of Science in Microbiology (Honors Scholar) Presented May 13, 2015 Commencement June 2015

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3 AN ABSTRACT OF THE THESIS OF Sanja Ognjenovic for the degree of Honors Baccalaureate of Science in Microbiology presented on May Title: Volumetric-modulated arc radiotherapy for pancreatic malignancies: Dosimetric comparison with helical TomoTherapy. Abstract approved: Krystina Tack Purpose: To compare target dose conformality and OAR sparing afforded by VMAT and HT for pancreatic cancer. Materials and Methods: A retrospective planning study was performed in 18 patients. Total treatment dose was 59.4Gy. OAR and PTV mean doses, conformity indices, isodose volumes, and integral doses were compared. The relationship between tumor volume, patient circumference, and these variables was also evaluated. Results: Mean doses to the left kidney (p<.001), right kidney (p<.001), and liver (p<.001) were smaller with VMAT. The mean dose to the PTV was smaller with HT (p=.002). The large field VMAT resulted in a smaller CI percent deviation from 1.0 (p=.025). There was no significant difference for the boost plan (p=.092). Integral dose was significantly lower with VMAT (p<.001). Integral dose was lower for smaller tumor volumes and patent circumferences with both techniques. Conclusion: There appears to be an advantage in using VMAT over HT in reducing radiation doses to the liver and kidneys, in obtaining tighter isodose volumes, and in obtaining a lower integral dose. VMAT may provide superior conformity indices for larger doses, but the techniques are comparable for low doses. Smaller tumor volume and patient circumference result in lower integral doses with both techniques. Key Words: pancreatic malignancy, VMAT, HT, integral dose Corresponding address: ognjenos@onid.orst.edu

4 Copyright by Sanja Ognjenovic May All Rights Reserved

5 Volumetric-modulated arc radiotherapy for pancreatic malignancies: Dosimetric comparison with helical TomoTherapy by Sanja Ognjenovic A PROJECT submitted to Oregon State University University Honors College in partial fulfillment of the requirements for the degree of Honors Baccalaureate of Science in Microbiology (Honors Scholar) Presented May 13, 2015 Commencement June 2015

6 Honors Baccalaureate of Science in Microbiology project of Sanja Ognjenovic presented on May 13, APPROVED: Krystina Tack, Mentor, representing OSU Nuclear Engineering and Radiation Health Physics James Tanyi, Committee Member, representing OHSU Department of Radiation Medicine Alena Paulenova, Committee Member, representing OSU Nuclear Engineering and Radiation Health Physics Toni Doolen, Dean, University Honors College I understand that my project will become part of the permanent collection of Oregon State University, University Honors College. My signature below authorizes release of my project to any reader upon request. Sanja Ognjenovic, Author

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8 Table of Contents Introduction... 1 Materials and Methods... 1 Patients... 1 Treatment Planning... 2 Comparison of Techniques... 2 Results... 3 Discussion... 3 Conclusions... 4 Limitations... 4 References... 5 Appendix... 7 Table Table Table Table

9 Introduction Pancreatic cancer treatment is commonly a tri-modality approach of chemotherapy, radiation therapy, and surgical resection. As the tumor is close to normal tissue and critical organs toxicity is a primary concern. Treatment with traditional radiotherapy techniques such as 3D-CRT can result in toxicity to critical organs such as the liver, stomach, small bowel, and kidneys. 1 Intensity-modulated radiotherapy (IMRT) has been shown to improve target dose conformality and reduce toxicity when compared to 3D-CRT. 2-5 The availability of even more refined radiation therapy techniques such as RapidArc (RA) and Helical TomoTherapy (HT) presents new opportunities to study dose conformality and sparing of these critical structures. RapidArc is a form of volumetric-modulated arc therapy (VMAT) in which the radiation dose is delivered through one or more dynamically modulated arcs. During treatment planning, the dose optimization algorithm simultaneously modulates the rotation speed of the gantry, the shape of the multi-leaf collimator (MLC) aperture, and the delivery dose rate allowing for shorter treatment times, improved conformality, and the delivery of fewer monitor units. 6-8 Helical TomoTherapy (HT) is an arc-based approach to IMRT in which the radiation dose is delivered slice by slice as opposed to the entire volume being irradiated at once. During HT the gantry rotates at a constant speed while the shape of the binary MLC aperture changes and the patient table moves in and out of the beam aperture. When compared with traditional IMRT techniques HT has been shown to reduce radiation doses to organs at risk thereby reducing gastrointestinal toxicity There are currently only a few analyses comparing these two techniques. Cao et al. and Fogliata et al. both compared VMAT and HT for the treatment of intracranial tumors. Cao et al. concluded that the techniques are generally comparable, but HT can provide superior results for more complex cases. 11 Fogliata et al. also concluded that the techniques are comparable in terms of conformality and organ sparing, but reported that more complex studies need to be done. Our goal was to dosimetrically compare target dose conformality and organ-at-risk sparing afforded by VMAT and HT in the treatment of pancreatic tumors. 12 We also sought to evaluate if tumor volume or patient circumference affects treatment quality for either technique. Materials and Methods Patients A retrospective planning study was performed on eighteen patients with advanced pancreatic cancer with and without previous resection. Data collection and analysis was approved by the Institutional Review Board of the Knight Cancer Institute at the Oregon Health and Science University. During treatment patients were immobilized using the BodyFix wholebody double vacuum immobilization system (Medical Intelligence, Schwabmuenchen, Germany) without diaphragmatic control and with abdominal compression. 13 All patients underwent a freebreathing computed tomography (CT) scan as well as a free-breathing respiratory-correlated, four-dimensional CT (4DCT) on a 16-slice helical big-bore simulator (Philips Medical Systems, Cleveland, OH) in the supine position. 1

10 Treatment Planning The 4DCT scans were reconstructed in 10 equally spaced time bins of 3mm slice thickness using respiratory phase binning. The 4D maximum intensity projection data set (MIP), the free breathing CT, and the average intensity projection CT were all exported to Eclipse v (Varian Medical Systems, Palo Alto, CA) for target and OAR segmentation. Using the MIP, free breathing CT, and the 10 respiratory phases of the 4DCT an internal target volume (ITV) was created. The ITV was expanded by a 5mm margin to create the planning target volume (PTV). Organs at risk such as the spinal cord, kidneys, liver, stomach, and bowel were contoured on the average intensity projection CT. The average-intensity projection CT was also used for dose calculation. Individual isodose constraints were placed to ensure that the maximal tolerated doses to the OARs per published Quantitative Analysis of Normal Tissue Effects in the Clinic guidelines were not exceeded 14.Plans were created so that the prescribed dose of 45Gy encompassed at least 95% of the PTV (tissue heterogeneity was accounted for). A boost plan was created on a new planning CT resulting in a cumulative dose of 59.4 Gy. All VMAT plans were created using 10MV photons and delivered on a Varian Clinac that is equipped with a 120-leaf Millennium multileaf collimator system, with forty 5-mm central leaf-pairs and twenty 10-mm peripheral leaf-pairs. VMAT plans were generated with two simultaneously optimized coplanar volumetric arcs with the same isocenter and with 360 rotation. HT plans were generated using the Hi-Art Helical Tomotherapy inverse planning software. Tomotherapy plans were designed to match the isodose constraints used on VMAT planning. Comparison of Techniques The CT data sets with contours and isodose lines were transferred to VelocityAl (Velocity Medical Solutions, Atlanta, Georgia) to generate the cumulative dose from the original plan and the boost plan. This was done through deformable registration, an optimization process that correlates anatomical features observed in two different images of the same patient and ROI. Once an optimal match is found between the input images (original and boost plan CTs) the system is able to provide a cumulative dose. 13. Cumulative dose volume histograms (cdvh) were obtained for the PTV and OARs for all patients. The following parameters were calculated for all patients and compared: Dmean (mean dose) and D95% (the dose received by 95% of the PTV) for the PTV, Dmean and V30 (the volume receiving more than 30Gy) for the liver, Dmean, V15 and V20 (volume receiving more than 15Gy and 20Gy, respectively) for the kidneys, and Dmax (maximum dose) for the spinal cord. No cdvhs were obtained for the stomach or the small bowel. Expanding the GTV to the PTV incorporates the dose to the small bowel so it is unnecessary to report this as a separate result. The conformity indices of the plans, as well as the volumes of the 25%, 50%, 90%, and 100% isodose lines, were also calculated. The conformity index of the plans was defined as the ratio between the volume of the 100% isodose line and the PTV volume. Conformity indices were compared by calculating their percent deviation from 1.0, as a value of 1.0 is ideal. The volumes encompassed by the isodose lines were obtained using the VelocityAl system. We also calculated the overall integral dose delivered to the patient. The integral dose was defined as the mean dose delivered to the total body minus the PTV 12,15,16. Additionally, all 18 patients were sorted into three groups based on tumor volume. The first group averaged a tumor volume of 438.0cm 3, the second group cm 3, and the third group cm 3. Dmean for the left kidney, right kidney, and liver as well as Dmax for the spine, integral dose, and CI deviation from 1.0 for both original 2

11 and boost plans were compared between tumor volume groups. Lastly, we compared the effect patient circumference had on these variables by sorting the patients into two groups based on their circumference. Circumference was estimated by calculating the circumferential length around the body at isocenter. The first group averaged a circumference of 295cm and the second group averaged 541cm. All statistical analyses were performed using a paired, two-sided Student s t-test with a significance level of p < Results Table 1 summarizes and compares the mean doses to the defined organs at risk for the two treatment techniques. Mean doses were lower with VMAT plans than HT plans for the left kidney (15.6 vs. 28.5, p<.001), the right kidney (15.0 vs. 27.4, p<.001), and the liver (13.0 vs. 28.8, p<.001). Maximum doses to the spinal cord were statistically insignificant (VMAT=35.1, HT=39.4, p=.053). The mean dose to the PTV was lower with the HT plans (55.6 vs. 60.9, p=.002). D95% was statistically insignificant (VMAT=56.6, HT=51.1, p=.826). Table 2 summarizes and compares the conformity indices as well as the volumes of the 25%, 50%, 90%, and 100% isodose lines. For the large field plan VMAT produced a smaller CI percent deviation from 1.0 (4.5% vs. 7.5%, p=.025). However, for the boost plan there was no significant difference in CI deviation (VMAT=4.2%, HT=10.4%, p=.092). For the 25%, 50%, 90%, and 100% large field isodose lines the HT plans had significantly larger volumes than the VMAT plans (p<.001 for 25%, 90%, 100%, p=.021 for 50%). The same trend was observed for the boost plan 25%, 50%, and 90% isodose volumes (p<.001 for 25%, 50%, p=.001 for 90%). There was no significant difference in the 100% boost plan isodose volumes (p=.145). Integral dose was significantly lower with the VMAT plans than with the HT plans (p<.001). Table 3 compares tumor volume and Dmean for the left kidney, right kidney, and liver, Dmax for the spine, integral dose, and CI deviation from 1.0 for both original and boost plans. There were no significant trends between tumor volume and any of these variables, except integral dose. Smaller tumor volumes resulted in significantly lower integral doses with both VMAT (G1-G2 P=.001, G1-G3 P<.001, G2-G3, P=.005) and HT (G1-G2 P=.002, G1-G3 P<.001, G2-G3, P=.012). Table 4 compares the same variables, but with patient circumference. Similarly, there was only a significant trend between patient circumference and integral dose. Patients with a smaller circumference had significantly lower integral dose delivery with both VMAT (P=.002) and HT (P=.009). Discussion In this study we dosimetrically compared target dose conformality and organ-at-risk sparing afforded by VMAT and HT for the treatment of pancreatic cancer. Our results indicate that double-arc 10MV VMAT plans may provide superior sparing of the kidneys and liver when compared with HT plans. Our results also indicate that VMAT may provide tighter isodose volumes for 25%, 50%, 90% and 100% isodose lines. To make a conclusion about conformity indices more research needs to be done. Our results suggest that VMAT may provide superior conformity indices for larger doses, but that for lower doses the treatment techniques may provide comparable results. Our results also indicate that VMAT provides significantly lower integral doses than HT. There appears to be no relationship between tumor volume or patient circumference and dose conformality or sparing of organs at risk for either of these two 3

12 techniques. Only integral dose is affected. Smaller tumor volumes and patient circumferences appear to result in lower integral dose delivery for both VMAT and HT. Cai et al. conducted a similar pancreatic study and found that single-arc 6MV and 15MV VMAT plans provide statistically comparable conformity indices when compared to HT plans for radiation doses of 50Gy. 17 The study by Cai et al. also found that there were small but significant decreases in the mean dose to the bowel, duodenum, kidneys, and liver with the VMAT plans. Pasquier et al. studied the treatment of prostate cancer with whole pelvic radiation therapy (WPRT) using VMAT and HT for radiation doses of 46Gy and 76Gy. 18 That study found that at high doses VMAT better spared the rectal wall, but HT better spared the bladder wall. No significant differences in mean dose to the rectal wall, bladder wall, or small bowel were found between the two techniques at the lower dose. Pasquier et al. also found that the integral dose was significantly lower with VMAT, as did Oliver et al 19. There are no published works evaluating the effects of either tumor volume or patient circumference on the effectiveness of these techniques. Conclusions Both VMAT and HT can deliver conformal dose distributions while limiting the dose to normal tissues regardless of tumor volume or patient circumference. There may be an advantage in using VMAT over HT in the reduction of radiation doses to certain organs at risk such as the kidneys and liver and in obtaining tighter isodose volumes. More research needs to be done to develop a conclusion about which technique, if either, provides superior conformity indices. Overall, VMAT provides a lower integral dose. However, both smaller tumor volume and smaller patient circumference result in lower integral doses for both treatment techniques. Limitations The dose constraints used by our institution are unique and there is no guarantee that another institution, using different dose constraints, will obtain the same results. Furthermore there is variability in amongst patients and because of our small sample size (n=18) we cannot confidently make a conclusion about the entire population of pancreatic cancer patients. 4

13 References [1] Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: A randomized controlled trial. JAMA : the journal of the American Medical Association 2008;299: [2] Landry JC, Yang GY, Ting JY, Staley CA, Torres W, Esiashvili N, Davis LW. Treatment of pancreatic cancer tumors with intensity-modulated radiation therapy (IMRT) using the volume at risk approach (VARA): employing dose-volume histogram (DVH) and normal tissue complication probability (NTCP) to evaluate small bowel toxicity.med Dosim Summer;27(2): [3] Poppe MM, Narra V, Yue NJ, Zhou J, Nelson C, Jabbour SK. A comparison of helical intensity-modulated radiotherapy, intensity-modulated radiotherapy, and 3D-conformal radiation therapy for pancreatic cancer. Med Dosim Winter;36(4): [4] Brown MW, Ning H, Arora B, et al. A dosimetric analysis of dose escalation using two intensity-modulated radiation therapy techniques in locally advanced pancreatic carcinoma. Int J Radiat Oncol Biol Phys 2006;65: [5] Yovino S, Poppe M, Jabbour S, et al. Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers. Int J Radiat Oncol Biol Phys 2011;79: [6] Otto K. Volumetric modulated arc therapy: Imrt in a single gantry arc. Medical physics 2008;35: [7] Palma D, Vollans E, James K, et al. Volumetric modulated arc therapy for delivery of prostate radiotherapy: Comparison with intensity-modulated radiotherapy and threedimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 2008;72: [8] White P, Chan KC, Cheng KW, Chan KY, Chau MC. Volumetric intensity-modulated arc therapy vs conventional intensity-modulated radiation therapy in nasopharyngeal carcinoma: a dosimetric study. J Radiat Res May;54(3): [9] Taylor R, Opfermann K, Jones BD, Terwilliger LE, McDonald DG, Ashenafi MS, Garrett-Meyer E, Marshall DT. Comparison of radiation treatment delivery for pancreatic cancer: Linac intensity-modulated radiotherapy versushelical TomoTherapy. J Med Imaging Radiat Oncol Jun;56(3): [10] Chargari C, Campana F, Beuzeboc P, Zefkili S, Kirova YM. Preliminary experience of helical TomoTherapy for locally advanced pancreatic cancer. World J Gastroenterol Sep 21;15(35): [11] Cao D, Holmes TW, Afghan MK, Shepard DM. Comparison of plan quality provided by intensity-modulated arc therapy and helical TomoTherapy. Int J Radiat Oncol Biol Phys Sep 1;69(1): [12] Fogliata A, Clivio A, Nicolini G, Vanetti E, Cozzi L. Intensity modulation with photons for benign intracranial tumours: a planning comparison of volumetric single arc, helical arc and fixed gantry techniques. Radiother Oncol Dec;89(3): [13] Fuss M, Salter BJ, Rassiah P, et al. Repositioning accuracy of a commercially available double-vacuum whole body immobilization system for stereotactic body radiation therapy. Technology in cancer research & treatment 2004;3:

14 [14] Marks, L.B.; Yorke, E.D.; Jackson, A.; et al. Use of normal tissue complication probability models in the clinic. Int. J. Radiat. Oncol. Biol. Phys. 76:S10 9, http//dx.doi.org/ /j.ijrobp [15] D Souza W, Isaac R. Nontumor integral dose variation in conventional radiotherapy treatment planning. Med. Phys Aug; 30(8): [16] Yang R, Xu S, Jiang W, Wang J, Xie C. Dosimetric comparison of postoperative whole pelvic radiotherapy for endometrial cancer using three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and helical Tomotherapy. Acta Oncol. 2010;49(2): [17] Cai J, Yue J, McLawhorn R, et al. Dosimetric comparison of 6 MV and 15 MV single arc rapidarc to helical TomoTherapy for the treatment of pancreatic cancer. Med Dosim Autumn; 36(3): [18] Pasquier D, Cavillon F, Lacornerie T, Touzeau C, Tresch E, Lartigau E. A dosimetric comparison of TomoTherapy and volumetric modulated arc therapy in the treatment of high-risk prostate cancer with pelvic nodal radiation therapy. Int J Radiat Oncol Biol Phys Feb 1;85(2): [19] Oliver M, Ansbacher W, Beckham WA. Comparing planning time, delivery time and plan quality for IMRT, RapidArc and Tomotherapy [abstract] J appl Med Phys. 2009;10:

15 Appendix Table 1 OAR Left kidney VMAT HT t-test VMAT vs. HT Dmean (Gy) 15.6± ±3.5 <.001 Range V15 (cc) 45.2± ±56.6 <.001 Range V20 (cc) 23.6± ±35.5 <.001 Range Right kidney Dmean (Gy) 15.0± ±4.6 <.001 Range V15 (cc) 44.9± ±36.3 <.001 Range V20 (cc) 24.6± ±20.5 <.001 Range Liver Dmean (Gy) 13.0± ±5.0 <.001 Range V30 (cc) 10.4± ±161.2 <.001 Range Spinal cord Dmax (Gy) 35.1± ± Range PTV Dmean (Gy) 60.9± ± Range D95% (Gy) 56.6± ± Range Integral Dose ± ± <.001 Range

16 Table 2 CI Deviation (%) VMAT HT t-test Large field 4.5± ± Range Boost 4.2± ± Range Iso 25% (cc) ± ± <.001 Range Iso 50% (cc) ± ± Range Iso 90% (cc) 884.7± ±449.2 <.001 Range Iso 100% (cc) 717.0± ±345.1 <.001 Range Boost Iso 25% (cc) ± ± <.001 Range Boost Iso 50% (cc) ± ±843.9 <.001 Range Boost Iso 90% (cc) 342.8± ± Range Boost Iso 100% (cc) 290.6± ± Range

17 Table 3 VMAT Average t-test G1 G2 G3 G1-G2 G1-G3 G2-G3 CI Large Deviation from 1.0 (%) Range CI Boost Deviation from 1.0 (%) Range L Kidney Mean (Gy) Range R Kidney Mean (Gy) Range Liver Mean (Gy) Range Spine Max (Gy) Range Integral Dose < Range HT CI Large Deviation from 1.0 (%) Range CI Boost Deviation from 1.0 (%) Range L Kidney Mean (Gy) Range R Kidney Mean (Gy) Range Liver Mean (Gy) Range Spine Max (Gy) Range Integral Dose < Range *G1 averaged a tumor volume of 438.0cm3, G cm3, and G cm3 9

18 Table 4 VMAT Average t-test G1 G2 G1-G2 CI Large Deviation from 1.0 (%) Range CI Boost Deviation from 1.0 (%) Range L Kidney Mean (Gy) Range R Kidney Mean (Gy) Range Liver Mean (Gy) Range PTV Mean Range Spine Max (Gy) Range Integral Dose (Gy) Range HT CI Large Deviation from 1.0 (%) Range CI Boost Deviation from 1.0 (%) Range L Kidney Mean (Gy) Range R Kidney Mean (Gy) Range Liver Mean (Gy) Range PTV Mean Range Spine Max (Gy) Range Integral Dose (Gy) Range *G1 averaged a patient circumference of 295cm, G2 averaged 541cm 10