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1 The use of IMRT in Distal Esophageal Carcinoma: A Case Study Authors: Bret Conrad, B.S. R.T.

(T) and Nishele Lenards, M.S., CMD, R.T.(R)(T), FAAMD Medical Dosimetry Program at the University of Wisconsin-La Crosse, WI Abstract: Introduction: The purpose of this study is to evaluate the use of intensity modulated radiation therapy (IMRT) for the treatment of cancers in the distal esophagus. Case Description: The IMRT treatment technique was used for 3 patients that were diagnosed with adenocarcinoma of the distal esophagus. All of the patients received radiation therapy and chemotherapy prior to surgery. All of the patients included were diagnosed with common signs and symptoms of esophageal cancer and all received a metastatic work-up before radiation therapy began. All of the cases included were treated to a cumulative dose of 5040 centigray (cGy) with an initial and boost PTV. Conclusion: The 3 patient cases were compared and evaluated with regard to the coverage of the PTV and the dose to the local normal structures. This was done by observing the dose volume histograms (DVH), reviewing the isodose lines and gantry angles in multiple plans, and striving to have the 95% isodose line cover the PTV. It was concluded that IMRT is beneficial in comparison to traditional three dimensional (3D) conformal radiation therapy. The dose to normal structures like the heart and lungs can be kept relatively low. However, more air in the lungs included within the PTV increases the difficulty of delivering an optimal conformal plan covering the target volume. Key Words: Intensity-Modulated Radiation Therapy (IMRT), distal esophageal cancer Introduction Esophageal cancer is usually diagnosed at an advanced stage.1 It is the 7th leading cause of cancer deaths in men in the United States. Men are typically affected 3 to 4 times more than women, with African American men more affected than white men. Most of the patients are diagnosed between the ages of 55 and 85 years old. Esophageal cancer has many risk factors associated with it. Some of the risk factors include tobacco use, alcohol use, Barretts esophagus,

2 longstanding gastroesophageal reflux disease (GERD), diets low in fruits and vegetables, achalasia, Plummer-Vinson syndrome, and tylosis. However, survival rates have been improving for white and African American patients due to the treatment techniques for these cancers. Many different treatment techniques and combinations have been studied for the treatment of esophageal cancer. Two of the most commonly used treatment regimens are definitive chemoradiation therapy and neoadjuvant preoperative chemoradiotherapy. In a study performed by Van Hagan et al,2 the results showed improved survival among patients undergoing preoperative chemoradiotherapy over patients with surgery alone. While this technique is one of the more common treatment regimens used for esophageal cancer, the question is how to deliver the radiation therapy. Esophageal cancer can be treated with the 3D conformal technique and with IMRT. The reason for using IMRT is to try and accomplish more conformal dose around the PTV and less dose to the normal structures. When treating the distal esophagus, the normal structures near PTV include the lungs, heart, and spinal cord. A study by Chandra et al3 demonstrated that more of the normal lung could be spared with IMRT over 3D conformal radiation therapy. If this was the case for every patient then IMRT would be the mainstay treatment for distal esophageal cancers. However using IMRT has disadvantages as well. A downfall of static IMRT is the increased amount of time a patient remains on the table. This is of great concern if the patient is noncompliant or in large amounts of pain. Normally the IMRT fields will have more gantry angles and the time at each angle will be longer. Another disadvantage is that IMRT causes a larger amount of integral dose throughout the body. Because of more gantry angles, the integral dose can cover a larger percentage of the body compared to the 3D conformal technique. Case Description Patient Selection The patients selected were all diagnosed with adenocarcinoma of the distal esophagus. The patients selected were all treated with IMRT to the gross tumor, lymph nodes, and microscopic disease. Patient 3 had inclusion of the celiac axis. Concurrent chemotherapy was used in conjunction with radiation therapy and surgery was planned for 5-8 weeks after the radiation was completed for all patients.

3 Patient Set-up Each patient was positioned in the supine position with the head towards the gantry. An angled sponge was placed under the knees and a pad under the buttocks. The arms were placed above the head with an alpha cradle molded under the thorax and head. All 3 patients were given 3 tattoos as reference marks for assistance in localizing the isocenter. A box was placed on the abdomen for a 4D scan (Figure 1). For the 4D scan a camera placed at the foot of the table tracked the movement of the box on the patients abdomen. This allowed for the PTV to be drawn on all phases of the breathing cycle. Target Delineation A CT simulation was performed on each patient and anatomical contours were delineated in the Varian Eclipse treatment planning system. The normal structures contoured by the medical dosimetrist included the spinal cord, heart, right and left lungs, right and left kidneys, stomach, liver, small and large bowel, and the carina. The radiation oncologist contoured the planning structures, which included a gross tumor volume (GTV), clinical target volume (CTV), internal target volume (ITV), and a PTV for the initial field and boost field using the 4D CT scan. An ITV is included by performing a 4D CT scan to capture images at all phases of the breathing cycle. A study by Dieleman et al4 showed that the distal esophagus moves during a 4D CT scan. This shows that during a normal CT simulation, the planning structures could move out of the treatment field during normal breathing. The spare structures used for optimization included a heart spare and cord spare for Patient 1; heart spare, lung spare, and cord spare for Patient 2; and heart spare, lung spare, and liver spare for Patient 3. The spare structures are contoured and assigned values to avoid overlap of the PTV and assist the treatment planning system in the optimization process. Treatment Planning All patient cases were planned using the Anisotropic Analytical Algorithm (AAA) and 6 MV. The prescription dose for all patient cases was 5040 cGy with a daily dose of 180 cGy for 28 fractions. According to Minsky et al,5 there are no survival or local control benefits to giving doses higher than 5040 cGy for esophageal cancers. The margins for the planning structures follow the model of the RTOG 1010 protocol. The CTV is expanded 4 cm superior and inferior and 1.0-1.5 cm laterally from the GTV. The ITV is created by combining the CTVs from all of

4 the different stages of breathing. The initial PTV is expanded 1.0-1.5 cm from the ITV. The boost PTV includes the GTV with a 0.5-1.0 cm expansion. The radiation oncologist preferred the PTV receiving 5040 cGy to be covered by 95% of the prescription dose. The normal structures that were observed in all of the cases included the heart, lungs, and spinal cord. The radiation oncologists guidelines for critical structures dose constraints included: only 40% of heart to receive 4000 cGy with a maximum dose less than 5200 cGy; less than 20% of both lungs to receive 2000 cGy; and a maximum spinal cord dose of 4500 cGy. The radiation oncologist also preferred to keep the overall plan hot spot under 110%. For Patient 1 the medical dosimetrist used 7 gantry angles for both the primary and boost plan. The angles included 190, 215, 240, 0, 120, 145, and 170. The structures were put into the optimization page along with their priority numbers for the initial PTV including the PTV with a priority of 120, the right and left lungs with a priority of 80, the cord spare structure with a priority of 65, the heart spare structure with a priority of 60, and the heart with a priority of 30. The structures inserted into the optimization page and their priority numbers for the boost PTV were the PTV with a priority of 125, the heart spare structure with a priority of 55, the cord spare structure with a priority of 40, and both lungs with a priority of 35. The priority of importance in the IMRT optimization page was decided by the medical dosimetrist. The initial PTV plan was normalized to the 100% isodose line. The boost plan was normalized to the 98% isodose line. The composite plan had a maximum hot spot of 106%. For Patient 2 the medical dosimetrist used a plan with 5 gantry angles. The gantry angles were 155, 80, 0, 280, and 205 for both the primary PTV and boost PTV. For the primary PTV optimization the medical dosimetrist gave the PTV a priority of 95, cord spare was 45, heart spare was 55, lung spare was 55, and liver was 20. The plan was normalized to the 96% isodose line. For the boost PTV, the priority for the PTV was 95, cord spare was 55, heart spare was 25, lung spare was 35, and liver was 10. The boost plan was normalized to the 98% isodose line. The composite plan had a maximum hot spot of 107%. For Patient 3 the medical dosimetrist used 7 gantry angles for both the initial PTV and the boost PTV. The gantry angles were 210, 260, 310, 0, 50, 100, and 150. The optimization for the initial PTV included giving the PTV a priority of 100, heart spare a priority of 60, lung spare a priority of 50, and liver spare a priority of 20. The initial PTV was normalized to the 97%

5 isodose line. The priorities used for the boost PTV included giving the PTV a priority of 100, heart spare a priority of 60, lung spare a priority of 50, and liver spare a priority of 20. The boost PTV was normalized to the 96% isodose line. The overall hot spot for the composite plan was 109%. Plan Analysis & Evaluation All of the cases presented were analyzed and evaluated based on PTV volume coverage, dose to normal structures, and the overall hot spot. The normal structures that were observed in all of the cases included the heart, lungs, and spinal cord. The radiation oncologist used objectives while reviewing the plans (Table 1). Patient 1 beam arrangement had 7 gantry angles which included 6 posterior beams and an Anterior-Posterior (AP) beam. The idea behind the arrangement was to avoid treating through the anterior portions of both lungs. With this arrangement the coverage of both the primary PTV and boost PTV were close to optimal. The 100% and 95% isodose lines conformed tightly around both PTVs (Figures 2 and 3). The DVH (Figure 4) showed the PTVs covered by at least 95% of the prescription dose. The spinal cord dose was less than 4500 cGy, lungs less than 20% at 2000 cGy, and heart under 40% at 4000 cGy. Due to the location of the PTV and the gantry angles used, the lung dose was kept low and PTV coverage was optimal. This plan had the least amount of lung in the PTV. Having less air in the PTV creates an easier optimization for the treatment planning system. The posterior beams allowed a majority of the anterior portion of the lungs to be kept to a minimal dose. The plan for Patient 2 included a different arrangement of gantry angles. The plan included 5 angles with an AP beam, 2 anterior obliques, and 2 posterior obliques. In a study by Nutting et al,6 the results showed that fewer IMRT fields when treating the distal esophagus could reduce the integral lung dose. The PTV coverage was close to optimal with tight conformal isodose lines surrounding both the primary PTV and boost PTV (Figures 5 and 6). The DVH (Figure 7) showed the PTVs closely covered by at least 95% of the prescription dose, the spinal cord under 4500 cGy, the lungs greater than 20% at 2000 cGy, and less than 40% of the heart at 4000 cGy. The PTV for Patient 2 expanded more superior than Patient 1, thus including more lung in the PTV. This created more air in the lungs included in the PTV, which made it harder to achieve maximum coverage for the planning system optimizer. The more PTV in lung also increased the

6 lung dose, even using 2 less gantry angles. The heart dose was the lowest in this plan due to the location of the PTV and the least amount of gantry angles. Patient 3 had a treatment plan that included 7 different gantry angles for both volumes. The isodose lines were conformal around the PTVs (Figures 8 and 9), however the initial PTV showed less than optimal coverage. The DVH (Figure 10) showed 98% of PTV45 being covered with 95% of the prescription dose, 100% of PTV50.4 being covered with 95% of the prescription dose, 15% of the heart receiving 4000 cGy, 26% of the lungs minus PTV receiving 2000 cGy, and the spinal cord under tolerance of 4500 cGy. This plan had a similar amount of lung in the PTV as Patient 2, however this plan used 7 gantry angles. This arrangement increased the heart and lung dose. With the addition of the 2 gantry angles, the PTV coverage did not become more optimal; it actually decreased. This is because the PTV included so much air in the volume, which created difficulty for the treatment planning optimizer. All of the plans were accepted by the radiation oncologist. The spinal cord dose was within tolerance for all plans. The heart dose was optimal in all of the plans, with the maximum dose to the heart highest in Patient 3. The biggest difference was seen in the lung dose (Table 1). The PTV coverage was optimal in Patient 1, while Patient 2 and Patient 3 had coverage slightly less than optimal. The maximum hot spot was optimal in all three patient cases. Conclusion There is no correct way to use IMRT for patients with distal esophageal cancer, although some gantry arrangements work better than others. This case study demonstrated that it is more challenging to get optimal PTV coverage if there is a large amount of air in the PTV. The air from the lungs is not well compensated for by the optimizer during the IMRT planning. When the plan calculates, it can result in less than optimal coverage, causing the medical dosimetrist to normalize the plan. This can result in a higher dose to normal structures while the coverage is still less than optimal. The less amount of air in the PTV will allow for more conformal isodose lines. The gantry angles affected the treatment plans to a large degree. The dose to the heart and lungs followed no trend when evaluating the 3 cases. Obviously the reason gantry angles and doses are different is due to different patient anatomy and PTV volumes. The gantry angles and number of

7 gantry angles is a key component in these IMRT cases. When a lower number of gantry angles are used, such as 4 or 5, more posterior beams appear to be an ideal set up for patient cases. While IMRT on the linear accelerator using photons was used in these cases, research has shown other modalities can lower the dose to normal structures when treating the esophagus. According to Welsh et al,7 intensity modulated proton therapy is able to lower doses to the normal structures around the esophagus. Tomotherapy can also be used to lower doses to the heart and lungs when treating the esophagus.8 Future research with photons should include evaluating the amount of air included in the PTV and methods to achieve a more optimal PTV coverage.

8 References 1. Washington CM, Leaver D. Principles and Practice of Radiation Therapy. 3rd ed. St. Louis, MO: Mosby Elsevier; 2010. 2. Yap JC, Malhotra HK, Yang GY. Intensity modulated radiation therapy in the treatment of esophageal cancer. Thorac Cancer. 2010;1(2):62-69. doi:10.1111/j.1759-7714.2010.00017.x 3. Chandra A, Guerrero TM, Liu HH, et al. Feasibility of using intensity-modulated radiotherapy to improve lung sparing in treatment planning for distal esophageal cancer. Radiother Oncol. 2005;77(3):247-253. doi:10.1016/j.radonc.2005.10.017 4. Dieleman EM, Senan S, Vincent A, et al. Four-dimensional computed tomographic analysis of esophageal mobility during normal respiration. Int J Radiat Oncol Biol Phys. 2007;67(3):775-780. doi:10.1016/j.ijrobp.2006.09.054 5. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) Phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002;20(5):1167-1174. http://dx.doi.org/10.1200/JCO.20.5.1167 6. Nutting CM, Bedford JL, Cosgrove VP, et al. A comparison of conformal and intensitymodulated techniques for esophageal radiotherapy. Radiother Oncol. 2001;61(2):157-163. http://dx.doi.org/10.1016/S0167-8140(01)00438-8 7. Welsh J, Gomez D, Palmer MB, et al. Intensity-modulated proton therapy further reduces normal tissue exposure during definitive therapy for locally advanced distal esophageal tumors: a dosimetric study. Int J Radiat Oncol Biol Phys. 2011;81(5):1336-1342. doi:10.1016/j.ijrobp.2010.07.2001 8. Nguyen NP, Krafft SP, Vinh-Hung V, et al. Feasibility of tomotherapy to reduce normal lung and cardiac toxicity for distal esophageal cancer compared to three-dimensional radiotherapy. Radiother Oncol. 2011;101(3):438-442. http://dx.doi.org/10.1016/j.radonc.2011.07.015

Figures

Figure 1. Location of 4D box that is followed by a camera to account for patient breathing.

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Figure 2. Patient 1 axial isodose lines showing 5040 cGy (purple), 4500 cGy (light blue), and 2000 cGy (orange), around the initial PTV (red).

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Figure 3. Patient 1 coronal isodose lines showing 5040 cGy (purple), 4500 cGy (light blue), and 2000 cGy (orange), around the initial PTV (red).

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Figure 4. Patient 1 DVH showing the PTVs covered by at least 95% of the prescription dose. The spinal cord < 4500 cGy, lungs < 20% at 2000 cGy, and heart under 40% at 4000 cGy.

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Figure 5. Patient 2 axial isodose lines showing 5040 cGy (light blue), 4788 cGy (green), 4500 cGy (dark blue), and 2000 cGy (yellow) around the initial PTV (purple).

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Figure 6. Patient 2 coronal isodose lines showing 5040 cGy (light blue), 4788 cGy (green), 4500 cGy (dark blue), and 2000 cGy (yellow) around the initial PTV (purple).

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Figure 7. Patient 2 DVH showing PTVs covered by at least 95% of the prescription dose, the spinal cord < 4500 cGy, lungs > 20% at 2000 cGy, and heart < 40% at 4000 cGy.

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Figure 8. Patient 3 superior axial isodose lines showing 5292 cGy (pink), 5040 cGy (yellow), 4788 cGy (green), and 4533 cGy (interior dark blue) around the PTV (purple).

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Figure 9. Patient 3 inferior axial isodose lines showing 5292 cGy (pink), 5040 cGy (yellow), 4788 cGy (green), and 4533 cGy (interior dark blue) around the PTV (purple).

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Figure 10. Patient 3 DVH showing 98% of PTV45 being covered with 95% of the prescription dose, 100% of PTV50.4 being covered with 95% of the prescription dose, 15% of the heart receiving 4000 cGy, 26% of the lungs minus PTV receiving 2000 cGy, and the spinal cord under tolerance of 4500 cGy.

19 Tables

PTV Coverage and Critical Structure Evaluation Patient 1 PTV Coverage (100% PTV covered by 95% of dose) Heart (40% of heart receives 4000 cGy) Heart (Maximum Dose 5200 cGy) Whole Lungs (20% of lungs receives 2000 cGy) Spinal Cord (Maximum Dose 4500 cGy) Overall Hot Spot (110% of prescription dose) 100% PTV 13% of heart 5298 cGy 11% of lungs 4410 cGy 106% Patient 2 99.5% PTV 8% of heart 5207 cGy 22% of lungs 3768 cGy 107% Patient 3 99% PTV 15% of heart 5562 cGy 26% of lungs 3406 cGy 109%

Table 1. Comparison of PTV coverage and normal structure doses for the 3 patients in the study.