1 Spencer Arnould Comprehensive Case Study February 3, 2014 3D Treatment Planning for Distal Esophageal Adenocarcinoma Abstract: Introduction:

This study aims to evaluate the treatment planning technique of treating distal esophageal adenocarcinoma over the course of four different patients. This technique was compared within the same anatomical site, cancer histology, and treatment modality for an overall comprehensive study of distal esophageal adenocarcinoma. Case Description: The treatment technique of planning for distal esophageal adenocarcinoma is demonstrated in the following 4 cases: Patient 1 represents a treatment plan containing 6 fields, 2 of which comprise of field-in-field segments treating the distal esophagus: Patient 2 represents a treatment plan containing 7 fields, 2 of which comprise of field-in-field segments treating the distal esophagus and gastroesophageal (GE) junction: and Patient 3 represents a treatment plan containing a four-field box technique treating both the distal esophagus and GE junction; and Patient 4 represents a treatment plan containing 8 fields, 4 of which comprise field-in-field segments treating the middle to distal esophagus and GE junction. All of these cases involve treating the lower distal esophagus to a total dose of 50.4 Gray (Gy) in 1.8 Gy per fraction (fx). These cases demonstrate the different methods, techniques, and procedures associated with developing adequate radiation treatment plans for distal esophageal adenocarcinoma treatment. Conclusion: All plans were evaluated and assessed on how well the planning objectives were met using the 4 different 3D conformal radiation therapy treatment plans. The plans were evaluated individually based on 95% dose coverage to the planning target volume (PTV), maximum and mean doses to the spinal cord and heart, the normal tissue complication probability (NTCP) of the lungs, and a dose volume histogram (DVH). Treatment of distal esophageal adenocarcinoma in these cases are presented and reinforced by additional literature as providing adequate and conformal dose coverage to the PTV, while sparing higher doses to critical structures.

2 Key Words: Gastrointestinal (GI), Gastroesophageal (GE), Esophagogastroduodenoscopy (EGD), 3D Conformal Radiation Therapy, Dose Volume Histogram (DVH). Introduction The esophagus is composed of a thin-walled, hollow tube that has an average length of 25 centimeters (cm).1 The American Joint Committee on Cancer states that the esophagus is anatomically divided into four regions: cervical, upper thoracic, midthoracic, and lower thoracic.1 The two main histology groups of esophageal cancer include squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma presents most often within the upper 2/3 region of the esophagus and adenocarcinoma normally presents within the distal 1/3 of the esophagus. Although squamous cell carcinoma is a large contributor, adenocarcinoma now accounts for 75% of all esophageal cancers in Caucasian males.1 There are a variety of different methods to treat the esophagus. It can be treated with single modalities including surgery or radiation therapy alone, or treated with a combined approach including radiation therapy and surgery, chemotherapy and surgery, and also chemo-radiotherapy prior to surgery. From a radiotherapeutic standpoint, preoperative irradiation is advantageous compared to postoperative irradiation because of the intact vascular supply allowing for improved oxygenation in the blood.2 The use of all three modalities-chemotherapy, radiation therapy, and surgery have the potential to increase survival by decreasing distant metastasis and eliminating the local disease with surgery after chemoradiation.3 The most common approach toward radiation fractionation when it comes to esophageal cancer has been in the range of 1.5 to 2.0 Gray Gy per fx delivered once a day for a total of 5 weeks. The total dose to the planning target volume (PTV) depending on physician choice is typically in the range of 50-55 Gy.1 This method of fractionation has proven to be the standard of treatment in radiation oncology to control disease while also preventing dose toxicity and complications when receiving radiation therapy. The typical course of radiation therapy for these 4 patient cases involved using a 3D conformal therapy technique, which follows the basic standard of treatment fractionation. Although intensity modulated radiation therapy (IMRT) has recently been used for treatment planning,

3 these 4 patient cases were planned with specific beam arrangements and traditional 3D conformal radiotherapy for comparison. They are all prescribing to 50.4 Gy in 1.8 Gy per fx for a total treatment of 28 scheduled appointments. Depending on the start date for each patient, the overall treatment duration lasted about 5.6 weeks in total, before the physician reassessed the patients condition, outlook, and current prognosis. Each case presented was planned with specific 3D conformal radiation therapy technique in an attempt to evaluate and assess the need for either additional or fewer beams throughout a treatment plan. The plans were evaluated individually based on 95% dose coverage to the PTV, maximum and mean doses to the spinal cord and heart, the NTCP of the lungs, and a DVH. For ease of discussion and to make comparative reference to PTVs and patients, the following nomenclature will be used: Example: PTV1 for Patient 1 used 6 fields in total for the treatment and will be written PTV1-P1-6 with similar nomenclature used for all cases to describe specific patients and their PTVs. Case Description Patient Selection All patient cases were evaluated based on the middle to distal esophagus disease in order to demonstrate and analyze the differences in radiation therapy treatment planning. Each case, although slightly different in tumor size, represents treatment to the distal esophagus and GE junction. The optimal coordination of surgery, chemotherapy, and radiation therapy continues to be studied by institutions on the basis of patients with GE cancers.4 All patients presented within this case study range in age from 55-74. They all presented to medical oncology with similar symptoms including heartburn, dysphagia, weight loss, and epigastric pain in the retrosternal area. They also were diagnosed with either stage IIIA or stage IIIB (stage 3 primary tumor), N1 or N2 (stage 1 or 2 regional lymph nodes), and M0 (no metastasis present). After the diagnosis, the patients radiation oncologist recommended that they receive both chemotherapy and radiation therapy. In some cases depending on diagnosis, the radiation oncologist will recommend surgical resection before or after the dual modality of

4 chemotherapy and radiation therapy. In patients who are medically and surgically fit, either chemo-radiotherapy alone or preoperative chemo-radiotherapy followed by surgery can be considered.1 Patient Set-up Each and every patient that was followed throughout the case study analysis was set-up in a specialized way. Every patient was computed tomography (CT) scanned in the supine position, lying in a Civco thorax board. Their arms were raised above the head and placed in specific locations for added support. They all used the same egg crate cushion and knee-fix for additional support and functionality. They were all CT referenced at the same location (at xiphoid tip) and given clear tegaderm stickers to cover not only the reference marks, but also leveling marks placed on the body. Target Delineation The Varian Eclipse contouring system and The University of Michigan Plan (UMPLAN) software were used throughout the treatment planning process to delineate targets and design treatment plans. For all patients, the radiation oncologist contoured the gross tumor volume (GTV) and outlined the planning directive to expand this volume into another structure. The voxel expander was used to obtain a margin for structure of 1 cm circumferentially, and 1.5 cm superior-inferior to produce a PTV. Because of the variation in patient anatomy, some patients PTV extent did not enter the GE junction, whereas others extended down through the GE junction area. The volumes were then completed and the normal structures could then be added. The normal structures defined within the planning directive included the lungs, heart, spinal cord, liver, and both kidneys. Treatment Planning For all 4 cases presented, the total prescribed dose was recommended to treat 50.4 Gy in 1.8 Gy fx daily. This recommendation falls within the patients receiving 5.6 weeks of radiation therapy or 28 treatment sessions given 5 days a week. For Patient 1, the planning directive dictated the treatment of the lower middle to distal portion of the esophagus. In order to achieve an adequate

5 treatment plan, the medical dosimetrist had to adhere to the planning guidelines that the radiation oncologist set of having 100% of PTV1-P1-6 covered by at least 95% of the dose (Figures 1). Other objectives to be included: left and right lung mean dose of <20 Gy, left and right lung NTCP of <15%, spinal cord maximum dose to 45 Gy, heart dose to a maximum of 55 Gy, liver to a mean dose of 20 Gy. The treatment plan consisted of having 6 different fields, 2 of which were in-field segments added to achieve correct dose to the target. The medical dosimetrist used a 0.7 cm blocking margin on each field and also dose weighted each field to compensate for coverage around the PTV1-P1-6. For Patient 2, the dose objectives were set in the planning directive. The directive dictated the treatment of the lower distal esophagus and GE junction. In order to achieve and adequate treatment plan, the medical dosimetrist had to adhere to the planning guidelines that the radiation oncologist set of having 99% of PTV2-P2-7 covered by at least 95% of the dose. Since the target volume in this specific case was much more inferior, the dose constraints in the planning directive were a bit different (Figure 2). The objectives to be included: left and right lung mean dose of < 18 Gy, left and right lung NTCP of <15 Gy, spinal cord maximum dose to 45 Gy, heart dose to a maximum of 55 Gy, liver to a mean dose of 20 Gy, and the right and left kidneys to <8 Gy. The treatment plan for Patient 2 consisted of having 7 fields directed at the target from completely different angles. This method allows dose to be manipulated around the PTV2-P2-7 in attempt to surround the structure with at least 95% dose coverage. The medical dosimetrist utilized an average of 0.7 cm blocking margin around the tumor and also dose weighted each field to compensate for coverage around the target volume. For Patient 3, the planning directive prescription was written for the treatment of the lower distal esophagus and GE junction. In order to achieve a sufficient treatment plan, the medical dosimetrist had to adhere to the directive guidelines that the radiation oncologist set of having 100% of PTV3-P3-4 covered by at least 95% of the dose (Figure 3). Some of the other objective to be included comprise: left and right mean lung dose of <20 Gy, left and right lung NTCP of <15%, heart dose to a maximum of 50 Gy, spinal cord dose to <45 Gy, liver to a mean dose of 20 Gy, and the right and left kidneys to <8 Gy. The treatment plan for this case consisted of 4 total fields. The treatment technique used was a 4-field box in order to encompass the entire target volume, which expanded steeply into the GE junction. The medical dosimetrist also used

6 a 0.8 cm blocking margin around the PTV3-P3-4 and dose weighted the fields to a ratio of anteriorposterior (AP) posterior-anterior (PA) 50% higher than both the lateral angles. For Patient 4, the planning directive prescription was written for the treatment of middle to distal esophagus and GE junction. In order to achieve an adequate treatment plan, the medical dosimetrist had to adhere to the planning guidelines that the radiation oncologist set of having 99% of PTV4-P4-8 covered by at least 95% of the dose (Figure 4). The objective included: left and right mean lung dose of <20Gy, left and right lung NTCP of <15%, heart dose to a maximum of 55 Gy, spinal cord dose to <45Gy, liver to a mean dose of 20 Gy, and the right and left kidneys to <8Gy. The treatment plan for this case consisted of 8 total fields. The treatment technique used was almost a 4-field box with the exception of oblique lateral fields. The medical dosimetrist also used a 0.7 cm blocking margin around the PTV4-P4-8 and dose weighted the fields to almost equal weight for each non-segmented field, and marginal weight for each segmented field. For each case study, it was the medical dosimetrist plan to maintain an adherence to the planning directive. For almost every case, the dose objective was to cover 100% of the PTV with 95% of the dose. Although this was one of the main objectives associated with each treatment plan, the higher priority was to eliminate high dose to the surrounding critical structures. Since the esophagus lies within an air cavity and is surrounded by the heart and spinal cord, it was extremely important to monitor these dose characteristics to maintain an adherence towards dose constraints. The ultimate goal when treatment planning with 3D conformal radiation therapy is to gain as much target coverage as achievable while preserving as much normal tissue and critical structure dose as possible. Plan Analysis & Evaluation The 4 patient cases demonstrated different 3D conformal planning techniques therefore individual analysis and evaluation was performed to compare planning dose objectives, dose constraints, and dose to critical structures. A summary of the dose prescription, mean dose, and maximum dose limits are presented in Tables 1 and 2.

7 For Patient 1, every dose objective and dose constraint was achieved (Figure 5). The overall maximum dose to the PTV1-P1-6 was 54.4 Gy, with 100% of the PTV getting 95% of the dose or higher. The mean lung dose for both right and left lungs was 13.2 Gy, with an NTCP of 4.59%. The spinal cord received a maximum dose of 42.3 Gy, and the heart received a mean dose of 33.2 Gy. Although the PTV1-P1-6 was much more superior to both the liver and kidneys, they still gained some dose. The liver received a mean dose of 6.2 Gy and both kidneys received a combined mean dose of 0.03 Gy. The plan for Patient 2 also achieved every dose objective and dose constraint (Figure 6). The maximum dose to the PTV2-P2-7 was 55.7 Gy, with 99% of the PTV getting 95% of the dose or higher. The mean lung dose for both the right and left lungs was 14.7 Gy, with and NTCP of 8.53%. The heart received a mean dose of 27 Gy, and the spinal cord received a maximum dose of 35 Gy. Since both the liver and kidneys were within closer proximity of the treatment fields, they were also examined for dose limitations. The liver received a mean dose of 13.3 Gy and both kidneys received a combined mean dose of 1.18 Gy. For Patient 3, although the fields were limited to only 4 beam angles, the dose limits were slightly higher than most of the case studies, and also closer to Patient 4 data. As Figure 7 presents, the maximum dose to the PTV3-P3-4 was 55.3 Gy, with 99% of the PTV getting 95% of the dose or higher. The mean lung dose for both right and left lungs was 15 Gy, with an NTCP of 9.72%. The heart received a mean dose of 24 Gy, and the spinal cord received a maximum dose of 37 Gy. Since both the liver and kidneys were again in close proximity to the treatment fields, they were examined for dose limitations. The liver received a mean dose of 15.3 Gy, and both kidneys received a combined mean dose of 7.2 Gy. The plan for Patient 4 also achieved every dose objective and dose constraint (Figure 8). This plan was much higher in every category than the other studies, which could possibly be due to the anatomical location and treatment volume. The maximum dose to the PTV4-P4-8 was 54.6 Gy, with 100% of the PTV getting 95% of the dose or higher. The mean lung dose for both the right and left lungs was 14.7 Gy, with and NTCP of 11.2%. The heart received a mean dose of 32.5 Gy, and the spinal cord received a maximum dose of 43.9 Gy. Since both the liver and kidneys

8 were close to the treatment area, they were also checked as a dose constraint. The liver received a mean dose of 15.3 Gy and both kidneys received a combined mean dose of 1.51 Gy. Although each plan fell within all clinical tolerances, they were noticeably different in not only the planning method (3D conformal radiation therapy treatment technique using a different number of beams), but also different in the beam angles used. Each PTV was also slightly different from the next when comparing not only the size, but also the volume and location. When planning for the distal esophagus and GE junction, the medical dosimetrist had to consider the interfractional displacement in the GE junction. According to a study by Wang et al, there is a substantial change in the position of the distal esophagus, not only within fx, but also between fx related to respiration.5 This showing how there can be a considerable difference in the treatment planning compared to the actual treatments being administered. In analyzing Table 1, both the maximum and mean doses to the PTV structures were within 1-2 Gy of each other. Although there was a greater difference in the amount of beams and beam angles used from patient to patient, the total dose only ranges a few percent different from one to the other. The main differences seen in the amount of beam angles and treatment beams used are also correlated to the dose planning objectives and dose constraints set out by the radiation oncologist. In Table 2, this relationship is shown as each patient has different dosing limits that are directly related to the amount of beams, beam angles, dose weighting factor, and also specific patient anatomy. The monitor unit (MU) validation of all 3D conformal radiation therapy plans presented in each of these 4 case studies passed both an independent UMPLAN check and also a mandatory physics check that were within the departments tolerance of 5%. Conclusion In each case, 95% of the PTV was covered by at least 95% of the dose. This dose coverage for all 4 patients within these cases was perfectly acceptable when it comes to adequately following and adhering to the departmental guidelines in treatments for esophageal cancer. The standard dose for esophageal cancer included in all modalities is typically 50.4 Gy, depending on whether the patient is a viable candidate for pre or postoperative surgery and chemotherapy. Minsky et al6 have shown through patient study research that any type of intensification of the radiation

9 dose to higher doses, including 64.8 Gy within the study, does not improve local/regional control or survival, and therein would not be recommended. Although this study shows the comparison in higher fractionated doses versus standard fractionated dose, it also needs to consider the dose conformity, tissue sparing, and possible setup error or daily variability during treatment. In a study by Chen et al,7 image-guided radiation therapy (IGRT) using megavoltage (MV) x-ray can effectively detect set-up errors and thereby reduce PTV margins. This technique will also reduce the radiation dose to critical organs and lead to the possibility of dose escalation. Although these types of 3D conformal radiation therapy treatments for distal esophageal cancer may or may not be overshadowed by future IMRT or volumetric modulated arc therapy (VMAT), they still prove to be a viable tool for treatment. In a study done by Patil et al, 8 all three modalities were compared and defined with obvious results. Although the IMRT and VMAT plans had better dose conformity around the target volume, they both had much higher doses to the lungs compared to the 3D conformal radiation therapy plan.7 In many cases, the use of 3D conformal radiation therapy can prove just as viable as any other, considering it has less of a time constraint in actual treatment planning and quality assurance (QA). Although all patients had adequate treatments for their esophageal cancers, some had much higher doses to critical structures than the others. From Table 2, it is shown that Patient 1 had much lower mean lung dose and NTCP than any of the other patients, but failed to achieve a lower dose on the heart and spinal cord. Patient 2 had a variable plan, showing marginal dose to all critical structures, but with the cost of using 7 total beams. Patient 3 had considerably the same results as Patient 2 but with the use of only 4 total beams and a slightly higher dose to the kidneys. Patient 4 had an adequate treatment plan, due to the location and tumor extension throughout the chest, with the cost of 8 total beams causing higher dose to critical structures. The treatment planning process for 3D conformal radiation therapy esophageal cases can deliver more than adequate dose to the PTV as well as sparing high dose to critical structures. From the cases presented, the differences in beam arrangement and number of beams used in planning depends upon the GTV location, previous treatment, specific patient anatomy, and dose constraints given on critical structures for the treatment planning process. Although most of these factors are linked with the planning results, there is always room for more data collection

10 and analysis on treatment planning for 3D conformal radiation therapy distal esophageal cancers. A future case study on more patients and outcomes would be ideal to explain more on the topic of dose toxicity to critical structures due to the 3D conformal radiation therapy planning technique.

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Figures

Figure 1. Central Axis (CA) axial cut showing the beam angles and dose distribution around the PTV1-P1-6.

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Figure 2. CA axial cut showing the dose distribution around the PTV2-P2-7.

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Figure 3. CA axial cut showing the dose distribution around the PTV3-P3-4.

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Figure 4. CA axial cut showing the dose distribution around the PTV4-P4-8. The Orange 47.8 Gy line indicated the 95% coverage line.

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Figure 5. DVH of PTV1-P1-6 showing the spinal cord, heart, liver, kidneys, and PTV.

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Figure 6. DVH of PTV2-P2-7 showing the spinal cord, heart, liver, kidneys, and PTV.

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Figure 7. DVH of PTV3-P3-4 showing the spinal cord, heart, liver, kidneys, and PTV.

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Figure 8. DVH of PTV4-P4-8 showing the spinal cord, heart, liver, kidneys, and PTV.

19 Tables Case Site Patient 1 Middle Lower Distal Esophagus Patient 2 Lower Distal Esophagus and GE Junction Patient 3 Lower Distal Esophagus and GE Junction Patient 4 Middle to Distal Esophagus and GE Junction

Beam Energy

6/16x

6/16x

6/16x

6/16x

Dose Prescribed 50.4 Gy to PTV

50.4 Gy

50.4 Gy

50.4 Gy

Number of Beams Gantry Angles

0, 125, 180, 300

0, 60, 120, 180, 270, 305

0, 90, 180, 270

0, 102, 180 268,

Planning

3D-CRT

3D-CRT

3D-CRT

3D-CRT

Table 1. This table lists the prescription and different planning traits for each patient.

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Case Mean Lung Dose L/R NTCP % Mean Heart Dose Max Spinal Cord Dose Mean Liver Dose Mean Kidney Dose L/R

Patient 1 13.2 Gy

Patient 2 14.7 Gy

Patient 3 15 Gy

Patient 4 14.7 Gy

4.59 % 33.2 Gy

8.53 % 27 Gy

9.72 % 24 Gy

11.2 % 32.5 Gy

42.3 Gy

35 Gy

37 Gy

43.9 Gy

6.2 Gy

13.3 Gy

15.3 Gy

15.3 Gy

0.03 Gy

1.18 Gy

7.2 Gy

1.51 Gy

Table 2. This table lists the differences in critical structures doses compared with each patient.

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References 1. Chao K, Perez C, Brady L. Esophagus. In: Chao K, Perez C, Brady L, Pine JL, eds. Radiation Oncology Management Decisions. 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2011:357-371. 2. Jabbour SK, Thomas CR. Radiation therapy in the postoperative management of esophageal cancer. J Gastroint Oncol. 2010;1(2):102-11. doi:10.3978/j.issn.2078-6891.2010.013. 3. Heath E, Heitmiller R, Forastiere A. Esophageal Cancer. In: Hall L, ed. Clinical Oncology. Atlanta, GA: American Cancer Society; 2001:331-343. 4. Callister MD, Ashman JB. Cancers of the Gastrointestinal Tract. In: Pine JW, ed. Treatment Planning in Radiation Oncology. 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2012:449-473. 5. Wang J, Lin S, Dong L, et al. Quantifying the interfractional displacement of the gastroesophageal junction during radiation therapy for esophageal cancer. Int J Rad Onc. 2012;83(2):e273-80. doi:10.1016/j.ijrobp.2011.12.048. 6. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (RTOG 94-05) Phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J of Clin Onc. 2001;20(5):1167-74. doi:10.1200/jco.20.5.1167. 7. Chen YJ, Han C, Schultheiss T, et al. Setup variations in radiotherapy of esophageal cancer: evaluation by daily megavoltage computed tomographic localization. Int J Rad Onc. 2007;68(5):1537-45. doi:10.1016/j.ijrobp.2007.04.023. 8. Patil SS, Hackett RA, Hales LD, et al. A comparison of VMAT, IMRT, and 3DCRT in the treatment planning of patients with distal esophageal cancer. Int J Rad Onc. 2011;81(2):S324-S325. doi: 10.1016/j.ijrobp.2011.06.530.