1

3D Treatment Planning for Distal Esophageal Adenocarcinoma: A Case Study Authors: George Spencer Arnould, B.S. R.T.(T), Nishele Lenards, M.S., CMD, R.T.(R)(T), FAAMD Medical Dosimetry Program at the University of Wisconsin - La Crosse, WI and The University of Michigan Radiation Oncology, Ann Arbor, MI 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 field-in-field segments treating the distal esophagus; Patient 2 represents a treatment plan containing 7 fields, 2 of which comprise field-in-field segments treating the distal esophagus and gastroesophageal (GE) junction; Patient 3 represents a treatment plan containing a four-field box technique treating 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 the 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

2 providing adequate and conformal dose coverage to the PTV, while sparing higher doses to critical structures. Key Words: Gastroesophageal (GE) Junction, 3D Conformal Radiation Therapy (3DCRT), Distal Esophagus Adenocarcinoma 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 a single modality including surgery or radiation therapy alone, or treated with a combined approach such as radiation therapy and surgery, chemotherapy and surgery, and 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 have the potential to increase survival by decreasing distant metastases and eliminating the local disease by using surgery after chemoradiation.3 The most common approach toward radiation fractionation for esophageal cancer has been in the range of 1.5 to 2.0 Gy per fx delivered once per day for a total of 5 weeks. The total dose to the PTV 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 to normal tissue. Although intensity modulated radiation therapy (IMRT) has recently been used for treatment planning, the 4 patient cases were planned with specific beam arrangements and traditional 3DCRT for comparison.

3 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 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 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 patient was computed tomography (CT) scanned in the supine position, lying in a Civco thorax board. Arms were raised above the head and placed in specific locations for added support. An egg crate cushion and knee-fix were used for additional support and functionality. All patients were CT referenced at the same location (at xiphoid tip) and given clear tegaderm stickers to cover the reference and 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 the volume into another structure. The voxel expander was used to obtain a margin of 1 cm circumferentially and 1.5 cm superior-

4 inferior to produce a PTV. Because of the variation in patient anatomy, some of the patient PTVs extended into the GE junction whereas others did not. The volumes were completed and the normal structures were 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 prescription was to treat 50.4 Gy in 1.8 Gy fx daily. The patients received approximately 5.6 weeks of radiation therapy or 28 treatment sessions given 5 days per week. Each of these cases were planned with a specific 3DCRT 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. 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 treatment plan, the medical dosimetrist had to adhere to the radiation oncologists planning guidelines that 100% of the PTV1-P1-6 must be covered by at least 95% of the dose (Figure 1). Other objectives included: mean left and right lung dose <20 Gy, left and right lung NTCP <15%, maximum spinal cord dose of 45 Gy, maximum heart of 55 Gy, and mean liver dose of 20 Gy. The treatment plan consisted of having 6 different fields, 2 of which were in-field segments added to achieve correct target dose. The medical dosimetrist used a 0.7 cm blocking margin on each field and also weighted dose to each field compensating 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 an adequate treatment plan, the medical dosimetrist had to adhere to the radiation oncologists planning guidelines that 99% of PTV2-P2-7 must be covered by at least 95% of the dose. Since the target

5 volume in this case was much more inferior, the dose constraints in the planning directive were different (Figure 2). The objectives included: mean left and right lung dose < 18 Gy, left and right lung NTCP <15 Gy, maximum spinal cord dose of 45 Gy, maximum heart dose of 55 Gy, mean liver of 20 Gy, and the right and left kidneys <8 Gy. The treatment plan for Patient 2 consisted of 7 fields directed at the target from completely different angles. This method allows dose to be manipulated around the PTV2-P2-7 in an 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 weighted dose to each field compensating 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 radiation oncologists planning guidelines that 100% of PTV3-P34 must

be covered by at least 95% of the dose (Figure 3). Other objectives included: left and right

mean lung dose <20 Gy, left and right lung NTCP <15%, maximum heart dose of 50 Gy, spinal cord dose <45 Gy, mean liver dose of 20 Gy, and the right and left kidneys <8 Gy. The treatment plan for this case consisted of 4 total fields. The treatment technique used was a 4field box in order to encompass the entire target volume that expanded steeply into the GE junction. The medical dosimetrist also used a 0.8 cm blocking margin around the PTV3-P3-4 and weighted dose to the AP/PA fields 50% higher than both the lateral angles. For Patient 4, the planning directive prescription was written to treat the middle to distal esophagus and GE junction. In order to achieve an adequate treatment plan, the medical dosimetrist had to adhere to the radiation oncologists planning guidelines that 99% of PTV4-P4-8 must be covered by at least 95% of the dose (Figure 4). The objectives included: mean left and right lung dose <20 Gy, left and right lung NTCP <15%, maximum heart dose of 55 Gy, spinal cord dose <45 Gy, mean liver dose of 20 Gy, and the right and left kidneys <8 Gy. The treatment plan for this case consisted of 8 fields. The medical dosimetrist used a 0.7 cm blocking margin around the PTV4-P4-8 and weighted dose nearly equal for each non-segmented field and marginal weighting for each segmented field.

6 In evaluating the cases, each PTV was slightly different from each other when comparing not only the size, but also the volume and location. Due to the location along the diaphragm, the distal esophagus moves in all directions. When planning for these cases, the physician has to account for the possibility of interfractional displacement within the GE junction. Although this was never an issue in any of these cases, the process is most often solved with the use of 4 dimensional CT scans which can account for respiratory motion and allow views in all breathing phases. According to a study by Wang et al,5 there is a substantial change in the position of the distal esophagus, within and between fractions, related to respiration. There can be considerable difference in the treatment planning compared to the actual treatments being administered. To account for this motion without utilizing a 4DCT, the physician provided expansion margins on the CTV to create an ITV. This process creates extra margin around the PTV in order to maintain coverage to the tumor volume. A study by Yaremko et al6 provided results on average tumor motion in all directions. They found that a radial margin of 0.6 cm and axial margin of 1.8 cm could be used to create an ITV. This technique not only accounts for respiratory motion and tumor movement along the diaphragm, but also increases treatment localization and better targeting. 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. For Patient 1, every dose objective and constraint was achieved (Figure 5). The overall maximum dose to the PTV1-P1-6 was 54.4 Gy with 100% of the PTV receiving 95% of the dose or greater. The mean lung dose for both right and left lungs was 13.2 Gy with a 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, the liver and kidneys still received 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 constraint (Figure 6). The maximum dose to the PTV2-P2-7 was 55.7 Gy, with 99% of the PTV receiving 95% of the dose or greater. The mean lung dose for both the right and left lungs was 14.7 Gy with a NTCP of

7 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 close 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 the other patient cases and more similar to Patient 4 data. As Figure 7 demonstrates, the maximum dose to the PTV3-P3-4 was 55.3 Gy with 99% of the PTV receiving 95% of the dose or greater. The mean lung dose for both right and left lungs was 15 Gy with a 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 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 constraint (Figure 8). This plan was much higher in every category compared to the other patient cases possibly 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 receiving 95% of the dose or greater. The mean lung dose for both the right and left lungs was 14.7 Gy with a 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 were close to the treatment area, they were also evaluated 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. In analyzing Table 1, both the maximum and mean doses to the PTV structures were within 1-2 Gy of each other. There were major differences in the number and angle of beams used among patient cases but the total dose was only a few percent different from one another. 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 determined 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. Conclusion

8 In each case, 95% of the PTV was covered by at least 95% of the dose. The dose coverage for all 4 patient cases was acceptable when following and adhering to the physician guidelines in the treatment of esophageal cancer. The standard dose for esophageal cancer is typically 50.4 Gy, depending on whether the patient is a viable candidate for pre or postoperative surgery and chemotherapy. Minsky et al7 have shown through research that any type of intensification of the radiation to higher doses, including 64.8 Gy, does not improve local or regional control, and therein would not be recommended. Although the Minsky et al7 study demonstrated the comparison in higher fractionated doses versus standard fractionated dose, there needs to be a consideration for possible set-up error or daily variability during treatment. Chen et al8 demonstrated that image-guided radiation therapy (IGRT) using megavoltage (MV) x-ray can effectively detect set-up errors and thereby reduce PTV margins. This technique also reduces the radiation dose to critical organs and provides the possibility of dose escalation. Although 3DCRT for distal esophageal cancer may or may not be overshadowed by future IMRT or volumetric modulated arc therapy (VMAT), it is still a viable treatment option for esophageal cancer. In a study by Patil et al,9 VMAT, IMRT, and 3DCRT were compared and defined with obvious results. Although the IMRT and VMAT plans had better dose conformity around the target volume, both had much higher doses to the lungs compared to the 3DCRT plan.7 The use of 3DCRT can prove viable, considering it has less of a time constraint in actual treatment planning and quality assurance (QA). Although patients in this case study had adequate treatments for their esophageal cancers, some had much higher doses to critical structures than the others. In Table 2, 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 approximately 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 3DCRT esophageal cases can deliver more than adequate dose to the PTV as well as sparing high dose to critical structures. Although this idea could also

9 be said about the use of IMRT or VMAT, the use of 3DCRT treatment planning provides the same basic constraint benefits with less QA, less calculation time, and overall quicker turnaround time for the patient. When evaluating the importance of these factors to both the patient and physician, perhaps one method is preferred over another depending on patient specific details. This concept of using 3DCRT techniques instead of other modalities is important because it showed that although we are moving towards more advanced technology in radiation treatments, the use of classic 3DCRT techniques still have a place in modern day distal esophageal cancer treatment. From the cases presented, the differences in beam arrangement and number of beams used in planning depends upon the GTV location, previous treatment, patient anatomy, and dose constraints given for critical structures during the treatment planning process. Although most of these factors are linked with the planning results, there is a need for more data collection and analysis for 3DCRT planning in the treatment of distal esophageal cancers. Future research with more patients and outcomes would be ideal to evaluate dose toxicity to critical structures due to the 3DCRT planning technique.

10

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):102-111. 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):e273-280. http://dx.doi.org/10.1016/j.ijrobp.2011.12.048 6. Yaremko BP, Guerrero TM, McAleer MF, et al. Determination of respiratory motion for distal esophagus cancer using four-dimensional computed tomography. Int J Rad Onc. 2008;70(1):145-153. http://dx.doi.org/10.1016/j.ijrobp.2007.05.031 7. 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):1167-1174. http://dx.doi.org/10.1200/JCO.20.5.1167 8. 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):1537-1545. http://dx.doi.org/10.1016/j.ijrobp.2007.04.023 9. 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. http://dx.doi.org/10.1016/j.ijrobp.2011.06.530

11 Figures

Figure 1. Central axis CT axial cut showing the beam angles and dose distribution around the PTV1-P1-6. The orange 47.8 Gy line indicated the 95% coverage line.

12

Figure 2. Central axis CT axial cut showing the dose distribution around the PTV2-P2-7. The orange 47.8 Gy line indicated the 95% coverage line.

13

Figure 3. Central axis CT axial cut showing the dose distribution around the PTV3-P3-4. The orange 47.8 Gy line indicated the 95% coverage line.

14

Figure 4. Central axis CT axial cut showing the dose distribution around the PTV4-P4-8. The orange 47.8 Gy line indicated the 95% coverage line.

15

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

16

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

17

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

18

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

19 Tables Case Anatomic Site Patient 1 Middle Lower Distal Esophagus Beam Energy PTV Rx Dose Number of Beams Gantry Angles 6/16x 50.4 Gy 6 0, 125, 180, 300 Plan Technique 3DCRT Patient 2 Lower Distal Esophagus and GE Junction 6/16x 50.4 Gy 7 0, 60, 120, 180, 270, 305 3DCRT Patient 3 Lower Distal Esophagus and GE Junction 6/16x 50.4 Gy 4 0, 90, 180, 270 3DCRT Patient 4 Middle to Distal Esophagus and GE Junction 6/16x 50.4 Gy 8 0, 102, 180 268, 3DCRT

Table 1. Prescription and planning traits for each patient

20

Case Mean Lung Dose L/R NTCP %

Patient 1 13.2 Gy

Patient 2 14.7 Gy

Patient 3 15 Gy

Patient 4 14.7 Gy

4.59%

8.53%

9.72%

11.2%

Mean Heart Dose

33.2 Gy

27 Gy

24 Gy

32.5 Gy

Max Spinal Cord Dose Mean Liver Dose

42.3 Gy

35 Gy

37 Gy

43.9 Gy

6.2 Gy

13.3 Gy

15.3 Gy

15.3 Gy

Mean Kidney Dose L/R

0.03 Gy

1.18 Gy

7.2 Gy

1.51 Gy

Table 2. Differences in critical structure doses compared with each patient