1 Eyob Mathias August Comprehensive Case Study July 19, 2013 Evaluation of Three-Dimensional Conformal Radiation Therapy (3DCRT),

Intensity Modulation Radiation Therapy (IMRT), and parallel AP/PA Planning Techniques in Lung cancer irradiation. Abstract: Introduction: The purpose of this study is to evaluate, compare and contrast 3DCRT, IMRT, and AP/PA treatment planning techniques for the treatment of lung cancer. Case Description: The treatment planning techniques of 3DCRT, IMRT and AP/PA will be demonstrated in the following three case studies. For patient 1, 3DCRT prone lung irradiation technique will be evaluated. Patient 2 will examine an IMRT technique that was utilized to treat right upper lobe (RUL) lung region. Patient 3 will investigate the use of AP/PA technique to irradiate right lower lobe (RLL) lung lesion. Each selected patients have a lung lesion located in the same region of interest. Conclusion: All plans were evaluated by the radiation oncologist for adequate dose coverage to the Gross tumor volume (GTV). Each plan was evaluated based on the dose given to the organs at risk (OR). The dose to the heart, spinal cord and total lung volume were compared between the three treatment techniques. The use of 3DCRT, with only 3 beam angles, has the ability to reduce normal-tissue toxicity, but has limited potential for dose escalation beyond a certain limit.1 IMRT is of additional value (compared to 3DCRT and AP/PA technique) in nodenegative cases, but is beneficial in node-positive cases and in cases with target volumes close to the spinal cord. Key Words: Adenocarcinoma of the lung, stage III lung cancer, IMRT, 3DCRT, AP/PA treatment technique. Introduction: Lung cancer radiation therapy (RT) treatment represents an ongoing challenge for radiation oncologists around the world.1 The radiation therapy approach in the treatment of lung cancers has consisted of different techniques that have been developed to provide a conformal

2 dose distribution within the target volume and spare the surrounding critical structures. Now that most RT facilities have the technology to perform IMRT and 3DCRT planning, the options for beam arrangement as well as treatment fiend numbers have significantly multiplied.1 Complex treatment techniques in lung irradiation consist of stereotactic body radiation therapy (SBRT) and inverse-planned IMRT. Intensity modulated radiation therapy offers wide range of gantry angle options in addition to improving dose homogeneity and decreased OR irradiation. In treating lung cancer, conventional AP/PA fields irradiate portions of the underlying healthy lung and surrounding critical structures, which may lead to dose toxicity. The use of IMRT for lung cancer has demonstrated that OR like the heart and total lung can be spared more effectively. This study will demonstrate three different techniques of RT used to treat adenocarcinoma of the lung and determine their efficacy in meeting multiple normal-tissue constraints while maximizing tumor coverage. Methods and materials: A total of three patients were selected based on their diagnosis, tumor location, cancer stage and utilized treatment planning technique. All patients were diagnosed with non-operable adenocarcinoma of the lung with or without the hilar and mediastinal lymph node involvement. These patients were treated at Geisinger Wyoming Valley Cancer Center. They all underwent computed tomography (CT) scan and Fluorodeoxyglucose positron emission tomography (FDG-PET) scan to aid with the treatment planning contouring process. Patient 1: A 73 year-old female who was diagnosed with stage IIIA papillary adenocarcinoma of the lung. Intense activity in the right posterior cardiophrenic sulcus concerning for recurrence was noted on PET result. Histopathology test revealed well to moderately differentiated papillary adenocarcinoma. Papillary lung adenocarcinoma has been reported as an aggressive variant of adenocarcinoma, frequently manifesting at high stage with a poor prognosis.2 Patient was recommended to undergo 3DCRT because the results of clinical investigations have shown that 3DCRT treatment planning has significant potential for improving RT planning for lung cancer, both for adequate tumor coverage to high doses and for minimizing normal tissue dosage.2 Total dose prescribed was 50.4 gray (Gy) at 1.8Gy per fraction for 28 fraction. Patient 2: A 67 year old female who was diagnosed with stage IIIA adenocarcinoma of the lung cancer. Patient also had a significant history of chronic obstructive pulmonary disease (COPD).

3 Lung cancer and COPD share a common risk factor in cigarette smoking and a large portion of patients with lung cancer suffer from COPD synchronously.3 Some epidemiologic studies found that smokers with COPD are up to five-fold more susceptible to lung cancer than smokers with normal lung function.3 Its not sufficient to make therapeutic decision solely based on only the stage of a cancer. Its important to assess individual features of the tumor before recommending treatment options.5 Implementing IMRT technique for this particular case helped to achieve adequate dose coverage while limiting the dose to OR. The radiation treatment plan was designed for the patient to receive a total of 5040 centigray (cGy) at 180cGy for 28 fractions using IMRT. For patient receiving 50.4 Gray (Gy) to the total tumor and lymph node volume, a conedown dose of up to 66Gy is permitted.4 In this case, the physician scheduled the patient to reevaluate the tumor after receiving 50.4 Gy. Depending on the tumor size reduction, tumor resection may become a possibility. Patient 3: A 76-year-old male diagnosed with adenosquamous carcinoma of the right lung. It was recommended by the tumor board that the patient can was a good candidate for combined modality treatment using RT and chemotherapy. External beam radiation therapy (EBRT) is the essential component in the treatment of stage III non-small cell lung cancer (NSCLC) and small Cell Lung Cancer (SCLC) patients.7 Definitive radiation concurrent with chemotherapy is the standard of care of stage III NSCLC.7 The radiation treatment plan was designed for the patient to receive a total of 6600 cGy at 200 cGy for 33 fractions. The first 40 Gy will be given to the GTV and the involved lymph nodes using parallel opposed AP/PA field treatment technique. Then a cone down dose of 26 Gy was prescribed only to the GTV. Patient set-up Each patient underwent a CT scan for simulation purpose. General electric (GE) CT scanner and Med-Tec incorporated wing board immobilization device was utilized during simulation process. Patient 2 and Patient 3 were CT simulated in supine position with both arms raised and positioned above the patients head on the breast board. Patient 1 was simulated in the prone position with both arms raised and positioned above the patients head. All patients had the radiopaque markers placed according to sagittal and lateral lasers to aid with patient poisoning reproducibility.

4 Target delineation Target delineation was completed using the Medical Image Merge (MIM) deformable fusion version 6 software. Positron emission tomography scans are usually taken on a curved couch in a non-treatment position, so obtaining an accurate GTV using PET image can be difficult due to the subjective nature of visual delineation. Medical Image Merge software can fuse multiple modalities in less than 10 seconds, and contours can be created from any plane on any modality. 8 Using this software, the medical dosimetrist localized the position of the tumor and the radiation oncologist contours the GTV on the PET-CT fused image (figure 2). After the radiation oncologist drew the GTV, the medical dosimetrist contoured the heart, spinal cord and a combined total lung volume (minus the GTV) for each patient. Treatment planning The dose prescription and planning parameters for the three lung cancer case studies are presented in Table 2. Patient 1 utilized a 3DCRT treatment planning technique with a prescription dose of 50.4Gy in 28 fractions (Figure 1). The prescription dose was prescribed to the isocenter point placed at the middle of the GTV. Patient was placed in prone position in order to avoid previously treated fields and increase patient comfort level. This positioning also helped to reduce the dose to the heart. Three beams were computed to deliver adequate prescription

dose to the GTV. Once adequate prescription dose coverage was achieved, the medical dosimetrist assessed the hotspots throughout the treatment area and adjusted the beam weight accordingly. Each right posterior oblique (RPO) and left posterior oblique (LPO) beams carried a weight of 42.5% and left lateral beam was given 15%. All fields utilized a 15MV photon energy beam. Moreover, control points were added manually on the RPO and LPO fields. After the appropriate beam weight was assigned for the control points, the hot spot was reduced to only 102%. The OR mean dose constraint for the heart was 46.4Gy, cord was 18.4 Gy, total lung (doesnt include the GTV) was 20.6 Gy and the esophagus was 49.2 Gy. Patient 2 utilized nine beams IMRT technique for a prescription dose of 50.4Gy in 28 fractions. The radiation oncologist contoured the GTV using the fused PET/CT image (Figure 1). The objective of using IMRT technique was to reduce the radiation toxicity to the total lung volume while maintaining a homogeneous dose distribution throughout the treatment volume. The dose

5 objectives for the left breast volume and the OR dose constraints were entered into the IMRT module of the treatment planning system (TPS) for optimization. The OR objectives for this treatment plan were to achieve a maximum dose (Dmax) to the heart < 52Gy, limit the total lung dose V20 to < 30%, reduce the left lung V20 to < 15%, and limit the total lung volume V20 to < 10%. The TPS utilized the direct machine parameter optimization (DMPO) feature to accomplish the IMRT objectives of this plan. Patient 3 utilized 2 AP/PA beams and field sizes were adjusted according to the GTV with 0.7 cm margin. The dosimetrist reviewed the digitally reconstructed radiograph (DRR) view of each field to make sure the collimator angle and the gantry angle were positioned properly (Figure 3). The medical dosimetrist assigned a prescription to both beams and employed the collapsed cone convolution superimposition (CCCS) algorithm calculation method to generate a treatment plan. After evaluating the dose distribution and hot spot location, the medical dosimetrist added 2 control points per beam. Plan analysis & Evaluation In each of these case studies, the medical dosimetrist optimized the prescription dose to the medially located lung tumor volume by utilizing components specific to each of the different treatment techniques. Each treatment technique employs one or more of these components to optimize the treatment plan which include: beam energies, beam weighting, forward planning control points, and an IMRT optimizing module in the TPS. Once the adequate prescription dose coverage was achieved, the medical dosimetrist reviewed the OR doses, the isodose lines, and the DVH for each treatment. A summary of the Dmax to the heart and the volume of heart receiving 30Gy (V30), and the volume of the total lung dose receiving 20Gy (V20) are presented in Table 2. For Patient 1, the evaluation of the 3DCRT prone forward planning technique demonstrated that adequate prescription dose coverage to the left lower lobe (LLL) GTV was achieved with a 105% hotspot. The OR on the DVH reflected the heart Dmax was 52Gy and the V30 was 15% and the total lung V20 was less than 5%. The prescription in this plan was normalized to 98%.

6 For Patient 2, the evaluation of the IMRT technique illustrated a much better conformity and dose coverage to the right upper lung (RUL) GTV. The OR on the DVH reflected the Dmax of the heart was 51.5Gy and the V30 was 1%, and the total lung V20 was 30%. The V20 for the total lung is higher in this case because the GTV volume is relatively larger than the other two cases. The prescription was normalized to 98% to achieve adequate prescription coverage and a homogenous dose distribution throughout the planned treatment volume (PTV) with a hotspot of 108%. The total lung V20 objective was not achievable due to the relatively higher GTV volume. Although the total lung V20 was exceeded, the left lung V20 was less than 5%. For Patient 3, the evaluation of the parallel opposed treatment technique demonstrated that all of the dose objectives and constraints were achieved. The OR on the DVH reported the Dmax of the heart was 41.5cGy and the V30 was 4%, and the total lung V20 was less than 30%. The prescription was normalized to 98%. This plan only utilized two AP and PA beams to achieve a homogeneous dose distribution throughout the right lower lobe GTV with a hotspot of 106%. With the 3DCRT technique in Patient 1, the DVH demonstrated a significant reduction in the V20total lung dose when compared to the IMRT and AP/PA treatment plan. However, the V30 heart dose illustrated in patient 1 was significantly higher than the other two plans. The Dmax in Patient 1 was comparable to Patient 2, but the Dmax for patient 3 was much lower since the initial prescription was only 40Gy. The significant total lung dose difference between patient 1 and the other two patients was likely caused by the prone positioning and the exact tumor location. The 3D-CRT treatment technique utilized for patient 1 is a preferable alternative to IMRT and parallel opposed technique. The use of 3D-CRT, particularly with only 3 to 4 beam angles, has the ability to reduce normal-tissue toxicity, but has limited potential for dose escalation beyond the current standard in node-positive patients. IMRT is of limited additional value (compared to 3D-CRT) in node-negative cases, but is beneficial in node-positive cases and in cases with target volumes close to the heart.6 Results and discussion The challenges that a medical dosimetrist encounters in many lung cancer treatment planning cases are mainly respiratory motion, daily setup errors and sometimes the size of the GTV limits the number of beam angles that can be used. The most important obstacle in achieving the

7 maximum dose deposition for lung tumors is the lung itself.7 It is a very important concern in lung irradiation treatment planning to achieve less than 30% volume of the total lung receive 20Gy or less. In all the three case studies, the V20 for the total lung volume was 30% or less. The 3DCRT forward planning technique illustrated an excellent V20 value for the total lung volume, but when creating such plans a large separation between the medial and lateral tangential beams maybe important to reduce the overall hotspot within the treatment volume and evenly distribute the dose utilizing beam weighting factor. It is also important for the medical dosimetrist to consider supine versus prone positioning to achieve an acceptable dose distribution and limit the dose to critical structures and attain superior treatment outcome. In this study, its proven that prone positioning can work to the best benefit of the patient due to the location of the tumor. In support of this study, other research findings indicated that 3DCRT technique for the treatment of recurrent lung cancer yields a highly conformal plan, homogeneous dose distribution and can be delivered efficiently with promising outcome.

8 Figures

Figure 1. Patient 1, Prone 3DCRT (98% isodose line represented by the pink line)

Figure 2. Patient 1, Beam orientation

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Figure 3. Patient 1, DVH

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Planning CT Image

PET image

Deformed and fused PET/CT image.

Figure 4. Patient 2, fused TPCT-CT/PET image.

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Figure 5. GTV (red volume) + 0.7 cm margin (PTV)

Figure 6. Patient 2, IMRT (98% isodose line represented by the pink line)

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Figure 7. Patient 2, Isodose distribution (green = 20%, orange = 50%, yellow = 80%, blue = 90%, green 95%, pink = 97%) and 3D beams eye view (BEV)

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Figure 8. Patient 2, DVH

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Figure 9. Patient 3, AP/PA technique, Isodose distribution (green = 20%, orange = 50%, yellow = 80%, blue = 90%, green 95%, pink = 98%)

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Figure 6. Patient 3, Isodose distribution and 3D BEV

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Composite Composite Clinical Case Stage TNM Location GTVprimary Volume (cm3) GTVnodal Volume (cm2) Respiratory motion on fluoroscopy (mm)

Right to left

Anterior Superior to posterior to inferior

IIIA

T1bN2M0 LLL

40.4

2.8

IIIA

T1bN2M0 RUL

49.5

10.08

1.9

1.4

IIIA

T2N2M0

RLL

23.1

6.67

3.5

2.2

Table 1. Clinical Patient characteristics

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Prescription and Treatment Planning Parameters Case Study Site Patient 1 LLL Prescription Beam Energy Dose to Left Breast Volume Planning Technique 6MV 50.4Gy in 28 fractions 1.8Gy/fraction 3D-CRT 6MV 50.4Gy in 28 fractions 1.8Gy/fraction IMRT 6MV 40Gy in 20 fractions 200cGy /fraction AP/PA Patient 2 RUL Patient 3 RLL

Treatment Planning Parameters Right posterior oblique (RPO), left

Beam Arrangements Parallel opposed AP/PA beams

posterior oblique (LPO) and left lateral beam.

9 co-planar beams

2250, 2600, 3000, 2400,

Gantry Angles 20, 280 and 325

200, 600, 1400 and 1800

0 and 180

*Note: The couch and collimator angles are set to 0 for all beams.
Table 2. Prescription and Treatment Planning Parameters

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Plan Analysis and Evaluation Patient 1 3DCRT Prone Dmax (Gy) Patient 2 IMRT Patient 3 AP/PA Total lung Cord V20 Dmax (%) (Gy) (%) (Gy) Dmax (%) (%) (Gy) (Gy) V30 V20 Dmax Cord Spinal

Heart Total Spinal Dmax Heart Total Spinal Dmax Heart lung V30 V20 (%) Cord (Gy) V30 lung

52.8

15%

18%

15.8

54.2

1%

30%

32.2

42.3

6%

~30%

41.8

Table 3: Plan Analysis and Evaluation.

20 References 1. Wu K, Jiang G, Qian H, et al. Three-dimensional conformal radiotherapy for locoregionally recurrent lung carcinoma after external beam irradiation: A prospective phase I-II clinical trial. Int J Rad Onc Biol Phys. 2003;57(5):1345-1350. 2. Achcar R, Nikiforova M, Yousem S. Micropapillary lung adenocarcinoma EGFR, K-ras, and BRAF mutation profile. Amer J of Clin Path. 2009;131(10):694-700. 3. Wang H, Yang L, Zou L et al. Association between chronic obstructive pulmonary disease and lung cancer: A case-control study in southern Chinese and a meta-analysis. PLoS ONE. 2012;7(9). 4. Hansen E, Roach M. Handbook of Evidence Based Radiation Oncology. 2nd ed. New York,NY: Springer Science + Business Media; 2010: 647-645. 5. Quint L. Lung cancer: assessing respectability. Int Canc Img Soc. 2004; 4(1): 1518. 6. Grills I, Yan D, Martinez A, et al. Potential for reducing toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: A comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation and elective nodal irradiation. Int J Rad Onc Bio Phys. 2003;57(3):876-890. 7. Soyfer V, Meir Y, Corn B, et al. AP-PA field orientation followed by IMRT reduces lung exposure in comparison to conventional 3D conformal and sole IMRT in centrally located lung tumors. Rad Onc J. 2012; 7:23. 8. MIM Maestro. MIM software. http://www.mimsoftware.com/products/maestro/. Accessed on June 6, 2013