1 Kevin Tsai November Case Study November 13, 2013 Intensity-Modulated Radiation Therapy (IMRT) using Simultaneous Integrated

Boost (SIB) fractionation scheme for Nasopharyngeal Carcinoma (NPC) Abstract: Introduction: This study was performed to evaluate the target coverage and dose to normal structures using IMRT technique with SIB fractionation scheme for NPC. Case Description: For this case study, 5 patients previously treated for NPC using conventional IMRT technique with SIB fractionation scheme were selected. Patient 1 was a 56 year-old male with NPC on his right side as well as bulky level II and level II lymph nodes. Patient 2 was a 52year-old male with NPC on his left side with enlarged lymph nodes. Patient 3 was another 56year-old male with NPC also with positive level II and level III lymph nodes. Patient 4 was a 74 year-old male with NPC with positive regional lymph nodes. Patient 5 was a 56 year-old female with a history of undifferentiated carcinoma of the left nasopharynx. Patient 1 through 4 received 2 cycles of Cisplatin and 5-FU chemotherapy prior to starting their radiation treatments. Patient 5 was treated with radiation alone. Conclusion: The 5 IMRT/SIB plans were compared and evaluated. The plans were evaluated by analyzing how well the targets were being covered, dose volume histogram (DVH), global maximum dose, maximum and median dose to the organs at risk (OR). The SIB fractionation scheme demonstrated in these case studies and in clinical practice has proven improved local and regional control while minimizing dose to critical structures. Intensity-Modulated Radiation Therapy with SIB together has proven to be a safe effective treatment modality for NPC as well as other disease sites. Key Words: Simultaneous Integrated Boost (SIB), Intensity Modulation Radiation Therapy (IMRT), SIB IMRT, Nasopharyngeal Carcinoma (NPC).

Introduction:

2 Nasopharyngeal carcinoma is a cancer that occurs in the nasopharynx, which is located behind the nasal cavities and above the level of the soft palate. The nasopharynx includes the posteriorsuperior pharyngeal wall and lateral pharyngeal wall, the Eustachian tube orifice, and the adenoids.1 Nasopharyngeal carcinoma is rare in the United States but occurs frequently in other parts of the world, specifically Southeast Asia. Nasopharyngeal carcinoma is difficult to detect early because the symptoms are usually similar to other common conditions. Due to late detection, patients are commonly diagnosed with advanced staged NPC with lymph node involvement. Approximately 75-85% of NPC patients have clinically positive cervical nodes, with about half of all cases having bilateral or contralateral disease.1 Historically, local control for early stage reaches 80-90%, whereas T3-T4 tumors have a control rate of 30-65%.2 Over the last 10-15 years, conventional IMRT techniques are commonly used because of its improved dose homogeneity and highly conformal dose distribution, allowing for improved sparing of normal tissues.2 Many literature studies have proven that IMRT allows more conformal dose coverage of the tumor especially in situations where the tumor is close to critical structures. This allows for dose escalation and improves local tumor control. With excellent clinical results, IMRT is becoming the standard for curative intent external beam radiation therapy. Currently there are 2 ways of planning IMRT treatments: Sequential (SEQ) and SIB. For a typical SEQ technique, the planning target volume-low risk (PTV-LR) is irradiated in the first plan and the dose is boosted to the planning target volume-high risk (PTV-HR) in the second plan with the same dose per fraction for the whole treatment. A standard IMRT fractionation of 1.8-2.0 Gray (Gy) per fraction (fx) are delivered everyday of the week for approximately 5-7 weeks total.3 Research and clinical practices have proven that standard IMRT fractionation show increase in radiobiological effectiveness. Planning with the SEQ technique requires a secondary boost plan after the initial plan is completed. This requires a plan summation that may affect the isodose distribution.3 It is also very difficult to optimize the remaining boost plan once a large portion of the dose has already been delivered.4 For SIB techniques, the PTV-LR and PTV-HR are all treated simultaneously with different doses per fraction. This technique shows better conformity than SEQ plans because SIB only requires a single optimization.3 Single optimization does not affect the isodose distribution because it does not require a plan summation. The dose constraints and objectives

3 for SIB are only entered once which is much more accurate. For SEQ, the constraints and objectives are entered once in the initial plan and then again in the boost plan. Selecting IMRT techniques between SEQ and SIB depend on the tumor shape and target planning. The IMRTSIB fractionation scheme is increasing in popularity because of its many advantages over IMRTSEQ.

The 5 patients presented in this case are all diagnosed with NPC and planned using IMRT with SIB fractionation scheme. The IMRT-SIB strategy not only produced dose distributions superior to those of optimized conventional treatment plans, but is much easier, more efficient, and a safer way of planning and delivering IMRT.3 Additionally, there are no field matching problems because the large IMRT fields necessary to cover all lymph nodes were delivered through a dynamic beam-splitting process.3 One main interest in IMRT-SIB technique is the sparing of the parotid glands which have been a main concern in previous planning techniques. The SIB technique has shown great tumor coverage and sparing of normal tissues such as the parotid glands. New technologies today including innovative treatment planning systems (TPS) and new techniques allow us to reach goals that were impossible in the past.

Methods and Materials Patient Selection The patients selected for this case study were all diagnosed with NPC and treated with IMRT and SIB fractionation. Patient 1 had a prescription of 3 PTVs (Figure 1). The first PTV (PTV1) was treated to a dose of 69.96 Gy in 33 fractions at 2.12 Gy per fx. The intermediate (PTV2) and low risk nodal volumes (PTV3) were treated to 59.40 cGy at 1.80 Gy per fx and 54.12 cGy at 1.64 Gy per fx for 33 fx each, respectively. Patient 2 had a prescription of 2 PTVs (Figure 2). This PTV1 consisted of the gross tumor with margin and was treated to 69.96 Gy in 33 fx at 2.12 Gy per fx. The PTV2 consisted of nodal volumes at risk and was treated to 54.12 Gy in 33 fx at 1.64 Gy per fraction. Patient 3 had a prescription of 3 PTVs (Figure 3). The first PTV consisted of the gross tumor volume (GTV) with 5 mm margin and was treated to a dose of 69.96 Gy in 33 fx at 2.12 Gy per fx. The second PTV consisted of intermediate nodal risk volumes and was treated to 59.40 Gy in 33 fx at 1.80 Gy per fx. The last PTV consisted of the low risk nodal volumes and

4 was treated to 54.12 Gy at 1.64 Gy per fx in 33 fx. Patient 4 was diagnosed with T4N2MX. A dose of 69.96 Gy in 33 fractions at 2.12 Gy fx was delivered to PTV1 and a dose of 59.4 Gy in 33 fx at 1.8 Gy fx was delivered to PTV2. The doses prescribed to all 3 patients are very similar but still demonstrate the benefits of the SIB technique effectively. Patient Set-up The set-up for all 3 patients was identical. The patients were scanned in a supine position on the CT simulation couch with both arms to their side (Figure 4). An Alpha-Cradle was created around the shoulders to prevent any movement. A Lite Cast (Figure 4) was then created around the chin and forehead to immobilize the patient. A knee wedge was also inserted under the patients knees for comfort and support. Target Delineation The Eclipse 10.0 TPS was used for target delineation for all patients. A computed tomography (CT) scan was performed with the set-up described previously. For all 3 patients, the radiation oncologist contoured the PTV on each axial planning CT slice as well as the intermediate (PTV2) and low risk nodal volumes (PTV3). Magnetic resonance images (MRI) and positron emission tomography-computed tomography (PET-CT) scans were fused with the treatment planning CT to help identify the tumor and lymph nodes. The GTV included the primary tumor and involved lymph nodes. The PTV was defined by adding a 5-millimeter (mm) margin to the GTV. The PTV2 covered areas with high risk of microscopic diseases and PTV3 included low risk nodal volumes at risk. The medical dosimetrist contoured all the OR for each patient, which included the brachial plexus, brain stem, spinal cord, esophagus, cochlea, larynx, eyes, lens, parotid, optic nerves, mandible, oral cavity, and temporal lobe. Before the optimization process, rings and margins were created around the PTV-ALL to delineate the target from critical structures and reduce dose to normal tissues. First, a 5 mm ring (GAP) was created around the PTV-ALL (Figure 5) and then a 20 mm ring (SHELL) was created around the PTV-ALL. The GAP structure was then removed from the SHELL leaving a moat shape (Figure 6). This was created to eliminate any splashes of doses into normal tissues and structures. The GAP and SHELL were used to push the prescription dose inside the inner ring and help the dose fall off quickly when it reached the 20 mm outer ring. A normal tissue structure (SKIN-PTV) was then

5 created by subtracting the SHELL and GAP from the body contour (Figure 7). This structure was used to reduce dose to normal tissues and structures near the PTV. Once the OR and ring structures had been contoured, the medical dosimetrist began the treatment planning process according to the doctors prescription. Treatment Planning The treatment plans for all 3 patients were planned using IMRT inverse planning technique. Instead of the medical dosimetrist trying multiple configurations of beams, wedges, and beam weights until a conformal dose was delivered to the PTV called forward planning, the reverse was attempted. All 3 of the cases were planned with Varian Eclipse 10.0 TPS and calculated using the Anisotrophic Analytical Algorithm (AAA). All treatment plans were designed using 6 Megavoltage (MV) energy. For the 3 selected NPC patients, the medical dosimetrist utilized 9 complex gantry angles to encompass the entire PTV simultaneously. The angles used were 200o, 240o, 280o, 320o, 0o, 40o, 80o, 120o, and 160o. During the optimization process, the medical dosimetrist set upper and lower constraints to the PTV and upper constraints to normal structures. The dose constraints the radiation oncologist wanted for the NPC patients were: V30 < 50% for at least one of the parotid glands, spinal cord maximum (max) dose 45 Gy, brainstem max dose < 54 Gy, eyes max dose 45 Gy, optic nerve max dose 54 Gy, cochlea mean dose < 45 Gy, mandible max dose 70 Gy, oral cavity mean dose 40 Gy, larynx mean dose 37 Gy, esophagus mean dose 40 Gy, and brachial plexus max dose 63 Gy. The medical dosimetrist decided the priorities for the PTV and critical organs. For patient 1, the prescription had 3 PTVs. A priority of 200 was given to the lowest upper objective and a priority of 125 to the lower objective for PTV1, PTV2, and PTV3. The 20 mm shell surrounding the PTV-ALL is given a priority of 200 and normal tissue objective (SkinPTV) was given a priority of 95 to reduce high doses to normal tissue outside the PTV. A priority of 200 is given to the spinal cord because of its proximity to the PTV, 85 to the brain stem, 65 to the left parotid gland, and 85 to the right parotid gland. Both of the parotid glands are partially inside PTV but more focus was put on the right parotid gland (Figure 8). All other critical structures are given a priority of 50 to minimize toxicity. Patient 2 had a prescription of 2 PTVs. A priority of 150 was given to the lowest upper objective and a priority of 100 to the lower objective for PTV1 and PTV2. The 20 mm SHELL and Skin-

6 PTV was both given a priority of 95. In this case, the PTV encompasses most of the left side of the head and neck as well as a large part of the left parotid gland (Figure 9). A higher priority of 75 was given to the right parotid compared to 50 for the left to save the right parotid gland. A priority of 80 was given to the spinal cord and 50 for all other critical organs. Patent 3 had a prescription of 3 PTVs. A priority of 150 was given to the lowest upper objective and a priority of 100 to the lower objective for PTV1, PTV2, and PTV3. The SHELL and SkinPTV was both given a priority of 95. Also in this case, most of the left parotid was inside the PTV (Figure 10). The right parotid was given a higher priority of 70 than the left parotid. The cord and brainstem both had a priority of 100. The PTV for patient 3 extends superiorly near the optic tracts therefore priorities of 100 were given to the eyes, optic chiasm, and optic nerves (Figure 11). All other normal structures were given 50 priorities. Plan Analysis & Evaluation All 3 plans were evaluated by studying the target coverage, DVH, global maximum dose, maximum and median dose to the OR. After evaluating the DVH, Most of the critical organ dose constraints and objectives for the patient 1 treatment plan were achieved (Figure 12). The brainstem was under 54 Gy and the spinal cord received 45 Gy. The left parotid gland received a high mean dose of 62 Gy but the spared right parotid gland only received a mean dose of 39 Gy. Higher dose than specified by the physician was the mandible at a maximum dose of 77 Gy. The plan was normalized to 95.6% to cover 95% of the prescription dose and the maximum dose of the entire plan was 116%. The results of the plan were acceptable to the radiation oncologist. Most of the critical organ dose constraints and objectives for the patient 2 treatment plan were achieved (Figure 13). It is difficult to satisfy all critical structures in the head and neck (H&N) regions because of the many critical structures. The brain stem received a maximum dose of 46 Gy and the cord received 45 Gy. The left parotid received a mean dose of 67 Gy and the right parotid received only 31 Gy. The mandible received a maximum dose of 77 Gy. The physician decided that the coverage of the PTV is more important than saving the mandible. The plan was normalized to 98.9% to cover 95% of the prescription dose and the maximum dose of the entire plan was 112.2%.

7 Patient 3 was very similar to patient 1. Most of the dose constraints and objectives for the critical structures were met except for the mandible at 76 Gy maximum dose (Figure 14). The brain stem was 52 Gy and spinal cord received 44 Gy. In this case, the right parotid gland was also being saved and received a lower mean dose of 36 Gy compared to the left parotid gland at 67 Gy mean dose. The plan was normalized to 99% to cover 95% of the prescription dose and the max dose of the entire plan was 110.6%. The monitor units (MU) from all the treatment plans were reviewed and compared with RadCalc. The Eclipse treatment plans were exported to RadCalc for comparisons and all were within the +/- 3% tolerance. Results and Discussion The IMRT-SIB for NPC is achievable and offers highly conformal dose distributions to the target. One of the main goals of IMRT-SIB is to reduce dose to the parotid glands to minimize xerostomia. From the cases presented, significant sparing of at least one of the parotid glands can be achieved with this technique. At the same time, high dose can be delivered to the target with satisfactory coverage. Treatment planning using IMRT-SIB is more streamlined, less error prone, and more precise than conventional IMRT planning and delivery.3 The ability to increase the dose per fx to the PTV and still minimize dose to normal tissues shows great biologic advantages. The true advantage is the delivery of escalated daily fx sizes to the gross disease and standard fx sizes to the electively treated clinical target volumes, while sparing normal tissues. Nasopharyngeal carcinoma has a tendency of cervical lymph node metastasis and the early boost to individual metastatic cervical lymph nodes may account for high control rate of regional disease.5 The downside of dose escalation to the PTV is that normal tissues near the target volume may be at a higher risk. The IMRT-SEQ may be more appropriate than IMRT-SIB if normal tissue is of more concern. Daily imaging for IMRT-SIB technique is recommended for precise treatment. Other benefits of SIB fractionation scheme include single optimization, greater conformity, improved local control, decrease toxicity, reduced overall treatment time by several days or up to 1 week, reduce charges to patients, and less physics quality assurance checks.4,5

Figures

Figure 1. Coronal View of PTV1 (red), PTV2 (orange), and PTV3 (purple), for Patient 1.

Figure 2. Coronal view demonstrating PTV1 (red) and PTV2 (purple) for Patient 2.

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Figure 3. Coronal view demonstrating PTV1 (red), PTV2 (orange), and PTV3 (purple), for Patient 3.

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Figure 4. Patient set-up for NPC

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Figure 5. Axial view demonstrating a 5 mm gap (blue ring) around the PTV (red) for patient X.

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Figure 6. Axial view demonstrating a 20 mm shell (green) around the PTV (red) for patient X.

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Figure 7. Axial view demonstrating the skin-PTV (purple) for patient X.

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Figure 8. Axial view demonstrating dose shown in color wash (95%) to display dose delivered to both parotid glands for Patient 1. Blue contour is the right parotid gland, cyan blue is the spinal cord, and yellow is the planning risk volume around the cord with 30 mm margin posterior.

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Figure 9. Axial view demonstrating dose shown in color wash (95%) to display dose delivered mostly to the left parotid gland for Patient 2. Blue color contour is the right parotid gland, green contour is the left parotid gland, and cyan contour is the spinal cord.

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Figure 10. Axial view demonstrating dose shown in color wash (95%) to display dose delivered mostly to the left parotid gland for Patient 3. Light blue contour is the right parotid gland, purple contour is the left parotid gland, and cyan contour is the spinal cord.

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Figure 11. Axial view demonstrating dose shown in color wash (50%) to display dose distribution near the optic tracts for Patient 3. The blue contour is the brain stem, light green is the optic chiasm, green and pink are the optic nerves, and blue and green are the eyes.

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Figure 12. Patient 1 DVH

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Figure 13. Patient 2 DVH

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Figure 14. Patient 3 DVH

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References 1. Washington CM, Leaver D. Principles and Practice of Radiation Therapy. 3rd ed. St. Louis, MO: Mosby-Elsvier; 2010:726-728. 2. Peponi E, Glanzmann C, Kunz G, et al. Simultaneous Integrated Boost-IntensityModulated Radiotherapy (SIB-IMRT) in Nasopharyngeal Cancer. Strahlentherapie und Onkologie. 2010;186:135-142. 3. Wu Q, Mohan R, Morris M, et al. Simultaneous Integrated Boost Intensity-Modulated Radiotherapy for Locally Advanced Head-and-Neck Squamous Cell Carcinomas: Dosimetric Results. Int J Radiat Oncol Biol Phys. 2003:56(2):573-585. 4. Dogan N, King S, Emami B, et al. Assessment of different IMRT boost delivery methods on target coverage and normal-tissue sparing. Int J Radiat Oncol Biol Phys. 2003;57(5):1480-1491. 5. Kim J, Cho J, Keum K, et al. IMRT with Simultaneous Integrated Boost and Concurrent Chemotherapy for Nasopharyngeal Cancer: Plan Evaluation and Treatment Outcome. Jpn J Clin Oncol. 2012;42(12):1142-1160.

23 Table 1. Patient Characteristics Patient 1 Site Gender Age Staging Energy Dose to PTV1 6MV 69.96 Gy in 33 fx @ 2.12 Gy fx Dose to PTV2 59.4 Gy in 33 fx @ 1.8 Gy fx Dose to PTV3 54.12 Gy in 33 fx @ 1.64 Gy fx # of beams Planning Technique TPS Varian Eclipse 10.0 Machine Varian 21EX Varian Eclipse 10.0 Varian 21EX Varian Eclipse 10.0 Varian 21EX Varian Eclipse 10.0 Varian 21EX Varian Eclipse 10.0 Varian 21EX 9 IMRT/SIB 9 IMRT/SIB 6MV 69.96 Gy in 33 fx @ 2.12 Gy fx 54.12 Gy in 33 fx @ 1.64 Gy fx n/a NPC Male 56 Patient 2 NPC Male 52 Patient 3 NPC Male 56 T4N2MX 6MV 69.96 Gy in 33 fx @ 2.12 Gy fx 59.4 Gy in 33 fx @ 1.8 Gy fx 54.12 Gy in 33 fx @ 1.64 Gy fx 9 IMRT/SIB 9 IMRT/SIB Patient 4 NPC Male 74 T4N2MX 6MV 69.96 Gy in 33 fx @ 2.12 Gy fx 59.4 Gy in 33 fx @ 1.8 Gy fx n/a Patient 5 NPC Female 56 T1N0MX 6MV 69.96 Gy in 33 fx @ 2.12 Gy fx 59.4 Gy in 33 fx @ 1.8 Gy fx 52.8 Gy in 33 fx @ 1.6 Gy fx 9 IMRT/SIB

24 Table 2. Prescription doses for planning target volumes and tolerance doses for main organs at risk. Structure Target Volume (PTV) Prescription 100% of the target volume receives 95% of the prescription dose. Shell (20 mm margin around PTV-ALL) Skin-PTV Brain Stem Spinal Cord Parotid Glands (at least 1 gland) Receives < 90% of prescription dose. Receives < 75% of prescription dose. Maximum dose < 54 Gy Maximum dose < 45 Gy Mean dose < 26 Gy, V30 < 50%, 20 cc for both parotids < 20 Gy Brachial Plexus Optic Nerves, Chiasm Eyes Lens Mandible, Temporomandibular joint Maximum dose < 66 Gy Maximum dose < 54 Gy Maximum dose < 45 Gy Maximum dose < 10 Gy 70 Gy, if not possible then no more than 1cc to exceed 75 Gy Oral cavity (excluding PTVs) Each Cochlea Glottic Larynx Esophagus Mean dose < 40 Gy V55 < 5% Mean dose < 45 Gy Mean dose < 45 Gy