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1 Amanuel Negussie Comprehensive Case Study November 2013 Effectiveness of sparing the mandible, larynx, and parotid glands

in oropharyngeal cancer treatment Abstract: Introduction: This study aims to compare and contrast sparing of the mandible, larynx, and parotid glands in treatment of oropharyngeal cancer using IMRT and VMAT techniques. Case Description: A treatment with IMRT or VMAT using multiple boost techniques was demonstrated in the following 3 cases. Patient 1 represents a case of 3 target volumes treated for a postoperative squamous cell carcinoma of the base of tongue using IMRT plus 3DCRT. Patient 2 represents a case of three target volumes treated for a postoperative squamous cell carcinoma of the tonsil using VMAT alone. Patient 3 represents a case of two target volumes treated for squamous cell carcinoma of the base of tongue using VMAT plus 3DCRT as a definitive treatment. Conclusion: Each case was individually evaluated on how well normal structures were spared and whether the plan met the objectives. The plans were evaluated based on RTOG and QUANTEC guidelines. Oropharyngeal cancer treatments using IMRT plus 3DCRT, VMAT alone, and VMAT plus 3DCRT have been demonstrated on how well the ipsilateral parotid, larynx, and mandible can be spared with optimal target coverage. Key Words: oropharyngeal cancer, 3DCRT, IMRT, VMAT, mandible, parotid glands, larynx Introduction The anatomy of oropharynx extends inferiorly to the hyoid bone and includes the base of tongue and tonsil.1 Oropharyngeal cancer commonly occurs in the base of tongue and tonsil and is less common in the soft palate and posterior pharyngeal wall.2 About 60% of oropharyngeal cancers are caused by human papilloma virus (HPV).3 The management of oropharyngeal cancer is multidisciplinary, which may include surgery, radiation therapy, or chemotherapy. The type of

2 treatment chosen for each patient may vary based on the stage and patients status. Radiation therapy is one of the most important treatment approaches that can either be used as a definitive treatment or as an adjuvant postoperative treatment. Radiation therapy alone is a standard approach for early staged oropharyngeal tumors.4 Radiation therapy alone or with chemotherapy is also more effective in HPV related oropharyngeal tumors.3 Since oropharyngeal cancers are often approached with a curative intent and are treated with high dose radiation, normal organ preservation is essential. The presence of various radiosensitive structures in the head and neck region make treatment planning a difficult task. Advanced treatment techniques such as intensity modulated radiation therapy (IMRT) and volumetric modulated radiation therapy (VMAT) are becoming standard treatment methods due to their ability to reduce dose to normal structures. Even with these techniques radiation therapy treatments can cause significant acute and late toxicities.5 Late reactions mainly includes xerostomia, dysphagia, and osteonecrosis.5 As a result, special attention must always be given to the parotid glands, mandible, and larynx when planning oropharyngeal cancer treatments. Maintaining salivary flow by preserving salivary glands is fundamental in oropharyngeal cancer treatments. Studies from University of Michigan showed that IMRT can reduce contralateral parotid dose to 32% compared with 93% using standard traditional technique.6 According to a study by Blanco et al.7, patients with bilateral parotid mean dose greater than 25 gray (Gy) have poor salivary function; whereas, decreased xerostomia was recorded when one or both parotids received a mean dose less than 25 Gy. Although sparing the contralateral parotid is of utmost important, the significance of sparing the ipsilateral parotid is debatable.8 Current radiation therapy oncology group (RTOG) and quantitative analysis of normal tissue effects in the clinic (QUANTEC) guidelines require minimizing mean dose for parotid below 26 Gy (Table 1). The incidence of osteonecrosis after oropharyngeal cancer treatment is 5-15% depending on the dose to mandible and patients dental hygiene.5 This can be reduced by dental extraction and limiting the dose to mandible below 60 Gy.5 A large number of patients who undergo surgery and radiation treatment for oropharyngeal cancer benefit from implant supported prosthesis. High dose radiation to the anterior mandible can lead to prosthesis implant failure to this region.9 Compared to other head and neck sites, the dose to the mandible is higher in oropharyngeal cancer treatments.10 Generally, risk of osteonecrosis is dependent on the volume of mandible

3 irradiated to high radiation dose. RTOG guideline recommends limiting the maximum dose for the mandible to below 66 Gy (Table 1). Sparing larynx is also essential in oropharyngeal cancer treatments to prevent dysphagia and aspiration. IMRT can be used in two different methods to achieve this; junctioned IMRT (JIMRT) and whole field IMRT (WF-IMRT). In J-IMRT, the upper portion of the target is treated with IMRT matched to an anterior (AP) field with a laryngeal block to treat the lower portion of the target.11 In WF-IMRT, the entire target is treated with IMRT fields.11 Multiple studies have shown that WF-IMRT can significantly reduce the mean dose for larynx when compared to JIMRT.11 QUANTEC recommends limiting the maximum dose for the larynx to below 66 Gy and the mean dose to below 50 Gy (Table 1). RTOG recommends the maximum dose to be kept below 45 Gy (Table 1). Methods and Materials Patient selection Patient 1 is a 63 year old male with a stage T2 (stage 2 primary tumor) N0 (no regional lymph nodes) M0 (no metastasis) squamous cell carcinoma of the base of tongue (BOT). A computer tomography (CT) scan of the neck showed an infiltrative mass that extended across the midline and invaded the left genioglossus and geniohyoid muscle. It also included the myohyoid muscle, left retromolar trigone region, left tonsil, midline of the left soft palate, and midline of the left hard palate. No definitive evidence of lymphadenopathy was recorded. The patient was initially treated with left hemiglossectomy and left selective neck dissection. The radiation therapy treatment plan was designed to target two planning target volumes (PTV) using simultaneous integrated boost (SIB) IMRT technique, followed by a boost to a third PTV using 3 dimensional conformal radiation therapy (3DCRT) technique. PTV1 was prescribed to 54 Gy and targeted the bilateral nodal chains. PTV2 was prescribed to 60 Gy and targeted the primary tumor bed plus regions of grossly involved lymphadenopathy. PTV3 was prescribed to 66 Gy and targeted regions that are high risk for recurrence. Patient 2 is a 61 year old male with HPV positive stage T1 (stage 1 primary tumor) N2 (stage 2 regional lymph nodes) M0 squamous cell carcinoma of the left tonsil. A positron emission tomography (PET)/CT demonstrated involvement in the superficial lobe of right parotid gland, lymph node in the tail of right parotid, intraparotid lymph nodes within the tail of the left parotid,

4 and left laryngeal tonsil. The patient was initially treated with tonsillectomy and neck dissection. The radiation therapy plan was designed to target three PTVs using sequential (SEQ) VMAT technique. PTV1 was prescribed to 50 Gy and targeted the bilateral nodal chains. PTV2 was prescribed to 64 Gy and targeted the primary tumor bed plus regions of grossly involved lymphadenopathy. PTV3 was prescribed to 70 Gy and targeted regions that are high risk for recurrence. Patient 3 is an 82 year old male with a stage T3 (stage 3 primary tumor) N2 M0 squamous cell carcinoma of BOT. An magnetic resonance imaging (MRI) of the neck demonstrated a soft tissue mass at the base of the tongue centered to the left of midline, but appearing to cross the midline. There was also extensive lymphadenopathy bilaterally including level I through IV and VI. The patient was not a surgery candidate due to his respiratory condition. Therefore, radiation therapy was given as a definitive treatment. A study by Chen et al12 showed that definitive radiation therapy without chemotherapy can provide higher rate of 3 year overall survival, locoregional control, and distant metastasis-free survival for patients with HPV positive head and neck cancer. The radiation therapy plan was designed to target two PTVs using SIB VMAT technique, followed by a boost to a third PTV using 3DCRT technique. PTV1 was prescribed to 50 Gy and targeted the bilateral nodal chains. PTV2 was prescribed to 70 Gy and targeted the tumor and involved lymph nodes. Patient 4 is a 56 year old male with HPV positive stage IVA T3 N2 M0 squamous cell carcinoma of a right sided BOT. A CT of the neck demonstrated an ulcerated BOT mass that extended into the right floor of mouth, vallecula, and free margins of the epiglottis. The mass also included the right and left geniohyoid muscles, right hyoglossus muscles, and right anterior belly of the digastrics. The PET scan showed involvement of level II lymph nodes. The patient was recommended a concurrent chemoradition treatment. The radiation treatment was planned targeting two PTVs using SIB VMAT technique, followed by an adjuvant boost to a third PTV using SEQ VMAT technique. PTV1 was prescribed to 54 Gy and targeted low risk nodal regions. PTV2 was prescribed to 60 Gy and targeted high-risk nodal regions. PTV3 was prescribed to 70 Gy and targeted the gross tumor volume. Patient 5 is a 66 year old male with HPV positive stage III T1 N1 (stage 1 regional lymph nodes) M0 squamous cell carcinoma of the left vallecula. A workup CT scan of the neck revealed an irregular enhancing mass in the left neck anterior to the left sternocleidomastoid. A PET scan

5 also demonstrated a level II lymph node of the left neck. The patient was recommended a concurrent chemoradiation. The radiation treatment was planned targeting three PTVs using SIB IMRT technique. PTV1 was prescribed to 56 Gy and targeted low risk nodal regions. PTV2 was prescribed to 63 Gy and targeted high risk nodal regions. PTV3 was prescribed to 70 Gy and targeted the gross tumor volume. Patient Set-up All five patients were scanned in a supine position on a head support. Patient 3 was positioned with this head and chest slightly inclined using a breast board due to his inability to lay flat on the CT couch. In all 5 cases, an aquaplast mask was used to immobilize the head, neck, and shoulders. A shoulder strap was used for Patients 2, 3, and 4 to further ensure that the shoulders were pulled away from the treatment area. A bite block was only used for Patient 2. In patients treated for a base of tongue where the contralateral neck is clinically negative, bite blocks should not be used in order to spare the contralateral parotid gland.12 A wire was placed on the surgical scar for Patients 1 and 2. Target Delineation The Pinnacle3 treatment planning system (TPS) version 9 was used to plan the treatment for Patients 1 and 5. The Eclipse TPS version 10 was used for Patients 2, 3, and 4. The CT scans were obtained with Philips large bore 16 slice CT unit for Patients 1 and 5 and General electric (GE) lightspeed CT unit for Patients 2, 3, and 4. The images were taken at 3 millimeter (mm) slices for Patient 1 and 5, and 2.5 mm for Patients 2, 3, and 4. The variation in slice thickness is due to difference in departmental preferences. Two CT scans were obtained for Patient 1, with and without non-iodinated intravenous (IV) contrast. The two scans were fused, the scan without an IV contrast being the primary planning image. The structures contoured by the medical dosimetrist included the surgical scar, spinal cord, brainstem, and mandible. The radiation oncologist contoured the brachial plexus, parotid glands, esophagus, larynx, oral cavity, and the targets. The PTVs included: PTV 54 (the PTV receiving 54 Gy), PTV 60 (the PTV receiving 60 Gy), and PTV66 (the PTV receiving 66 Gy). For Patient 2, no diagnostic images were fused with the planning CT scan. The medical dosimetrist contoured the eyes, lenses, lungs, inner ears, optic nerves, mandible, shoulders and

6 larynx. The radiation oncologist contoured the parotid glands, oral cavity, optic chiasm, pituitary gland, submandibular gland, thyroid, and the targets. The PTVs included: PTV 50 (the PTV receiving 50 Gy), PTV 64 (the PTV receiving 64 Gy), and PTV 70 (the PTV receiving 70 Gy). For Patient 3, the planning CT was fused with a diagnostic MRI of the neck. The normal structures contoured by the medical dosimetrist were the brain, brainstem, eyes, lenses, lungs, inner ears, optic nerves, mandible, shoulders, and larynx. The radiation oncologist contoured the parotid glands, optic chiasm, oral cavity, and the targets. The PTVs included PTV 50 and PTV 70. For Patient 4, the planning CT was fused with a diagnostic CT and PET scans. The medical dosimetrist contoured the majority of normal structures; including the brain, brainstem, eyes, lenses, lungs, inner ears, optic nerves, mandible, shoulders, and larynx. The radiation oncologist contoured the parotid glands, optic chiasm, oral cavity, and the targets. The targets included PTV 54, PTV 60, and PTV 70. Two CT scans were obtained for Patient 5, with and without IV contrast (Visipaque). The scan without a contrast was used as a primary image to plan the treatment. The CT scan with a contrast and the PET scan were fused with the primary image. The structures contoured by the medical dosimetrist included the spinal cord, brainstem, mandible, and eyes. The radiation oncologist contoured the parotid glands, esophagus, larynx, oral cavity, and the targets. The targets included PTV 56 (the PTV receiving 56 Gy), PTV 63 (the PTV receiving 63 Gy), and PTV 70. Treatment Planning The dose prescription and planning parameters of each case are presented in Table 2. The dental artifacts were contoured and assigned a density equivalent to water for all patients. Metal artifacts can distort dose distribution by creating cold and hot spots.13 This correction method helped reduce such complication. The initial plan for Patient 1 targeted PTV 54 and PTV 60. The treatment was planned using SIB step-and-shoot IMRT technique with a 9-field beam arrangement. Since PTV 54 incorporate PTV 60, a structure named PTV 54-60 was created. The structure crops PTV 60 out of PTV 54. This allowed the medical dosimetrist to effectively distribute separate doses to the two PTVs. The posterior neck that lied below the spinal cord was contoured for optimization purpose. The inverse planning included clinical goals to PTV 60,

7 PTV 54-60, spinal cord, spinal cord planning organ at risk volume (PRV) (spinal cord + 5 mm), brain stem, brain stem PRV (brain stem + 3 mm), parotids, larynx, posterior neck, and mandible. A higher priority was given to meet the spinal cord and brainstem constraints per RTOG guideline. The plan was optimized multiple times with changes made to minimize the dose to organs at risk (OR) while adequately covering the PTVs. The boost for PTV 66 was planned using 3DCRT technique with two lateral beams. The fields were constructed with 1.3 cm margin around PTV 66. The spinal cord was blocked out of the treatment field by 7 mm. A 15o wedge was used to account for the curvature of the neck and increase dose homogeneity. The heels were positioned anteriorly for the right lateral field and inferiorly for the left lateral field. The weighting for the right and left beams was adjusted to 48% and 52%. The treatment for Patient 2 was planned using SEQ VMAT technique. The initial plan for PTV 50 included three arc fields, two in clockwise (CW) direction and one in counter clockwise (CCW) direction. The plans for PTV 64 and PTV 70 included two arcs, in CW and CCW direction. Due to weight loss and change in anatomical contour, the patient was re-simulated after the completion of the initial treatment. All three plans were carried out with a similar approach. The PTVs were enlarged by 1 mm in all directions for optimization purpose. This allowed the medical dosimetrist effectively distribute the prescribed dose to the entire PTV. A 1 cm wide ring was constructed 2 cm away from the PTVs. The OR that overlapped with the PTVs were cropped 3 mm away from the PTV for optimization purpose. This included the parotids, mandible, and oral cavity for PTV 50; the left parotid and mandible for PTV 64; and left parotid for PTV 70. This technique allowed to effectively minimize the dose to the OR without affecting the PTV coverage. Each plan was optimized with objectives set for the enlarged PTV, the ring, parotids, mandible, oral cavity, spinal cord PRV, brain stem, and shoulders. The initial plan for Patient 3 targeted PTV 50. The treatment was planned using VMAT technique with three arcs, two in CW direction and one in CCW direction. PTV 50 was enlarged by 1 mm in all directions for optimization purpose. A 1 cm wide ring was constructed 2 cm away from the PTVs. The OR that abutted with the target were cropped 3 mm away from PTV 50. This included mandible, parotids, and oral cavity. The plan was optimized with objectives set for the enlarged PTV 50, the ring, parotids, mandible, oral cavity, spinal cord PRV, brain stem, and shoulders. The boost for PTV 70 was planned using 3DCRT with right anterior oblique (RAO) and left anterior oblique (LAO) beams. The collimator was rotated to 55o for the RAO and 33o

8 for the LAO to exclude the spinal cord from the treatment field. The treatment fields were constructed with 1cm margin around PTV 70. A 45o wedge was used for the RAO field with the heel positioned anteriorly. The weighting for the RAO and LAO beams was adjusted to 51% and 49%. For patient 4, the initial treatment targeted PTV 54 and PTV 60. The treatment was planned using SIB VMAT technique with three arcs, two in CW direction and one in CCW direction. A PTV 54-60 was constructed, which excluded PTV 60 from PTV 54. The OR that overlapped with the PTVs were cropped 3 mm away from PTV 54 for optimization purpose. The structures included left parotid, mandible, and oral cavity. A 1 cm wide ring was constructed 2 cm away from PTV 56. The inverse planning included clinical goals to PTV 54-60, PTV 60, right and left parotids, spinal cord PRV, mandible, shoulders and the ring. The patient was treated with 23 fractions of the initial treatment, but was re-simulated due to weight loss. The simulation was done with the same setup position and slice thickness as the initial simulation. However, a new thermoplastic mask was constructed. All OR and PTVs were re-contoured. A similar approach was taken for the re-planning. The objectives used for optimization included PTV 54-60, PTV 60, right and left parotids, spinal cord PRV, mandible, and the ring. The benefit of adaptive replanning is to effectively spare the parotid gland throughout the treatment course.14 The boost for PTV 70 was planned using SEQ VMAT technique with two arcs, in a CW and CCW direction. PTV 70 was enlarged by 1 mm in all directions for optimization purpose. A 1 cm ring was constructed 2 cm away from PTV 70. The plan was optimized by dose objectives set for the enlarged PTV 70, the ring, parotids, shoulders and mandible. The treatment for Patient 5 was planned using SIB step-and-shoot IMRT technique targeting PTV 56, PTV 63, and PTV 70. A 9-field equidistance beam arrangement was used. A PTV 63-70 and PTV 56-70 were constructed to detach each PTV with different dose level. The OR that overlapped with the target were cropped 3 mm away from PTV 54 for optimization purpose. This included the oral cavity, mandible, parotids, and larynx. The posterior neck that lied below the spinal cord was contoured for optimization purpose. The inverse planning included clinical goals to PTV 56-70, PTV 63-70, PTV 70, spinal cord, spinal cord PRV, brain stem, brain stem PRV, parotids, larynx, oral cavity, posterior neck, and mandible. Plan Analysis & Evaluation

9 Traditionally, head and neck cancer patients were treated with parallel-opposed lateral photon fields. The spinal cord was blocked after 40 Gy and electron fields were used to boost the posterior neck. The oral cavity may be blocked throughout the treatment. A reduced photon fields were used to boost the gross tumor volume. An additional anterior photon field may also be used to treat the supraclavicular nodes. IMRT and VMAT have enhanced the sparing of the parotids compare to the conventional treatments. However, the anterior mucosa and the posterior neck would be more exposed unless purposely spared by the planner.15 In order to minimize the dose to the anterior mucosa, the oral cavity was contoured in all five patients and dose objectives were established. The posterior neck was contoured in patients 1 and 5, who were treated with IMRT. Dose objectives were set aiming to spare the posterior neck from 50% of the prescribed dose. In Patients 2, 3, and 4, who were treated with VMAT, the posterior neck was spared by avoiding an entrance beam posteriorly. These approaches allowed to develop plans that resembled the positive of conventional treatments. The most notable difference between VMAT and IMRT is variation in monitor unit (MU) and treatment time. Various studies have proven that VMAT can provide lower MU per fraction with shorter delivery time. VMAT is also known to provide better dose conformity than IMRT. However, IMRT can generate plans with better dose homogeneity.16 A study by Clemente et al17 showed that, in oropharyngeal cancers, higher larynx sparing can be achieved with IMRT but better ipsilateral parotid sparing can be achieved with VMAT. Another study by Teoh et al18 demonstrated a lower contralateral parotid sparing can be achieved with VMAT than IMRT. Patient 1s treatment was planned using the RTOG guidelines. The ipsilateral parotid gland was spared with a mean dose of 21.64 Gy. The constraints for the mandible and larynx were not met. The mean and maximum dose to the mandible was 44.69 Gy and 69.61 Gy. The mean and maximum dose to the larynx was 36.69 Gy and 56.85 Gy. The PTVs were well covered with the 95% isodose line and a maximum dose of 107% (Figure 1 and Table 3). The plan was acceptable to the physician since a large volume of both the mandible and larynx overlapped with the targets. Patient 2s treatment was planned using the QUNTEC guidelines. The ipsilateral parotid was spared with a mean dose of 16.4 Gy. For the larynx, the mean dose was met with 51 Gy. Although QUANTEC does not provide a dose limit for the mandible, the dose was minimized to

10 a mean dose of 38.4 Gy and maximum dose of 65 Gy. This met the RTOG guidelines with a close margin. All targets were covered with the 95% isodose line and a maximum dose of 109% (Figure 2 and Table 3). The plan was acceptable to the physician since the parotid, larynx, and the rest of OR were effectively spared. For patient 3, the QUANTEC guidelines were used for planning. The ipsilateral parotid gland was spared with a mean dose of 19.6 Gy. The dose constraints for the larynx were not met. The mean dose was 69.4 Gy and the maximum dose was 72.9 Gy. The mean and maximum dose for mandible was 40.3 Gy and 69.3 Gy. These did not meet the RTOG guidelines. All targets were covered with the 95% isodose line and a maximum dose of 105% (Figure 3 and Table 3). The treatment for Patient 4 was planned with a goal to meet the QUANTEC guidelines. The ipsilateral parotid gland was spared successfully with a mean dose of 17.3 Gy. The mean dose for the larynx was 61.4 Gy, which met one of the QUANTEC guidelines. The mean and maximum dose to the mandible were 40.5 Gy and 72.6 Gy, and did not meet the RTOG guidelines. This was mainly due to the mandible overlapping with the PTVs. All three PTVs were covered with the 95% isodose line (Figure 4). The maximum dose was 106% (Table 3). Patient 5s treatment was planned with a goal to meet the ROTG guidelines. The ipsilateral parotid gland was spared with a mean dose of 20 Gy. The maximum and mean dose of the larynx were 41.4 Gy and 53.5 Gy. These met both the QUANTEC and RTOG guidelines. The mean and maximum dose to mandible was 45.4 Gy and 74.6 Gy, which did not meet the RTOG guideline. All three PTVs, were successfully covered with 95% of the prescribed dose (Figure 5). The plan was finalized with maximum dose of 109% (Table 3). The constraints for the remaining OR including the brainstem, oral cavity, and spinal cord were met for all patients. The ipsilateral parotid gland was spared with a mean dose less than 22 Gy for all cases. A study by Clemente et al17 showed that VMAT is better in sparing the ipsilateral parotid gland than IMRT. A similar outcome was seen in these five cases. The ipsilateral parotid was spared the most in Patient 2, where three separate VMAT plans were developed for each PTV. The ipsilateral parotid was spared the least in Patient 1, who was treated with SIB IMRT technique along with a boost using 3DCRT. Comparatively, the parotids were spared better in the patients treated with VMAT (Table 3).

11 From all five cases, the plan for Patient 2 was the only one that met the mandible constraints recommended by RTOG (Table 3). The remaining four patients did not meet the RTOG constraints for both the maximum and mean dose. Early onset necrosis mainly occurs if the maximum dose is above 70 Gy.10 This was taken in to consideration during the planning processes. The maximum dose for Patients 1, 2 and 3 were kept below 70 Gy. However, this was not achieved for Patient 4 and 5, whose treatment was planned using SIB techniques. Patient 5, whose plan was done with SIB IMRT, had the highest mandible dose. Since more priority was given to the PTVs, higher dose to the mandible was acceptable by the physicians. A study by Clemente et al17 has shown that IMRT can spare the larynx better than VMAT. A similar outcome was seen in the five cases (Table 3). There are multiple recommended dose constraints for larynx by RTOG and QUANTEC. None of the five patients met the RTOG constraints, which recommends a maximum dose below 45 Gy. The plan for Patient 5 was the only one that met the both the mean and maximum constraints of QUANTEC. Patient 1 also met the maximum dose constraint of QUANTEC. The larynx for Patient 3, whose treatment was given using VMAT and 3DCRT, was spared the least. Results and Discussion All techniques utilized for the five patients, IMRT plus 3DCRT, SEQ VMAT, VMAT plus 3DCRT, SIB plus SEQ VMAT, and SIB IMRT, provided clinically acceptable plans. The ipsilateral parotid was effectively spared for all cases. Patients 3 and 4 were re-simulated in between the treatment course due to weight loss. The initial plan was no longer acceptable because of uncertainties in patient immobilization. An adaptive re-planning technique was utilized to carry out the treatment and account for the change in contour. This technique was proven to identify dosimetric changes and recover parotid glands sparing.14,19 The larynx and mandible presented the greatest challenge. In each case, the PTVs abutted with the mandible and surrounded the larynx. This made it difficult to minimize the dose to these structures while adequately covering the PTVs. Due to the extent of the PTVs, minimizing the maximum dose to the larynx and mandible below 66 Gy would compromise the target coverage. The prescribed dose to the tumor, tumor bed or involved lymph nodes was 66 Gy for Patient 1 and 70 Gy for the remaining patients. Since more priority was given to the PTVs, a maximum

12 dose above 66 Gy to the larynx and mandible was accepted. The maximum point dose did not fall within either of these structures for all five patients (Table 3).

13 References 1. Arruda FF, Puri DR, Zhung J, et al. Intensity-modulated radiation therapy for the treatment of oropharyngeal carcinoma: The Memorial Sloan Kettering Cancer Center experience. Int J Radiat Oncol Biol Phy. 2006;64(2):363-373. doi:10.1016/j.ijrobp.2005.03.006 2. Haigentz M, Silver CE, Corry J, et al. Current trends in initial management of oropharyngeal cancer: the declining use of open surgery. Eur Arch Oto-Rhino-L. 2009;266(12):1845-1855. doi:10.1007/s00405-009-1109-2 3. Hong AM, Dobbins TA, Lee CS, et al. Human papilloma virus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy. Br J Canc. 2010;103:1510-1517. doi:10.1038/sj.bjc.6605944 4. Hong TS, Tome WA, Harari PM. Heterogeneity in head and neck IMRT target design and clinical practice. Radiother Oncol. 2012;103(1):92-98. doi: 10.1016/j.radonc.2012.02.010 5. Bhide SA, Newbold KL, Harrington KJ, et al. Clinical evaluation of intensity-modulated radiotherapy for head and neck cancers. Br J Radiol. 2012;85(1013):487-494. doi:10.1259/bjr/85942136 6. Eisbrush A, Ship JA, Martel MK, et al. Parotid gland sparing in patients undergoing bilateral head and neck irradiation: techniques and early results. Int J Radiat Oncol Biol Phys. 1996;36:469-480. doi:10.1016/S0360-3016(96)00264-7 7. Blanco AI, Chao C, Naqa IE, et al. Dose volume modeling of salivary functioning patient with head and neck cancer receiving radiotherapy. Int J Radiat Oncol Biol Phys. 2005;62(4):1055-1069. doi:10.1016/j.ijrobp.2004.12.076 8. Claus F, Duthoy W, Boterberg T, et al. Intensity modulated radiation therapy for oropharyngeal and oral cavity tumors: clinical use and experience. Oral Oncol. 2002;38(6):597-604. doi:10.1016/S1368-8375(01)00111-7 9. Verdonck HWD, De Jong JMA, Granzier MEPG, et al. Intensity-modulated radiation therapy for oropharyngeal cancer: Radiation dosage constraint at anterior mandible. Radiat Oncol. 2009;45(6):511-514. doi:10.1016/j.oraloncology.2008.07.007 10. Nguyen NP, Vock J, Chi A, et al. Effectiveness of intensity modulated and image guided radiotherapy for spare the mandible from excessive radiation. Oral Oncol. 2012:48(7);653657 doi:10.1016/j.oraloncology.2012.01.016

14 11. Ad VB, Lin H, Hwang WT, et al. Larynx-sparing techniques using intensity-modulated radiation therapy for oropharyngeal cancer. Med Dosim. 2012;37(4):383-386. doi:10.1016/j.meddos.2012.02.004 12. Chen AM, Zahra T, Daly ME, et al. Definitive radiation therapy without chemotherapyfor human papillomavirus-positive head and neck cancer. Head Neck.2013;35(11):1652-1656. doi:10.1002/hed.23209 13. Kim Y, Tome WA, Bal M, et al. The impact of metal artifacts on head and neck IMRT dose distribution. Radiother Oncol. 2006;79(2):198-202. doi:10.1016/j.radonc.2006.03.022 14. Wu Q, Chi Y, Chen PY, et al. Adaptive replanning strategies accounting for shrinkage in head and neck IMRT. Int J Radiat Oncol Biol Pys. 2009;75(3):924-932. doi:10.1016/j.ijrobp.2009.04.047 15. Ezzell GA, Galvin JM, Low D, et al. Guidance document on delivery, treatment planning, and clinical implementation of IMRT: Report of the IMRT subcommittee of the AAPM radiation therapy committee. Am Assoc Phys Med. 2003;30(8):2089-2115. doi:10.1118/1.1591194 16. Harrison LB, Sessions RB, Hong WK. Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Philadelphia, PA. Lippincott Williams and Wilkins; 2009:331-332. 17. Clemente S, Wu BB, Giuseppe S, et al. Smartarc based volumetric modulated arc therapy for oropharyngeal cancer: a dosimetric comparison with both intensity modulated radiation therapy and helical tomotherapy. Int J Radiat Oncol Biol Pys. 2011;80(4):1248-1255. doi:10.1016/j.ijrobp.2010.08.007 18. Teoh M, Beveridge S, Wood K, et al. Volumetric-modulated arc therapy (RapidArc) vs. conventional fixed field intensity modulated radiotherapy for F-FDG-PET-guided dose escalation in oropharyngeal cancer: A planning study. Med Dosim. 2013;38(1):18-24. doi: 10.1016/j.meddos.2012.05.002 19. Schwartz DL, Garden AS, Thomas J, et al. Adaptive radiotherapy for head and neck cancer: Initial clinical outcomes from a prospective trial. Int J Radiat Oncol Biol Phys. 2012;83(3):986-993. doi:10.1016/j.ijrobp.2011.08.017 20. Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue complication probability models in clinic. Int J Radiat Oncol Biol Phys. 2010;76(3):S10-S19. doi:10.1016/j.ijrobp.2009.07.1754

15 21. Machtay M. A phase III study of postoperative radiationtherapy (IMRT)+/- Cetuximab for locally advanced resected head and neck cancer. http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0920. 2013. Accessed August 1, 2013. 22. Lee N. Radiation therapy with or without chemotherapy in reducing mouth dryness in patients with nasopharyngeal cancer http://www.cancer.gov/clinicaltrials/search/view?cdrid=269314&version=HealthProfessional #StudyIdInfo_CDR0000269314. 2013. Accessed November 22, 2013.

16 Figures

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Figure 1. Patient 1: The sagittal, axial, and coronal views of dose distribution for the cumulative plan

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Figure 2. Patient 2: The sagittal, axial, and coronal views of dose distribution for the cumulative plan

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Figure 3. Patient 3: The sagittal, axial, and coronal views of dose distribution for the cumulative plan

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Figure 4. Patient 4: The sagittal, axial, and coronal views of dose distribution for the cumulative plan

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Figure 5. Patient 5: The sagittal, axial, and coronal views of dose distribution for the cumulative plan

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Figure 6. Patient 1: Dose volume histogram (DVH) of the cumulative plan demonstrating dose distribution to PTV66, PTV60, PTV54, mandible, larynx, and contralateral parotid (CLAT Parotid)

Figure 7. Patient 2: DVH of the cumulative plan demonstrating dose distribution to PTV70, PTV60, PTV54, mandible, larynx, CLAT parotid, and ipsilateral parotid (ILAT Parotid)

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Figure 8. Patient 3: DVH of the cumulative plan demonstrating dose distribution to PTV70, PTV50, mandible, larynx, CLAT parotid, and ILAT Parotid

Figure 9. Patient 4: DVH of the cumulative plan demonstrating dose distribution to PTV70, PTV60, mandible, larynx, CLAT parotid, and ILAT Parotid

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Figure 10. Patient 5: DVH of the cumulative plan demonstrating dose distribution to PTV70, PTV63, PTV56, mandible, larynx, CLAT parotid, and ILAT Parotid Tables Table 1: QUANTEC and RTOG dose constraints for parotid glands, mandible, and larynx. Organ Volume Bilateral whole parotid glands Parotid Unilateral whole parotid gland (when sparing both parotids) Mandible N/A Dmax < 66 Gy Dmean < 38 Gy Dmean < 20 Gy QUANTEC20 Dmean < 25 Gy RTOG21, 22 20 cc < 20 Gy Dmean < 26 Gy V50 < 30Gy

29 Whole organ Dmax < 66 Gy Dmean < 50 Gy Larynx [Aspiration] Dmean < 44 Gy [Edema] V50 < 27% *Note: Dmean (mean dose), Dmax (maximum dose) Table 2: Prescription and Treatment Planning Parameters Prescription and Treatment Planning Parameters Case Site Patient 1 BOT Patient 2 Tonsil Patient 3 BOT Patient 4 BOT Patient 6 Vallecula Dmax < 45 Gy

Prescription Technique IMRT (SIB) + 3DCRT Fractionation Beam Energy Dose to PTV1 Dose to PTV2 Dose to PTV3 Standard 6 MV 54 Gy 60 Gy 66 Gy Standard 6 MV 50 Gy 64 Gy 70 Gy Treatment Planning Parameters Beam Arrangement (9) Co-planar beams for the initial fields (2) Coplannar beams for the boost fields (3) Coplanar arc beams for PTV1 (2) Coplanar arc beams for PTV2 and (3) Co-planar arc beams for PTV1 (2) Co-planar beams for PTV2 (3) Co-planar arc beams for PTV1 and PTV2 (2) Co-planar beams for PTV3 (9) Co-planar beams for the initial fields VMAT (SEQ) VMAT (SIB) + 3DCRT Standard 6 MV 50 Gy 70 Gy Standard 6 MV 54 Gy 60 Gy 70 Gy Standard 6MV 56 Gy 63 Gy 70 Gy VMAT (SIB + SEQ) IMRT (SIB)

30 PTV3 Gantry Angles/ Rotations PTV1 & PTV2 160 , 120 , 80o, 40o, 0o, 320o, 280o, 240o, 200o
o o

PTV1 205 155 coll 5o 155o 205o coll 355o 205o 155o coll 5o
o o

PTV1 235 105 coll 5o 105o 235o coll 355o 235o 105o coll 5o PTV2 270o and 90o
o o

PTV1 & PTV2 200 160 coll 10o 160o 200o coll 350o 200o 160o coll 10o PTV3 200o - 160o coll 10o 160o - 200o coll 350o
o o

PTV1, PTV2, & PTV3 160o, 120o, 80o, 40o, 0o, 320o, 280o, 240o, 200o

PTV3 270o and 90o

PTV2 210o -179o coll 10o 179o - 210o coll 350o PTV3 210o - 150o coll 20o 150o - 210o coll 340o

*Note: BOT (base of tongue), MV (megavoltage), SIB (simultaneous integrated boost,) coll (collimator) Table 3. Plan Analysis and Evaluation Plan Analysis and Evaluation Structures Patient 1 (Gy) Dmean PTV1 PTV2 PTV3 Ipsilateral parotid 58.4 61.7 64.6 17.3 Dmax 64.6 64.6 61.6 58.8 Patient 2 (Gy) Dmean 51 65.3 71.4 16.4 Dmax 55 69.8 76.3 63 Patient 3 (Gy) Dmean 49 69.7 N/A 19.6 Dmax 52.2 73.7 N/A 70.4 Patient 4 (Gy) Dmean 56/7 69 71.5 17.3 Dmax 70.9 74.1 74.1 70.8 Patient 6 (Gy) Dmean 63.4 70.1 72.7 20.0 Dmax 76.2 76.2 76.2 58.6

31 Mandible Larynx Brain stem Spinal cord Oral cavity 39.7 36.6 1.65 23.3 30.2 63.3 56.8 9.99 45.2 59.2 38.4 51 4.4 26.3 37.8 65 67.8 31.5 35.3 52 40.3 69.4 13.5 22.7 37.2 69.3 72.9 40 38.5 53 40.5 61.4 12.9 21.6 35.5 73.9 72.6 35.5 38.5 64.4 45.4 41.4 17.9 21.8 36.2 74.6 53.5 44.8 42.3 69.5

*Note: the Dmean and Dmax shown here represent the result of the composite plan