Individualization of Clinical Target Volume Delineation Based on Stepwise Spread of Nasopharyngeal Carcinoma: Outcome of More Than a Decade of Clinical Experience

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation

Individualization of Clinical Target Volume Delineation Based on Stepwise Spread of Nasopharyngeal Carcinoma: Outcome of More Than a Decade of Clinical Experience Nina N. Sanford, MD,* Jackson Lau, CMD,* Miranda B. Lam, MD,* Amy F. Juliano, MD,y Judith A. Adams, CMD,* Saveli I. Goldberg, PhD,* Hsiao-Ming Lu, PhD,* Yue C. Lu, BS,* Norbert J. Liebsch, MD, PhD,* Hugh D. Curtin, MD,y and Annie W. Chan, MD* *Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and yDepartment of Radiology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts Received Mar 9, 2018. Accepted for publication Oct 8, 2018.

Summary Toxicity from radiation therapy for nasopharyngeal carcinoma is common, likely in part because of nonstandardized clinical target volume (CTV) delineation. There are no well-established guidelines for CTV delineation with clinical outcome. In this study, we evaluated outcomes for patients with nasopharyngeal carcinoma treated with definitive radiation therapy using a technique of individualized CTV contouring based on stepwise

Purpose: Radiation-related toxicity in nasopharyngeal carcinoma (NPC) is common. There are no well-established guidelines for clinical target volume (CTV) delineation with long-term follow-up. Current consensus continues to rely heavily on bony landmarks and fixed margins around the gross tumor volume (GTV), an approach used to define fields in the conventional 2- and 3-dimensional radiation therapy era. Methods and Materials: We retrospectively evaluated patients with newly diagnosed nonmetastatic NPC treated with definitive radiation therapy using a technique of CTV delineation based on individual tumor extent and the orderly stepwise pattern of tumor spread. Dosimetric comparisons were made between national protocol HN001 and our contouring strategies on a representative early- and advanced-stage NPC. The primary endpoints were patterns of failure and local control; secondary endpoints included regional control and survival, estimated using the Kaplan-Meier method. Results: Between 1999 and 2013, 73 patients (88% with stage 3-4 disease) were treated with median follow-up of 90 months for surviving patients. Median dose to GTV was 70 Gy. Four patients developed local recurrence and 1 patient developed regional recurrence. All locoregional recurrences occurred within the high-dose GTV. The 5-year local control, regional control, and overall survival was 94% (95%

Reprint requests to: Annie W. Chan, MD, Department of Radiation Oncology, 100 Blossom St, Cox 308 Boston, MA 02114. Tel: (617) 7245184; E-mail: [email protected] M.B. Lam is currently at the Department of Radiation Oncology, Brigham and Women’s Hospital, Harvard Medical School, Boston,

Int J Radiation Oncol Biol Phys, Vol. 103, No. 3, pp. 654e668, 2019 0360-3016/$ - see front matter Ó 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ijrobp.2018.10.006

Massachusetts. N.N. Sanford is currently at the Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas. Conflicts of Interest: none AcknowledgmentdWe acknowledge the late C.C. Wang, MD, a pioneer in head and neck radiation oncology. His training, inspiration, and contributions form a firm basis on which our study is bulit upon.

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tumor spread. Despite an overall reduction in target volumes, we achieved high local control and low rates of toxicity with long-term follow-up.

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confidence interval [CI], 85%-98%), 99% (95% CI, 90%-100%), and 84% (95% CI, 73%-91%), respectively. Compared with HN001, our contouring strategy resulted in 62% and 36% reduction in CTV for T1 and T4 disease, respectively. In the T1 tumor, the reduction of doses to the contralateral parotid, optic nerve, and cochlea were 54%, 50%, 34% respectively. In the T4 case, there was a decrease of optic chiasm dose of 46% and contralateral optic nerve of 37%. There were 10 grade 3 toxicities. There was no grade 2 or higher xerostomia and no grade 4/5 toxicity. Conclusions: Our long-term experience with individualized CTV delineation based on stepwise patterns of spread results in excellent local control, with no recurrence outside the GTV. Ó 2018 Elsevier Inc. All rights reserved.

Introduction Patients with nasopharyngeal carcinoma (NPC) are often nonsmokers, nondrinkers, and on average 10 to 20 years younger than those with cancers of other head and neck sites. Because of the anatomic location of NPC, the backbone of local treatment has remained definitive radiation therapy, resulting in control rates of 80% to 90%.1-12 Given excellent tumor control rates compared with other head and neck cancers, good baseline health status, and young age at diagnosis, patients with NPC typically have long projected life expectancies and can experience late effects from treatment.13,14 Technological advancements in radiation therapy technique over prior decades have reduced the rate of xerostomia, but the incidence of other treatment-related morbidities, including hearing loss, endocrine dysfunction, cranial nerve deficits, and temporal lobe radiation necrosis,15-21 remains a concern, leading to lower quality of life and occasionally treatment regret.22,23 Most prior efforts in advancing care of patients with NPC have focused on technologic improvements, including the evaluation of different radiation therapy modalities in clinical trials. Current efforts are centered on immunotherapy and optimization of chemotherapy regimens. Yet perhaps the most important and most costeffective endeavor needed to improve treatment outcomes is accurate delineation of the target volume, which has consistently presented a challenge to radiation oncologists. In the era of 2-dimensional (2D) and 3-dimensional (3D) radiation therapy, the primary tumor was treated with laterally opposed fields.24 Despite the advent of modern imaging techniques including computed tomography (CT), magnetic resonance imaging (MRI), and advanced radiation therapy planning systems, these 2D and 3D borders, or mild modifications of them, continue to be used, including in the ongoing HN001 trial.25 Recently, international guidelines for the delineation of clinical target volume (CTV) for NPC was published, and we await follow-up of their clinical outcomes.26 These guidelines, however, continue to rely heavily on bony landmarks used in eras preceding intensity-modulated radiation therapy (IMRT).

The objective of our study was to evaluate the outcomes of our long-term experience using a technique of CTV delineation based on the orderly, stepwise pattern of NPC tumor spread and individual tumor extent.

Methods and Materials Patients and pretreatment evaluation Between June 1999 and December 2013, 73 patients with consecutive, newly diagnosed NPC with no distant metastasis were treated with CT-based definitive radiation therapy using photon IMRT or protons at the Massachusetts General Hospital (MGH) (Table 1). Patients who had received prior radiation therapy to the head and neck region (n Z 3) were excluded. The median follow-up time from diagnosis for surviving patients was 90 months. Pretreatment evaluation for patients included a direct fiberoptic endoscopic examination, high-resolution MRI of the base of skull, and CT or positron emission tomography (PET)/CT scan of skull base and neck. All initial scans were rereviewed and tumors restaged for this study using the seventh edition (2010) of the American Joint Committee on Cancer TNM staging system.

Treatment Immobilization Patients receiving IMRT were immobilized in the supine position with custom Aquaplast masks. Patients receiving protons before 2008 were immobilized a base-of-skull frame to allow for radiation to the neck nodes. This device was replaced with a Q-fix frame after 2008. A bite block was used when the nasal cavity, soft palate, hard palate, or maxillary sinus was involved or would be included in the CTV to displace these structures from the uninvolved mucosal surfaces. Simulation A high-resolution, thinly cut (at most 2.5 mm) CT scan was obtained in the immobilization position. Approximately 1 to 2 mL/kg per second of intravenous contrast was

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Table 1

Patient, tumor, treatment characteristics

Characteristic Patients Male sex Median age at diagnosis (range), y Race White Asian Hispanic African American Other Tumors AJCC Staging I II III IV T Stage 1 2 3 4 EBV status Positive Negative Unknown Treatment Chemotherapy Induction only Induction plus concurrent Concurrent only Concurrent plus adjuvant Radiation Protons IMRT Median dose to GTV, Gy (range) Median dose to CTV and upper neck, Gy (range) Median dose to lower neck, Gy (range) Median duration of RT, Gy (range)

Number of patients (%) 56 (75) 51 (14-78) 46 18 5 2 2

(63) (25) (7) (3) (3)

2 7 21 43

(3) (10) (29) (59)

10 10 15 38

(14) (14) (20) (52)

39 (53) 18 (25) 16 (22)

3 18 21 28

(4) (25) (29) (38)

61 12 70 60

(84) (16) (70-76) (44-66)

54 (44-70) 60 (42-66)

Abbreviations: AJCC Z American Joint Committee on Cancer; CTV Z clinical target volume; EBV Z Epstein-barr virus; GTV Z gross tumor volume; IMRT Z intensity-modulated radiation therapy; RT Z radiation therapy.

administered. The field of view and the tube current were optimized for each case. Delineation of target volumes Gross tumor volume (GTV), defined as the macroscopic tumor extent, was delineated using a combination of imaging modalities, including high-resolution contrastenhanced MRI, high-resolution contrast-enhanced CT, and PET. These images were used in conjunction with findings on endoscopic examination performed independently by the attending radiation oncologist. An individualized CTV was created using the stepwise pattern of nasopharyngeal tumor spread and tumor extent.

Take, for example, the following: (1) for well-lateralized tumors, only the ipsilateral parapharyngeal space (PPS) was covered so that the contralateral PPS was spared thereby minimizing trismus; (2) the nasal cavity, maxillary sinus, or ethmoid sinus were not routinely covered unless involved or at risk; (3) the pharyngeal airway was omitted to minimize the dose to the oral cavity and soft palate, thereby decreasing incidence of mucositis or dry mouth and velopharyngeal insufficiency, respectively; (4) the sphenoid sinus was not covered routinely unless it was involved or at risk; (5) pterygopalatine fossa and foramen ovale were always covereddipsilaterally for lateralized and bilaterally for bilateral tumors; (6) the foramen lacerum was always covered bilaterally to prevent recurrence in the skull base; (7) the Meckel’s cave and cavernous sinus were always covered for potential retrograde perineural tumor spreadd ipsilaterally for lateralized and bilaterally for bilateral tumors; and (8) the brain parenchyma was never included unless there was gross involvement. We did not rely on bony landmarks to locate the areas at risk. Instead, we used our understanding of anatomy and high-quality planning images to delineate areas at risk precisely. Our CTV delineation technique is described in detail in Table 2 and compared with other protocols and studies. All target volumes were defined on each axial treatmentplanning CT slice. MRI and PET or CT were used to assist in target delineation. In addition to the T1-weighted contrast-enhanced MRI sequence, the noncontrast T1weighted sequence without fat suppression was examined to define the presence or absence of perineural spread in the skull base. The intermediate enhancement of tumor tissues (“evil gray”), which results from obliteration of hyperintense of fat by tumor in areas such as pterygopalatine fossa or PPS, was used to define perineural spread in these regions.

Treatment planning and dosing All patients were treated with external beam radiation therapy with either 6-MV photons with IMRT technique (n Z 12) or 160-MeV or 230-MeV protons using passive scattering technique with a double-scattered proton beam (n Z 61). Proton planning was accomplished using a noncommercial in-house-modified XiO treatment planning system (CMS Inc, St. Louis, MO). Treatment fields were shaped by apertures and range compensators designed for each patient in the treatment planning system. Modulator wheels were selected to spread out the proton Bragg peak. Each treatment plan was divided into 3 sections: primary tumor, upper neck, and lower neck. For treatment of the primary tumor, a 3-field plan consisting of anterior obliques to spare the cochlea and a posterioreanterior beam to maximize both temporal lobe and cochlea sparing was generally used. Given proximity of irregular target volumes to normal

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Clinical target volume delineation protocol HN00127

T1 (well-lateralized) Lateral Bilateral PPS Bilateral pterygoid fossa

Anterior Posterior 1/4 of nasal cavity Posterior 1/4 of maxillary sinus

Superior Skull base (including foramen ovale and rotundum bilaterally) Inferior sphenoid sinus

Posterior Anterior 1/3 clivus

Inferior

Sun Yat-Sen University Cancer Center13

MGH (current study)*

Bilateral PPS (all cases)

Ipsilateral: lateral border of PPS including V3 in PPS; foramen ovale Contralateral: lateral border of nasopharynx Posterior part of nasal cavity (all cases) Ipsilateral: PPF, pterygoid plates Contralateral: anterior border of Pterygoid process (all cases) nasopharynx If nasal cavity involved / median or Nasal cavity only if it is involved anterior; part of nasal cavity, PPF, ethmoid sinus Ipsilateral: foramen lacerum, PPF, Petrous apex (all cases) foramen rotundum, superior orbital Foramen lacerum (all cases) fissure, cavernous sinus, Meckel’s Basis of sphenoid bone (all cases) cave Contralateral: foramen lacerum Prevertebral muscle (all cases) Ipsilateral: at least prevertebral muscle Clivus (all cases) Contralateral: posterior border of the nasopharynx If oral cavity involved, then downward Ipsilateral: tonsillar fossa at least 10 mm Contralateral: inferior border of the nasopharynx

T3 bilateral with base of skull involvement Lateral Bilateral PPS Bilateral pterygoid fossa

Lateral border of PPS including V3 in Bilateral PPS (all cases) PPS and foramen ovale bilaterally If pterygoid process involved, then medial pterygoid muscle, PPF, lateral pterygoid muscle, greater wing of sphenoid bone If foramen ovale involved, then great wing of sphenoid, cavernous sinus Anterior Posterior 1/4 of nasal cavity Posterior part of nasal cavity (all cases) Bilateral PPF and pterygoid plates Posterior 1/4 of maxillary sinus Pterygoid process (all cases) If PPF involved, then infratemporal fossa, inferior orbital fissure, maxillary sinus. Bilateral foramen lacerum, foramen Superior Skull base including foramen ovale and Petrous apex (all cases) rotundum, superior orbital fissure, Foramen lacerum (all cases) rotundum bilaterally cavernous sinus, and Meckel’s cave Basis of sphenoid bone (all cases) Entire sphenoid sinus If basis of sphenoid bone involved, then Cavernous sinus sphenoid sinus, great wing of sphenoid bone If petrous apex involved, then foramen ovale, cavernous sinus, jugular foramen If foramen lacerum involved, then great wing of sphenoid bone, foramen ovale, cavernous sinus If sphenoid sinus involved, then posterior part of ethmoid sinus, cavernous sinus If ethmoid sinus involved, then sphenoid sinus (continued on next page)

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Table 2 (continued ) HN00127

Sun Yat-Sen University Cancer Center13

Posterior Anterior 1/3 clivus (entire if involved) Prevertebral muscle (all cases) Clivus (all cases) If clivus involved, then hypoglossal canal, sphenoid sinus, cavernous sinus If hypoglossal canal involved, then jugular foramen, cistern Inferior T4 with ipsilateral foramen rotundum, ipsilateral PPF involvement Lateral Bilateral parapharyngeal space Bilateral parapharyngeal space (all Bilateral pterygoid fossa cases) -If medial pterygoid muscle involved, then lateral pterygoid muscle, PPF -If lateral pterygoid muscle involved, then infratemporal fossa, great wing of sphenoid bone Anterior Posterior 1/4 of nasal cavity Posterior part of nasal cavity (all cases) Posterior 1/4 of maxillary sinus Pterygoid process (all cases)

Petrous apex (all cases) Foramen lacerum (all cases) Basis of sphenoid bone (all cases) If cavernous sinus involved, then sphenoid sinus, inferior orbital fissure, orbital apex Posterior Anterior 1/3 clivus (entire if involved) Prevertebral muscle (all cases) Clivus (all cases) Superior Skull base (including foramen ovale and rotundum bilaterally) Entire sphenoid sinus Cavernous sinus

Inferior

MGH (current study)* Entire clivus and basiocciput

Tonsillar fossa bilaterally Ipsilateral: lateral border of PPS including V3 in PPS and foramen ovale Contralateral: lateral border of nasopharynx

Ipsilateral: PPF, pterygoid plates, inferior orbital fissure -Contralateral: anterior border of nasopharynx. Bilateral foramen lacerum Ipsilateral: foramen rotundum, superior orbital fissure, cavernous sinus, Meckel’s cave

Amount of clivus and basiocciput coverage depends on the posterior extent of tumor Ipsilateral: Tonsillar fossa Contralateral: inferior border of the nasopharynx

Abbreviations: PPF Z pterygopalatine fossa; PPS Z parapharyngeal space. * For T1-T2 bilateral disease, the same border for the ipsilateral side is used for the contralateral side.

structures, a patch combination technique was often used to optimize dose distribution.28 Given the unique physical properties of the proton beam, in particular the sensitive dependence of beam penetration on various uncertainties, the approach of using a planning target volume, as typically practiced in photon treatment, might not provide robust target coverage with optimal normal tissue avoidance. As a result, measures to ensure plan robustness must be taken per beam and per specific uncertainty. These include adjustments in the following: (1) lateral margins to account for uncertainties in beametarget alignment, (2) smearing of compensator to account for beam penetration uncertainties owing to anatomic misalignments and variations, (3) beam range to account for uncertainties in relative stopping power calculations to ensure distal coverage, and (4) modulation width of the spread-out Bragg peak to ensure dose coverage on the proximal side. We used forward planning to achieve these goals, not inverse optimization. In this study, robustness of the proton plans was achieved by adding the following

margins: a 3.5% þ 1 mm was added to the range, a compensator smearing of 3 mm was applied to account for setup uncertainty, and an aperture margin of 8 mm to account for the lateral penumbra and setup uncertainty. Beginning in 2012, patients underwent resimulation 3 to 5 weeks into treatment and were replanned if there was significant reduction or increase in tumor size or a change in aeration of nasal or sinus cavities. During treatment, digital 2D imaging to confirm isocenter and portal imaging of the treatment fields was performed daily. IMRT patients were planned using Corvus (Nomos, Sewickley, PA) or Raystation (RaySearch Medical Laboratories, Stockholm, Sweden) which uses multicriteria optimization to balance tradeoffs between optimizing target volume coverage and minimizing radiation to healthy structures. A 3-mm planning target volume was used to account for setup uncertainty. Daily cone beam CT was used for setup verification. The median delivered dose to the GTV was 70 Gy (range, 69.96-76 Gy), to the CTV and upper neck nodes was

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60 Gy (range, 44-66 Gy), and to the lower neck nodal levels IV and V was 54 Gy (range, 44-69.96 Gy). Sixty-one patients (83.5%) were treated with proton radiation therapy; a relative biologic effectiveness value of 1.1 was used for these patients.29 The median overall treatment time was 50 days (range, 42-66 days). Our study was approved by the institutional review board at MGH. Chemotherapy Seventy patients (96%) received chemotherapy, including 3 (4%) receiving induction chemotherapy alone, 18 (25%) receiving induction and concurrent, 21 (29%) receiving concurrent alone, and 28 (38%) receiving concurrent and adjuvant (Table 1). Follow-up A baseline posttreatment MRI of the nasopharynx and CT scan of the neck was obtained 2 months after completion of treatment, then every 4 to 6 months for the first 2 years, and annually thereafter. Acute and late normal tissue toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) toxicity scale version 4.30 For cases of local failure, the diagnostic CT or MRI documenting recurrence was directly compared with the planning CT scan with superimposed isodose lines to determine the relationship between the site of failure and radiation therapy plan.

Dosimetric comparison We chose 2 representative cases from our cohort, one early stage and one locally advanced, and recontoured both patients per the HN001 protocol guidelines.26 These 4 volumes were replanned with volumetric-modulated arc therapy (VMAT) by an experienced planner. For this comparison, we used one of the dosing regimens on protocol, which involved treating the CTV1 (GTV plus 3 mm expansion for both HN001 and MGH) to 70 Gy in 2-Gy fractions while simultaneously treating the CTV2 (as specified in Table 2) to 56 Gy in 1.6-Gy fractions. Target coverage was per protocol. Constraints to organs at risk were the same or more restrictive compared with the protocol (Table 3). After the best optimized plans were achieved, we compared dose to normal structures between the 2 contouring strategies.

Statistical methods The primary endpoints were patterns of failure and local control. The secondary endpoints included regional control, freedom from distant metastasis, disease-specific survival, disease-free survival, and overall survival. Locoregional control and freedom from distant metastasis were measured from the end date of radiation treatment to the date of local or regional relapse and date of distant metastasis, respectively, censoring patients at last follow-up or death.

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Locoregional and distant failures include all known recurrences and were not limited to first failure. Disease-free survival was calculated from end of radiation until evidence of disease (local, regional, or distant) or death, censoring at last follow-up for patients who were alive and without evidence of disease at last follow-up. Disease-specific survival was calculated from end of radiation until death of disease. Overall survival was calculated from the end of radiation until death, censoring at last follow-up for patients who were alive. The Kaplan-Meier product-limit method was used to estimate local control, regional control, freedom from distant metastasis, and survival probabilities. The log-rank test was used to compare the toxicity between the IMRT and proton treatment groups.

Results Stepwise patterns of spread of NPC Based on review and studying of many NPC cases by the 2 senior authors in the current investigation, we conclude that NPC spreads in a stepwise and orderly fashion. The delineation of CTV should therefore be based on this organized and predictable pattern of spread. NPC spreads initially by direct extension, commonly along the path of lesser resistance. Perineural spread, exclusively, is uncommon. Perineural spread is a result of direct tumor extension or invasion into the nerve; the tumor then uses the nerve as a conduit for anterograde or retrograde spread. NPC commonly spreads through the pathways outlined as follows. 1. Lateral tumor extension. Tumor commonly spreads laterally to the parapharyngeal region. The pharyngobasilar fascia bridges the gap between the superior border of the superior constrictor and the base of skull. There is a gap between the upper margin of the pharyngobasilar fascia and the skull base called the sinus of Morgagni, through which the levator veli palatini and the eustachian tube pass on their way from the skull base to the soft palate and nasopharynx, respectively. This natural gap permits the tumor to escape laterally into the parapharyngeal region in the area of the third division of the trigeminal nerve just inferior to foramen ovale. Retrograde perineural spread can carry tumor along V3 into foramen ovale, then to the gasserian (trigeminal) ganglion and Meckel’s cave, and finally along the preganglionic segment of the trigeminal nerve toward the pons. Tumor can then continue to spread anterograde from the gasserian ganglion along V2 through the foramen rotundum toward the pterygopalatine fossa. 2. Superior tumor extension. Through direct superior extension, NPC reaches the inferior surface of the basiocciput and basisphenoid. Just off midline, the tumor accesses the foramen lacerum and petroclival fissure. At

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Table 3

Comparison of doses to organs at risk, normal tissues, and target coverage Case 1 (early stage)

Organs at risk Brain stem Right mastoid Left mastoid Optic chiasm Right cochlea Left cochlea Right temporal lobe Left temporal lobe Right parotid Left parotid Right optic nerve Left optic nerve Oral cavity Right lens Left lens Right pterygoid muscles Left pterygoid muscles Right lacrimal gland Left lacrimal gland Right retina Left retina Normal tissues Right maxilla Left maxilla Nasal cavity Ethmoid sinus Sphenoid sinus Right frontal lobe Left frontal lobe Target coverage PTV70 Gy V100% D99% D0.03 mL PTV 56 Gy V56 Gy

Maximum, 54 Mean, 10 Gy Mean, 20 Gy Maximum, 54 Mean, 20 Gy Mean, 30 Gy Maximum, 60 Maximum, 60 Mean, 26 Gy Mean, 26 Gy Maximum, 54 Maximum, 54 Mean, 25 Gy Maximum, 10 Maximum, 10 Mean, 40 Gy Mean, 60 Gy Mean, 10 Gy Mean, 20 Gy Mean, 15 Gy Mean, 15 Gy Mean Mean Mean Mean Mean Mean Mean

dose dose dose dose dose dose dose

90%-95% 90%-93% 115%-120% 90%-95%

Gy

Gy

Gy Gy

Gy Gy Gy Gy

Case 2 (advanced stage)

HN001 Plan (cGy)

MGH Plan (cGy)

Difference (%)*

HN001 Plan (cGy)

MGH Plan (cGy)

Difference (%)*

5368 921 1740 1767 2659 2994 5977 5994 959 1245 3298 3540 1092 696 971 3915 4744 354 523 835 861

5392 757 1535 2654 1747 2877 3717 5985 445 1235 1637 3762 772 468 719 2012 4386 213 428 540 639

þ0.4 e18 e12 þ50 e34 e4 e38 e0.1 e54 e1 e50 þ6 e29 e33 e26 e49 e8 e40 e18 e35 e26

5865 1027 2035 4197 1709 7147 5956 6701 1777 2338 5105 4994 1814 908 986 4473 6054 419 630 1208 1328

5641 902 1956 2260 1461 6786 5927 6718 1487 2261 3226 4266 1680 665 537 3896 5840 327 509 1012 1011

e4 e12 e4 e46 e15 e5 e0.4 0.2 e16 e3 e37 e15 e7 e27 e46 e13 e4 e22 e19 e16 e24

5072 5311 5288 3828 5942 157 136

3505 4828 4585 2569 4728 126 152

e31 e9 e13 e33 e20 e20 þ12

4949 5229 4633 3768 6491 178 176

4530 5425 4305 2427 6248 135 142

e8 þ4 e7 e36 e4 e24 e19

95% 97% 107%

95% 97% 107%

N/A N/A N/A

91% 95% 108%

95% 95% 108%

N/A N/A N/A

95%

96%

N/A

94%

95%

N/A

* A negative percent indicates that dose in the MGH plan was lower whereas a positive percent indicates higher dose in the MGH plan.

the foramen lacerum, the tumor can reach and encase the internal carotid artery and can gain access to the cavernous sinus. Tumor can spread directly through the bone to involve the foramen ovale, Meckel’s cave, and cavernous sinus. 3. Anterior tumor extension into posterior aspect of nasal cavity and into the pterygopalatine fossa. From the pterygopalatine fossa, the tumor can spread to the following: (1) inferior and superior orbital fissures and into the orbit, (2) infratemporal fossa, (3) vidian canal, and (4) foramen rotundum. Perineural spread can carry tumor posteriorly along the maxillary division of the trigeminal nerve (V2) into the cavernous sinus region. Tumor reaching the foramen ovale and Gasserian

ganglion can also pass anterograde through foramen rotundum into the pterygopalatine fossa. 4. Posterior tumor extension into the prevertebral muscles and basiocciput. 5. Caudal tumor extension along the lateral pharyngeal wall and the anterior and posterior tonsillar pillars.

Tumor control During a median follow-up of 90 months, there were 4 local recurrences. The median time to local recurrence was 13 months (range, 7-26 months). Three patients had

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B

100 80 60 40 20

80 60 40 20 0

0 0

2

4

6

0

8

2

4

6

8

Follow-up Time (years)

Follow-up Time (years)

C

D 100

100

80

80

Probability (%)

Probability (%)

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100

Probability (%)

Probability (%)

A

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60 40 20 0

60 40 20 0

0

2

4

6

8

0

Follow-up Time (years)

2

4

6

8

Follow-up Time (years)

Fig. 1. (A) Local control, (B) regional control, (C) disease-specific survival, and (D) overall survival of the entire cohort. The shaded gray bands represent the 95% confidence interval. isolated local recurrence including 2 with stage IVA (T4N0, T4N2) disease at diagnosis and one who was initially stage III (T3N2). One patient with simultaneous local and regional recurrence had initial stage II T1N1 left NPC that recurred in the left nasopharynx, 2 left level II nodes, and one left retropharyngeal node. All local recurrences recurred within the 70-Gy GTV target. For the entire cohort, the rates of 2-, 5- and 7-year local control rates were 96% (95% confidence interval [CI], 87%-99%), 94% (95% CI, 85%-98%), and 94% (95% CI, 85%-98%), respectively (Fig. 1A). There was one case of regional recurrence, as described earlier, that also occurred in the initial 70-Gy target volume. The 2-, 5- and 7-year regional control rates were all 99% (95% CI, 90%-100%; Fig. 1B). Seven patients developed distant metastasis at a median time of 13.5 months (range, 1-67 months). The overall rates of 2- and 5-year freedom from distant metastases were 91% (95% CI, 82%-96%) and at 7 years was 89% (95% CI, 82%-95%). The rates of disease-free survival at 2-, 5-, and 7-years were 85% (95% CI, 74-91%), 80% (95% CI, 69%-88%), and 78% (95% CI, 66%-86%), respectively. The rates of disease-specific survival at 2-, 5- and 7-years were 96% (95% CI, 87%-99%), 92% (95% CI, 83%-97%), and 91% (95% CI, 80%-96%), respectively (Fig. 1C). The 2-, 5- and 7-year rates of overall survival were 92% (95% CI, 82%96%), 84% (95% CI, 73%-91%), and 83% (95% CI, 71%90%), respectively (Fig. 1D).

Toxicity Treatment toxicity was scored using the CTCAE version 4.0.30 For patients who received combined modality treatment with chemotherapy, treatment toxicity was recorded as radiation related even though they could also have been related to chemotherapy. Adverse effects were considered late if occurrence was greater than 90 days after completion of radiation treatment.

Acute toxicity During radiation therapy, 3 patients were hospitalized for dehydration and poor oral intake necessitating intravenous fluid therapy. Six patients had a treatment break with reasons including cholecystitis requiring acute surgery (n Z 1), severe nausea (n Z 1), gastrostomy tube placement (n Z 2), and technical issues with our radiation equipment (n Z 1). One patient required a weeklong treatment break while hospitalized in the intensive care unit for 5-FUeassociated colitis. Twenty-nine patients underwent gastrostomy tube placement before or during radiation treatment.

Late toxicity Proton There were 8 grade 3 late toxicities and no grade 4 or 5 toxicities. There was no grade 2 or higher xerostomia. Four

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Fig. 2. (A) Representative axial slices showing our contouring strategy for an early-stage and (B) locally advanced case of nasopharyngeal carcinoma. The gross tumor volume (GTV) is in solid red and the clinical target volume (CTV) is outlined in thick bright yellow. (C) Comparison of CTV delineation techniques of HN001 (left panel) versus MGH (right panel) for early-stage and (D) locally advanced (2-dimensional) nasopharyngeal carcinoma. The GTV is in solid red, and CTV is in solid green. The 70-Gy line is in red, the 56-Gy line is in green, the 30-Gy line is in blue, and the 20-Gy line is in yellow. Only selected avoidance structures are shown.

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Fig. 2.

patients (7%) experienced grade 3 hearing loss (requiring hearing aids) at a median time of 10 months (range, 214 months) after completion of radiation therapy; 3 were unilateral and 1 was bilateral. One patient developed grade 3 deficit of cranial nerves X, XI, and XII at 48 months. Two patients developed aspiration pneumonia at 24 and 108 months, requiring intravenous antibiotics. There was one grade 3 treatment effect in the temporal lobe requiring transient steroid and long-term antiepileptic medication. IMRT Among the 12 patients treated with IMRT, 1 patient (8.3%) experienced bilateral grade 3 hearing loss 9 months after radiation therapy. There was also 1 case (8.3%) of

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(continued).

aspiration pneumonia at 15 months. There was no grade 4 or 5 toxicities and no grade 2 or higher xerostomia.

Dosimetric comparison Case 1 (early stage) Our representative early stage case consisted of a T1N0 left superior nasopharyngeal tumor that extended above the pharyngobasilar fascia but not into adjacent muscle, fat, or bone. The mass approached but did not cross midline and abutted the left carotid artery. There was no radiographic evidence of perineural invasion. Target coverage in both the HN001 and MGH plan was met (Fig. 2A). Our contouring

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Table 4

Literature review T3-T4 stage (%) and AJCC III-IV (%)

Median follow-up (years)

84 (all concurrent [cisplatin] and adjuvant [cisplatin, 5-FU])

34 59

2.6 (surviving patients only)

100 (all concurrent [cisplatin, bevacizumab] and adjuvant [cisplatin, bevacizumab, 5-FU]) 83 (all concurrent [cisplatin])

57 89

2.5

71 83

3.9

57 69

4.2

concurrent + adjuvant [cisplatin, 5-FU], and 5 neoadjuvant or adjuvant) 2009-2010, 869 IMRT 85z (34 induction retrospective 66 Gy/30 fx (GTV npx, T1-T2), + concurrent, 28 70.2 Gy/32 fx (GTV npx), T3induction + adjuvant, T4), 66 Gy/30-32 fx (GTV 12 induction, 11 node), 60 Gy/30-32 fx (CTV concurrent  adjuvant)

40 64

4.5

Lin, 2016; Sun Yat-Sen University, Guangzhou, China10

2009-2012, prospective

67 75

4.2

Yang, 2018; Multicenter, China12

2012-2015, prospective

100 (all induction [ocetaxel/cisplatin or cisplatin/5-FU] + concurrent [cisplatin])

61 100

2.9

Sanford, 2018; MGH (current study)

1999-2013, prospectivee retrospective

96 (4 induction [docetaxel, cisplatin, 5-FU], 25 induction + concurrent [cisplatin], 29 concurrent, 38 concurrent + adjuvant [carboplatin/5-FU])

72 88

7.5

Study

Study period and design

N

RT (modality, dose)

2003-2005, Lee, 2009; prospective RTOG 0225, multi-institutional, USA1 2006-2009, Lee, 2012; prospective RTOG 0615, multi-institutional, international, USA2

68 IMRT

Wang, 2013; Guangxi 2006-2008, prospective Medical University, Nanning, China3

300 IMRT

Sun, 2014; Sun Yat-Sen University, Guangzhou, China4

Ou, 2015; Fudan University, Shanghai, China9

70 Gy/33 fx (GTV), 59.4 Gy/33 fx (CTV), 50.4 Gy/28 fx (lower neck)

44 IMRT 70 Gy/33 fx (GTV), 59.4 Gy/33 fx (CTV high-risk), 54 Gy/ 28 fx (CTV low risk), 50.4 Gy (lower neck)

Chemotherapy (% receiving, type)

68-72 Gy/30-32fx (GTV npx), 66-70 Gy/30-32 fx (GTV node), 60-64 Gy/30-32 fx (CTV high-risk), 52-56 Gy/3032 fx (CTV low risk), 50.455.8 Gy/28-31 fx (lower neck) 2001-2008, 868 IMRT 76 (29 concurrent retrospective 68/30 fx Gy (GTV npx), 60[cisplatin], 26 induction 66 Gy/30 fx (GTV nodes), [paclitaxel, carboplatin, 60 Gy/30 fx (CTV high-risk), cisplatin, 5-FU] 54 Gy/30 fx (CTV low risk), + concurrent, 6 50 Gy/25 fx (lower neck)

high-risk), 54 Gy/30-32 fx (CTV low risk) 220 IMRT 86 (not specifieddmixture 68-70 Gy/33 fx (GTV npx), 64of neoadjuvant, 70 Gy/33 fx (GTV node), concurrent, adjuvant) 60 Gy/30 fx (CTV high-risk), 54-56 Gy/30 fx (CTV low risk)

233 IMRT 70 Gy/33 fx (GTV npx), 70 Gy/33 fx (GTV node), 64 Gy/33 fx (CTV high-risk), 54 Gy/33 fx (CTV low risk)

73 IMRT: 16% Protons: 84% 70 Gy/35 fx (GTV), 60 Gy/30 fx (CTV), 54 Gy/30 fx (lower neck)

Abbreviations: AJCC Z American Joint Cancer Committee; CTCAE Z Common Terminology Criteria for Adverse Events; CTV Z clinical target volume; GTV Z gross tumor volume; IMRT Z intensity modulated radiation therapy; npx Z nasopharynx; NR Z not reported. * Toxicity includes grade 3 plus late toxicity and any grade 5 toxicity. Grading was via RTOG and EORTC, unless otherwise specified. y Estimated from Kaplan-Meier curve. z Regimens of induction and adjuvant chemotherapy including cisplatin/5-FU/docetaxel, docetaxel/cisplatin, cisplatin/5-FU, or gemcitabine/cisplatin. x Local recurrence-free survival. k Regional recurrence-free survival. { Grade not specified.

Volume 103  Number 3  2019 Table 4

CTV delineation guidelines for NPC

Literature review (continued)

Local control, 5-year (%)

Regional control, 5-year (%)

Disease-free survival, 5-year (%)

Overall survival, 5-year (%)

93 (2-year)

91 (2-year)

73 (2-year)

80 (2-year)

Grade 3: 20% Grade 4: 0% Grade 5: 4.4%

NR

75 (2-year)

91 (2-year)

Grade 3: 17% Grade 4: 0% Grade 5: 0%

NR

84 (locoregional control) (2-year)

Toxicity*

Patterns of relapse

90y

85y

NR

80y

Grade 3: 11% Grade 4: 0% Grade 5: 0% (CTCAE)

NR

92

96

77

NR

Grade 3: 6.3% Grade 4: 0% Grade 5: 0%

NR

90 (LRFS)x

95 (RRFS)k

76

84

Grade 3-4: 4% Grade 5: 0%

NR

95y

95y

87y

90y

Grade 3 xerostomia: 0.5% Temporal lobe injury: 6% (grade not specified) Grade 5: 0%

60y

74y

80

84

Grade 3 xerostomia: 6% Vision damage{: 6% Hearing loss: 21% Tinnitus: 13% Grade 4: 0% Grade 5: 0% Proton: Grade 3: 12% Grade 4: 0% Grade 5: 0% IMRT: Grade 3: 17% Grade 4: 0% Grade 5: 0% (CTCAE)

76y (local-regional failure-free survival)

94

665

99

10/11 local recurrence were in-field, 1 marginal recurrence; 5 of 6 regional recurrences in the previously treated level IIB, 1 in level I (not previously treated) NR

All local and regional recurrences (level IIA and retropharyngeal nodes) were within the high-dose GTV

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Sanford et al.

strategy resulted in dose reduction to multiple ipsilateral normal structures (Table 3). The maximal dose to the optic chiasm was 50% higher in our plan given our elective ipsilateral coverage of the superior orbital fissure, Meckel’s cave, and cavernous sinus, but still well under the maximum dose constraint of 54 Gy (Fig. 2C). The volume of CTV56 was 145.5 mL and 55.4 mL, respectively, for the HN001 and MGH, respectively. With the use of MGH CTV delineation strategy, there was a 62% reduction in CTV volume for early-staged NPC. Case 2 (advanced stage) Our locally advanced T4 case consisted of a large, bilateral nasopharyngeal mass appearing to originate in the left fossa of Rosenmu¨ller. Posteriorly, the mass invaded into the clivus on the left side. Superiorly and anteriorly, the mass involved the left pterygoid plates and medial and lateral pterygoid muscles on the left side, left cavernous sinus, left pterygopalatine fossa, and left foramen ovale. Target coverage was achieved using both the HN001 and MGH contouring strategy (Fig. 2B). Our strategy again resulted in dose reduction to several normal structures (Fig. 2D, Table 3). The volume of CTV56 was 245.8 mL and 156.7 mL, respectively, for the HN001 and MGH, respectively. With the use of MGH CTV delineation strategy, there was a 36% reduction in CTV volume for advancedstaged NPC.

Discussion This report summarizes our long-term treatment outcome of radiation therapy for NPC using a refined CTV delineation method. Our CTV was based on the following: (1) the individual tumor extent, (2) the distinctive orderly and stepwise pattern of spread of NPC, and (3) the visualization of the pathways of spread in our high-resolution planning CT and MRI. With our customized CTV protocol, we achieved a 5-year local control of 94% in a cohort of patients with advanced tumors (88% stage III-IV disease, 72% T3-T4). Importantly, with a median follow-up of 90 months in surviving patients, there was no marginal or out-of-field recurrence with our individualized-volume technique. Treatment of NPC with IMRT has been reported in a series of studies with favorable outcomes. As detailed in Table 4, most of these studies have median follow-up of 2 to 4 years.1-4,9,10,12 Rates of local control ranged from 81% to 95% at 2 to 5 years. Compared with the majority of these studies, ours has the longest follow-up and one of the highest local control rates. The method of CTV delineation for NPC has not been addressed adequately. Even in the IMRT era, coverage of microscopic disease spread has largely been based on target volumes from the 2D and 3D conventional radiation therapy era. For example, in RTOG 0225, a phase 2 study evaluating IMRT published in 2009, the CTV included the

International Journal of Radiation Oncology  Biology  Physics

entire clivus, skull base, parapharyngeal space, inferior sphenoid sinus, posterior third of the nasal cavity, and maxillary sinuses.1 In RTOG 0615, published 3 years later, the high-risk CTV was nearly identical with the exception that in certain lower risk cases, half of the clivus and the posterior fourth of the nasal cavity were included.2 Since the publication of these important trials, several radiation oncology teams around the world have made attempts to refine the CTV. In 2016, a study by Lin et al10 at Sun YatSen University reported the outcomes of 220 patients with NPC treated with IMRT using a customized CTV.10 Although patients in both their and our studies received individualized radiation therapy treatment plans where prophylactic irradiation is delivered downstream to sites of gross tumor invasion, there are important differences in the actual target volumes between the 2 studies, as detailed in Table 2. International guidelines for NPC contouring were recently published.26 Several points regarding this valuable and important study merit discussion. First, no clinical outcome was reported with the use of these guidelines. Second, there is significant discordance among experts in the consensus panel regarding certain aspects of CTV delineation. For example, only 55% of panelists agreed to include the entire nasopharynx in the high-risk CTV, 76% of the experts favored using a 5 mm expansion around the high-risk primary CTV as the intermediate-risk primary CTV, and 65% of panelists advocated for excluding air cavities within the CTV regions. Third, these guidelines continue to use traditional bony landmarks to cover microscopic disease. For example, rather than delineating specifically the foramen ovale and vidian canal in the CTV, a 5-mm expansion around the posterior wall of the maxillary sinus was advised to include these structures. These guidelines therefore highlight the marked variation in practice among radiation oncologists, and they provide an important landmark to serve as a comparison for future guidelines and studies. In comparison to such guidelines, our CTV does not involve routine and mandated coverage of bone, air, and fluid cavities. For example, we do not routinely cover the nasal cavity, maxillary sinus, and sphenoid sinus unless they are involved or at risk. We do not cover the pharyngeal airway anterior to the nasopharynx to minimize dose to the soft palate, thereby decreasing the risk of long-term velopharyngeal insufficiency and nasal regurgitation. We also have more accurate coverage of privileged neural foramina, which might explain our excellent local control rate and absence of margin or out-of-field recurrence, despite decreased radiation therapy to normal tissues. Radiation toxicity and poor quality of life are common among long-term survivors of nasopharyngeal carcinoma.22 By decreasing the dose to critical normal structures, our contouring strategy aims to minimize late effects of treatment. With the use of concurrent cisplatin, hearing loss continues to be one of the most common and debilitating side effects, even in the IMRT era. Bilateral deafness has

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been associated with social isolation and depression in patients with NPC.27 As cisplatin cannot be omitted in the treatment of NPC, it is of utmost importance to lower radiation dose to the cochleae. Our CTV delineation results in significant decreased dose to the contralateral cochlea, with dose reduction of 34% and 15% in the early and advanced NPC cases, respectively (Table 3). Other common however less frequently discussed toxicities of radiation therapy for NPC include trismus, middle ear effusion, mastoiditis, and long-term sinonasal congestion; the incidence of such complications is likely underestimated in the sparse current literature addressing these symptoms.31-34 By decreasing radiation therapy to the pterygoid muscles and air spaces including the mastoids, nasal cavity, and paranasal sinus, our contouring strategy aims to reduce the incidence of these late toxicities. Our contouring technique results in dose reduction of 49% and 13% to the contralateral pterygoid muscles in early and advanced cases, respectively. There was also dose reduction of 33% and 36% to the ethmoid sinuses in the early and advanced cases, respectively (Table 3). By minimizing dose to the oral cavity, we aim to reduce the incidence of acute mucositis, which contributes to pain, weight loss, and need for G-tube experienced during treatment, increased incidence of treatment breaks, and dysphagia post treatment. In the long term, decreased radiation therapy dose to the minor salivary glands in the oral cavity and the contralateral parotid gland should decrease the incidence of xerostomia, whose incidence remains high11 despite the advent of IMRT. Our contouring technique results in dose reduction of 54% and 16% to the contralateral parotids in the early and advanced cases, respectively (Table 3). There are several important limitations to our study. Although all patients were treated with a protocolized target volume, the study was retrospective with small patient numbers. In addition, there was variation in treatment modality, radiation therapy dosing, and the use of chemotherapy among our cohort. We overcame this shortcoming by including consecutive patients who were treated at a single center, performing an in-depth review of medical records and imaging studies, and providing continuous, long-term follow-up. In conclusion, our individualized, stepwise CTV delineation method is feasible in a wide range of NPC patients, and it results in excellent clinical outcomes. We did not observe an increase in rate of local or regional recurrence despite an overall reduction in the CTV. Selective individualized treatment might effectively avoid unnecessary radiation to critical normal structures, thereby decreasing the risk of long-term toxicity.

CTV delineation guidelines for NPC

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

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