Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Nasopharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy

Key Points Question Is intensity-modulated proton therapy (IMPT) associated with fewer treatment-related adverse events and comparable oncologic outcomes for patients with nonmetastatic nasopharyngeal carcinoma (NPC) compared with patients treated with intensity-modulated radiation therapy (IMRT)? Findings In this cohort study of 77 patients with nonmetastatic NPC treated with curative-intent radiotherapy, IMPT treatment was associated with significantly fewer acute adverse events compared with standard-of-care IMRT, with rare late complications. Propensity score–matched analysis demonstrated equally excellent oncologic outcomes in both groups, including 100% locoregional control rate at 2 years in the IMPT group. Meaning These findings suggest that IMPT should be discussed with patients as the potential primary radiotherapy modality for nonmetastatic NPC when it is available because it was associated with less acute toxicity burden compared with IMRT, with potential oncologic benefit in locoregional control.


eMethods. Details of Pretreatment Evaluation, Radiation Technique, Chemotherapy Regimen, and Follow-up Strategy Pretreatment Workup
Pretreatment evaluation included history and physical examination, endoscopic evaluation of the nasopharynx, computed tomography (CT) and/or magnetic resonance imaging (MRI) of the nasopharynx including the neck, pre-treatment EBV status (plasma/tissue), baseline audiogram and dental evaluation, pre-chemotherapy laboratory tests including complete blood count, renal and hepatic function tests. Positron emission tomography (PET)/CT was done to rule out distant metastasis.

Treatment
Patients with stage I disease were treated with radiation alone. Stage II-IVA patients were treated with either concurrent chemoradiation followed by adjuvant chemotherapy or per protocol if patient is enrolled in NRG-HN001: Randomized Phase II and Phase III Studies of Individualized Treatment for Nasopharyngeal Carcinoma Based on Biomarker Epstein Barr Virus (EBV) Deoxyribonucleic Acid (DNA). In brief, after concurrent chemoradiation with cisplatin, patients on NRG-HN001 (ClinicalTrials.gov ID: NCT02135042) were reassessed using post-chemoradiation plasma EBV DNA to determine adjuvant therapy options. Induction chemotherapy was allowed in off-protocol patients.

Radiation therapy
Planning CT and MRI were acquired in the supine position with five-point thermoplastic mask immobilization and co-registered with baseline PET/CT. Gross tumor volume (GTV) was delineated based on imaging studies and clinical exam findings for both primary disease (GTVp) and involved lymph nodes (GTVn). Three-millimeter (mm) margin was added to the GTV to generate clinical target volume (CTV). High-risk CTVs including areas at risk of subclinical disease were generated as CTVp and CTVn. High-risk CTVp included the GTVp along with all the normal areas of spread, i.e skull base, parapharyngeal fat, posteriorly maxillary sinus. High-risk CTVn included GTVn and encompassed bilateral nodal level II-V and bilateral retropharyngeal nodal regions. Low-risk subclinical areas including level IV, VB and supraclavicular area without grossly involved lowlying nodes may be treated with the next lower dose level. Level IB was not included for node negative patients. Inclusion of IB level was at the discretion of the treating radiation oncologist for node positive patients. For IMRT planning, PTVs were generated from CTVs plus 3-5 mm margin to account for daily setup variation. For IMPT, CTV_eval was generated from CTVs plus 2-3 mm margin for optimization. The prescription doses were delivered to PTVs in IMRT and to CTV_eval in IMPT. The prescription doses to the gross disease/high-risk areas/low-risk subclinical areas were 69.96/56-59.4/54.12 GyE in 33 fractions or 70/59-63/56 GyE in 35 fractions. Radiation therapy was delivered once daily, five days per week. All target volumes were treated simultaneously in IMRT with integrated boost and sequentially in IMPT.
Radiation planning was done on Eclipse treatment planning system (Varian, Palo Alto, CA). Radiation therapy was delivered by linear accelerators (Varian, Palo Alto, CA) for IMRT and by the Proteus 235 system (Ion Beam Applications, Louvain-la-Neuve, Belgium) for IMPT. The Monte Carlo algorithm was used for plan calculation accounting for 3-5 mm setup variations and 3.5% range uncertainties for robustness. A relative biological effectiveness (RBE) of 1.1 was used for IMPT optimization. IMPT planning was done using either singlefield optimization or multi-field optimization. Proton beam orientation was selected to avoid potential heterogeneity within structures, for example, air in the nasal cavity and fluid in the sinuses. Typically, 3 beam directions of posterior, left anterior oblique and right anterior oblique fields were used for IMPT. All patients were aligned on a 6 degree-of-freedom treatment couch and underwent daily image-guided radiation therapy.

Chemotherapy
Concurrent chemotherapy was administered with cisplatin, either weekly (40mg/m 2 ) up to 7 cycles or every three weeks (100mg/m 2 ) up to 3 cycles. Induction chemotherapy regimen was administered at the discretion of treating medical oncologist and included cisplatin, carboplatin, gemcitabine, paclitaxel, 5-fluorouracil (5-FU). Adjuvant chemotherapy for patients on NRG-HN001 included cisplatin/5-FU or gemcitabine/paclitaxel. Adjuvant chemotherapy for off-protocol patients was administered at the discretion of treating medical oncologist.

Follow up
All patients were seen by treating radiation oncologist weekly for toxicity evaluation during treatment. Patients were subsequently followed at 8-12 weeks post radiation, then at 3-month interval for the first 2 years, then every 6-12 months thereafter. Follow up imaging included MRI of the nasopharynx and the neck, and PET/CT at appropriate intervals determined by the treating physician. Fiberoptic nasolaryngoscopy examination, focused head and neck physical examination, and toxicity evaluation were done at every radiation oncology follow up visit.