Ethical permissions and consent
This single-arm study was approved by the Fudan University Shanghai Cancer Center Institutional Review Board (Reference Number 1410140-8). All patients signed informed consent forms before being enrolled in the present study.
Patients and pretreatment evaluation
Between January 2009 and November 2013, newly diagnosed, non-metastatic, histologically confirmed T4 NPC patients were prospectively recruited at our center. Inclusion criteria were as follows: (1) pathologically confirmed NPC with imaging evidence of intracranial extension (including the extension to the cranial nerves, the cavernous sinus or the parasellar region, or the prepontine region or the posterior cranial fossa); (2) adequate hematologic, hepatic, and renal functions; (3) Karnofsky performance score of 70 or higher; (4) absence of pregnancy or lactation; and (5) absence of previous malignancy or other concomitant malignant disease. Eligible patients were assigned to receive sequential chemoradiotherapy (two cycles of induction chemotherapy + IMRT + two cycles of adjuvant chemotherapy). During analyses, all patients were restaged according to the AJCC 2010 staging classification . Initial evaluation included the following: medical history and physical examination, blood chemistry tests, chest X-ray radiography/computed tomography (CT), abdominal ultrasound/CT, enhanced magnetic resonance imaging (MRI) of the nasopharynx and neck, and nasopharyngoscopy and bone emission CT. Additional investigations were performed only for those patients with suspicious findings. Dental extraction, if deemed necessary, was performed before radiotherapy.
All MRI images were acquired on the same 1.5-T system (Signa Excite HD, General Electric, Milwaukee, WI, USA) with a head and neck coil. The area from the upper border of the orbit to the inferior margin of the sternal end of the clavicle was scanned. Non-enhanced series included T1-weighted fast spin-echo (FSE) images in the axial and sagittal planes [repetition time (TR) 400–500 ms and echo time (TE) 10–15 ms] and T2-weighted FSE images in the axial plane (TR 4000–5000 ms and TE 80–100 ms). T1-weighted fast spoiled gradient echo fat-suppressed axial and coronal sequences (TR 150–250 ms and TE 2–10 ms) were obtained after intravenous injection of gadopentetic acid (Gd-DTPA) at a dose of 0.1 mmol/kg body weight. The thickness/slice gap was 6 mm/1 mm for the axial plane and 3.5 mm/0.5 mm for the sagittal and coronal planes. Images were assessed by a multidisciplinary team of head and neck cancer specialists in our center, which included experienced radiologists and clinicians.
Radiotherapy and dosimetric parameters
Patients were immobilized in the supine treatment position with thermoplastic masks. Intravenous contrast-enhanced CT using a slice thickness of 5.0 mm was performed for planning. An 85-cm aperture CT (Philips, Amsterdam, The Netherlands) was used for analog positioning, and the CT images were transferred to the Pinnacle3 treatment planning system (Philips Medical Systems, Pinnacle v8.0 m, Milpitas, CA, USA) through local area network. For target delineation, images of the T1 sequences with gadolinium-enhanced MRI were fused with the CT simulation images.
The primary gross tumor volume of the nasopharynx (GTVp) and involved lymph nodes (GTVnd) covered all gross tumors found in clinical and imaging examinations. For the GTVp, involved retropharyngeal lymph nodes and the nasopharynx lesions were delineated according to the post-chemotherapy volume. Intracavity lesions were not delineated if they exhibited regression after induction chemotherapy, whereas involved tissues (e.g., the pterygopalatine fossa) were delineated according to the pre-chemotherapy volume of the primary lesion as shown on initial MRI images. Post-chemotherapy volumes of involved neck lymph nodes were used for GTVnd delineation. The clinical target volume (CTV) included the nasopharynx, retropharyngeal lymph node, skull base, entire clivus, pterygoid fossa, parapharyngeal space, entire sphenoid sinus, posterior one-third of the nasal cavity and maxillary sinus, and drainage of the neck (levels II, III, and Va in patients with N0 lesion and levels II–Vb in patients with N1–3 lesions). Critical normal structures, including the brainstem, spinal cord, optic nerves, optic chiasm, lens, eyeballs, temporal lobes, larynx, and parotid glands, were carefully delineated. The prescribed dose was 66.0–70.4 Gy to the primary planning target volume of the nasopharyngeal tumor (PTVp; i.e., GTVp + 5.0 mm) and 66.0 Gy to the planning target volume of involved lymph nodes (PTVnd; i.e., GTVnd + 5.0 mm) in 32 fractions. The PTV60 (high-risk CTV + 5.0 mm) was prescribed 60 Gy in 32 fractions. The PTV54 (low-risk CTV + 5.0 mm) was prescribed 54 Gy in 32 fractions. All patients were irradiated with 1 fraction daily, 5 days per week.
The planning goal was to deliver at least 99% of the prescribed dose to 95% of the GTVp, without exceeding the dose tolerance of the critical neurological organs at risk (OARs). The dose constraints for each normal organ were set according to the Radiation Therapy Oncology Group protocol 0225 . In brief, the ideal maximum point dose (Dmax) was constrained to ≤ 45 Gy for the spinal cord; ≤ 54 Gy for the brainstem, optic chiasma, and optic nerves; and ≤ 60 Gy for the temporal lobes. In exceptional circumstances, the dose constraints could be relaxed to ≤ 50, 60, and 65 Gy, respectively, to 1% volume of the PTV for the above OARs. The dosimetric parameters for each patient were obtained from the dose–volume histogram, including volumes (V), Dmax, dose to 95% of the target volume (D95), dose to 50% of the target volume (D50), minimum point dose (Dmin), and maximum dose to 1% of the volume (D1).
All patients received chemotherapy using the TPF regimen (docetaxel 60 mg/m2 intravenous drip on day 1; cisplatin 25 mg/m2 per day intravenous drip on days 1–3; and 5-fluorouracil 500 mg/m2 per day with a 120-h infusion). One cycle constituted 3 weeks. Induction chemotherapy was designed for two cycles, followed by IMRT 2 weeks later. Four weeks after the completion of radiotherapy, adjuvant chemotherapy was administered.
Assessment and follow-up
Adverse events related to chemotherapy and radiotherapy were graded according to the National Cancer Institute Common Toxicity Criteria version 3.0  and Criteria of the Radiation Therapy Oncology Group in 1995 , respectively. Late neurological toxicities, such as cranial nerve palsy, temporal lobe necrosis, and spinal cord and brain stem injuries, were assessed according to symptoms, physical examinations, and MRI at the time of local failure or the last follow-up. Assessment of tumor response was based on MRI according to the Response Evaluation Criteria for Solid Tumors version 1.1 . Treatment failure, including relapse or progression, was confirmed with nasopharyngoscopy and biopsy or with unambiguous radiologic evidence of progression on MRI. Local failure-free survival (LFFS) was calculated as the time from the date of treatment to the date of first local failure or the last follow-up; regional failure-free survival (RFFS) was calculated as the time from the date of treatment to the date of the first regional failure or the last follow-up; distant failure-free survival (DFFS) was calculated as the time from the date of treatment to the date of the first distant failure or the last follow-up; and overall survival (OS) was calculated as the time from the date of treatment to the date of death or the last follow-up.
Patients were evaluated weekly during radiotherapy. After treatment completion, follow-up occurred every 3 months for the first 2 years, every 6 months for the following 3 years, and annually thereafter. The last follow-up was in October 2016. Each follow-up included medical history, physical examination, and nasopharyngoscopy. Enhanced MRI of the nasopharynx and neck areas was performed every 6–12 months after treatment. Chest X-ray radiography and ultrasonography of the abdomen were conducted annually. Additional tests were conducted when clinically indicated.
SPSS 22.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. In all, missing time-to-event data (due to loss to follow-up or no event observed at the time of predefined time of analysis) were censored. If patients were lost to follow-up, the time-to-event data were censored at the time of previous recorded follow-up. If no events were observed at the time of predefined time of analysis, the time-to-event data were censored at the time of last follow-up. LFFS, RFFS, DFFS, and OS were determined using Kaplan–Meier analysis, and survival rates between different groups were compared using the log-rank test. P values less than 0.05 were considered statistically significant. Survival curves were generated using GraphPad Prism, version 6.0 (GraphPad Software, La Jolla, CA, USA).