**2.2 Treatment**

124 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

complete history, physical and neurologic examination, hematology and biochemistry profiles, MRI scan of the neck and nasopharynx, chest radiography, and abdominal sonography. Medical records and imaging studies were reviewed retrospectively, and all patients were staged according to criteria in the 6th edition of the AJCC Cancer Staging

**Imaging Protocol:** MR scanning was performed with a 1.5-Tesla system (Signa CV/i, General Electric Healthcare) and a head and neck combined coil. The area from the suprasellar cistern to the inferior margin of the sternal end of the clavicle was examined. T1 weighted fast spin-echo images in the axial, coronal, and sagittal planes (repetition time of 500–600 milliseconds, echo time of 10–20 milliseconds, 5-mm slice thickness with 1-mm interslice gap for the axial plane, 6-mm slice thickness with 1-mm interslice gap for coronal and sagittal planes, and a 512\*512 matrix) and T2-weighted fast spinecho MR images in the axial plane (repetition time of 4000–6000 milliseconds, echo time of 95–110 milliseconds, 5 mm slice thickness with 1-mm interslice gap, and a 512\*512 matrix) were obtained before injection of contrast agent. After intravenous gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA; Magnevist, Schering, Berlin) injection at a dose of 0.1 mmol/kg of body weight, spin-echo T1-weighted axial and sagittal sequences, and spin-echo T1- weighted fatsuppressed coronal sequences were performed sequentially, with parameters similar to

Medical records and imaging studies were retrospectively analyzed. Cranial nerve palsy was diagnosed separately by two radiation oncologists who were unaware of the clinical findings, and clinical nerve palsy was diagnosed by others on the basis of clinical symptoms and a physical examination before treatment. Any disagreements were resolved by consensus. Two radiologists specializing in head and neck cancers, who were unaware of the clinical findings, evaluated the MRI images separately. Any disagreements were resolved by consensus. Soft tissue tumor was observed as intermediate signal intensity on pre-Gd-DTPA T1- and T2-weighted images and an enhancing mass on post-Gd-DTPA T1 weighted images, replacing the normal anatomy of the structure. MRI-detected CN involvement had to meet one of the following criteria: 1) enhancement of soft tissue tumor along the course of the ipsilateral related nerve and replacing the normal structures of the CN on gadolinium-enhanced T1-weighted images [Fig.1]; or 2) perineural spread, defined as an enlargement or abnormal enhancement of the nerve, obliteration of the neural fat pads adjacent to the neurovascular foramina, and neuroforaminal enlargement [Fig.1] [1-3]. Because CNs in the parapharyngeal space could not be identified as isolated structures on MRI, parapharyngeal space invasion could not be regarded as evidence of CN involvement

MRI-detected CN involvement at the following sites were assessed: extracranial segment of the maxillary nerve (V3), pterygopalatine fossa, foramen rotundum, foramen ovale, jugular foramen, hypoglossal canal, inferior orbital fissure, orbital apex, superior orbital fissure, cavernous sinus segment of CNs III-VI, trigeminal ganglion, and CNs in the cistern. By AJCC criteria, parapharyngeal and skull base invasion were classified as T2 and T3, respectively, and intracranial, infratemporal, hypopharynx, or orbital disease was classified

Manua.

in our study.

those used before Gd-DTPA injection.

**2.1 Image assessment and diagnostic criteria** 

All patients were treated by definitive-intent radiation therapy. Our policy was to cover the nasopharynx and the retropharyngeal lymph nodes within the primary target in every radical attempt, and to treat patients with gross lymphadenopathy with whole-neck irradiation. Most patients (773 of 924 or 83.7%) were treated with conventional techniques, 12.7% (118 of 924) with intensity-modulated radiation therapy (IMRT), and 3.6% (33 of 924) with 3-dimensional conformal radiation therapy (3-DCRT). Details regarding the radiation therapy techniques at the Cancer Center of Sun Yat-sen University have been reported previously [5-7].

Most patients (517 of 629 or 82.2%) with stage III or stage IV disease (classified as T3-T4 or N2-N3) received neoadjuvant (137 of 629 or 21.8%), concomitant (374 of 629 or 59.5%), or adjuvant chemotherapy (6 of 629 or 1.0%), in conjunction with a platinum-based therapeutic clinical trial. When possible, salvage treatments (including afterloading, surgery, and chemotherapy) were provided in the event of documented relapse or when the disease persisted despite therapy.

MRI-Detected Cranial Nerve Involvement in Nasopharyngeal Carcinoma 127

(11.2%) paralyzed CNs; among these 15 CNs, carotid sheath (n=13) or retropharyngeal lymph node (n = 1) invasion could be identified along the course of the CNs paralyzed on the ipsilateral side; no tumor could be detected along the course of the remaining paralyzed CNs on the MRI images. Of the 92 divisions of palsied trigeminal nerves, 91 trigeminal nerve palsies (98.9%) showed MRI evidence of 1 or more trigeminal nerve involvements. However, no evidence could be found for the remaining 1 palsied V1 case on MR images.

MRI-detecded CN involvement Sites number\* Palsied CNs, Sites number

Superior orbital fissure 6 III,1; IV,2; V1, 2; VI, 1

Table 1. The Correlation between MRI-detected CN Involvement and the Ipsilateral Related

In 514 T3-4 patients, significant differences were observed in 3-year OS (75.7% vs 89.2%, *P* = 0.001) and DMFS (77.1% vs 87.8%, *P* = 0.002) rates, with better rates observed in the 182 patients who did not demonstrate MRI-detected CN involvement. No significant difference was observed in 3-year LRFS (86.8% vs 91.8%, *P* = 0.067) rates between the patients with and

Because most (97.5%) T4 patients had MRI-detected CN involvement, the prognoses between the T3 patients with and without MRI-detected CN involvement were also compared. All patients with local advanced disease (T3 and T4) in this series were classified into 3 groups: Group 1, T3 disease without MRI-detected CN involvement; Group 2, T3 disease with MRI-detected CN involvement; and Group 3, T4 disease. Significant differences were observed in OS and DMFS rates between Groups 1 and 2 (*P* = 0.009 and *P* = 0.011,

Orbital apex 11 II, 5 Inferior orbital fissure 36 V2, 14 Cavernous segment of III 41 III,10 Cavernous segment of IV 75 IV, 11 Cavernous segment of V1 130 V1, 20 Cavernous segment of V2 144 V2, 31 Cavernous segment of VI 125 VI, 30 Trigeminal ganglion 86 V, 24 Cisternal part of V CN 9 V, 5 Cisternal part of IX-XI 4 IX-XI, 0 Cisternal part of XII 9 XII, 2

\*: Sites number means the number of MRI-detected CN involvement

without MRI-detected CN involvement in T3-4 patients.

**3.3 Prognosis of MRI-detected CN Involvement in T3-4 disease** 

Extracranial part of V3 264 V3, 28 Ovale foramen 223 V3, 28 Pterygopalatine fossa 177 V2, 30 Rotundum foramen 86 V2, 19 Jugular foramen 48 IX, 1; X, 2;XI, 0 Hypoglossal foramen 108 XII, 11

*Basicranial or extracranial*

*Intracranial or orbital*

CN Palsy.

#### **2.3 Statistical analysis**

Patients were followed up at least every 3 months during the first 2 years; thereafter, patients were followed up every 5 months until death. The median follow-up period for the whole group was 40 months (range, 2-56 months). All events were measured from the date of commencement of the treatment. The following endpoints (time to the first defining event) were assessed: overall survival (OS); local relapse-free survival (LRFS); and distant metastasis-free survival (DMFS). Local recurrence was established by fiberoptic endoscopy and biopsy and/or MRI. Distant metastases were diagnosed based on clinical symptoms, physical examination, and imaging methods including chest radiograph, bone scan, CT, and abdominal sonography.

Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL) 12.0 software. The actuarial rates were calculated by the Kaplan-Meier method [8], and the differences were compared by using the log-rank test. Multivariate analyses with the Cox proportional hazards model were used to test independent significance by backward elimination of insignificant explanatory variables [9]. Host factors (age and sex) were included as the covariates in all tests. The chi-square test was used to analyze the relationship between MRI findings and CN palsies. The criterion for statistical significance was set at a = 0.05. The *P* values were based on 2-sided tests.
