[18F] FDG PET/CT and Head and Neck MRI in the Diagnosis and Prognosis of Moroccan Patients With Nasopharyngeal Carcinoma

Purpose: While nasopharyngeal carcinoma (NPC) management in Morocco is still based on conventional work-ups: a head and neck computed tomography (HN-CT), thoracic and abdominal CT and bone scan, the combination of HN magnetic resonance imaging (HN-MRI) and 2-Deoxy-2-[ 18 F] uoro-D-glucose positron emission tomography/computed tomography ([ 18 F] FDG PET/CT) is now widely used in the diagnostic and follow-up of this malignancy. Methods: In this prospective study, [ 18 F] FDG PET/CT and HN-MRI outcomes of 117 NPC patients diagnosed between January 2017 and December 2018 were investigated in order to assess their usefulness in routine management of Moroccan patients with NPC. The concordance between HN-MRI and [ 18 F] FDG PET/CT in Tumor (T) and Nodal (N) classication was assessed and the association between [ 18 F] FDG PET/CT metabolic parameters (Tumor- maximum standardized uptake value (T-SUV max), Nodal (N-SUV max), node-to-tumor SUV ratio (NTR) and distant metastasis (M-SUV max), TNM staging system, NPC stages and patient’s survival outcomes was evaluated. Results: Our results showed a moderate concordance between T-TEP and T-MRI categories with a Cohen kappa coecient (k) at 0.45, and a mediocre concordance between N-TEP and N-MRI (k=0.3). Metabolic parameters of the [ 18 F] FDG PET/CT were assessed; N-SUV max values were signicantly higher in patients with advanced nodal involvement, with a mean of 7.4, 9.7 and 11.0 for patients with N1, N2 and N3 nodal categories, respectively (p<0.05). overall, N-SUV max, NTR were independent prognostic markers for overall survival and progression free survival in Moroccan NPC patients (p<0.05). Conclusion: Our ndings provide additional evidence into the complementary roles of HN-MRI and [ 18 F] FDG PET/CT in TNM and overall staging of NPC. To the best of our knowledge, this is the rst Moroccan study to highlight N-SUV max and NTR derived from [ 18 F] FDG-PET/CT as promising metabolic biomarkers for NPC prognosis. The present study was designed to assess the usefulness of HN-MRI and [ 18 F] FDG PET/CT in routine diagnosis and prognosis of NPC for a better management of this disease in Morocco. The concordance between HN-MRI and [ 18 F] FDG PET/CT in Tumor and Nodal classication was assessed and the association between 18 F-FDG-PET/CT metabolic parameters (T-SUV max, N-SUV max, NTR and Metastatic (M-SUV max), TNM staging system, NPC stages and patient’s survival outcomes (overall survival (OS), loco-regional recurrence -free survival (LRRFS) and progression free survival (PFS)) were evaluated. our results revealed that patients without parapharyngeal tumor extension, skull base bone tumor invasion and neurologic involvement have better with a trend of signicance, compared to those with parapharyngeal tumor extension, bone 18 FDG pretreatment [ 18 F] PET/CT HN-MRI Time-dependent receiver operating characteristic curve analysis of OS prediction based on the T-SUV max, N-SUV max and NTR in patients with NPC. The area under the curve was 0.48 (p < 0.36, 95% CI 0.36–0.61), and 10.5 was determined as the best T-SUV max cutoff value for survival prediction. The area under the curve was 0.67 (p < 0.05, 95% CI 0.56–0.79), and 7.9 was determined as the best N-SUV max cutoff value for survival prediction. The area under the curve was 0.70 (p < 0.001, 95% CI 0.59–0.81), and 0.82 was determined as the best NTR cutoff value for survival prediction.


Introduction
Nasopharyngeal carcinoma (NPC) is the second most common head and neck cancer and is characterized by a deep anatomy and a distinct geographical distribution (Chua et al. 2016). NPC is rare in most parts of the world with an annual incidence of < 1/100,000. However, in high endemic areas (southern China, Southeast Asia and Arctic region), the annual incidence of NPC varies between 30 and 80 cases per 100,000 per year (Bray et al. 2018). In Morocco, an intermediate incidence for NPC, the incidence of NPC is 4.2/100.000 in men and 1.2 /100.000 in women yearly (Benider et al. 2012). NPC clinical symptoms are extremely variable and typically non-speci c in the early disease stages (I-II) (Lo et al. 2004). Therefore, it remains clinically silent for a long period of time, and more than 60% of NPC patients have advanced loco-regionally stage at diagnosis (III-IV) (Wang et al. 2017). Moreover, it has been widely assumed that early detection of NPC is associated with favorable treatment outcomes and a long survival rate; the 5-year survival rate for patients in early locoregional stage (Tumor (T) 1, T2, Nodal (N) 0-1) being around 85%, while for patients with advanced locoregional stages (T3, T4, N2 and N3), it's estimated at 65% (Lee et al. 2005).
Worldwide, NPC diagnosis is based on tripod: clinical examination with nasopharyngeal endoscopy, radiological imaging and histo-pathological con rmation. Head and neck magnetic resonance imaging (HN-MRI), HN computed tomography (CT), thoracic and abdominal CT and whole-body bone scan are the conventional work-ups (CWUs) currently used for NPC diagnosis and staging (Goh and Lim 2009). Despite their long clinical use, these conventional approaches have a number of limitations. Given that CWUs show limited contrast and can result in small metastatic lesions escape, this may considerably impact disease staging and treatment protocols (Brouwer et al. 2005 In Morocco, a great attention was given to cancer management and substantial support was accorded to set up facilities with the most developed technologies for both diagnosis and therapy. In this eld, two companies have been set up to produce [ 18 F] FDG radioactive tracer by cyclotron technology and there are currently 7 medical centers using the [ 18 F] FDG PET/CT technology, while, others are planned for the next years. This technology is often used in the management of the most prevalent cancers in Morocco, including, lymphoma, lung, breast etc…, but its use in NPC is still limited. The present study was designed to assess the usefulness of HN-MRI and [ 18 F] FDG PET/CT in routine diagnosis and prognosis of NPC for a better management of this disease in Morocco. The concordance between HN-MRI and [ 18 F] FDG PET/CT in Tumor and Nodal classi cation was assessed and the association between 18 F-FDG-PET/CT metabolic parameters (T-SUV max, N-SUV max, NTR and Metastatic (M-SUV max), TNM staging system, NPC stages and patient's survival outcomes (overall survival (OS), loco-regional recurrence -free survival (LRRFS) and progression free survival (PFS)) were evaluated.

Materiel And Methods
Patients' recruitment and study design A total of 117 newly diagnosed patients with NPC, were prospectively recruited in Mohammed VI Center for Cancer Treatment in Casablanca-Morocco, between January 2017 and December 2018. Face-to-face interviews were conducted with all patients to collect information on epidemiological data. Clinical data were retrieved from medical records. All included patients underwent whole body [ 18 F] FDG PET/CT or thoracoabdominopelvic CT scan (TAP-CT) and HN-MRI scanning or HN-CT imaging before treatment. The study protocol was approved by the Ethics Committee of Ibn Rochd University Hospital, Casablanca -Morocco and written informed consent was obtained from each recruited patient. Resonance Imaging (HN-MRI) HN-MRI was performed in the Radiology Department of 20 August Hospital in Casablanca using the General Electric1.5 Tesla machine. Axial and coronal T1-fast spin echo sequence, sagittal T2 cube and axial T2 fast spin echo sequence; without frequency selected fat suppression (in the neck for diagnosis of cervical adenopathy areas) and with frequency selected fat suppression (in the nasopharynx to determine local tumor extension); were obtained before injection of the contrast material. Intravenous administration of gadopentetate dimeglumine (Gd-DTPA) (Magnevist; Schering, Berlin, Germany) was done with a dose of 0.1 mmol/kg body weight, and contrast-enhanced fat-suppressed T1spin echo sequences in axial and coronal planes were performed. All MRI imaging were captured with a section thickness of 4 mm and imaging matrix of 256 × 256. Interpretation and strati cation of MRI results were recorded by an expert radiologist and performed from MRI images and reports.

Head & neck Magnetic
[18F] FDG PET/CT imaging Post-treatment follow-up and clinical endpoints All patients received post-treatment follow-up every 3 months during the rst year, every 6 months during the second and third years, and annually thereafter. Clinical examinations, nasopharyngeal endoscopy and imaging follow-up were performed routinely according to the clinical evolution of each patient. Overall survival was de ned as the interval from the date of diagnosis to the last follow-up or date of death from any cause. Locoregional recurrence -free survival (LRRFS) was de ned as the interval from the date of diagnosis to the rst evidence of radiological or histological loco-regional recurrence, death from any cause or last follow-up. Progression free survival (PFS) was de ned as the time from the diagnosis to progression of disease, death or last follow-up (whichever occurred rst).

Statistical analysis
Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software version 22.0 (SPSS Inc., Chicago, IL, USA). Descriptive analysis was carried out to characterize patients' sociodemographic and clinical variables. The concordance between T and N categories was performed using the Cohen kappa coe cient. The kappa coe cient (κ) was used as a descriptive indicator of concordance and varies between 0 and 1 (≤ 0.2: poor concordance; 0.21-0.4: fair concordance; 0.41-0.6: moderate concordance; 0.61-0.8: good concordance and ≥ 0.81 very good concordance). The association between TNM staging system, NPC stages and [ 18 F] FDG PET/CT metabolic parameters (T-SUV max, N-SUV max, NTR and M-SUV max) was analyzed using the ANOVA test. The optimal cut-offs of T-SUV max, N-SUV max, and NTR were obtained using the receiver operating characteristic (ROC) curve analysis. OS, LRRFS, and PFS curves were plotted with the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards regression models to identify the radiological prognostic factors in uencing OS, LRRFS, and PFS. Results were expressed as hazard ratios (HRs) with their 95% con dence intervals (CIs). The following variables were entered as covariates into the model: tumor size, nodal classes, metastatic status and overall stages. Statistical signi cance was assumed at a p value less than 0.05. Only signi cant factors (p-value < 0.05) on univariate analysis were included in multivariate models.

Patients' characteristics
The socio-economical and clinical characteristics of the 117 studied patients are presented in Table 1. The mean age of patients was 43.2 with extreme ages of 12 and 80 years old. NPC was more prevalent in men (64.1%) than women (35.9%), with a sex ratio of 1.7. The main symptoms reported by patients at disease onset showed that most patients presented with lymph node syndromes (82.1%) and headache (79.5%) as early-onset symptoms. The other common presenting symptoms were otologic issues and nasal obstruction reported in 70.9% (83/117) and 61.5% (72/117) of patients, respectively. The non-keratinizing undifferentiated carcinoma prevails and was found in 95.7% of patients (112/117). According to the 7th edition of the AJCC/UICC staging system, 23.9% of patients with NPC were classi ed in group III (28/117) and 65.0% in group IV (76/117). Imaging outcomes showed that most patients had tumor stages T3 (38/117) and T4 (50/117) and nodal stages N1 (30/117) and N2 (52/117). Furthermore  which makes a total of six (7.7 %) misclassi ed patients (Table 2).      (Tables 4 and 5). Among all the radiological and metabolic factors studied, we identi ed N-SUV max and NTR as independent prognostic factors for both OS and PFS (p < 0.05), and skull base bone invasion as independent prognostic factor for PFS in patients with NPC (p = 0.001).

Conclusions
Our ndings clearly provide additional evidence on the complementary roles of HN-MRI and [ 18 F] FDG PET/CT in TNM and overall staging of NPC. To the best of our knowledge, this is the rst Moroccan study to highlight N-SUV max and NTR derived from [ 18 F] FDG PET/CT and Skull base bone invasion de ned by HN-MRI as promising metabolic and radiologic biomarkers for NPC prognosis. The present results could be a good basis for future studies con rming the need to introduce these two imaging modalities in the standard management of NPC and the others cancer in Morocco.

Declarations Informed Consent
Informed consent was obtained from all individual participants included in the study

Availability of data and material
The prospective data that support the ndings of this study are available from the corresponding author upon reasonable request.

Con ict of interest statement
The authors declare that they have no competing interests.  Figure 1