18F-NaF uptake in skull-base bone as a predictor of treatment response in advanced nasopharyngeal carcinoma (2024)

Nasopharyngeal carcinoma (NPC) is the most common form of head and neck squamous cell carcinoma, particularly prevalent in Southeast Asia. Annually, it accounts for approximately 129,000 new cases and 73,000 deaths globally¹. Due to its distinctive anatomical location, about 70–80% of NPC patients are diagnosed at an advanced stage. The standard treatment protocol for these advanced-stage patients involves adding induction chemotherapy to concurrent platinum-based chemoradiotherapy². Despite this approach, around 20% of patients experience treatment failure due to resistance to chemotherapy or radiotherapy, which significantly affects survival outcomes³.

The current AJCC/UICC 8th edition TNM classification for NPC categorizes patients with skull-base bone invasion (SBBI) as T3 stage, significantly influencing treatment choices, response to therapy, and prognosis^4,5. Previous studies have demonstrated that SBBI is associated with reduced bone metastasis-free survival in patients with locally advanced NPC, emphasizing its role as a risk factor for bone metastasis⁶. Furthermore, Li et al. found that the extent of SBBI visible on anatomic images correlated with 5-year overall survival and progression-free survival⁷. In a comprehensive analysis of 8,834 newly diagnosed NPC patients, Du et al. proposed reclassifying T3 NPC cases with early SBBI as T2, due to their similarly favorable prognosis with contemporary treatments⁸. These findings indicate that SBBI is a significant risk factor for poorer outcomes in NPC patients. However, because obtaining biopsies for SBBI is impractical, current evaluations of SBBI in NPC patients rely primarily on MRI, which reflects anatomical changes but lacks information on the metabolic alterations within the SBBI.

¹⁸F-NaF PET/CT leverages the high affinity of fluoride ions for areas of active bone remodeling⁹ and combines this with the advanced imaging capabilities of PET/CT. This technique allows for accurate and sensitive detection and assessment of bone metastases in patients with malignancies¹⁰. Studies have shown that ¹⁸F-NaF PET/CT achieves a patient-level sensitivity of 97.1% and specificity of 94.6%, and a lesion-level sensitivity of 99.5% and specificity of 91.5%. These results surpass the performance of ¹⁸F-NaF PET alone and planar ^99mTc-MDP bone scintigraphy in detecting bone metastases in patients with NPC¹¹. Furthermore, ¹⁸F-NaF PET/CT has demonstrated efficacy in detecting SBBI and exhibits high interobserver agreement¹², establishing its value as a crucial imaging modality for the initial management of NPC¹³. Additionally, ¹⁸F-NaF uptake in bone disease has been identified as a predictive biomarker for response to anti-tumor therapy^14,15,16. SBBI may reflect significant osteoblastic activity driven by tumor invasion and represent a more aggressive tumor phenotype that potentially exhibits greater resistance to standard chemotherapy and radiotherapy. The high ¹⁸F-NaF uptake detected at the skull base in cases of SBBI may, therefore, correlate with treatment resistance. Therefore, investigating the differences in ¹⁸F-NaF uptake at the skull base and its association with treatment response in patients with advanced NPC undergoing standard treatment is warranted.

In this study, we evaluated the differences in ¹⁸F-NaF uptake at the skull base in patients with advanced NPC and investigated whether baseline ¹⁸F-NaF uptake at the skull base is associated with response to standard treatment.

Patients

This retrospective study received ethical clearance and the requirement to obtain informed consent was waived by the institutional review boards of Affiliated Hospital of Guilin Medical University (ID: 2023QTLL-16). The study protocol adheres to the tenets of the 1964 Declaration of Helsinki. The study cohort comprised 142 patients diagnosed with NPC, confirmed through pathological evaluation, who underwent ¹⁸F-NaF PET/CT for staging at the Affiliated Hospital of Guilin Medical University between December 2020 and December 2023. Inclusion criteria were as follows: newly diagnosed, pathologically confirmed NPC; advanced disease stage (AJCC stage III or IV) at initial diagnosis; absence of other malignancies at presentation; pre-treatment whole-body ¹⁸F-NaF PET/CT imaging; pre-treatment MRI of the head and neck regions; standardized treatment regimen followed by comprehensive clinical and imaging follow-up data for over six months (including CT, MRI, and PET/CT); completion of induction chemotherapy (IC) followed by intensity-modulated radiation therapy (IMRT) without treatment interruption for locally advanced NPC.

Treatment protocol

For locally advanced NPC, the IC regimen comprised taxane and cisplatin: docetaxel 75mg/m² or paclitaxel 135–175mg/m² administered intravenously on day 1, and cisplatin or nedaplatin at 80mg/m² intravenously on day 1, every 3weeks for 2–3 cycles. Concurrent chemoradiotherapy (CCRT) was initiated within 21 to 28days after the final IC cycle.

Radiation therapy involved IMRT with 6 MV photon irradiation. The prescribed doses were: 66–70Gy for the planning target volume derived from the primary nasopharyngeal gross tumor volume, 64–70Gy for the PTV from the nodal gross tumor volume, 60–62Gy for the PTV from the high-risk clinical target volume, and 54–56Gy for the PTV from the low-risk clinical target volume, delivered in 30–33 fractions. Concurrent chemotherapy with cisplatin or nedaplatin was administered intravenously at 80mg/m² every 3weeks on days 1, 22, and 43 during radiotherapy. The number of chemotherapy cycles was adjusted based on the patient’s physical condition.

Evaluation of treatment response

Two radiologists (X.L and Y.J.) independently assessed tumor response by comparing pre-treatment and 1–3months post-CCRT MRI scans. Clinical responses of primary tumor at 1–3months post-CCRT were categorized according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). For analysis, patients were grouped into CR and non-CR (combining PR, SD, and PD). Any discrepancies between the radiologists’ evaluations were resolved through discussion.

¹⁸F-NaF PET/CT protocol

The ¹⁸F-NaF PET/CT scans were performed following guidelines from the Society of Nuclear Medicine and the European Association of Nuclear Medicine¹⁷. Imaging was conducted using the Ingenuity TF PET/CT scanner (Philips, Amsterdam, Netherlands). Patients received an intravenous injection of 259.0MBq (interquartile range [IQR]: 233.1–299.7MBq) of ¹⁸F-NaF and rested for 74.5min (IQR: 58.3–90.8min) before image acquisition from the head to the feet.

A low-dose CT scan for attenuation correction was acquired with the following parameters: tube voltage of 120kV, tube current of 50 mAs, slice thickness of 5.0mm, and a reconstruction slice thickness of 1.0mm. Subsequently, PET imaging was performed with a duration of 0.5min per bed position, covering 20–21 bed positions, in accordance with the manufacturer’s recommendations. Image reconstruction was carried out using a fully three-dimensional maximum likelihood ordered subsets expectation–maximization algorithm.

Interpretation of ¹⁸F-NaF PET/CT images

Two experienced nuclear medicine physicians (X.M. and Z.L.) independently evaluated the ¹⁸F-NaF PET/CT images in a randomized order for each patient, blinded to all clinical information except for the NPC diagnosis. The final diagnosis was determined by consensus, with any inconsistencies resolved through the decision of an additional experienced physician (W.F.). Visual analysis was employed for image interpretation, rather than semiquantitative analysis (e.g., standardized uptake value [SUV] cutoffs).

For the ¹⁸F-NaF PET/CT scans, areas of focally increased ¹⁸F-NaF uptake at the skull-base bone were recorded as positive for SBBI, unless a benign etiology (e.g., degenerative changes or hemangioma) was identified at the same location on the corresponding CT images. This assessment included the sphenoid body, clivus, bilateral pterygoid processes, and bilateral petrous apices.

For semiquantitative analysis, regions of interest (ROI) were placed on positive findings in the ¹⁸F-NaF PET/CT images. In patients without positive skull-base bone findings, ROIs were placed on the sphenoid body with a diameter of 1 cm². The maximum standardized uptake values (SUV_max) and mean standardized uptake values (SUV_mean) at the skull-base bone were recorded for each patient. The skull-base bone-to-background ratio (SBR) was calculated by dividing the SUV_max of the SBBI or skull-base bone by the SUV_mean of the occipital bone.

Reference standard

The final diagnosis was determined based on a combination of imaging results and clinical follow-up. Due to the impracticality of obtaining biopsies for all SBBI and osseous metastases lesions, the presence of skull-base bone invasion in patients was verified using pre-treatment contrast-enhanced MRI and follow-up imaging modalities (PET/CT, MRI, or CT). In MRI imaging, the diagnosis of skull base invasion was primarily based on T1WI and contrast-enhanced T1WI. If the skull base adjacent to the tumor appeared hypointense on T1WI and showed enhancement on post-contrast T1WI, skull base invasion was considered positive. Additionally, six-month follow-up imaging was utilized to confirm skull-base invasion in NPC. Skull-base invasions that persisted or increased in size on images taken after six months confirmed the existence of bone invasion. Lesions that were indeterminate or showed no significant changes during follow-up were considered benign lesions (verified negatives) in the analysis.

Statistical analysis

Statistical analyses were performed using GraphPad Prism 10.1 (GraphPad Software Inc., La Jolla, CA, USA) by X.M. Categorical variables were presented as counts and percentages. For continuous variables, normally distributed data were reported as means ± standard deviation (SD), while skewed variables were described using medians and IQR. Differences between two groups were evaluated using the Mann–Whitney U test. For comparisons among multiple groups, the Kruskal–Wallis test followed by Dunn’s multiple comparison test was used. The receiver operating characteristic (ROC) curve was utilized to assess discriminative power, with the area under the ROC curve (AUC) calculated. Univariate and multivariable logistic regression analyses were carried out to evaluate the relationship between risk factors and treatment outcomes. All statistical tests were two-sided, with a P-value < 0.05 indicating statistical significance.

Baseline clinical and PET/CT characteristics

This study included 142 patients diagnosed with advanced NPC, comprising 105 males and 37 females, with a mean age of 52.2 ± 10.7years. Upon undergoing ¹⁸F-NaF PET/CT, 18 patients were found to have bone metastases, while the remaining 124 showed no evidence of such metastases (Fig.1). Table 1 presents the baseline clinical characteristics of the patients.

¹⁸F-NaF uptake analysis based on T stage

Using the AJCC staging system, patients were classified as follows: 31 (22%) T2 stage, 75 (52%) T3 stage, and 36 (25%) T4 stage. A significant increase in ¹⁸F-NaF uptake at the skull-base was observed with advancing clinical T stage (Fig.2). T4 stage patients exhibited markedly higher SUV_max and SUV_mean values in the skull-base region compared to T3 and T2 stages (median SUV_max: 13.8 vs. 9.7 vs. 4.8, p < 0.0001; median SUV_mean: 8.1 vs. 5.3 vs. 3.0, p < 0.0001). Similarly, the SBR on ¹⁸F-NaF PET/CT was significantly elevated in T4 stage patients compared to T3 and T2 stages (median SBR: 8.2 vs. 5.4 vs. 2.6, p < 0.0001).

Comparison of skull-base ¹⁸F-NaF uptake in patients with and without bone metastases

Among the 18 patients with bone metastases, 15 (83.3%) showed SBBI on ¹⁸F-NaF PET/CT. All 18 patients also demonstrated positive findings for distant bone metastases. A notable difference in ¹⁸F-NaF uptake was observed between patients with and without distant bone metastases (all p < 0.05; Table 2). Patients with distant bone metastases showed higher skull-base SUV_max (17.6 [7.1, 27.9]) compared to those without (7.8 [5.3, 12.8], p = 0.01). Skull-base SUV_mean was also elevated in patients with distant bone metastases (11.4 [4.0, 15.4]) compared to those without (4.4 [3.1, 7.6], p = 0.01). Using occipital bone SUV_mean as background, patients with distant bone metastases exhibited a higher SBR (10.7 [4.5, 17.8]) than those without (5.1 [2.9, 7.9], p = 0.02).

¹⁸F-NaF uptake analysis based on treatment outcome

Of the 124 patients without distant bone metastases, SBBI was detected in 77 patients. ¹⁸F-NaF PET/CT confirmed positive findings for skull-base invasion in 72 of these patients (93.5%). The diagnostic performance of ¹⁸F-NaF PET/CT for SBBI detection was as follows: sensitivity 93.5%, specificity 91.5%, accuracy 92.7%, positive predictive value 94.7%, and negative predictive value 89.6%.

Baseline ¹⁸F-NaF PET/CT parameters were compared between patients achieving CR and those with non-CR after IC followed by CRRT. Patients with non-CR showed significantly higher ¹⁸F-NaF uptake than those with CR, according to RECIST 1.1 criteria (Table 3, p < 0.001). Specifically, non-CR patients exhibited higher skull-base SUV_max (11.8 vs. 6.1, p < 0.0001) and SUV_mean (6.6 vs. 3.6, p < 0.001) compared to CR patients. Using occipital bone SUV_mean as background, non-CR patients demonstrated a higher SBR (6.2 [4.7, 10.8]) than CR patients (3.7 [2.6, 6.7], p = 0.0002). Figures3 and 4 show representative PET/CT images of responders and non-responders after IC followed by CRRT.

ROC curve analysis of ¹⁸F-NaF PET/CT parameters for differentiating between CR and non-CR after IC and CRRT revealed the following: SUV_max > 10.0 showed an AUC of 0.77 (95% CI: 0.68–0.83), sensitivity 78.4%, specificity 70.0% (p < 0.0001); SUV_mean > 5.2 demonstrated an AUC of 0.76 (95% CI: 0.68–0.83), sensitivity 74.3%, specificity 72.0% (p < 0.0001); and SBR > 5.1 showed an AUC of 0.70 (95% CI: 0.61–0.78), sensitivity 66.2%, specificity 74.0% (p = 0.0001) for distinguishing between CR and non-CR (Fig.5).

Univariate and multivariable analyses

We investigated the association between various clinical and imaging risk factors and treatment response in locally advanced NPC patients (Table 4). Univariate analysis identified T stage, ¹⁸F-NaF PET/CT results, SUV_max, SUV_mean, and SBR as significant predictors of treatment response (p < 0.05). Due to collinearity between SUV_max and SUV_mean for SBBI on ¹⁸F-NaF PET/CT, SUV_mean was excluded from the multivariable analysis. In the multivariable analysis, only SUV_max remained a significant predictor (p < 0.05) with an odds ratio of 7.03 (95% CI: 1.97–25.13).

This study assessed the potential of ¹⁸F-NaF PET/CT for predicting treatment response in patients with advanced NPC by evaluating ¹⁸F-NaF uptake at the skull-base bone. The results indicate a significant association between higher ¹⁸F-NaF uptake and more advanced T stages, the presence of bone metastasis, and poorer treatment outcomes. ROC analysis further confirmed the discriminatory power of ¹⁸F-NaF PET/CT parameters in differentiating CR from non-CR, with SUV_max > 10 and SUV_mean > 5.2 showing AUC of 0.77 and 0.76, respectively. In addition, the multivariable analysis demonstrated that SUV_max is an important risk factor for treatment response, with an odds ratio of 7.03 (95% CI: 1.97–25.13). These findings underscore the potential of ¹⁸F-NaF PET/CT as a promising predictor of treatment response in patients with advanced NPC.

The role of SBBI in the staging and prognosis of NPC has been extensively documented⁴. Previous studies identified a correlation between SBBI and advanced T stages, with MRI findings often serving as a reference for anatomical changes associated with SBBI¹⁸. Our study expands on these findings by demonstrating that higher T-stage NPC not only correlates with greater anatomical invasion but also with increased ¹⁸F-NaF uptake at the skull base, indicating elevated bone activity. This aligns with the known association between SBBI and poor treatment response, reflecting the substantial tumor burden and anatomical complexity involved. The observed higher ¹⁸F-NaF uptake in patients with distant bone metastasis corroborates prior reports linking SBBI-positive NPC with a higher incidence of bone metastasis⁶. Our results support the hypothesis that increased bone activity at the skull base is indicative of metastatic potential, potentially serving as a marker for subsequent bone metastasis. Further studies are required to determine whether elevated bone activity at the skull base will lead to metachronous bone metastasis, resulting in a worse prognosis for NPC patients¹⁹.

Patients with locally advanced NPC often receive IC followed by CCRT, which generally improves prognosis²⁰. However, despite similar treatment regimens, approximately 20% of these patients exhibit unsatisfactory outcomes due to individual differences and tumor heterogeneity²¹. This leads to residual masses and poorer prognoses. The anatomical location of the skull base, near critical neural and vascular structures, further complicates treatment, often resulting in inadequate delivery and a higher risk of residual disease or recurrence²². Our findings on the predictive value of ¹⁸F-NaF PET/CT parameters for treatment outcomes resonate with prior studies that employed ¹⁸F-NaF PET/CT parameters for similar purposes^14,23,24. A plausible explanation is that high ¹⁸F-NaF uptake is indicative of extensive tumor invasion and burden, which may affect the delineation of radiotherapy target areas or contribute to chemotherapy resistance, leading to non-CR to standard treatment. Further studies are necessary to confirm if patients with non-CR and high SBBI bone activity have poorer prognoses compared to those with lower bone activity. The significant correlation between ¹⁸F-NaF uptake and treatment response emphasizes the metric’s potential as a non-invasive biomarker for predicting treatment outcomes. The high discriminatory power of ¹⁸F-NaF PET/CT parameters, as evidenced by the ROC analysis, reinforces its clinical applicability in predicting outcomes and guiding therapeutic decisions. While ¹⁸F-FDG PET/CT is widely recognized for its utility in assessing metabolic activity and is particularly effective for evaluating soft tissue involvement and overall disease burden, ¹⁸F-NaF PET/CT offers unique advantages in detecting bone activity, particularly in the context of SBBI, which is often missed or less well characterized by ¹⁸F-FDG PET/CT. By incorporating ¹⁸F-NaF PET/CT findings into current protocols, clinicians can better delineate radiotherapy targets and predict chemotherapy efficacy, potentially reducing the incidence of residual disease and recurrence. Additionally, early identification of patients unlikely to respond to standard IC + CRRT can facilitate timely adjustments to treatment regimens, such as intensifying therapy or exploring alternative modalities, thereby optimizing clinical outcomes.

While our study provides compelling evidence for the utility of ¹⁸F-NaF PET/CT in predicting treatment response in advanced NPC, several limitations should be acknowledged. The retrospective nature of the study and the relatively small sample size may limit the generalizability of our findings. Prospective studies with larger cohorts are warranted to validate these results and establish standardized ¹⁸F-NaF PET/CT protocols for NPC management. A key limitation of our study is the absence of a direct comparison between ¹⁸F-NaF PET/CT and conventional imaging modalities such as MRI, CT, or ¹⁸F-FDG PET/CT, which limits our ability to fully assess the added value of ¹⁸F-NaF PET/CT over these standard anatomical techniques for detecting SBBI. Future studies that incorporate direct comparisons with these modalities are necessary to validate the potential advantages of ¹⁸F-NaF PET/CT, establish its complementary role in imaging NPC patients with SBBI, and confirm its robustness in predicting treatment response. Additionally, the mechanistic underpinnings of increased ¹⁸F-NaF uptake at the skull base in relation to NPC progression and metastasis remain unclear. Investigating the biological factors driving elevated bone activity at this site could provide deeper insights into NPC pathophysiology and inform more effective therapeutic strategies.

¹⁸F-NaF:

Fluorine-18 sodium fluoride

PET/CT:

Positron emission tomography/computed tomography

SBBI:

Skull-base bone invasion

NPC:

Nasopharyngeal carcinoma

RECIST:

Response evaluation criteria in solid tumors

CR:

Complete response

ROC:

Receiver operating characteristic

SUV:

Standardized uptake value

AUC:

Area under the curve

MRI:

Magnetic resonance imaging

IC:

Induction chemotherapy

IMRT:

Intensity-modulated radiation therapy

CCRT:

Concurrent chemoradiotherapy

PR:

Partial response

SD:

Stable disease

PD:

Progressive disease

SBR:

Skull-base bone-to-background ratio

Author notes

1. Xingyu Mu and Jingze Li: contributed equally to this work.

Authors and Affiliations

1. Department of Nuclear Medicine, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi Zhuang Autonomous Region, People’s Republic of China

   Xingyu Mu,Jingze Li,Jingquan Huang,Zhenzhen Wang,Zuguo Li&Wei Fu

2. Department of Radiology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi Zhuang Autonomous Region, People’s Republic of China

   Xun Li,Yu Jiang&Zhipeng Zhou

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by XM, JL, JH, ZW, ZL, XL and YJ. ZZ and WF coordinated the study. The first draft of the manuscript was written by XM and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Corresponding authors

Correspondence to Zhipeng Zhou or Wei Fu.

Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

This retrospective study received ethical clearance and the requirement to obtain informed consent was waived by the institutional review boards of Affiliated Hospital of Guilin Medical University (ID: 2023QTLL-16). The study protocol adheres to the tenets of the 1964 Declaration of Helsinki.

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