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Abstract

Distant metastasis has become the predominant model of treatment failures in patients with locoregionally advanced nasopharyngeal carcinoma. Effort should therefore be made to stratify locoregionally advanced nasopharyngeal carcinoma patients into different groups based on the risk of metastasis to improve prognosis and tailor individualized treatments. This study aims to assess the value of primary gross tumor volume and the maximum standardized uptake value for predicting distant metastasis–free survival of patients with locoregionally advanced nasopharyngeal carcinoma. A total of 294 locoregionally advanced nasopharyngeal carcinoma patients who were identified from prospectively maintained database and underwent fluor-18-fluorodeoxyglucose positron emission tomography/computed tomography imaging before treatment were included. The maximum standardized uptake value was recorded for the primary tumor (SUVmax-P) and neck lymph nodes (SUVmax-N). Computed tomography-derived primary gross tumor volume was measured using the summation-of-area technique. At 5 years, the distant metastasis–free survival rate was 83.7%. The cut-off of the SUVmax-P, SUVmax-N, and primary gross tumor volume for distant metastasis–free survival was 8.95, 5.75, and 31.3 mL, respectively, by receiver operating characteristic curve. In univariate analysis, only SUVmax-N (hazard ratio: 7.01; 95% confidence interval: 1.70–28.87; p < 0.01) and clinical stage (hazard ratio: 3.03; 95% confidence interval: 1.67–5.47; p = 0.007) were confirmed as independent predictors of distant metastasis–free survival. A prognostic model was derived by SUVmax-N and clinical stage: low risk (SUVmax-N < 5.75 regardless of clinical stage), medium risk (stage III and SUVmax-N ≥ 5.75), and high risk (stage IV and SUVmax-N ≥ 5.75). Multivariate analysis revealed that SUVmax-N and the prognostic model remained independent prognostic factors for distant metastasis–free survival (p = 0.023 and p < 0.001, respectively), but the clinical stage became insignificant (p = 0.133). Furthermore, the adjusted hazard ratios for the prognostic model were higher than SUVmax-N (hazard ratio = 6.27 vs 5.21, respectively). In summary, compared with SUVmax-P, SUVmax-N may be a better predictor of distant metastasis–free survival for patients with locoregionally advanced nasopharyngeal carcinoma. Combining SUVmax-N with clinical stage gives a more precise picture in predicting distant metastasis.

Keywords

Nasopharyngeal carcinoma distant metastasis tumor volume maximum standardized uptake value locoregionally advanced

Introduction

The highest incidence of nasopharyngeal carcinoma (NPC) reportedly occurs in southern China, with the yearly incidence rate varying between 20 and 50 cases per 100,000 population.¹ According to the 7th American Joint Commission on Cancer (AJCC) staging system,² 60%–70% of patients present with locoregionally advanced NPC (LA-NPC).^3,4 With the advancing of the radiation technologies, such as intensity-modulated radiotherapy (IMRT) and concurrent chemoradiotherapy, the locoregional control rates are reported to be >90%,⁵ and distant metastasis has been the predominant model of treatment failures in LA-NPC.⁶ Effort should therefore be made to stratify LA-NPC patients into different groups based on the risk of metastasis to improve prognosis and tailor individualized treatments.

Primary gross tumor volume (GTV-P) has previously been used to predict the prognosis of patients with malignancies including lung and breast cancer.^7,8 Given the biological heterogeneity of NPC, the present staging system remains inadequate for predicting prognosis, even in combination with GTV-P.^9,10 In respect to recent studies,^11–18 the fluor-18-fluorodeoxyglucose (¹⁸F-FDG) uptake on positron emission tomography (PET)/computed tomography (CT) was useful to detect biological and physiological processes in NPC, providing the opportunity for a semi-quantitative measure of tumor glycolysis using the maximum standardized uptake value (SUVmax). In order to get more benefits from the ¹⁸F-FDG PET/CT, we measured the SUVmax of primary tumor (SUVmax-P) and neck lymph nodes (SUVmax-N).

On the basis of this premise, we hypothesized that the combination of GTV-P with SUVmax could improve the accuracy of predicting distant metastasis for LA-NPC patients. Thus, we here gain insight into the possible relationship between GTV-P, SUVmax, and disease stage and evaluate the prognostic value of GTV-P and SUVmax for distant metastasis in LA-NPC.

Materials and methods

Patient eligibility

From December 2009 and February 2012, a total of 1811 patients with NPC diagnosed and treated in our center were reviewed. All patients were staged according to the 7th edition AJCC staging system.² Inclusion criteria were as follows: pathologically diagnosed NPC; stage III–IVB; Karnofsky score ≥ 80 points; normal blood, liver, and kidney parameters; treated with concurrent chemotherapy with or without neoadjuvant chemotherapy; and without distant metastasis before treatment. Figure 1 showed the flowchart of patients. There were 480 (26.5%) patients with stage I–II disease and 1331 (73.5%) patients with stage III–IVB disease. Of the 1331 patients, ¹⁸F-FDG PET scan was performed in 345 patients (25.9%). Of the 345 patients, 51 patients were excluded in order to ensure minimal heterogeneity in host factors and treatment modalities for the assessment of patients with LA-NPC. Excluded patients consisted of 26 treated with radiotherapy alone, 17 with liver or kidney function deficiency, and 8 with Karnofsky score <80 points. The study group therefore contained a total of 294 patients. This study was approved by the Institutional Review Board at our center, and individual informed consent was waived given the anonymous analysis of routine data.

Figure 1.

Flowchart of patients.

¹⁸F-FDG-PET examination

A whole-body/head–neck ¹⁸F-FDG-PET scan was performed using a dedicated PET-CT system (Discovery ST-16; General Electric Company) before treatment. Patients fasted for at least 6 h before the scan. Serum glucose level was measured prior to intravenous administration of 4.4–7.4 MBq/kg of ¹⁸F-FDG. The ¹⁸F-FDG had a radiological purity >95% and was produced by Beijing Atom Hi-Tech, Guangzhou Branch. After intravenous injection, patients were kept at rest in a quiet, dimly-lit room for 30–40 min. Next, a whole body and head/neck 2D PET-CT scan was performed in 5–7 bed positions, all supine, with a scan time of 2.5 min per position. Patients were scanned from the cranial to either the middle of femur (whole body scan) or to 3 cm below the clavicle (head/neck scan). Attenuation-corrected PET images with CT data were reconstructed using an ordered-subset expectation maximization iterative imaging reconstruction algorithm, with a slice thickness of 3.75 mm. SUVs were found using semi-quantitative evaluation based on region-of-interest (ROI) analysis. The SUVmax within the ROI was used to minimize partial volume effects.

Radiotherapy

All patients received IMRT as primary treatment while immobilized in the supine position using a thermoplastic head and shoulder mask. Contrast-enhanced planning CT (3 mm-slice thickness) images from the superior border of frontal sinus to 2 cm below sternoclavicular joint were obtained and transferred to the Monaco treatment planning system (version 3.02; Elekta Instrument AB, Stockholm, Sweden).

Target volumes and organs at risk (OARs) were delineated on each slice of CT images as previously described,¹⁹ in agreement with International Commission on Radiation Units and Measurements Reports 62²⁰ and 83.²¹ The gross tumor volume (GTV) including primary nasopharyngeal tumor (GTV-P) and involved lymph nodes (GTV-N) was delineated on the basis of clinical, endoscopic, and magnetic resonance imaging (MRI) findings. Retropharyngeal lymph node (RLN) involvement was included as part of the GTV-P, as the RLN and primary tumor are difficult to distinguish in NPC;^22,23 clinically involved neck lymph nodes were designated as GTV-N. Two clinical target volumes (CTVs) were delineated according to the GTV: CTV1, high-risk regions encompassing GTV-P plus 5–10 mm, including entire nasopharyngeal mucosa and 5 mm submucosal region; and CTV2, low-risk regions containing CTV1 plus 5–10 mm, encompassing sites of microscopic extension and lymphatic regions. The planning target volumes (PTVs), termed PTV-P, PTV1, PTV2, and PTV-N, were constructed by expanding the GTV-P, CTV1, CTV2, and CTV-N, respectively, by 3 mm; a 3-mm margin was added to the brainstem and spinal cord to generate planning organ at risk volume (PRV).

The prescribed doses to PTV-P, PTV-N, PTV1, and PTV2 were 66–72, 64–70, 60–63, and 54–56 Gy, respectively, in 28–33 fractions (66–70 Gy to PTV-P for T1 NPC, 68–72 Gy for T2-4 NPC, 68–70 Gy to nodes >1 cm, and 64–68 Gy to clinically involved nodes ≤1 cm).²⁴ The dose constraints for OARs and PRVs were as described for the RTOG-0225 trial.²⁵ All patients were treated following a routine schedule (one fraction daily 5 days per week).

Chemotherapy

For patients with stage III to IVB, our institutional guidelines recommended concurrent chemoradiotherapy ± neoadjuvant/adjuvant chemotherapy. Neoadjuvant chemotherapy was given when it was considered advantageous to reduce bulky tumors or when the waiting time for radiotherapy was considered to be longer than acceptable. Neoadjuvant or adjuvant chemotherapy consisted of cisplatin (80 mg/m²) with 5-fluorouracil (800 mg/m²/day over 120 h) or cisplatin (80 mg/m²) with taxanes (80 mg/m²) administered at 3-week intervals for two or three cycles. Concomitant chemotherapy consisted of cisplatin (80 or 100 mg/m²) given in weeks 1, 4, and 7 of radiotherapy or cisplatin (40 mg/m²) given weekly during radiotherapy, beginning on first day of IMRT. Deviations from the institutional guidelines were due to organ dysfunction (suggesting intolerance to the chemotherapy) or patient refusal.

Follow-up

The duration of follow-up was calculated from the first day of therapy to either the day of death or the day of the last examination. Patients were required to be followed up every 3 months during the first 3 years, every 6 months during the next 2 years, and then annually thereafter. At each follow-up visit, endoscopy, physical examination, and basic chemical profiles chest X-ray, abdominal ultrasound, and head and neck MRI were performed every 6 months. Bone scan and CT of the chest or abdomen and even PET/CT were performed when clinically indicated. Until the last follow-up in June 2016, 11 patients were lost follow-up and 229 patients were alive with the median follow-up of 62.7 months (range: 41.1–76.3 months). Overall, the median follow-up was 59.6 months (range: 3.6–76.3 months) for all patients.

Statistical analysis

Our primary endpoint was distant metastasis–free survival (DMFS). It was determined from the date of initial treatment to the date of distant relapse or death from any cause or patient censoring at the date of the last follow-up. Demographic and clinical variables studied included patient age, sex, histology, T stage, N stage, clinical stage, SUVmax, GTV-P, and treatment method. Receiver operating characteristic (ROC) curve was performed to determine the cut-off value of SUVmax and GTV-P for DMFS. Patient survival was calculated using the Kaplan–Meier method and a log-rank test was used to calculate the significance of differences between survival curves. Multivariate analyses using a Cox proportional-hazards model were used to test the independent significance of different factors by backward elimination. Two-tailed Spearman’s correlation was used to analyze the relationship between SUVmax-P, SUVmax-N, and tumor–node–metastasis (TNM) stages. All statistical tests were conducted at a two-sided level of significance of 0.05. Statistical analysis was performed using R3.1.2.

Results

The clinical characteristics of the 294 LA-NPC patients are listed in Table 1. Locoregional recurrence occurred in 26 cases (13 local, 9 regional, and 4 both local and regional). The 5-year control rates were as follows: local 94.2% (95% confidence interval (CI): 90.4%–98.1%), regional 95.6% (95% CI: 91.6%–99.2%), and local–regional 91.2% (95% CI: 86.1%–95.7%). Distant metastasis occurred in 48 cases (16 in bone, 17 in the lung, 13 in the liver, and 12 in multiple sites) and 55 patients died. The 5-year DMFS rate was 83.7% (95% CI: 78.2%–88.5%), the 5-year overall survival (OS) rate was 81.6% (95% CI: 75.3%–87.3%), and the 5-year progression-free survival (PFS) rate was 75.9% (95% CI: 70.2%–81.2%).

Table 1.

Characteristics of patients.

Characteristics	No. of patients (n = 294)	(%)
Age (years)
<60	249	84.7
≥60	45	15.3
Sex
Male	216	73.5
Female	78	26.5
Histology
WHO II	11	3.7
WHO III	283	96.3
T classification
T1	16	5.4
T2	23	7.8
T3	184	62.6
T4	71	24.1
N classification
N0	21	7.1
N1	153	52.0
N2	73	24.8
N3	47	16.1
Clinical stage
III	183	62.2
IVA	79	26.8
IVB	32	10.9
Treatment strategy
CCRT	115	39.1
NACT + CCRT	179	60.9

WHO: World Health Organization; CCRT: concurrent chemoradiotherapy; NACT: neoadjuvant chemotherapy.

The median GTV-P of all patients was 31.6 mL (interquartile range (IQR): 19.9–50.8 mL). For patients with stage III, the median GTV-P was 28.1 mL (IQR: 18.4–43.3 mL). For patients with stage IVA-B, the median GTV-P was 42.3 mL (IQR: 21.1–76.2 mL). Patients with stage IVA-B were more likely to have GTV-P >31.6 mL. We analyzed the prognostic significance of GTV-P in patients with LA-NPC. The cut-off of GTV-P for DMFS was 31.3 mL (sensitivity 0.604, specificity 0.508; area under the curve (AUC) = 0.537). Patients with GTV-P < 31.3 mL trended toward superior DMFS rates (86.7% vs 80.7%) in comparison with those who had GTV-P ≥ 31.3 mL, but this difference was insignificant (p = 0.149, Suppl. Figure S1).

The cut-off of the SUVmax-P for DMFS was 8.95 (sensitivity 0.917, specificity 0.191; AUC = 0.509) by ROC curve, and the cut-off of the SUVmax-N for DMFS was 5.75 (sensitivity 0.958, specificity 0.448; AUC = 0.678). Patients with SUVmax-P ≥ 8.95 had an inferior DMFS rate in comparison with those who had SUVmax-P < 8.95, but there was no significant difference between two groups (87.9% vs 92.2%, p = 0.076; Suppl. Figure S2). In contrast, the 5-year DMFS rates of patients with SUVmax-N ≥ or < 5.75 were 66.7% and 76.6%, respectively, with a significant difference (p = 0.002, Figure 2). Compared with SUVmax-P, SUVmax-N may be a better predictor of DMFS for patients with LA-NPC.

Figure 2.

Kaplan–Meier curves of distant metastasis–free survival according to the SUVmax-N (<5.75 vs ≥5.75) for subgroup analysis.

In univariate analysis (Suppl. Table 1), two factors (SUVmax-N and clinical stage) showed a significant correlation with DMFS (hazard ratio (HR) = 7.01; 95% CI = 1.70–28.87; p < 0.001 and HR = 3.03; 95% CI = 1.67–5.47; p = 0.007, respectively). The N stage was only marginally correlated with DMFS (HR = 1.74; 95% CI = 0.99–3.07; p = 0.055). There was no significant association between age, sex, histology, T stage, SUVmax-P, GTV-P, or treatment method and DMFS (all p > 0.05). Using SUVmax-N and clinical stage, patients were divided into four subgroups: Group 1 (stage III and SUVmax-N < 5.75), Group 2 (stage III and SUVmax-N ≥ 5.75), Group 3 (stage IV and SUVmax-N < 5.75), and Group 4 (stage IV and SUVmax-N ≥ 5.75). The 5-year DMFS rates of those patients in Groups 1–4 were 97.6%, 83.7%, 95.2%, and 74.4%, respectively.

As shown in Table 2, when the DMFS rates were compared between each of the two groups, no significant differences could be found between Group 1 and Group 3 (p = 0.999). However, the DMFS rate of Group 4 was significantly poorer than that of the other three groups (all p < 0.05), and the DMFS rate of Group 2 was significantly poorer than that of Group 1 and Group 3 (p = 0.013 and p = 0.024, respectively). Consequently, a prognostic model was derived as follows: low risk (SUVmax-N < 5.75 regardless of clinical stage), medium risk (stage III and SUVmax-N ≥ 5.75), and high risk (stage IV and SUVmax-N ≥ 5.75). And cumulative survival curves were separated clearly (p < 0.001; Figure 3).

Table 2.

Comparison of DMFS in subgroups of NPC patients.

	Group 1		Group 2		Group 3		Group 4
	χ²	p value	χ²	p value	χ²	p value	χ²	p value
DMFS (5 years)	97.6%		83.7%		95.2%		74.4%
Group 1
Group 2	2.693	0.013
Group 3	1.121	0.999	2.451	0.024
Group 4	4.679	0.001	2.786	0.011	3.982	0.001

DMFS: distant metastasis–free survival; NPC: nasopharyngeal carcinoma.

Group 1: stage III and SUVmax-N < 5.75; Group 2: stage III and SUVmax-N ≥ 5.75; Group 3: stage IV and SUVmax-N < 5.75; Group 4: stage IV and SUVmax-N ≥ 5.75.

The values in boldface are significant (p < 0.05).

Figure 3.

Prognostic model for distant metastasis–free survival using SUVmax-N and clinical stage. Low risk (SUVmax-N < 5.75 regardless of clinical stage), medium risk (stage III and SUVmax-N ≥ 5.75), and high risk (stage IV and SUVmax-N ≥ 5.75).

After adjusting for the various prognostic factors, SUVmax-N and prognostic model remained independent prognostic factor for DMFS in multivariate analysis (p = 0.023 and p < 0.001, respectively; Table 3), but the clinical stage became insignificant (p = 0.133). Furthermore, the adjusted HRs for the prognostic model were higher than SUVmax-N (HR = 6.27 vs 5.21, respectively). This suggests that the prognostic model had better prediction than SUVmax-N and clinical stage for DMFS.

Table 3.

Multivariable analyses of prognostic factors for DMFS.

Variables	Hazard ratio (95% CI)	p value*
N stage, N0–N1 versus N2–N3	1.35 (0.76–2.41)	0.310
Clinical stage, III versus IVA-B	1.53 (0.88–2.66)	0.133
SUVmax-P, <8.95 versus ≥8.95	2.11 (0.75–5.89)	0.156
SUVmax-N, <5.75 versus ≥5.75	5.21 (1.44–15.1)	0.023
Prognostic model	6.27 (1.78–21.7)	<0.001

SUVmax-P: the maximum standardized uptake value for primary tumor; SUVmax-N: the maximum standardized uptake value for lymph nodes; CI: confidence interval; DMFS: distant metastasis–free survival.

The p values were calculated with an adjusted Cox proportional-hazards model.

Discussion

We excluded stage I–II patients due to their relatively low risk of distant metastasis.²⁶ In this study, we found no significant correlation between DMFS and either GTV-P or SUVmax-P, but a significant correlation with both SUVmax-N and DMFS. It was unexpected that N stage was not significantly prognostic for DMFS, which may be due to the small proportion of N3 stage disease patients included. Our results indicated that combining SUVmax-N with clinical stage improved the accuracy of prognosis more than individual factors alone.

Several previous studies^23,27,28 found a positive correlation between GTV-P and various survival outcomes in NPC patients. Recently, Guo et al.²⁸ retrospectively reviewed 694 NPC patients staged with I–IVB and reported a significantly higher incidence of distant metastasis in patients with GTV-P ≥ 19 mL. In contrast, our analyses that were confined to a homogenous patient population of stage III–IVB disease do not suggest that GTV-P adds prognostic value to predict DMFS. Consistent with our study, Zeng et al.²⁹ analyzed the mode of relapse patterns and survival of patients with stage IVA-B NPC, providing additional evidence that GTV-P was not a significant predictor of DMFS. This inconsistency might be due to some obvious differences between the patients included in the study by Guo et al.²⁸ and this study. Only patients with stage III–IVB were eligible for this study. However, compared with this study, nearly 35% of patients (234 of 694 patients) included in the study by Guo et al. were stage I–II. Moreover, in comparison with the study by Guo et al., nearly 90% (259/294) patients had a GTV-P of >19 mL in our study, which may partly account for the present result.

In recent years, a series of retrospective and prospective studies have identified the potential value of SUVmax in predicting the survivals of NPC patients.^11–18 Xiao et al.¹² prospectively investigated the prognostic significance of ¹⁸F-FDG PET/CT performed before treatment for the DMFS of NPC patients and found that SUVmax-P was a useful biomarker to predict distant metastasis of NPC patients, but failed to confirm the correlation between SUVmax-N and DMFS. Surprisingly, we found that the SUVmax-N was the strongest prognostic factors for predicting DMFS. Although patients with SUVmax-P < 5.75 had a higher 5-year DMFS rate than patients with SUVmax-P ≥ 5.75 (92.2% vs 87.9%), there were no significant difference (p = 0.076) between two groups in our study. The difference between our observations and previous studies may partially be explained by the patient’s inclusion. Only patients with advanced disease (Stage III–IVB) were eligible for this study. In contrast, nearly 30% of the patients (48 of 179 patients) included in the study by Xiao et al.¹² were staged with I–II. Furthermore, patients were staged according to the 7th edition of AJCC system in this study, while patients in the study by Xiao et al.¹² were staged according to the 6th edition of AJCC system.

In this study, SUVmax-N did not always increase with the clinical stage. The most likely explanation may be that SUVmax-N and clinical stage represent different pathways which contribute to tumor load. Combining SUVmax-N and clinical stage altered the risk of distant metastasis in three groups: low risk (SUVmax-N < 5.75 regardless of clinical stage), medium risk (stage III and SUVmax-N ≥ 5.75), and high risk (stage IV and SUVmax-N ≥ 5.75). This prognostic model generated a balanced distribution and offered superior hazard discrimination compared to SUVmax-N and clinical stage and remained independent prognostic factor for DMFS in multivariate analysis.

Despite the promising results, our study has some limitations. A major limitation of our study is that we failed to exclude the volume of RLN from GTV-P, as a clear distinction between the RLN and primary tumor remains difficult in NPC, which might possibly enlarge the volume of GTV-P. Second, plasma Epstein–Barr viral (EBV) DNA levels have been demonstrated to be a valuable prognostic factor in NPC, but these data were only available for a few patients in our cohort and could not be incorporated in the prognostic model. Further studies are therefore needed to investigate whether adding plasma EBV DNA data could further improve prediction of metastasis.

In summary, SUVmax-N was a strong independent prognostic factor for distant metastasis after definitive treatment in LA-NPC patients. Combining SUVmax-N with clinical stage allows an alteration of the risk definition of patients with LA-NPC, which may prove useful for predicting survival outcomes and aiding treatment decisions. Further new strategies combining different treatment modalities to reduce the rate of distant metastasis effectively also need to be developed in the future.

Footnotes

Acknowledgements

The authors thank the anonymous reviewers for their insightful comments and great help to improve this work. Y-N.J. and J-J.Y. contributed equally to this work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the Science and Technology Project of Guangzhou City, China (No. 14570006), the National Natural Science Foundation of China (No.81372409), the Sun Yat-sen University Clinical Research 5010 Program (No.2012011), and the National Natural Science Foundation of China (No. 81402532).

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Supplementary Material

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Prognostic value of primary gross tumor volume and standardized uptake value of 18 F-FDG in PET/CT for distant metastasis in locoregionally advanced nasopharyngeal carcinoma

Abstract

Keywords

Introduction

Materials and methods

Patient eligibility

18F-FDG-PET examination

Radiotherapy

Chemotherapy

Follow-up

Statistical analysis

Results

Discussion

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

References

Supplementary Material

¹⁸F-FDG-PET examination