Identifying optimal candidates for local treatment of the primary tumor among patients with de novo metastatic nasopharyngeal carcinoma: a retrospective cohort study based on Epstein–Barr virus DNA level and tumor response to palliative chemotherapy

Background To evaluate the clinical outcome in patients with de novo metastatic nasopharyngeal carcinoma (NPC) treated or not treated with locoregional radiotherapy (LRRT) based on plasma Epstein–Barr virus (EBV) DNA level and tumor response after palliative chemotherapy (PCT). Methods From 2007 to 2016, 502 patients with de novo metastatic NPC were included in this study. All patients were treated with PCT and 315 patients received LRRT. Our primary study endpoint was overall survival (OS). Results EBV DNA was detected in 461 patients (91.8%) before treatment but was undetectable in 249 patients (49.6%) after PCT. Three hundred and seventeen patients (63.1%) achieved satisfactory response (complete response or partial response) to PCT. Both the post-PCT EBV DNA level and tumor response were independent prognostic factors. Among low-risk patients (patients with undetectable EBV DNA and satisfactory tumor response after PCT), the 3-year OS rate was 80.4% in LRRT-treated patients and 45.3% in patients not treated with LRRT (P < 0.001). Multivariate analyses demonstrated that LRRT was an independent prognostic factor of OS in the low-risk patients (P < 0.001). However, among the high-risk patients (patients with detectable EBV DNA and/or unsatisfactory response after PCT), no statistically significant survival differences were observed between the LRRT and non-LRRT groups. Conclusions EBV DNA level and tumor response after PCT both correlate with the prognosis of de novo metastatic NPC. In such cases, LRRT may benefit the patients with undetectable EBV DNA levels and satisfactory tumor response after PCT. Electronic supplementary material The online version of this article (10.1186/s12885-019-5281-5) contains supplementary material, which is available to authorized users.


Background
Nasopharyngeal carcinoma (NPC) is a malignancy endemic in Southern China, where about 50-80 cases per 100,000 populations are reported each year [1]. According to its geographic distribution and biological characteristics, NPC is distinct from other head and neck cancers [2,3]. Concurrent chemoradiation therapy (CCRT) is the standard treatment method among local advanced NPC patients [4,5]. However, there are 6-15% of patients developing distant metastatic lesions before receiving any treatment. Bone, the lung, and the liver are the common metastatic sites [6,7]. Treatment mostly relies on palliative chemotherapy (PCT) in these patients, with a median overall survival (OS) duration of 12-15 months [8,9]. However, it was reported that survival rates could exceed 4 years for selected patients with metastatic NPC [10,11]. Therefore, there is a need to identify the suitable factors for classifying high-or low-risk patients with metastatic NPC. According to National Comprehensive Cancer Network (NCCN) guidelines, chemotherapy combined with locoregional radiotherapy (LRRT) benefits selected patients with distant metastases at limited sites or with low tumor burden [12]. However, which type of patient should receive LRRT remains unclear. If the patients who would benefit from LRRT can be identified, a more intensive treatment strategy could be used to achieve a better clinical outcome.
Several studies have verified that plasma EBV DNA levels measured by real-time quantitative PCR are associated with NPC and can be used as a detection, monitoring, and prognostic prediction marker of non-metastatic NPC [13][14][15][16][17]. Besides, gross tumor volume showed a decreasing trend during treatment. In other types of cancer, tumor response to initial chemotherapy is related to outcome [18][19][20][21]. We have also verified the prognostic value of tumor response to neoadjuvant chemotherapy (NACT) among patients with locoregionally advanced NPC [22]. Hence, plasma EBV DNA level and tumor response to chemotherapy might aid the identification of patients who would benefit from LRRT. However, studies regarding plasma EBV DNA level and tumor response in metastatic NPC, especially de novo metastatic NPC are rare. Therefore, we initiated the present study to investigate the prognostic value of these two factors in patients with de novo metastatic NPC and to determine whether radiotherapy benefits these patients based on these two factors.

Patients
Between 2007 and 2016, 502 previously untreated patients with de novo metastatic NPC at our institute were included in the study. The eligibility criteria were: (1) biopsy-proven NPC; (2) received platinum-based PCT; (3) radiologically measurable disease; (4) Karnofsky performance score (KPS) > 60; (5) no secondary pregnancy, lactation, and other malignant disease; (6) normal renal and liver function; (7) available hematological sample results. Routine evaluations were applied on each patient: physical examination, head and neck magnetic resonance imaging (MRI) with contrast, chest radiography/ chest computed tomography (CT), abdominal sonography/ abdominal CT, nasopharyngoscopy and biopsy, bone scan and complete blood count that included differential cell counts, biochemical profile and EBV serology. Positron emission tomography/computed tomography (PET-CT) was also recommended if clinically indicated. The study is approved by Research Ethics Committee of our center.
Quantification of plasma EBV DNA levels and tumor response assessment Plasma EBV DNA levels were measured before treatment and after the completion of PCT. Plasma EBV DNA was extracted and subjected to real-time quantitative PCR. We established the post-chemotherapy cut-off value (0 copies/mL) previously [22]. To evaluate the tumor response to therapy, all patients underwent CT, MRI scan or bone scan (for bone metastases) and were classified as having complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors criteria [27]. Patients achieving CR or PR were considered as the satisfactory responders.

Outcome and follow-up
The primary endpoint of this study was overall survival (OS), which was defined as the time from the date of treatment to the date of death of any cause. After treatment completion, patients were inspected every 3 months in the first 3 years and every 6 months thereafter until death. MRI with contrast of head and neck, CT with contrast of the metastatic sites, Nasopharyngoscopy, chest radiography, abdominal sonography, bone scan, and plasma EBV DNA measurement were routinely performed or upon clinical indication of tumor relapse. PET-CT was considered if necessary.

Statistical analyses
The statistical analysis was performed using SPSS for Mac version 21.0 (SPSS Inc., Chicago, IL). The relationship between EBV DNA level or tumor response after PCT and the clinical patient characteristics of NPC were evaluated using the χ 2 test and Fisher's exact test. Kaplan-Meier survival curves were used to estimate the OS curves; survival rates were compared using the log-rank test.
Step-wise multivariate analyses using Cox proportional hazard model were performed with the following variables: post-PCT EBV DNA level, tumor response to PCT, sex, age, T stage, N stage, metastatic site, chemotherapy regimen and LRRT. All analyses were 2-side. The level of significance was set at P < 0.05.
The median follow-up time was 26.3 months (range, 2-126 months). 272 patients died during follow-up. Among them, 269 patients died of tumor progression, 2 patients died of treatment-related toxicities (1 patient because of infection caused by leucopenia and 1 patient because of hepatic failure) and 1 patient died of cardiac disease. EBV DNA levels could be detected in 461 patients before PCT. However, only 253 patients had detectable EBV DNA levels after PCT. Among the entire cohort, two patients had CR, 315 patients had PR, 114 patients had SD, and 71 patients had PD. As shown in Additional file 1: Table S1, the tumor responses were significantly different between patients with post-PCT undetectable plasma EBV DNA levels (CR/PR = 208 of 249 assessable patients) and patients with detectable levels (CR/PR = 109 of 253 assessable patients) (P < 0.001).

Risk stratification
Post-PCT EBV DNA level and tumor response were significantly correlated with prognosis in de novo metastatic NPC. Moreover, the patients with undetectable post-PCT EBV DNA and satisfactory tumor response (CR/PR) had significantly better clinical OS than the patients with either detectable post-PCT EBV DNA or unsatisfactory tumor response (SD/PD); the 3-year OS rates were 73.9 and 36.5% (P < 0.001) respectively (Fig.  2c). Accordingly, we divided the patients into low-risk (undetectable EBV DNA and satisfactory tumor response post-PCT) and high-risk groups (detectable EBV DNA and/or unsatisfactory tumor response post-PCT). Table 3 lists the patient characteristics according to risk group.
The relationship between post-PCT LRRT and outcome in patients according to risk group In the low-risk group, the 3-year OS rate was 80.4% in LRRT-treated patients and 45.3% in patients not treated with LRRT (P < 0.001). However, in the high-risk group, the 3-year OS rate was similar in patients treated or not treated with LRRT (40.2% vs. 31.0%, P = 0.111). Figure 3a, b shows the Kaplan-Meier survival curves. Landmark analyses were performed for patients surviving ≥1 year. Similarly, the survival benefit of LRRT for the survivors was only found in low-risk group (Fig. 3c, d). We carried out two separate multivariate analyses of the low-and high-risk patients. Table 4 shows that in the low-risk group, a strong prognostic value was indicated for LRRT for OS (HR 0.35, 95% CI 0.21-0.58, P < 0.001). However, LRRT did not show significant survival benefits for the high-risk group.

Discussion
Distant metastasis has been a leading cause of death in patients with NPC, and there is no effective treatment for such patients [28,29]. The management of metastatic NPC remains a crucial clinical challenge. The development of modern treatment modalities (e.g., IMRT, tomotherapy, targeted therapy, biotherapy) makes individualized treatment increasingly important, as these   [32]. In our study, 315 patients were followed by LRRT after PCT and 187 patients received PCT only. The median cycle of PCT was five (three weeks a cycle). Between chemotherapy and RT initiation, the median of time intervals were 21 days (range: 10-38 days). There is potential for immortal time bias. Only patients that survive long enough can actually receive radiation and patients that die or progress before they can get LRRT cannot possibly receive LRRT. The observations of consistent benefits with RT on landmark analyses suggest that this form of bias could not affect our results. Plasma EBV DNA level and tumor response correlate with the tumor burden and prognosis [13][14][15]. In the present study, patients with undetectable plasma EBV DNA levels after PCT had significantly better clinical outcome than patients with detectable EBV DNA levels. Similarly, satisfactory tumor response predicted better OS compared with unsatisfactory response. The results are accordance with our previous study of patients with locoregionally advanced NPC [22]. For patients with metastatic or recurrent NPC, An et al. have suggested that undetectable post-treatment plasma EBV DNA indicates better tumor response [33]. Moreover, it was inspiring to observe that patients in our study with both undetectable plasma EBV DNA and satisfactory tumor response post-PCT had a 3-year OS rate of 73.9%, which is significantly higher than that in patients with detectable EBV DNA and/or unsatisfactory tumor response post-PCT (36.5%). Accordingly, considering these two factors, we divided the patients into low-risk (undetectable EBV DNA and satisfactory tumor response post-PCT) and high-risk groups (detectable EBV DNA and/or unsatisfactory tumor response post-PCT). We explored the efficacy of additional post-PCT LRRT in the patients according to risk group. Interestingly, in the low-risk group, patients who received post-PCT LRRT had significantly better OS compared to the patients who did not. This might be because the low-risk patients were sensitive to PCT and that the distant lesions were under better control. Local control may be important to long-term survival in this kind of patients. Therefore, it is more important to control the locoregional disease by post-PCT LRRT. However, for high-risk patients, the distant lesions were not under control and the post-PCT LRRT might have been insufficient for controlling the   [34,35]. Therefore, we did not observe a significant survival benefit of post-PCT LRRT in these patients.
There are several limitations to this study. First, the study involved only 502 patients, and the number of patients between subgroups differed which is an unavoidable bias because of the small sample size. Second, the data were from one center; the results should be validated by a multi-centric clinical study. The third limitation is that the median follow-up duration was 26.3 months. A longer follow-up period is necessary to evaluate the long-term outcomes of these patients and to validate our results.

Conclusion
In conclusion, EBV DNA level and tumor response after PCT are closely related with the clinical outcome of de novo metastatic NPC. Patients with undetectable EBV DNA and satisfactory tumor response after PCT could benefit from the addition post-PCT LRRT. This finding would identify patients at different risk of treatment failure and guide individualized therapy. Further investigation is necessary to confirm our findings.