Background
Nasopharyngeal carcinoma (NPC), particularly the undifferentiated subtype, is prevalent in South Asia and South China.1,2 Radiotherapy (RT) is the mainstay treatment of NPC. With the innovation of modern imaging and radiation techniques, a high cure rate has been achieved for patients with early-stage NPC. However, due to its deep-seated location, 70% to 80% of patients are not diagnosed until the disease is at the advanced stage.3 For advanced-stage disease, RT in combination with concurrent chemotherapy has been shown to be the standard treatment protocol.4,5 Despite the use of concurrent chemotherapy, distant metastasis is still a major component of treatment failures, occurring in 18% to 27% of patients.5,6 To improve these results, additional systemic therapy has been explored, such as adding neoadjuvant or adjuvant chemotherapy (NACT or ACT, respectively) to concurrent chemoradiotherapy (CCRT).7–12 However, due to inconsistent results of several prospective randomized trials, the additional benefit of adding NACT or ACT to CCRT remains controversial.
Currently, therapeutic decisions are based primarily on TNM stage. However, given tumor heterogeneity, patients with similar stages and histologic classifications have markedly different survival outcomes. Infection with Epstein-Barr virus (EBV) is strongly linked to NPC.13,14 Previous studies have shown that patients with high levels of pretreatment plasma EBV DNA have higher rates of distant relapse and death.15,16 Thus, plasma EBV DNA level, as a supplement to disease stage, could help to stratify patients into different groups of risk of treatment failure. Patients in the high-risk group might benefit from the addition of NACT or ACT to CCRT. The ongoing NRG-HN001 study (ClinicalTrials.gov identifier: NCT02135042) is using EBV DNA to risk-stratify patients and determine ACT; no previous studies have used plasma EBV DNA to select eligible treatment participants. The goal of our study was to compare patients in different risk groups who received different chemotherapy treatments to determine the optimal therapeutic strategy for individuals with NPC.
Patients and Methods
From January 2004 to December 2012, we identified 6,996 patients in our institute who were newly diagnosed with NPC. Eligibility criteria included (1) biopsy-proven WHO histopathologic type II or III NPC; (2) age ≥18 years; (3) stages III–IVb disease according to the seventh edition of the International Union Against Cancer/AJCC TNM staging system; (4) ECOG performance status of 0 or 1; (5) treatment with intensity-modulated RT; (6) received CCRT ± NACT or ACT; (7) complete data of pretreatment plasma EBV DNA level; and (8) adequate hematologic, liver, and renal function. Exclusion criteria included history of previous or synchronous malignant tumors, additional use of targeted therapy or immunotherapy, pregnancy or lactation, primary distant metastasis, and insufficient follow-up data. A total of 2,263 eligible patients were included in the study (Figure 1). This study was approved by Sun Yat-sen University Cancer Center's Clinical Research Committee.
Flowchart of patients included in the study.
Abbreviations: ACT, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; EBV, Epstein-Barr virus; NACT, neoadjuvant chemotherapy; NPC, nasopharyngeal carcinoma.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 6; 10.6004/jnccn.2018.7270
Flowchart of patients included in the study.
Abbreviations: ACT, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; EBV, Epstein-Barr virus; NACT, neoadjuvant chemotherapy; NPC, nasopharyngeal carcinoma.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 6; 10.6004/jnccn.2018.7270
Flowchart of patients included in the study.
Abbreviations: ACT, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; EBV, Epstein-Barr virus; NACT, neoadjuvant chemotherapy; NPC, nasopharyngeal carcinoma.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 6; 10.6004/jnccn.2018.7270
Pretreatment Evaluation
All patients underwent a complete physical examination, fiberoptic nasopharyngoscopy, electrocardiography, MRI of the nasopharynx and neck, chest radiography, abdominal ultrasound, skeletal scintigraphy or whole-body fluorodeoxyglucose PET/CT, CBC count, biochemical profile, and EBV serology with plasma EBV DNA level.
RT and Chemotherapy
All patients were treated with concurrent cisplatin (100 mg/m2) at weeks 1, 4, and 7 of the RT cycle. Among them, 970 patients received CCRT alone, 1,073 received 2 or 3 cycles of NACT followed by CCRT, and 220 received CCRT followed by 1 to 4 cycles of adjuvant PF (cisplatin, 80 mg/m2 on day 1 with 5-fluorouracil, 800–1,000 mg/m2 for 96 hours of continuous intravenous infusion).17 The regimen of NACT included PF, TP (cisplatin with docetaxel, 75 mg/m2 on day 1), and TPF (cisplatin, 75 mg/m2 on day 1 and docetaxel, 75 mg/m2 on day 1, with 5-fluorouracil, 750 mg/m2 for 96 hours of continuous intravenous infusion).7,9,18 The intensity-modulated RT plan was designed according to previous studies, and treatment followed the general design at our institute (supplemental eAppendix 1, available with this article at JNCCN.org).19,20
Plasma EBV DNA–Level Assessment
Plasma EBV DNA concentrations were measured with real-time quantitative PCR before treatment.21,22 Pretreatment EBV DNA levels were divided into a low and high group based on the cutoff value of 4,000 copies/mL, which was established as a prognostic value in previous studies.15,23
Clinical Outcome and Follow-Up
Our primary study end point was distant metastasis–free survival (DMFS), which was calculated from the first day of treatment to the date of distant metastasis. The secondary end point included overall survival (OS), which was calculated from the start of treatment to the date of death of any cause, and progression-free survival (PFS), which was calculated from the first day of treatment to the date of any treatment failure or death of any cause. Patients were censored if they were still alive on August 4, 2017, the date of last follow-up. After treatment, patients were examined at 3-month intervals for the first 3 years and every 6 months thereafter or until death.
Statistical Analysis
Categorical variables were compared using the chi-square or Fisher exact test. The Kaplan-Meier method was used to estimate the cumulative survival rates, and survival curves were compared using the log-rank test. Hazard ratios (HRs) with 95% CIs were calculated using the Cox proportional hazards model. Univariate and multivariate analyses using Cox proportional hazards models were performed to evaluate the independent significance of the treatment group (different timing of chemotherapy to CCRT) and other potential prognostic factors, including age, sex, tumor stage, history of NPC, early antigen immunoglobulin A, and viral capsid antigen immunoglobulin A. Tests were 2-sided, and a P value <.05 was considered significant.
Results
The characteristics of the 2,263 patients in the different treatment groups are presented in Table 1. In the NACT + CCRT group (N=1,073), 81.5% of patients (n=875) received 3 cycles and 18.5% (n=198) received 2 cycles of NACT, and 45.5% (n=483) received 3 cycles and 55.0% (n=590) received 2 cycles of CCRT. In the CCRT + ACT group (N=220), 5.9% of patients (n=13) received 4 cycles, 31.4% (n=69) received 3 cycles, 44.5% (n=98) received 2 cycles, and 18.2% (n=400) received 1 cycle of ACT, and 68.6% (n=151) received 3 cycles and 31.4% (n=69) received 2 cycles of CCRT. In the CCRT group (N=970), 55.1% of patients (n=534) received 3 cycles of CCRT and 44.9% (n=436) received 2 cycles. For the entire cohort (N=2,263), within the median follow-up of 68 months (range, 3–128 months), 17.8% of patients (n=403) died, 14.8% (n=335) developed distant metastasis, and 9.7% (n=220) exhibited locoregional relapse. For all end points, significant survival curve separations were not observed among the 3 treatment groups (supplemental eTable 1, Figure 2). Significant survival benefit was not achieved with the addition of NACT or ACT to CCRT (supplemental eFigure 1). In addition, the survival curves of different chemotherapy regimens of NACT were not significantly segregated (supplemental eFigure 2). Therefore, we further analyzed the relationship between treatment method and clinical outcome in different risk groups.
Patient Characteristics
Comparison of the probability of different treatment methods with regard to (A) distant metastasis–free survival, (B) overall survival, and (C) progression-free survival rates.
Abbreviations: ACT, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; NACT, neoadjuvant chemotherapy.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 6; 10.6004/jnccn.2018.7270
Comparison of the probability of different treatment methods with regard to (A) distant metastasis–free survival, (B) overall survival, and (C) progression-free survival rates.
Abbreviations: ACT, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; NACT, neoadjuvant chemotherapy.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 6; 10.6004/jnccn.2018.7270
Comparison of the probability of different treatment methods with regard to (A) distant metastasis–free survival, (B) overall survival, and (C) progression-free survival rates.
Abbreviations: ACT, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; NACT, neoadjuvant chemotherapy.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 6; 10.6004/jnccn.2018.7270
Risk Stratification
As we reported earlier,24 N stage and pretreatment EBV DNA were significantly correlated with distant metastasis. Moreover, patients with N0–1 stage disease with high EBV DNA (≥4,000 copies/mL) and those with N2–3 stage disease with low EBV DNA (<4,000 copies/mL) had similar likelihoods of developing distant metastasis.24 In this study, 6.6% of patients (54 of 818) with N0–1 disease and low EBV DNA exhibited distant metastasis, 14.4% (118 of 818) with N0–1 disease and high EBV DNA or N2–3 disease and low EBV DNA exhibited distant metastasis, and 26.0% (163 of 627) with N2–3 disease and high EBV DNA developed distant metastasis. Thus, eligible patients in our study were divided into 3 different risk groups: low-risk (N0–1 and low EBV DNA), intermediate-risk (N0–1 disease and high EBV DNA or N2–3 disease and low EBV DNA), and high-risk (N2–3 disease and high EBV DNA). Characteristics of patients treated with different methods in different risk groups are shown in supplemental eTable 2. Survival curves were significantly segregated among patients in different risk groups for DMFS (P<.001), OS (P<.001), and PFS (P<.001) (supplemental eFigure 3).
Relationship Between Treatment and Clinical Outcome in Low-Risk Group
Patients who received NACT followed by CCRT achieved significantly better 5-year DMFS than those treated with CCRT alone (96.2% vs 91.3%; P=.008) (Table 2, eFigure 4. In multivariate analyses, additional NACT significantly reduced the risk of distant metastasis and was also the only independent prognostic factor for DMFS (HR, 0.42; 95% CI, 0.22–0.80; P=.009). Multivariate analyses also demonstrated that smoking was an independent prognostic factor for PFS (HR, 1.53; 95% CI, 1.02–2.31; P=.040) (Table 3).
Comparison of Cumulative Survival Rates
Multivariate Analyses of Potential Prognostic Factors in Clinical Outcomes
Relationship Between Treatment and Clinical Outcome in Intermediate-Risk Group
Patients treated with NACT or ACT in addition to CCRT in the intermediate-risk group had no significantly better survival than those in the CCRT-alone group (Table 2). When adjusting for other factors at multivariate analysis, T stage was an independent prognostic factor for DMFS (HR, 2.17; 95% CI, 1.13–4.17; P=.020), OS (HR, 2.17; 95% CI, 1.20–3.93; P=.011), and PFS (HR, 2.12; 95% CI, 1.31–3.46; P=.002) (Table 3). Sex was an independent prognostic factor for DMFS (HR, 2.06; 95% CI, 1.21–3.51; P=.008) and OS (HR, 1.79; 95% CI, 1.10–2.90; P=.019). However, the treatment group was not an independent prognostic factor for all end points.
Relationship Between Treatment and Clinical Outcome in High-Risk Group
In the high-risk group, comparison of NACT or ACT + CCRT versus CCRT alone still indicated no significantly better survival (Table 2, eFigure 4). Multivariate analyses demonstrated that no prognostic factor was correlated with DMFS, OS, and PFS (Table 3).
Discussion
To our knowledge, the efficacy of systemic chemotherapy in addition to RT in patients with advanced-stage disease at different risk levels of distant metastasis was not well established in previous studies. Results of our study showed that NACT followed by CCRT could significantly reduce the risk of distant metastasis compared with CCRT alone in patients in the low-risk group. However, no significant OS benefit was observed for either the addition of NACT or ACT.
Since the landmark Intergroup 0099 trial,17 studies concerning the interaction between the timing of chemotherapy and the effect on various end points have been ongoing. Several meta-analyses showed that the survival benefit primarily comes from the concurrent phase.5,25 Although high locoregional control rates are currently achieved with CCRT for advanced-stage NPC, distant metastasis has become the leading cause of treatment failure.5,6 Our study investigated the efficacy of NACT or ACT in addition to CCRT. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers recommend CCRT followed by ACT for stages II–IVb NPC, and this recommendation is supported by level IIA evidence.26 The combined analyses of the NPC-9901 and NPC-9902 trials also demonstrated that ACT contributed to improving distant control.27 A retrospective study by Twu et al28 showed that ACT could reduce distant failure and improve OS (71.6% vs 28.7%; P<.001) in patients with persistently detectable EBV DNA after CCRT. However, the phase III trial by Chen et al29 showed no statistically significant improvement in failure-free survival with additional ACT. Notably, compliance with ACT is poor. In previous studies, only 52% to 61% of patients completed 3 cycles of ACT, and half of these had dose reductions.17,29–32 Theoretically, changing to NACT might improve tolerance and early eradication of potent micrometastases. Therefore, NACT followed by CCRT became the research focus. In 2009, a phase II trial conducted by Hui et al5 reported that adding neoadjuvant cisplatin and docetaxel to CRT increased PFS by 28.7%. Another phase II trial by Fountzilas et al8 and a phase II/III trial by Tan et al12 both failed to show a significant survival benefit at 3 years. Preliminary results of the NPC-0501 trial indicated that the benefit of changing to an induction-concurrent sequence remains uncertain.9 However, Sun et al33 more recently reported that NACT + CCRT could improve survival outcomes in NPC. Thus, there are differing opinions regarding whether the addition of NACT or ACT to CCRT should be recommended.
In our study, analysis of all 2,263 patients failed to show a significant survival benefit among the 3 treatment groups. We believe one possible reason for these controversial results was the therapeutic decisions in the aforementioned studies, which were simply based on TNM stage. As reported previously, pretreatment plasma EBV DNA level significantly correlated with clinical outcome. Patients with high pretreatment EBV DNA levels were more likely to develop treatment failure, especially distant metastases.15,16,23 N stage also correlated with distant metastasis.19 Therefore, taking these 2 factors into consideration, patients in our study were divided into 3 different risk groups. We further explored the efficacy of adding NACT and ACT to CCRT in patients with different risk levels. Interestingly, we found that patients in the low-risk group (N0–1 disease and EBV DNA <4,000 copies/mL) achieved significantly better DMFS from NACT + CCRT than from CCRT alone. Furthermore, NACT + CCRT was the only independent prognostic factor for DMFS. Similarly, the trial by Sun et al33 also demonstrated a significant reduction in distant metastases in patients with N1 disease but not in those with N2–3b disease. The possible reason for these results is that patients with N2–3 or EBV DNA ≥4,000 copies/mL might have already had distant metastasis that could not be detected by imaging examination. In this case, an additional 2 or 3 cycles of NACT might not be enough to eradicate the metastasis. Therefore, a significant reduction in distant metastasis was not observed in these patients. The results could provide the basis for a trial that addresses additional NACT or ACT in the low-risk group.
In our study, patients in the high-risk group treated with CCRT + ACT experienced relatively higher DMFS rates than those treated with CCRT alone (82.4% vs 70.2%). This result was in line with findings of a recent meta-analysis conducted by Ribassin-Majed et al.34 However, survival rates in our study failed to show significant differences between the 2 groups. Compliance with ACT and the small sample size of patients treated with ACT could potentially affect treatment outcome. In the high-risk group, only 53 patients underwent ACT, which underpowered the results. Furthermore, among them, 69.8% of patients (37 of 53) received only 1 to 2 cycles of ACT and had dose reductions, and therefore improvement in survival benefit was inevitably hampered by the suboptimal treatment intensity. Therefore, giving combinations of new drugs with low toxicities to improve compliance with ACT might result in further improvements in survival.
In addition, multivariate analyses showed that male patients had poorer prognosis than their female counterparts in the intermediate-risk group, suggesting that a biologic difference in tumor behavior might exist between male and female patients in this group. The sex difference in prognosis might be due to genetic variants, inappropriate diet, environmental tobacco smoke, and occupational exposures to formaldehyde and dusts in the intermediate-risk group.35–37 Future studies on the mechanisms of sex differences in NPC progression are needed.
Our study has several limitations. First, this was a retrospective study in a single center; therefore, results must be validated by other datasets and prospective studies. Second, only 220 patients in our study received CCRT + ACT; thus, the sample size in each risk group was relatively small. A larger sample size of patients treated with CCRT + ACT is needed to evaluate the long-term outcomes of these patients. Finally, the lack of integrated toxicity data for different treatment methods makes these results underpowered. In the future, a well-designed, multicenter, prospective, randomized study is needed to validate our results.
Conclusions
Our study demonstrated that patients with NPC in the low-risk group who were treated with NACT + CCRT had significantly reduced hazards of distant metastasis compared with patients treated with CCRT alone. Disappointingly, the addition of NACT or ACT failed to achieve OS benefit. Future results of the ongoing NRG-HN001 study using EBV DNA to risk-stratify patients might provide more information on individualized treatment of NPC. Further investigation is necessary to confirm our findings.
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