Tumor residue in patients with stage II–IVA nasopharyngeal carcinoma who received intensity-modulated radiation therapy: development and validation of a prediction nomogram integrating postradiotherapy plasma Epstein–Barr virus deoxyribonucleic acid, clinical stage, and radiotherapy dose

Nasopharyngeal carcinoma (NPC) is malignant disease of multidimensional spatiotemporal unity of ecology and evolution, often manifesting with invasive growth at the primary site and metastatic cervical lymph node(s) [1, 2]. Although the implementation of intensity-modulated radiotherapy (IMRT) has attained satisfactory tumor control and survival benefits in NPC [3‐5]. Intertumor and intratumor heterogeneities in the ecosystem of NPC have caused diverse response patterns among patients [1].

Due to the different regression rate in tumor and disturbance of (chemo) radiotherapy-induced inflammation, 12 weeks after the completion of radiotherapy (RT) is proposed as a proper time point for initial evaluation of total tumor control [6, 7]. By then, inflammation would have largely resolved, most tumors would have regressed, and delayed tumor regression within 12 weeks would not impair overall control [8, 9]. Beyond this window time (12 weeks), the incidence of residue increased [8]. Reportedly, 3–13% of patients had persistent disease after 12 weeks and were diagnosed as tumor residue [10, 11]. Residual tumor stem cells have evolved aggressively and grow more rapidly during treatment cessation [12]. Thus, most patients with residual disease ultimately develop disease failure [10, 11].

Residue may be a reflection of treatment insensitivity, inadequate RT dose, or geographic miss in irradiated field [12]. Timely additional treatment (including surgery, boost radiation, and chemotherapy) at the end of RT may enhance or strengthen the curative effect and reduce the probability of residue after 3–6 months [13‐15]. Controversially, the blind administration of additional intervention at the end of RT may be surplus for some patients whose tumor may spontaneous regressed. However, there is no sound tool at the end of RT to predict whether tumor will residue or not after observation for 3–6 months.

In NPC, Epstein–Barr virus (EBV) deoxyribonucleic acid (DNA) serves as a liquid circulating biomarker that reflects the tumor burden [16]. Reportedly, postradiotherapy EBV DNA has an even stronger association with recurrences and poor prognosis in NPC [17, 18]. Elevated plasma EBV DNA level has been shown to predate clinical recurrence by 3 to 7 months, which may present a biomarker of subclinical residual disease [18, 19]. But its predictive value on residue is unexcavated.

Here, we hypothesized that the probability of tumor residues could be reduced through immediate additional intervention at the end of IMRT by leveraging a predictive tool. In this study, we aimed to develop and validate a nomogram model integrating clinical characteristics at the end of IMRT for predicting whether tumor will residue or not after 3–6 months. Thus, NPC patients with a high risk of residue event might benefit from immediate additional intervention. Meanwhile, low-risk patients who will have tumor complete regressed after 3 months will be spared from overtreatment.

Despite the advancement of IMRT, 3–13% of patients with NPC experienced tumor residue 3–6 months after radical RT [10, 11]. Over the past two decades, considerable efforts have been made to investigate the prognostic value of [31‐34], compare the capability to diagnose and differentiate residues among available medical procedures [35, 36], and develop predictive models for prognostic stratification and risk adjustment [32] in this field. Unfortunately, little is known about the forecasting tumor residue for the preventive effects at the end of RT. In a large retrospective cohort, we developed and validated a nomogram, integrating clinical stage, postradiotherapy plasma EBV DNA, and RT dose, to estimate the probability of tumor residue after 3–6 months in stage II–IVA NPC patients treated with curative IMRT. The comprehensive nomogram showed better discrimination than clinical stage or postradiotherapy EBV DNA level alone. To the best of our knowledge, this study is the first to investigate the role of postradiotherapy status in predicting residue after 3–6 months.

The tumor-derived EBV DNA load in the plasma represents a microscopic disease in NPC [3]. A detectable or higher level of this pretreatment liquid biomarker is associated with worse outcomes and inferior survival [37]. While it can be eradicated during treatment in most patients, 9.2–28.8% of patients have microscopic tumor residue in the circulation after treatment [18, 38, 39]. Chan et al. conducted several prospective studies to investigate their prognostic significance. In 170 NPC patients receiving a uniform RT protocol, 28.8% of patients had detectable posttreatment EBV DNA (at 6–8 weeks after RT) and exhibited inferior PFS (HR 11.9, 95% CI 5.53–25.43) and OS (HR 8.6, 95% CI 3.69–19.97) compared to patients with higher pretreatment EBV DNA [18]. Similarly, a better risk discrimination concerning different endpoints in the postradiotherapy EBV DNA level than pretreatment level was observed in our study. In a large prospective plasma EBV DNA screening study for identification of high-risk NPC patients for adjuvant chemotherapy, the positive relationship between detectable or higher levels of postradiotherapy EBV DNA (within 120 days) and disease failures was highlighted. Unfortunately, patients with detectable postradiotherapy liquid biomarker levels did not benefit from adjuvant chemotherapy [38]. Therefore, detectable postradiotherapy EBV DNA levels are not a determinant factor in identifying high-risk patients. In their post-hoc analysis, a combination of postradiotherapy EBV DNA and clinical stage improved risk stratification for NPC using recursive partitioning analysis compared to either the clinical stage or postradiotherapy EBV DNA alone (concordance-index (C-index): 0.712 vs. 0.604 vs. 0.675) [39]. The aforementioned series of investigations implied the potential of a combination of clinical stage and postradiotherapy EBV DNA level in predicting tumor residue. In our study, plasma EBV DNA was detectable in 10.6% of patients after RT, consistent with a previous study [39]. In Chan’s study, a postradiotherapy EBV DNA level yielded a C-index of 0.675 in predicting 5-year OS [39]. Tumor residue is an early failure pattern that can be plausibly predicted by postradiotherapy EBV DNA which has been related to minimal residual disease at the end of RT. In our study, the postradiotherapy EBV DNA level alone achieved a higher AUC in predicting residue compared to the pretreatment EBV DNA level (0.627 vs. 0.593). The performance in predicting tumor residue was improved by a combination of clinical stage and posttreatment liquid biomarkers (AUC: 0.733), which verified the aforementioned hypothesis.

In this study, 69.96 Gy was employed as a cut-off value for sectionalisation for the RT dose. The reason for choosing this prescribed dose was that it was uniformly recommended to all NPC patients for its good balance between the tumor-killing effect and normal tissue tolerance according to the National Comprehensive Cancer Network. Notably, the RT dose to the primary tumor site and involved lymph nodes was significantly associated with tumor residue in our model. This result demonstrated that the tumor residue is associated with tumor radiation insensitivity or an insufficient dose. This is likely a reflection of the underlying biological heterogeneity of patients with NPC. We reasoned that a uniformly prescribed dose may be insufficient for patients with potential radiation resistance. Several studies have shown that boost RT dose for residual lesions can improve tumor control and survival rates [40, 41]. Fei et al. conducted a study on 398 NPC patients with T4 stage disease who had local residue after radical IMRT (70 Gy). In their study, 114 patients received boost dose of 4–6.75 Gy in local residual lesions (2–3 fractions, 2–2.25 Gy per fraction, 1 fraction per day, 5 fractions per week). After follow-up, the boost group exhibited better 3-year OS (86.6% vs. 71.3%, P=0.008), PFS (79.0% vs. 69.1%, P=0.019), and LRRFS (93.4% vs. 82.4%, P=0.012) than the non-boost group [14]. In our study, patients receiving a dose under 70.00 Gy were more likely to have residue, which implies that a dose boost may reverse the outcome. Meanwhile, others argue that the boost dose should not be delivered indiscreetly if the delivered dose for the gross tumor volume is sufficient. In a retrospective study by Han et al., the tumor residual rate was 6.1% (12/196) three months after IMRT. All 12 residual lesions resolved completely 4–9 months after RT [42]. In the era of IMRT, the blind administration of additional RT to the residual tumor seems unwise. Thus, the challenge lies in patient selection to maximise the magnitude of the benefit. Although the prediction nomogram built in our study cannot predict residual tumor pretherapy, we provided a compromise at the end of IMRT. After receiving a uniform standard dose, timely salvage treatment is necessary for patients at risk of tumor residue.

However, this study has some limitations. First, it was a retrospective study. Second, the timing of postradiotherapy plasma EBV DNA levels was not standardised within the studied patients. In most clinical trials of adjuvant therapy for NPC, the therapy is usually planned to start within 4 weeks after the completion of RT. To cover this range, we extended the time of measuring plasma EBV DNA levels to 4 weeks after RT. Third, our prediction nomogram was built and validated at a single center. Further external validation will help to attain high-level evidence of clinical feasibility. Also, prospective clinical studies with large cohorts are warranted to investigate strategies for tumor residue prevention.

In summary, we developed a nomogram integrating clinical stage, postradiotherapy plasma EBV DNA level, and RT dose for the primary tumor and metastatic lymph nodes for predicting whether tumor residue or not after 3–6 months in patients with stage II–IVA NPC disease after completion of IMRT. The proposed nomogram proved to be a reliable tool for estimating residue risk and appears to provide an opportunity for timely improvement or consolidation of efficacy.