External validity of a prognostic nomogram for locoregionally advanced nasopharyngeal carcinoma based on the 8th edition of the AJCC/UICC staging system: a retrospective cohort study

Nasopharyngeal carcinoma (NPC) arises from the squamous cells of the epithelial lining of the nasopharynx. Radiotherapy is the primary treatment modality because of NPC’s confined anatomical location and high sensitivity to radiation. The non-specificity of nasal and aural symptoms accounts for locoregionally advanced disease in 70% of patients upon initial diagnosis [1]. Subsequently, these patients have a high risk of distant metastasis and mortality [2, 3] even if treated with concurrent chemoradiotherapy. Accordingly, induction chemotherapy is commonly administered before radiotherapy in clinical practice although randomized controlled trials have not yet contributed to a consensus about its survival benefit [4–8]. In addition, there are no effective adjuvant chemotherapy regimens that have been identified for these patients after radiotherapy [9–13]. Although the tumor, node and metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) was the main tool used to identify patients in these clinical trials, however, the findings of these trials advocate that future clinical trials require more effective stratification method for the identification of high-risk patients, instead of enrolling every patient with locoregionally advanced NPC.

Pan et al. [14] have developed a nomogram comprising of patient’s age, gross primary tumor volume (GTVp), lactate dehydrogenase (LDH) level, and the 8th edition of the AJCC/UICC staging system [15, 16] using a population of 1197 patients treated at the Fujian Provincial Cancer Hospital. Its performance was tested in a cohort of 416 patients from Pamela Youde Nethersole Eastern Hospital, which achieved a concordance index (C-index) of 0.760 [95% confidence interval (CI), 0.723–0.796], which demonstrated significantly superior (P < 0.01) discriminatory power compared to the 8th AJCC/UICC staging system (C-index, 0.654; 95% CI, 0.622–0.686).

Although Pan’s nomogram may have greater potential than the 8th AJCC/UICC edition to identify patients for inclusion in clinical trials, however, since it was developed from a cohort of patients with stage I–IVa disease, its validity for specifically identifying patients with locoregionally advanced disease remains unknown. Additionally, external validation is important before clinical application to individualized randomized controlled trials of induction or adjuvant chemotherapy. As such, we first assessed Pan’s nomogram discriminatory accuracy and calibration by using a large external cohort of patients with stage III–IVb NPC who underwent intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy alone. Second, we performed a direct comparison of its performance with that of Epstein–Barr virus deoxyribonucleic acid (EBV DNA), the most recent and potential biomarker for NPC [17], in an attempt to improve Pan’s nomogram.

Our findings demonstrated that Pan’s nomogram [14] underestimated the 5-year OS of patients with locoregionally advanced NPC. When the discriminatory accuracy was compared with EBV DNA, the 7th and 8th AJCC/UICC staging system, the accuracy of Pan’s nomogram was found to be superior. However, Pan’s nomogram did not demonstrate significant 5-year OS predictive ability as compared to the combination of EBV DNA together with the 8th AJCC/UICC staging system. Its discrimination performance was marginally inferior compared with that of the best predictive model, which fitted age, BMI, LDH, GTVp, and the 8th AJCC/UICC N-classification system.

The calibration ability of Pan’s nomogram derived from our database differed from the training and validation cohort of Fujian Provincial Cancer Hospital and Pamela Youde Nethersole Eastern Hospital, respectively [14]. This can be largely explained the by following. First, given that tumor stage primarily indicates tumor burden and determines treatment outcomes [28], patients with early-stage NPC usually receive only radiotherapy, whereas, for locoregionally advanced disease, concurrent chemotherapy is strongly recommended; wherein certain cases induction or adjuvant chemotherapy is also administered before or after radiotherapy. Since we included only patients with locoregionally advanced NPC, the individual treatment approaches varied by tumor stage and consequently demonstrated different treatment outcomes between the different investigated cohorts [29].

Second, the patients in our database received concurrent chemoradiotherapy alone, whereas the patients in the study by Pan et al. [14] received additional chemotherapy before or after radiotherapy. Similar to randomized controlled trials [4, 7], differences in chemotherapy approaches can also lead to differences in OS, even for tumors with similar stage. Therefore, our finding of non-accurate prediction by Pan’s nomogram was not unexpected, particularly considering the intrinsic differences in the predictions of prognosis between our independent cohort and the original training and validation cohorts [14].

In contrast, the differences among other characteristics suggest that the prediction of Pan’s nomogram was not precise enough. For example, the LDH levels of patients in our database were significantly lower compared with those of patients included in the study by Pan et al. [14] (Table 1) and the LDH level was strongly predictive of the OS of Pan’s nomogram. It is, therefore, possible that the difference in the LDH levels lowered calibration accuracy. Furthermore, a significant interaction effect was observed between the GTVp and the clinical stage according to the 8th AJCC/UICC staging system. A similar interaction effect was likely to exist when both variables were included in Pan’s nomogram during its development, for which the inferior calibration may be associated. Moreover, induction chemotherapy in clinical practice is commonly administered to patients with locoregionally advanced disease with large tumor volumes. Thus, our inclusion criteria restricting patients with locoregionally advanced disease who received concurrent chemoradiotherapy alone naturally selected patients with a relatively smaller GTVp compared with a previous report [30]. But notably, the average GTVp was not larger in our study compared with that of Pan et al. [14], which included patients with any tumor stage. So, selection bias may have exerted little effect on the underestimation of 5-year OS, because the median or average GTVp in the study by Pan et al. [14] was much larger compared with the others, in which an enlarged retropharyngeal lymph node was delineated in the GTVp [31–33].

Pan’s nomogram discriminated outcomes better compared with other single predictors such as EBV DNA and the 7th and 8th AJCC/UICC staging system. This was expected because Pan’s nomogram combined several prognostic factors with tumor stage. Unfortunately, Pan’s nomogram did not achieve significant superiority over the combination of EBV DNA and the tumor stage based on the 8th edition of the AJCC/UICC staging system. Moreover, it was marginally inferior to the model, which included independent prognostic factors such as the age, BMI, LDH, GTVp, and N-classification based on the 8th AJCC/UICC staging system.

Risk prediction programs [26, 34–37] other than Pan’s nomogram are available [14]. However, Pan’s nomogram incorporates several important and well-known clinical predictors. In particular, it is the only one developed using a cohort of patients other than those from our cancer center. However, the underestimation of OS in this external validation indicates that Pan’s nomogram cannot accurately identify authentic high-risk patients from all patients with locoregionally advanced NPC.

The limitations of this study are as follows. The lack of unified treatment approaches, chemotherapy regimens, and radiation or chemotherapy doses determined by the nature of retrospective design may, to a certain extent, bias the findings of this study. Also, due to the small sample size of patients analyzed, this could have possibly lowered the confidence of validation derived from this study. Lastly, validation by a single institution does not essentially provide a strong evidence and further large cohort, multi-institutional analysis is still required.

Pan’s nomogram was observed to significantly underestimate the 5-year OS of patients with locoregionally advanced NPC. It failed to precisely identify high-risk participants for inclusion in randomized controlled trials.