Depicting distant metastatic risk by refined subgroups derived from the 8th edition nasopharyngeal carcinoma TNM
Introduction
The application of intensity-modulated radiotherapy (IMRT) has significantly improved loco-regional control (LRC) of nasopharyngeal carcinoma (NPC); however, about 15% to 30% patients experience failure at distant sites [1]. In fact, distant metastasis (DM) has become the principal form of failure and main cause of death for NPC patients following IMRT [1], [2]. Therefore, precise evaluation of DM risk and appropriate stratification is an important first step to tailoring more individualized treatment and improving survival.
The anatomic tumor-node-metastasis (TNM) staging system has long been recognized as the most important survival indicator for NPC patients, and is critical in facilitating treatment planning. While invaluable for cancer treatment, and with additional advantages from simplicity and ease of use worldwide, the TNM classification was recognized at its genesis as having limitations. Thus, it has always been appreciated that many factors in addition to TNM contribute to prognosis (including age, sex, social determinants of health and numerous pathological factors) [3]. Moreover, other outcomes may be governed by separate prognostic factors compared to overall survival (OS), the usual end-point used in cancer staging[4], [5]. For this reason, the UICC and AJCC have attempted to refine knowledge and processes to address important prognostic factors relevant to outcomes following specific treatments [6]. To date for NPC, there has not been a comprehensive process to address the prediction of DM, potentially the most important outcome that governs survival in this disease. This may largely be a consequence of the traditional concern about achieving local control in the protected sanctuary of the skull base; however, this emphasis has diminished with the contemporary high LRC rates due to IMRT, high quality imaging, and cisplatin chemotherapy as a potential radiotherapy sensitizer. Effectively the challenge has shifted to the risk of DM, which may have its own unique characteristics and may be receptive to new approaches that may target DM separately.
Although many biomarkers, such as blood EBV-DNA [7], [8], and serum lactate dehydrogenase (LDH) [9], [10], have been identified as DM predictors, TNM categories and stage groups represent the basic anatomic building blocks needed to explore incorporation of these biomarkers. Unfortunately, significant heterogeneity in risk of DM is often observed for different T-N subgroups of patients within apparently equivalent clinical TNM stage [11], [12], [13], [14], [15], [16]. The UICC/AJCC staging system was updated to the 8th version (TNM-8)[17], in which both T and N categories were modified. Whether the heterogeneity of DM risk still exists within the updated stage groupings remains unknown. Hence, we conducted this retrospective analysis of a series of non-metastatic NPC patients treated with IMRT in our institution to evaluate the predictability of DM risk within each TNM-8 stage. We used recursive-partitioning analysis (RPA) to construct a framework intended to provide high sensitivity to predict DM risk using the anatomic components of the 8th edition T and N. It is envisioned that additional biomarkers factors could subsequently be employed to refine the risk and determine with precision subgroups of patients with the greatest need for novel systemic treatments to reduce DM. Such factors could comprise tissue-based factors such as microRNA signatures [18], [19] or circulating blood indices such as EBV copy number or LDH levels.
Section snippets
Patients and treatment
Patients with histologically-proven NPC who received definitive IMRT with or without chemotherapy at our institution between June 2005 and December 2011 were candidates for this retrospectively study. Other eligible criteria included: (1) no history of previous treatment or prior malignancy; (2) a completed pretreatment evaluation according to our institutional protocol [20], (3) availability of imaging data that permitted re-staging according to the TNM-8 [17]. With these criteria, 1616
Statistical analyses
The primary endpoint was DMFS (time to DM) where death without DM was censored. An additional endpoint was OS (time to death due to any causes). Descriptive statistics were provided with median and ranges for continuous variables, and frequency and percentages for categorical variables. Survival curves were created with the Kaplan–Meier method and compared by log-rank test. Multivariate analyses (MVA) by Cox proportional hazards model were performed to evaluate the stage prognosis on DMFS and
Patients’ characteristics and performance of the TNM-8 in predicting risk of DM
The clinical characteristics of the 1616 eligible patients are listed in Table 1. The majority were nonkeratinizing (undifferentiated) carcinoma (1483, 91.8%) according to the World Health Organization (WHO) classification. Median follow-up time was 53 months. A total of 93 (5.8%) local, 72 (4.5%) regional, and 273 (16.9%) distant failures were identified. The 5-year DMFS for TNM-8 stage I, II, III and IV were 97.4% (95% CI: 93.9–100), 90.7% (87.8–93.6), 82.5% (79.4–85.6) and 71.6% (67.1–76.1),
Discussion
This large single institution cohort of non-metastatic NPC treated with IMRT showed that, similar to the 6th and 7th edition UICC/AJCC staging system, TNM-8 has limitations in portraying the risk of DM consistently within each stage. Using an RPA algorithm, we generated the following four distinctly different DM risk groups: RPA-I (T1-3N0 and T1N1), RPA-II (T2-3N1), RPA-III (T4N0-1 and T1-3N2) and RPA-IV (T4N2 and T1-4N3) [Fig. 2]. This RPA risk grouping performed better in depicting risk of DM
Conclusions
This large single institution study of a contemporary treated NPC cohort shows that DM risk increases with higher TNM-8 stage, although significant heterogeneity exists for DMFS within each stage. Deriving relatively homogeneous DM risk groups would help refine treatment strategies. Using an RPA algorithm, we generated four groups based on TNM-8T and N definitions, namely RPA-I (T1N0-1 and T2-3N0), RPA-II (T2-3N1), RPA-III (T4N0-1 and T1-3N2) and RPA-IV (T4N2 and T1-4N3). These RPA risk
Conflict of interest statement
None declared
Acknowledgement
This work was sponsored by National Clinical Key Specialty Construction Program and Key Clinical Specialty Discipline Construction Program of Fujian, China. This research is also supported by grant from the Fujian Provincial Natural Science Foundation of China (grant No. 2018 J01275). We acknowledge the Bartley-Smith Wharton Fund and the O. Warwick Prize of the Canadian Cancer Society for supporting BO’S academic activities.
References (51)
- et al.
The TNM classification of malignant tumours-towards common understanding and reasonable expectations
Lancet Oncol
(2017) - et al.
Clinical utility of epstein-barr virus DNA testing in the treatment of nasopharyngeal carcinoma patients
Int J Radiat Oncol Biol Phys
(2017) - et al.
Improvement of survival after addition of induction chemotherapy to radiotherapy in patients with early-stage nasopharyngeal carcinoma: subgroup analysis of two Phase III trials
Int J Radiat Oncol Biol Phys
(2006) - et al.
Nasopharyngeal carcinoma treated with reduced-volume intensity-modulated radiation therapy: report on the 3-year outcome of a prospective series
Int J Radiat Oncol Biol Phys
(2009) - et al.
Application of circulating plasma/serum EBV DNA in the clinical management of nasopharyngeal carcinoma
Oral Oncol
(2014) - et al.
Prognostic efficacy of combining tumor volume with Epstein-Barr virus DNA in patients treated with intensity-modulated radiotherapy for nasopharyngeal carcinoma
Oral Oncol
(2016) - et al.
Promising treatment outcomes of intensity-modulated radiation therapy for nasopharyngeal carcinoma patients with N0 disease according to the seventh edition of the AJCC staging system
BMC Cancer
(2012) - et al.
Long-term outcomes of early-stage nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy alone
Int J Radiation Oncol Biol Phys
(2012) - et al.
The long term results of adding chemotherapy to intensity-modulated radiation therapy in the treatment of stage II nasopharyngeal carcinoma - a multicenter phase 2 study
Int J Radiat Oncol Biol Phys
(2018) - et al.
Chemotherapy may not be necessary in stage II nasopharyngeal carcinoma treated with intensity-modulated radiation therapy
Int J Radiat Oncol Biol Phys
(2018)
The prognostic significance of parapharyngeal tumour involvement in nasopharyngeal carcinoma
Radiotherapy Oncol : J European Soc Therapeutic Radiol Oncol
Prognostic influence of parapharyngeal space involvement in nasopharyngeal carcinoma
Int J Radiat Oncol Biol Phys
Prognostic value of parapharyngeal extension in nasopharyngeal carcinoma treated with intensity modulated radiotherapy
Radiotherapy Oncol : J European Soc Therapeutic Radiol Oncol
Update report of T4 classification nasopharyngeal carcinoma after intensity-modulated radiotherapy: an analysis of survival and treatment toxicities
Oral Oncol
Plasma Epstein-Barr viral DNA load at midpoint of radiotherapy course predicts outcome in advanced-stage nasopharyngeal carcinoma
Annals Oncol : Official J European Soc Medi Oncol
Management of nasopharyngeal carcinoma: current practice and future perspective
J Clinical Oncol : Official J Amer Soc Clin Oncol
Intensity-modulated radiotherapy prolongs the survival of patients with nasopharyngeal carcinoma compared with conventional two-dimensional radiotherapy: a 10-year experience with a large cohort and long follow-up
European J Cancer (Oxford, England)
Risk Models for Individualized Prognosis in the Practice of Precision Oncology
Introduction
Chapter 3: Prognosis and classification of cancer
Epstein-Barr virus DNA level as a novel prognostic factor in nasopharyngeal carcinoma: a meta-analysis
Medicine
Prognostic nomogram for refining the prognostication of the proposed 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy
Cancer
High pretreatment serum lactate dehydrogenase level correlates with disease relapse and predicts an inferior outcome in locally advanced nasopharyngeal carcinoma
European J Cancer (Oxford, England)
Long-term survival of nasopharyngeal carcinoma patients with stage II in intensity-modulated radiation therapy era
Jpn J Clin Oncol
Comparison of the efficacy between concurrent chemoradiotherapy with or without adjuvant chemotherapy and intensity-modulated radiotherapy alone for stage II nasopharyngeal carcinoma
Oncotarget
Cited by (9)
Administration of oral maintenance chemotherapy for 1 year following definitive chemoradiotherapy may improve the survival of patients with stage N3 nasopharyngeal carcinoma
2021, Oral OncologyCitation Excerpt :With improvements in radiotherapy techniques and the combined application of radio- and chemotherapy, the 5-year overall survival of NPC has reached ~85% [2]; however, the 5-year distant metastasis (DM) rate remains high at 20–30%, even after standard treatment [3,4]. This has come to represent the main cause of treatment failure in patients with locally advanced NPC [5–8]. Nodal (N) 3 stage is an independent adverse prognostic factor for both DM-free survival (DMFS) and overall survival (OS) of patients with NPC [9].
Risk factors for lymph node metastasis in rectal neuroendocrine tumors: A recursive partitioning analysis based on multicenter data
2021, Journal of Surgical Oncology
- 1
Both Qiaojuan Guo and Tianzhu Lu contributed equally to this study.