Subdivision of metachronous metastatic nasopharyngeal carcinoma based on the framework of TNM-9: A recursive partitioning analysis of real-world data

Subdivision of metachronous metastatic nasopharyngeal carcinoma based on the framework of TNM-9: A recursive partitioning analysis of real-world data | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Subdivision of metachronous metastatic nasopharyngeal carcinoma based on the framework of TNM-9: A recursive partitioning analysis of real-world data Daqiang Huang, Hanchuan Xu, Xiaoya Xie, Yiyun Huang, Kexin Lin, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9310030/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Purpose: To validate the prognostic value of the M1 category in version nine of the AJCC/UICC TNM staging system (TNM-9) in metachronous metastatic nasopharyngeal carcinoma (mmNPC) and to develop a refined M1 classification for improved risk stratification. Methods: Patients with newly diagnosed mmNPC (2015–2024) were analyzed and restaged per TNM-9 M1 criteria. Independent prognostic factors from multivariate Cox analysis were integrated using recursive partitioning analysis (RPA) to establish an RPA-based M1 classification (RPA-M1). Model performance was assessed using Harrell's C-index, time-dependent AUC, and Akaike information criterion (AIC). Results: Among 218 patients, 111 (50.9%) were M1a and 107 (49.1%) M1b. The M1a subgroup demonstrated significantly higher 3-year overall survival (OS) than the M1b subgroup (63.2% vs. 40.8%, P < 0.001). Both the TNM-9 M1 category and disease-free interval (DFI) were independent prognostic factors for OS (both P 12 months) and RPA-M1b (> 3 lesions or DFI ≤ 12 months), with 3-year OS rates of 74.6% and 40.6%, respectively (P < 0.001). The RPA-M1 classification showed superior prognostic discrimination compared with the TNM-9 M1 stage, evidenced by higher C-index, time-dependent AUCs, and lower AIC. Metastasis-directed therapy improved OS only in the RPA-M1a subgroup, while intensified systemic therapy primarily benefited the RPA-M1b subgroup. Conclusion: The TNM-9 M1 category is applicable to mmNPC. The novel RPA-M1 classification, which integrates metastatic burden and DFI, offers superior risk stratification and enables more precise prognostication and individualized management. metachronous metastatic nasopharyngeal carcinoma M1 category RPA-M1 classification metastatic burden disease-free interval Figures Figure 1 Figure 2 Introduction Distant metastasis remains the predominant pattern of treatment failure in nasopharyngeal carcinoma (NPC), occurring as metachronous metastasis (mmNPC) in approximately 15%-30% of patients after curative-intent radical chemoradiotherapy.( 1 , 2 ) Like de novo metastatic NPC (M1-NPC),( 3 , 4 ) mmNPC represents a distinct clinical entity with highly heterogeneous outcomes,( 5 – 7 ) underscoring the urgent need for effective risk stratification to guide personalized management. The recent introduction of the ninth edition of the AJCC/UICC TNM staging system (TNM-9) marks a significant advancement by incorporating, for the first time, a subdivision of the M1 category for NPC into M1a (≤ 3 metastatic lesions) and M1b (> 3 lesions).( 3 ) This classification has demonstrated robust prognostic value in patients with newly diagnosed M1-NPC. However, a pivotal and unresolved question is whether this M1 stratification, derived from de novo metastatic disease, can be effectively applied to prognosticate and guide treatment in patients with mmNPC. Prior to TNM-9, several studies( 5 – 7 ) attempted to subclassify mmNPC and identified prognostic factors including metastatic lesion count, specific organ involvement, EBV-DNA copy number, and disease-free interval (DFI)—the time from initial diagnosis to metastasis detection. However, these classification systems were limited by substantial heterogeneity in patient selection, particularly with regard to treatment intensity—not all enrolled patients receiving standardized systemic chemotherapy.( 5 , 6 ) Moreover, inter-laboratory variability in EBV-DNA detection poses a persistent challenge across many institutions,( 8 – 10 ) complicating its generalizability and clinical translation. To address these limitations, we conducted this study to validate the TNM-9 M1 category—a globally unified staging framework—in a consecutive cohort of mmNPC patients from our institution. We further evaluated additional prognostic factors, particularly DFI, to assess the need for refining M1 stratification specifically for mmNPC. By integrating these variables using recursive partitioning analysis (RPA), we aimed to develop an optimized M1 subclassification tailored to this distinct clinical entity, thereby enabling more precise risk stratification and individualized therapeutic decision-making. Materials and Methods Study Population After obtaining institutional review board approval, we identified patients with newly diagnosed mmNPC treated at our institution between 2015 and 2024 as potential candidates. Inclusion criteria were: ( 1 ) age 18–70 years; ( 2 ) measurable metastatic lesions; ( 3 ) availability of complete baseline clinical and imaging data for efficacy assessment, with all cases restaged according to the TNM-9 classification; and ( 4 ) receipt of at least two cycles of palliative chemotherapy (PCT). The primary exclusion criteria were: ( 1 ) metastatic disease was identified within 6 months interval between diagnosis of metastatic disease and primary diagnosis; or ( 2 ) a history of other concurrent or prior malignancies. Imaging Assessment for Restaging and Data Collection All patients underwent comprehensive baseline imaging for metastatic restaging, including physical examination, fiberoptic nasopharyngoscopy, magnetic resonance imaging or computed tomography (CT) of the head and neck, chest CT, abdominal ultrasonography or CT, whole-body bone scan, hematologic profiling, and positron emission tomography/CT (PET/CT) when indicated. The number of metastases and involved organ sites were determined by centralized review of baseline imaging studies by specialized radiologists. For this analysis, the liver, lungs, bones, and distant lymph node basins (defined as those beyond the cervical region) were each considered distinct metastatic organs. Furthermore, within the category of lymph node involvement, each major lymphatic drainage area—such as the axillary, mediastinal, retroperitoneal, or inguinal regions—was counted as a single metastatic lesion.( 4 , 11 , 12 ) Treatment All patients received at least two cycles of systemic therapy. The chemotherapeutic regimens included GP (gemcitabine and platinum), TP (docetaxel and platinum), PF (platinum and 5-fluorouracil), TPF (docetaxel, platinum, and 5-fluorouracil), and TPC (docetaxel, platinum, and capecitabine). The immune checkpoint inhibitors (ICIs) used included toripalimab, camrelizumab, sintilimab, tislelizumab, pembrolizumab, penpulimab, and nivolumab. These treatments were administered in 3-week cycles. Following 2018,( 13 – 16 ) ICIs were increasingly adopted for mmNPC cases. Based on physician assessment and patient preference, maintenance therapy (MT) consisted of ICIs, capecitabine/S-1, or a combination thereof. Select patients received metastasis-directed therapy (MDT)—including palliative radiotherapy, surgical resection, or ablation—to alleviate local symptoms and eradicate metastases in sites such as bone, liver, and lungs. MDT was applied either comprehensively to all metastatic sites or selectively to a subset. Follow-up Tumor response was assessed every two to three cycles during systematic treatment and every 3–6 months thereafter. Primary lesions were evaluated via head and neck MRI, while distant metastases were monitored via PET-CT, MRI, CT, or whole-body bone scans. The final follow-up date was March 2025. The primary endpoint was overall survival (OS), calculated from the mmNPC diagnosis to the last confirmed survival date or death. The secondary endpoint was progression-free survival (PFS), defined as the time from diagnosis of mmNPC to the first recorded disease progression or death. The disease-free interval (DFI) was defined as the interval between the onset of the primary treatment for non-metastatic NPC and the time of the first detection of distant metastasis. The following progression patterns—polymetastatic disease, repeat oligorecurrence, induced oligorecurrence, repeat oligoprogression, and repeat oligopersistence—were defined according to the EORTC/ESTRO consensus on oligometastatic disease established by Matthias et al.( 17 ) Consistent with the TNM-9 framework, oligometastasis was defined as ≤ 3 lesions and polymetastasis as > 3 lesions. Statistical Analysis Continuous variables were described using medians and interquartile ranges (IQRs), analyzed and compared using the Mann–Whitney U or Kruskal–Wallis test. Categorical data were presented as frequencies with percentages and compared using the chi-square test or Fisher's exact test, as appropriate. The optimal cutoff value for DFI was determined and visualized using X-tile software (version 3.6.1; Yale University, New Haven, CT, USA). A 10‑fold cross‑validation was subsequently performed using R packages (survival, maxstat, and caret) to validate the stability of the identified cutoff. Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify independent prognostic factors. Recursive partitioning analysis (RPA) was performed using an online website ( http://rpa.renlab.org ). Predictive performance was evaluated via AUC and Harrell's C-index. All analyses used SPSS 29.0.1.0 and R 3.6.3, with two-tailed P-value < 0.05 considered statistically significant. Result Patient Characteristics Patient selection details are depicted in Figure S1 . A total of 218 patients were included, comprising 173 males (79.4%) and 45 females (20.6%). Using X‑tile software, 12 months was identified as the optimal DFI cutoff (Figure S2 ), which was subsequently confirmed by 10‑fold cross‑validation. According to this cutoff, 79 patients (36.2%) had a DFI ≤ 12 months and 139 (63.8%) had a DFI > 12 months. Detailed clinical characteristics are outlined in Table 1 . According to the TNM-9 classification, 111 patients (50.9%) were categorized as M1a and 107 (49.1%) as M1b. Compared with the M1a group, the M1b group had a significantly higher proportion of multiple-organ metastases, concurrent with locoregional recurrence, bone involvement, and distant lymph node (LN) involvement. Both M1 subgroups received similar intensity of PCT and MT. Additionally, a higher proportion of M1a patients underwent MDT compared to M1b patients (67.5% vs. 27.1%, P < 0.001). Furthermore, among those receiving MDT, a higher proportion of M1a patients received treatment for all lesions compared to M1b patients (84.4% vs. 27.6%). Table 1 Patient and treatment characteristics in the entire cohort and the M1a and M1b subgroups. Characteristic Entire cohort, n (%) M1a, n (%) M1b, n (%) P value n = 218 n = 111 (50.9%) n = 107 (49.1%) Age, median (IQR), y 48 (37,55) 46 (41,54) 49 (38,55) 0.961 Sex 0.716 Male 173 (79.4%) 87 (78.4%) 86 (80.4%) Female 45 (20.6%) 24 (21.6%) 21 (19.6%) No. of metastatic organs < 0.001 Single organ 130 (59.6%) 92 (82.9%) 38 (35.5%) Multiple organs (≥ 2) 88 (40.4%) 19 (17.1%) 69 (64.5%) Locoregional recurrence 0.047 No 184 (84.4%) 99 (89.2%) 85 (79.4%) Yes 34 (15.6%) 12 (10.8%) 22 (20.6%) Bone involvement 0.002 No 133 (61%) 79 (71.2%) 54 (50.5%) Yes 85 (39%) 32 (28.8%) 53 (49.5%) Liver involvement 0.292 No 146 (67%) 78 (70.3%) 68 (63.6%) Yes 72 (33%) 33 (29.7%) 39 (36.4%) Lung involvement 0.142 No 123 (56.4%) 68 (61.3%) 55 (51.4%) Yes 95 (43.6%) 43 (38.7%) 52 (58.6%) Distant LN involvement < 0.001 No 154 (70.6%) 92 (82.9%) 62 (57.9%) Yes 64 (29.4%) 19 (17.1%) 45 (42.1%) PCT 0.777 < 4 cycles 114 (52.3%) 57 (51.4%) 57 (53.3%) ≥ 4 cycles 104 (47.7%) 54 (48.6%) 50 (46.7%) MDT < 0.001 No 125 (57.3%) 47 (42.3%) 78 (72.9%) Yes 93 (42.7%) 64 (67.5%) 29 (27.1%) MT 0.253 No 73 (33.5%) 33 (29.7%) 40 (37.4%) Yes 145 (66.5%) 77 (70.3%) 67 (62.6%) DFI (months) 0.141 ≤ 12 79 (36.2%) 45 (31.5%) 44 (41.1%) > 12 139 (63.8%) 76 (68.5%) 63 (58.9%) Oncological outcomes Of 166 patients who experienced disease progression, 121 died from disease, including two fatalities from treatment-related complications. Progression patterns at metastatic sites were evaluable in 119 patients and categorized as follows (Table S1 ): polymetastatic disease (72, 60.5%), repeat oligorecurrence (38, 31.9%), induced oligorecurrence (6, 5.0%), repeat oligoprogression (2, 1.7%), and repeat oligopersistence (1, 0.9%). With a median follow-up of 32 months (IQR: 19–59), the median PFS (mPFS) and OS (mOS) for the entire cohort were 16 and 42 months, respectively. The corresponding 3-year PFS and OS rates were 31.6% and 52.1%. The M1a subgroup revealed a significantly better OS (mOS: not reached vs. 29 months; 3-year OS: 63.2% vs. 40.8%, P < 0.001, Fig. 1 B) and PFS (mPFS: 35 vs. 11 months; 3-year PFS: 49.2% vs. 13.9%, P 12 months) was also associated with significantly improved OS (mOS: 59 vs. 24 months; 3-year OS: 58.1% vs. 41.7%, P = 0.005, Fig. 1 C) and PFS compared to a shorter DFI (≤ 12 months) (mPFS: 24 vs. 8 months; 3-year PFS: 37.2% vs. 21.5%, P < 0.001, Fig. 1 F). Corresponding univariate analysis results are presented in Table 2 and Table S2 . Multivariate analysis (MVA), adjusted for age, sex, and specific organ involvement, identified both the TNM-9 M1 category (HR, 1.831; 95% CI, 1.178–2.845; P = 0.007) and DFI (HR, 1.635; 95% CI, 1.121–2.384; P = 0.011) as independent adverse prognostic factors for OS (Table 2 ). Consistent results were observed for PFS (both P < 0.05; Table S2 ). Table 2 Univariate and multivariate Cox regression analysis of OS in the whole cohort. Characteristics Univariate Cox regression Multivariate Cox regression Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value Age, median (IQR), y 1.014 (0.997–1.031) 0.101 1.018 (1.002–1.035) 0.031 Sex Female Reference Reference Male 1.581 (0.969–2.582) 0.067 1.477 (0.891–2.449) 0.130 No. of metastatic organs Single organ Reference Reference Multiple organs (≥ 2) 1.533 (1.072–2.191) 0.019 1.226 (0.607–2.477) 0.571 Locoregional recurrence No Reference Reference Yes 1.443 (0.908–2.295) 0.121 1.139 (0.588–1.959) 0.596 M1 category in TNM-9 M1a Reference Reference M1b 2.148 (1.486–3.105) < 0.001 1.831 (1.178–2.845) 0.007 Bone involvement No Reference Reference Yes 1.393 (0.971–1.999) 0.072 1.073 (0.588–1.959) 0.819 Liver involvement No Reference Reference Yes 1.371 (0.949–1.979) 0.093 1.058 (0.567–1.976) 0.860 Lung involvement No Reference Reference Yes 0.867 (0.604–1.244) 0.439 0.897 (0.468–1.719) 0.744 Distant LN involvement No Reference Reference Yes 1.128 (0.768–1.657) 0.538 0.894 (0.497–1.609) 0.708 DFI (months) ≤ 12 Reference Reference > 12 1.668 (1.164–2.390) 0.005 1.635 (1.121–2.384) 0.011 Proposal for future refinement of the M1 category in TNM-9 for mmNPC Using the RPA algorithm (Fig. 1 A), we stratified the cohort into two distinctly prognostic subgroups: RPA-M1a (n = 76; ≤ 3 metastatic lesions and DFI > 12 months); and RPA-M1b (n = 142; > 3 lesions or DFI ≤ 12 months), which exhibited markedly distinct OS (mOS: not reached vs. 29 months; 3-year OS: 74.6% vs. 40.6%, P < 0.001) and PFS (mPFS: 45 vs. 10 months; 3-year PFS: 56.0% vs. 19.0%, P < 0.001) (Fig. 1 D, G). The Cox regression model, adjusting for age, sex, and specific organ involvement, confirmed that higher RPA groupings conferred a higher risk of death and disease progression (Table 3 and S3). Table 3 Multivariate Cox regression analysis of OS in the PRA-M1 cohort. Characteristics Hazard ratio (95% CI) P value Age, median (IQR), y 1.015 (0.999–1.032) 0.064 Sex Female Reference Male 1.465 (0.886–2.423) 0.137 No. of metastatic organs Single organ Reference Multiple organs (≥ 2) 1.257 (0.630–2.508) 0.516 Locoregional recurrence No Reference Yes 1.106 (0.681–1.797) 0.638 PRA-M1 subgroups RPA-M1a Reference PRA-M1b 2.862 (1.768–4.632) < 0.001 Bone involvement No Reference Yes 1.051 (0.573–1.927) 0.873 Liver involvement No Reference Yes 1.001 (0.541–1.854) 0.997 Lung involvement No Reference Yes 0.850 (0.442–1.634) 0.626 Distant LN involvement No Reference Yes 0.876 (0.482–1.595) 0.666 The RPA model demonstrated superior prognostic discrimination for OS compared to the TNM-9 M1 stage. This was evidenced by a higher C-index (0.657 vs. 0.635), higher time-dependent AUC values (1-year: 0.660 vs. 0.635; 3-year: 0.708 vs. 0.672), and a lower AIC (1175.1 vs. 1186.7) (Table S4 ). Efficacy of PCT, MDT and MT in the RPA-M1 subdivisions Baseline characteristics of the RPA-M1 subgroups are detailed in Tables S5 and S6. In the entire cohort, receipt of PCT (≥ 4 cycles), MDT, or MT was associated with significantly improved OS and PFS compared to non-receipt (all P < 0.05, Fig. 2 A-C and S3A-C). MVA confirmed PCT and MT as independent prognostic factors for OS (both P < 0.05), whereas MDT showed only a trend (P = 0.074; Table 4 ). All three modalities were independent prognostic factors for PFS (Table S7 ). In the favorable RPA-M1a subgroup, MDT significantly improved both OS (mOS: not reached vs. 63 months; 3-year OS: 85% vs. 60%, P = 0.005; Fig. 2 E) and PFS (P = 0.027; Figure S3 E). Notably, more intensive PCT failed to demonstrate significant improvements in either OS or PFS (all P > 0.05; Figs. 2 D and S3D). These findings were further validated after adjustment for potential confounders in MVA as detailed in Tables 4 and S7. MT was associated with a significant OS benefit in univariate analysis (mOS: not reached vs. 48 months; 3-year OS: 81.4% vs. 59.5%, P = 0.007; Fig. 2 F). However, after adjusting for confounders in MVA, this effect was attenuated to a non-significant trend (P = 0.057; Tables 4 ). Although MT yielded numerically higher PFS rates (mPFS: 49 vs. 29 months; 3-year PFS: 60.0% vs. 47.4%), this difference did not reach statistical significance in univariate analysis (P = 0.147; Figure S3 F), and MVA confirmed the absence of a significant independent effect on PFS (P > 0.05; Table S7 ). Notably, despite these negative findings for conventional survival endpoints, MT did significantly prolong polymetastatic-free survival (median: not reached vs. 42 months; 3-year: 79.6% vs. 65.9%, P < 0.05; Figure S4 ), underscoring its potential clinical value in delaying extensive metastatic dissemination beyond what is captured by standard PFS assessment. Table 4 Multivariate analysis of OS in the whole cohort and each RPA-M1 subgroups. Characteristics Whole cohort RPA-M1a cohort RPA-M1b cohort Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value Age, median (IQR), y 1.011 (0.994–1.028) 0.204 0.998 (0.948–1.049) 0.925 1.010 (0.992–1.028) 0.293 Sex Female Reference Reference Reference Male 1.491 (0.903–2.465) 0.119 1.980 (0.428–9.160) 0.382 1.305 (0.760–2.240) 0.335 No. of metastatic organs Single organ Reference Reference Reference Multiple organs (≥ 2) 1.232 (0.606–2.505) 0.564 1.647 (0.243–11.151) 0.609 1.337 (0.610–2.933) 0.469 Locoregional recurrence No Reference Reference Reference Yes 1.128 (0.680–1.872) 0.641 1.439 (0.314–6.593) 0.639 1.106 (0.613–1.995) 0.737 Bone involvement No Reference Reference Reference Yes 1.220 (0.666–2.236) 0.519 0.574 (0.090–3.676) 0.558 1.219 (0.621–2.3939) 0.565 Liver involvement No Reference Reference Reference Yes 1.058 (0.557–2.009) 0.866 0.380 (0.039–3.666) 0.403 1.186 (0.583–2.413) 0.637 Lung involvement No Reference Reference Reference Yes 0.738 (0.383–1.423) 0.364 0.273 (0.027–2.797) 0.274 0.831 (0.399–1.734) 0.622 Distant LN involvement No Reference Reference Reference Yes 0.932 (0.502–1.733) 0.825 0.660 (0.061–7.104) 0.731 0.884 (0.450–1.734) 0.719 PCT < 4 cycles Reference Reference Reference ≥ 4 cycles 0.589 (0.398–0.871) 0.008 0.527 (0.202–1.374) 0.190 0.526 (0.334–0.828) 0.005 MDT No Reference Reference Reference Yes 0.667 (0.428–1.040) 0.074 0.252 (0.093–0.685) 0.007 0.893 (0.533–1.498) 0.699 MT No Reference Reference Reference Yes 0.382 (0.261–0.559) < 0.001 0.368 (0.131–1.030) 0.057 0.388 (0.249–0.604) < 0.001 RPA-M1 subgroups RPA-M1a Reference - - - - RPA-M1b 2.385 (1.437–3.958) < 0.001 - - - - Abbreviations : CI, confidence interval;LN, lymph node; MDT, metastasis-directed therapy; MT, maintenance therapy; OS, overall survival; PCT, palliative chemotherapy; RPA, recursive-partitioning analysis. In the higher-risk RPA-M1b subgroup, both PCT (≥ 4 cycles) and MT were associated with significantly improved outcomes. Patients receiving ≥ 4 PCT cycles had superior OS (mOS: 36 vs. 24 months; 3-year OS: 49.5% vs. 34.6%, P = 0.011; Fig. 2 G) and a trend toward better PFS (mPFS: 14 vs. 9 months; 3-year PFS: 19.7% vs. 18.6%, P = 0.081; Figure S3 G). Similarly, MT was associated with superior OS (mOS: 38 vs. 18 months; 3-year OS: 51.2% vs. 21.1%, P < 0.001; Fig. 2 I) and PFS (mPFS: 13 vs. 8 months; 3-year PFS: 25.1% vs. 8%, P 0.05; Figs. 2 H and S3H). These prognostic findings were further validated after adjustment for potential confounders as detailed in Table 4 and S7. Discussion To our knowledge, both mmNPC( 5 – 7 ) and M1-NPC( 4 ) are highly heterogeneous diseases with considerable prognostic variability. Although TNM-9 subdivides M1-NPC into distinct categories, its applicability to mmNPC has remained uncertain. This study yielded several important findings. First, we demonstrated that the TNM-9 M1 category is applicable to mmNPC and that both this category and DFI independently predict prognosis. By integrating these factors via RPA, we developed a refined two-tier system: RPA-M1a (≤ 3 metastases and DFI > 12 months) and RPA-M1b (> 3 metastases or DFI ≤ 12 months). This RPA-M1 system demonstrated robust discriminatory power, with 3-year OS rates of 74.6% versus 40.6% (mOS: not reached versus 29 months, P < 0.001). Moreover, it effectively stratified therapeutic benefit: MDT improved outcomes exclusively in the RPA-M1a subgroup, whereas intensified systemic therapy only improved outcomes in the RPA-M1b subgroup. This study represents the first validation of the prognostic utility of the TNM-9 M1 category in mmNPC and introduces an enhanced risk stratification model that integrates both metastatic burden and DFI. Prior to TNM-9,( 3 ) several subclassification systems were proposed for mmNPC.( 5 – 7 ) The earliest and largest study to date, conducted by Shen et al. from Sun Yat-sen University Cancer Center (SYSUCC),( 5 ) analyzed a multicenter cohort of 1,172 mmNPC patients and proposed a three-tiered system based on anatomic features: M1a (single lesion in a single organ), M1b (multiple lesions in a single organ), and M1c (metastases in multiple organs). With 86.3% of patients receiving PCT, median OS was 25.6 months. Another SYSUCC study( 6 ) by Zheng et al. (n = 817) stratified patients into four prognostic groups as follows: M1a (low EBV DNA + oligo lesion ≤ 2), M1b (low EBV DNA + multiple lesions > 2), M1c (high EBV DNA + no liver involvement), and M1d (high EBV DNA + liver involvement). With 65% of patients receiving chemotherapy, they reported a mOS of 17.7 months, with 1- and 3-year OS rates of 75.9% and 30.5%, respectively. In both studies, DFI was not identified as a significant prognostic factor. Despite this, the prognostic value of DFI has been demonstrated in three SYSUCC studies( 18 – 20 ) focusing on liver-only( 19 ) or bone-only( 20 ) metastases, and a subsequent analysis from Fujian encompassing the full mmNPC spectrum.( 21 ) In 2022, Peng et al. from Jiangsu( 7 ) developed a prognostic nomogram for mmNPC that incorporated DFI alongside metastatic burden and other clinical variables. The 1- and 3-year OS rates were 76.1% and 39.8%, respectively. Consistent with Peng et al’s study, the current series demonstrated that DFI retains independent prognostic significance beyond TNM-9 M1 category. The inconsistency in the prognostic value of DFI across studies likely reflects differences in study populations, particularly regarding inclusion criteria and treatment intensity. Both the study by Peng et al.( 7 ) and our cohort had uniformly high rates of chemotherapy exposure—all patients in Peng's study received at least one cycle of chemotherapy, while 100% of patients in our cohort received chemotherapy of at least two cycles and 23.9% of them received ICI during PCT phase. Our cohort demonstrated superior survival outcomes (mOS 42 months; 3-year OS 52.1%), suggesting that ensuring a minimum standard of treatment intensit y is essential for elucidating the true prognostic impact of metastatic burden and temporal factors such as DFI. Systemic therapy remains the cornerstone of treatment for metastatic NPC.( 22 – 24 ) However, the integration of comprehensive strategies, including MDT( 6 , 7 , 18 – 21 , 25 – 28 ) and MT( 14 – 16 , 29 , 30 ) has substantially improved outcomes in recent years. Consistent with previous reports,( 7 , 21 ) the present study confirmed that a higher number of PCT cycles (≥ 4) was associated with significantly improved OS in the overall cohort (HR, 0.589; 95% CI, 0.398–0.871, P = 0.008), corroborating findings from Zheng et al.( 21 ) and Peng et al.( 7 ) Notably, none of the aforementioned studies performed subgroup analyses to explore whether the benefit of intensified PCT varied according to patient risk profiles. In the present study, subgroup analysis revealed that survival benefit of intensified PCT was confined to the RPA-M1b subgroup, with no significant benefit observed in the RPA-M1a subgroup. This finding suggests that for patients with low metastatic burden, enhancing PCT intensity may be unnecessary—particularly in the immunotherapy era, where the optimal PCT duration remains to be defined. Moreover, the potential contribution of MDT and maintenance therapy in this population may further diminish the incremental value of intensified PCT. Our findings underscore the need for well-designed prospective studies to determine the optimal intensity of palliative chemotherapy within the context of multimodality treatment. Following three landmark prospective phase III immunotherapy trials( 14 – 16 ) and two pivotal non-immunotherapy studies( 29 , 30 ) establishing capecitabine maintenance as a standard option, both immunotherapy and oral maintenance therapy have been widely adopted in real-world practice and are now recommended by treatment guidelines for metastatic NPC. However, whether all patients with metastatic NPC derive equivalent benefit from MT remains unclear, particularly given the limited data specifically addressing mmNPC. In the present study, MT was associated with improved survival in the overall cohort. Subgroup analysis further revealed that the survival benefit of MT was more pronounced in the RPA-M1b subgroup, whereas no significant benefit was observed in the RPA-M1a subgroup. This differential effect may be attributable to the confounding impact of effective prior PCT and MDT in the low-risk subgroup, potentially attenuating the incremental contribution of MT. These findings suggest that in the context of sufficiently intensive PCT and MDT, whether MT confers additional benefit—and the optimal regimen and duration thereof—warrants further investigation through well-designed prospective studies. Emerging evidence suggests that dynamic monitoring of EBV DNA may inform maintenance treatment strategies.( 31 , 32 ) MDT is currently recommended as a treatment option for patients with oligometastatic disease by major clinical practice guidelines, including those of the National Comprehensive Cancer Network (NCCN). Multiple retrospective series have shown that MDT—such as surgery or radiotherapy directed at limited metastatic lesions—is associated with improved survival in selected low-risk mmNPC patients.( 6 , 7 , 33 ) Patient selection in these studies has typically been guided by metastatic burden, EBV-DNA level, DFI, and nomogram-based risk models. Aligning with these findings, the present study demonstrated that MDT significantly improved outcomes in the RPA-M1a subgroup, further corroborating prior evidence from multiple centers. However, our analysis also revealed that the survival benefit of MDT was limited in the RPA-M1b subgroup, suggesting that for patients with polymetastatic disease, treatment strategies should prioritize more effective systemic therapy, such as the combination of antibody-drug conjugates (ADCs)( 34 ) and ICIs( 13 – 16 ), to achieve maximal tumor burden reduction. Notably, only 23.8% of patients in our cohort incorporated ICIs in the PCT phase. Several limitations should be considered when interpreting our findings. First, the retrospective, single-center design may introduce selection bias and limit the generalizability of the results. Second, the moderate sample size constrains statistical power for certain subgroup analyses and precluded a detailed evaluation of therapy efficacy across specific metastatic sites. Third, reflecting the real-world adoption curve of immunotherapy, only a subset of patients in this cohort received ICIs, which may affect the extrapolation of outcomes to the current treatment landscape. With the advent of more effective systemic regimens, including the integration of immune checkpoint inhibitors with chemotherapy for all patients, the net impact of MDT to metastatic lesions should be re-evaluated. Finally, our model did not incorporate plasma EBV DNA, a known prognostic biomarker in NPC. While this strategy enhances the model's practicality by avoiding inter-laboratory assay variability of EBV DNA detection,( 8 – 10 ) future iterations could be strengthened by including standardized biomarker data. Conclusion This study validates the prognostic utility of the TNM-9 M1 subclassification in mmNPC and identifies DFI as an independent prognostic factor beyond anatomic metastatic burden. By integrating these two factors through RPA, we established a refined RPA-M1 classification that stratifies patients into two distinct prognostic subgroups: RPA-M1a (≤ 3 metastases and DFI > 12 months) and RPA-M1b (> 3 metastases or DFI ≤ 12 months). This novel system demonstrates superior prognostic discrimination compared to the TNM-9 M1 category alone and, importantly, informs treatment decision-making. Our findings provide a practical, staging-aligned framework that addresses a critical gap left by prior classification systems and recent prospective trials. Prospective studies are warranted to validate this risk-stratified approach and to further refine prognostic precision and individualized therapeutic strategies making. Abbreviations AIC akaike information criterion AUC area under receiver operating characteristic curve ADCs antibody-drug conjugates CI confidence interval C-index harrell’s concordance index CT computed tomography DFI disease-free interval GP gemcitabine and platinum LN lymph node MDT metastasis-directed therapy MT maintenance therapy M1-NPC de novo metastatic NPC MVA multivariate analysis mmNPC metachronous metastatic nasopharyngeal carcinoma NCCN national comprehensive cancer network NPC nasopharyngeal carcinoma OS overall survival PFS progression-free survival PCT palliative chemotherapy PET/CT positron emission tomography/CT PF platinum and 5-fluorouracil RPA recursive partitioning analysis ICIs immune checkpoint inhibitors IQRs interquartile ranges TP docetaxel and platinum TPF docetaxel,platinum and 5-fluorouracil TPC docetaxel,platinum and capecitabine Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Boards of Fujian Cancer Hospital. The study was conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study. Clinical trial number Not applicable Consent for publication Not applicable Competing interests All the other authors declare that he/she has no conflict of interest. Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request. Funding This work was sponsored by the National Key Clinical Specialty Construction Program and Key Clinical Specialty Discipline Construction Program of Fujian, China. This research is also supported by Youth Talents Project of the Fujian Eagle Program, and Fujian Provincial Clinlical Research Center for Cancer Radiotherapy and Immunotherapy (Grant number 2020Y2012). Fujian Clinical Research Center for Radiation and Therapy of Digestive, Respiratory and Genitourinary Malignancies (2021Y2014), Natural Science Foundation of Fujian Province (Grant number 2023J011252 and 2025J01223), Fujian Cancer Hospital Program (2021YNDT02, 2023YNG05 and 202411002). Acknowledgements We acknowledge the clinicians and research staff of Fujian Cancer Hospital for their assistance in data collection and management. Authors' contributions DH, HX and XX contributed equally to this work. DH, HX and SL conceived and designed the study. DH, HX, XX, YYH, KL, YH, LZ, YZ and CH collected and curated the data. DH and HX performed the statistical analysis and interpreted the data. DH drafted the manuscript. HX, JP, YX, JW and QG critically revised the manuscript for important intellectual content. JP, SL, JW and QG supervised the study. All authors read and approved the final manuscript. References Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. 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Anti-PD-1 antibody with or without capecitabine as maintenance therapy after first-line therapy of recurrent or metastatic nasopharyngeal carcinoma. Oncologist. 2025;30(7). Liu Y, Zuo ZC, Zeng XY, Ma J, Ma CX, Chen RZ, et al. Establishing subdivisions of M1 stage nasopharyngeal carcinoma based on decision tree classification: A multicenter retrospective study. Oral Oncol. 2024;153:106834. Yang Y, Zhou H, Tang L, Qiu S, Han Y, Ji D, et al. Izalontamab brengitecan, an EGFR and HER3 bispecific antibody-drug conjugate, versus chemotherapy in heavily pretreated recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 study in China. Lancet. 2025;406(10516):2235–43. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable1.docx SupplementaryTable2.docx SupplementaryTable3.docx SupplementaryTable4.docx SupplementaryTable5.docx SupplementaryTable6.docx SupplementaryFigure1.tiff Supplementary Figure 1. Flowchart illustrates patients’ selection SupplementaryFigure2.tiff Supplementary Figure 2. X-tile analysis for determining the optimal cutoff point of disease-free interval for overall survival. SupplementaryFigure3.tiff Supplementary Figure 3. Kaplan–Meier estimates of progression free survival by treatment modality in the entire (A–C), RPA-M1a (D–F) and RPA-M1b (G–I) cohorts. ( Abbreviations : MDT, metastasis-directed therapy; MT, maintenance therapy; PCT, palliative chemotherapy) SupplementaryFigure4.tiff Supplementary Figure 4. Kaplan–Meier estimates of polymetastatic-free survival by MT in the RPA-M1a cohort. ( Abbreviation : MT, maintenance therapy) Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 03 May, 2026 Reviews received at journal 02 May, 2026 Reviewers agreed at journal 02 May, 2026 Reviews received at journal 01 May, 2026 Reviewers agreed at journal 01 May, 2026 Reviewers agreed at journal 29 Apr, 2026 Reviewers invited by journal 29 Apr, 2026 Editor invited by journal 06 Apr, 2026 Editor assigned by journal 06 Apr, 2026 Submission checks completed at journal 06 Apr, 2026 First submitted to journal 03 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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07:26:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9310030/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9310030/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108947375,"identity":"7c628198-7181-4af4-abcb-8c16a9832f36","added_by":"auto","created_at":"2026-05-11 06:28:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":126637,"visible":true,"origin":"","legend":"\u003cp\u003e(A) RPA flowchart for classifying metachronous metastatic nasopharyngeal carcinoma. Kaplan–Meier estimates of OS (B–D) and PFS (E–G) by TNM-9 stage (B, E), DFI (C, F) and RPA-M1 subgroups (D, G). (\u003cem\u003eAbbreviations\u003c/em\u003e: DFI, disease-free interval; mmNPC, metachronous metastatic nasopharyngeal carcinoma; OS, overall survival; PFS, progression free survival; RPA, recursive-partitioning analysis)\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/a167fb45412bec634c379aac.png"},{"id":108947403,"identity":"d5b70ead-6145-4927-beb0-037d25e209ce","added_by":"auto","created_at":"2026-05-11 06:28:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":125915,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of overall survival by treatment modality in the entire (A–C), RPA-M1a (D–F) and RPA-M1b (G–I) cohorts. (\u003cem\u003eAbbreviations\u003c/em\u003e: MDT, metastasis-directed therapy; MT, maintenance therapy; PCT, palliative chemotherapy)\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/82e902372fdfe28774f5a766.png"},{"id":108947581,"identity":"856100bd-492b-4687-a028-9509cb33e8e9","added_by":"auto","created_at":"2026-05-11 06:29:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1075414,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/383cc77c-4b3f-4ca5-a1c9-8a4787398ca2.pdf"},{"id":108947494,"identity":"1d6d1406-856f-41be-b5f4-99d1352f1256","added_by":"auto","created_at":"2026-05-11 06:29:27","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12942,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/e4b36b4948e20bb35647ce94.docx"},{"id":108947401,"identity":"cced00d2-fa90-4dbe-819c-c549fedb41b1","added_by":"auto","created_at":"2026-05-11 06:28:32","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20462,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/4be9a5d5e147d4c298fc7140.docx"},{"id":108947419,"identity":"e71738d5-71c5-433b-8591-89afabca3ed7","added_by":"auto","created_at":"2026-05-11 06:28:45","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":16202,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable3.docx","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/e163dd3b1900a31b5734e33b.docx"},{"id":108947463,"identity":"f3a40ed8-b9b8-4187-9688-fd4a6c6b6c78","added_by":"auto","created_at":"2026-05-11 06:29:15","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":12305,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable4.docx","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/709ff3c5fae659f354ad2ba8.docx"},{"id":108947454,"identity":"a1461755-537d-466e-9802-56e8219051fe","added_by":"auto","created_at":"2026-05-11 06:29:07","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":19461,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable5.docx","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/87ad541dc5fcb7a969c91d18.docx"},{"id":108947400,"identity":"c11b82d5-74ff-4a33-b5e7-0e525e0b7305","added_by":"auto","created_at":"2026-05-11 06:28:32","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":16380,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable6.docx","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/5c441fa69893c408d6201ef4.docx"},{"id":108947472,"identity":"940f331b-d72f-4232-b66a-b19b231df01a","added_by":"auto","created_at":"2026-05-11 06:29:18","extension":"tiff","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":955772,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 1\u003c/strong\u003e. Flowchart illustrates patients’ selection\u003c/p\u003e","description":"","filename":"SupplementaryFigure1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/c689329eaf56a181b33d73dc.tiff"},{"id":108947374,"identity":"d9620739-f49e-4204-af51-17503d1e089f","added_by":"auto","created_at":"2026-05-11 06:28:12","extension":"tiff","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":915144,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 2\u003c/strong\u003e. X-tile analysis for determining the optimal cutoff point of disease-free interval for overall survival.\u003c/p\u003e","description":"","filename":"SupplementaryFigure2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/2b7a4313771b063427a8fb43.tiff"},{"id":108947420,"identity":"e61a600c-5900-427e-96a4-622326f8274a","added_by":"auto","created_at":"2026-05-11 06:28:45","extension":"tiff","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":576838,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 3\u003c/strong\u003e. Kaplan–Meier estimates of progression free survival by treatment modality in the entire (A–C), RPA-M1a (D–F) and RPA-M1b (G–I) cohorts. (\u003cem\u003eAbbreviations\u003c/em\u003e: MDT, metastasis-directed therapy; MT, maintenance therapy; PCT, palliative chemotherapy)\u003c/p\u003e","description":"","filename":"SupplementaryFigure3.tiff","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/b6c22532be7784026c8ebedf.tiff"},{"id":108947399,"identity":"8d7a7432-021a-4ddd-a0b6-a5f04916c7e8","added_by":"auto","created_at":"2026-05-11 06:28:32","extension":"tiff","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":130452,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 4\u003c/strong\u003e. Kaplan–Meier estimates of polymetastatic-free survival by MT in the RPA-M1a cohort. (\u003cem\u003eAbbreviation\u003c/em\u003e: MT, maintenance therapy)\u003c/p\u003e","description":"","filename":"SupplementaryFigure4.tiff","url":"https://assets-eu.researchsquare.com/files/rs-9310030/v1/9ae0173a92999dff845aa6a9.tiff"}],"financialInterests":"No competing interests reported.","formattedTitle":"Subdivision of metachronous metastatic nasopharyngeal carcinoma based on the framework of TNM-9: A recursive partitioning analysis of real-world data","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDistant metastasis remains the predominant pattern of treatment failure in nasopharyngeal carcinoma (NPC), occurring as metachronous metastasis (mmNPC) in approximately 15%-30% of patients after curative-intent radical chemoradiotherapy.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Like de novo metastatic NPC (M1-NPC),(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) mmNPC represents a distinct clinical entity with highly heterogeneous outcomes,(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) underscoring the urgent need for effective risk stratification to guide personalized management.\u003c/p\u003e \u003cp\u003eThe recent introduction of the ninth edition of the AJCC/UICC TNM staging system (TNM-9) marks a significant advancement by incorporating, for the first time, a subdivision of the M1 category for NPC into M1a (\u0026le;\u0026thinsp;3 metastatic lesions) and M1b (\u0026gt;\u0026thinsp;3 lesions).(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) This classification has demonstrated robust prognostic value in patients with newly diagnosed M1-NPC. However, a pivotal and unresolved question is whether this M1 stratification, derived from de novo metastatic disease, can be effectively applied to prognosticate and guide treatment in patients with mmNPC.\u003c/p\u003e \u003cp\u003ePrior to TNM-9, several studies(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) attempted to subclassify mmNPC and identified prognostic factors including metastatic lesion count, specific organ involvement, EBV-DNA copy number, and disease-free interval (DFI)\u0026mdash;the time from initial diagnosis to metastasis detection. However, these classification systems were limited by substantial heterogeneity in patient selection, particularly with regard to treatment intensity\u0026mdash;not all enrolled patients receiving standardized systemic chemotherapy.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Moreover, inter-laboratory variability in EBV-DNA detection poses a persistent challenge across many institutions,(\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) complicating its generalizability and clinical translation.\u003c/p\u003e \u003cp\u003eTo address these limitations, we conducted this study to validate the TNM-9 M1 category\u0026mdash;a globally unified staging framework\u0026mdash;in a consecutive cohort of mmNPC patients from our institution. We further evaluated additional prognostic factors, particularly DFI, to assess the need for refining M1 stratification specifically for mmNPC. By integrating these variables using recursive partitioning analysis (RPA), we aimed to develop an optimized M1 subclassification tailored to this distinct clinical entity, thereby enabling more precise risk stratification and individualized therapeutic decision-making.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Population\u003c/h2\u003e\n \u003cp\u003eAfter obtaining institutional review board approval, we identified patients with newly diagnosed mmNPC treated at our institution between 2015 and 2024 as potential candidates. Inclusion criteria were: (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) age 18\u0026ndash;70 years; (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e) measurable metastatic lesions; (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e) availability of complete baseline clinical and imaging data for efficacy assessment, with all cases restaged according to the TNM-9 classification; and (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e) receipt of at least two cycles of palliative chemotherapy (PCT). The primary exclusion criteria were: (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) metastatic disease was identified within 6 months interval between diagnosis of metastatic disease and primary diagnosis; or (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e) a history of other concurrent or prior malignancies.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eImaging Assessment for Restaging and Data Collection\u003c/h3\u003e\n\u003cp\u003eAll patients underwent comprehensive baseline imaging for metastatic restaging, including physical examination, fiberoptic nasopharyngoscopy, magnetic resonance imaging or computed tomography (CT) of the head and neck, chest CT, abdominal ultrasonography or CT, whole-body bone scan, hematologic profiling, and positron emission tomography/CT (PET/CT) when indicated. The number of metastases and involved organ sites were determined by centralized review of baseline imaging studies by specialized radiologists. For this analysis, the liver, lungs, bones, and distant lymph node basins (defined as those beyond the cervical region) were each considered distinct metastatic organs. Furthermore, within the category of lymph node involvement, each major lymphatic drainage area\u0026mdash;such as the axillary, mediastinal, retroperitoneal, or inguinal regions\u0026mdash;was counted as a single metastatic lesion.(\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eAll patients received at least two cycles of systemic therapy. The chemotherapeutic regimens included GP (gemcitabine and platinum), TP (docetaxel and platinum), PF (platinum and 5-fluorouracil), TPF (docetaxel, platinum, and 5-fluorouracil), and TPC (docetaxel, platinum, and capecitabine). The immune checkpoint inhibitors (ICIs) used included toripalimab, camrelizumab, sintilimab, tislelizumab, pembrolizumab, penpulimab, and nivolumab. These treatments were administered in 3-week cycles. Following 2018,(\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e) ICIs were increasingly adopted for mmNPC cases.\u003c/p\u003e\n\u003cp\u003eBased on physician assessment and patient preference, maintenance therapy (MT) consisted of ICIs, capecitabine/S-1, or a combination thereof. Select patients received metastasis-directed therapy (MDT)\u0026mdash;including palliative radiotherapy, surgical resection, or ablation\u0026mdash;to alleviate local symptoms and eradicate metastases in sites such as bone, liver, and lungs. MDT was applied either comprehensively to all metastatic sites or selectively to a subset.\u003c/p\u003e\n\u003ch3\u003eFollow-up\u003c/h3\u003e\n\u003cp\u003eTumor response was assessed every two to three cycles during systematic treatment and every 3\u0026ndash;6 months thereafter. Primary lesions were evaluated via head and neck MRI, while distant metastases were monitored via PET-CT, MRI, CT, or whole-body bone scans. The final follow-up date was March 2025. The primary endpoint was overall survival (OS), calculated from the mmNPC diagnosis to the last confirmed survival date or death. The secondary endpoint was progression-free survival (PFS), defined as the time from diagnosis of mmNPC to the first recorded disease progression or death. The disease-free interval (DFI) was defined as the interval between the onset of the primary treatment for non-metastatic NPC and the time of the first detection of distant metastasis. The following progression patterns\u0026mdash;polymetastatic disease, repeat oligorecurrence, induced oligorecurrence, repeat oligoprogression, and repeat oligopersistence\u0026mdash;were defined according to the EORTC/ESTRO consensus on oligometastatic disease established by Matthias et al.(\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e) Consistent with the TNM-9 framework, oligometastasis was defined as \u0026le;\u0026thinsp;3 lesions and polymetastasis as \u0026gt;\u0026thinsp;3 lesions.\u003c/p\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n \u003cp\u003eContinuous variables were described using medians and interquartile ranges (IQRs), analyzed and compared using the Mann\u0026ndash;Whitney U or Kruskal\u0026ndash;Wallis test. Categorical data were presented as frequencies with percentages and compared using the chi-square test or Fisher\u0026apos;s exact test, as appropriate. The optimal cutoff value for DFI was determined and visualized using X-tile software (version 3.6.1; Yale University, New Haven, CT, USA). A 10‑fold cross‑validation was subsequently performed using R packages (survival, maxstat, and caret) to validate the stability of the identified cutoff. Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify independent prognostic factors. Recursive partitioning analysis (RPA) was performed using an online website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://rpa.renlab.org\u003c/span\u003e\u003c/span\u003e). Predictive performance was evaluated via AUC and Harrell\u0026apos;s C-index. All analyses used SPSS 29.0.1.0 and R 3.6.3, with two-tailed P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered statistically significant.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Result","content":"\u003ch2\u003ePatient Characteristics\u003c/h2\u003e\u003cp\u003ePatient selection details are depicted in Figure \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e. A total of 218 patients were included, comprising 173 males (79.4%) and 45 females (20.6%). Using X‑tile software, 12 months was identified as the optimal DFI cutoff (Figure \u003cspan class=\"InternalRef\"\u003eS2\u003c/span\u003e), which was subsequently confirmed by 10‑fold cross‑validation. According to this cutoff, 79 patients (36.2%) had a DFI ≤ 12 months and 139 (63.8%) had a DFI \u0026gt; 12 months. Detailed clinical characteristics are outlined in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. According to the TNM-9 classification, 111 patients (50.9%) were categorized as M1a and 107 (49.1%) as M1b. Compared with the M1a group, the M1b group had a significantly higher proportion of multiple-organ metastases, concurrent with locoregional recurrence, bone involvement, and distant lymph node (LN) involvement. Both M1 subgroups received similar intensity of PCT and MT. Additionally, a higher proportion of M1a patients underwent MDT compared to M1b patients (67.5% vs. 27.1%, P \u0026lt; 0.001). Furthermore, among those receiving MDT, a higher proportion of M1a patients received treatment for all lesions compared to M1b patients (84.4% vs. 27.6%).\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab1\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient and treatment characteristics in the entire cohort and the M1a and M1b subgroups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eEntire cohort, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eM1a, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eM1b, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" rowspan=\"2\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003en = 218\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003en = 111 (50.9%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003en = 107 (49.1%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAge, median (IQR), y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e48 (37,55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e46 (41,54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e49 (38,55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.961\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.716\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e173 (79.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e87 (78.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e86 (80.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e45 (20.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e24 (21.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e21 (19.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo. of metastatic organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSingle organ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e130 (59.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e92 (82.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e38 (35.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMultiple organs (≥ 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e88 (40.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e19 (17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e69 (64.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLocoregional recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e184 (84.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e99 (89.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e85 (79.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e34 (15.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e12 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e22 (20.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eBone involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e133 (61%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e79 (71.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e54 (50.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e85 (39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e32 (28.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e53 (49.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLiver involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.292\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e146 (67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e78 (70.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e68 (63.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e72 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e33 (29.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e39 (36.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLung involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.142\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e123 (56.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e68 (61.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e55 (51.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e95 (43.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e43 (38.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e52 (58.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eDistant LN involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e154 (70.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e92 (82.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e62 (57.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e64 (29.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e19 (17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e45 (42.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003ePCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.777\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e\u0026lt; 4 cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e114 (52.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e57 (51.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e57 (53.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e≥ 4 cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e104 (47.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e54 (48.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e50 (46.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMDT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e125 (57.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e47 (42.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e78 (72.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e93 (42.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e64 (67.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e29 (27.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.253\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e73 (33.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e33 (29.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e40 (37.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e145 (66.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e77 (70.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e67 (62.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eDFI (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.141\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e≤ 12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e79 (36.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e45 (31.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e44 (41.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e\u0026gt; 12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e139 (63.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\"\u003e \u003cp\u003e76 (68.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e63 (58.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/table\u003e\u003c/div\u003e\u003ch3\u003eOncological outcomes\u003c/h3\u003e\u003cp\u003eOf 166 patients who experienced disease progression, 121 died from disease, including two fatalities from treatment-related complications. Progression patterns at metastatic sites were evaluable in 119 patients and categorized as follows (Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e): polymetastatic disease (72, 60.5%), repeat oligorecurrence (38, 31.9%), induced oligorecurrence (6, 5.0%), repeat oligoprogression (2, 1.7%), and repeat oligopersistence (1, 0.9%).\u003c/p\u003e\u003cp\u003eWith a median follow-up of 32 months (IQR: 19–59), the median PFS (mPFS) and OS (mOS) for the entire cohort were 16 and 42 months, respectively. The corresponding 3-year PFS and OS rates were 31.6% and 52.1%. The M1a subgroup revealed a significantly better OS (mOS: not reached vs. 29 months; 3-year OS: 63.2% vs. 40.8%, P \u0026lt; 0.001, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB) and PFS (mPFS: 35 vs. 11 months; 3-year PFS: 49.2% vs. 13.9%, P \u0026lt; 0.001, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eE) than the M1b subgroup. A prolonged DFI (\u0026gt; 12 months) was also associated with significantly improved OS (mOS: 59 vs. 24 months; 3-year OS: 58.1% vs. 41.7%, P = 0.005, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eC) and PFS compared to a shorter DFI (≤ 12 months) (mPFS: 24 vs. 8 months; 3-year PFS: 37.2% vs. 21.5%, P \u0026lt; 0.001, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eF). Corresponding univariate analysis results are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table \u003cspan class=\"InternalRef\"\u003eS2\u003c/span\u003e. Multivariate analysis (MVA), adjusted for age, sex, and specific organ involvement, identified both the TNM-9 M1 category (HR, 1.831; 95% CI, 1.178–2.845; P = 0.007) and DFI (HR, 1.635; 95% CI, 1.121–2.384; P = 0.011) as independent adverse prognostic factors for OS (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Consistent results were observed for PFS (both P \u0026lt; 0.05; Table \u003cspan class=\"InternalRef\"\u003eS2\u003c/span\u003e).\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab2\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate Cox regression analysis of OS in the whole cohort.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\"\u003e \u003cp\u003eUnivariate Cox regression\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\"\u003e \u003cp\u003eMultivariate Cox regression\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAge, median (IQR), y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.014 (0.997–1.031)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.018 (1.002–1.035)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.581 (0.969–2.582)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.477 (0.891–2.449)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo. of metastatic organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSingle organ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMultiple organs (≥ 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.533 (1.072–2.191)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.226 (0.607–2.477)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.571\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLocoregional recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.443 (0.908–2.295)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.139 (0.588–1.959)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.596\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eM1 category in TNM-9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eM1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eM1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e2.148 (1.486–3.105)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.831 (1.178–2.845)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eBone involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.393 (0.971–1.999)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.073 (0.588–1.959)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.819\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLiver involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.371 (0.949–1.979)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.093\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.058 (0.567–1.976)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.860\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLung involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.867 (0.604–1.244)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.897 (0.468–1.719)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.744\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eDistant LN involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.128 (0.768–1.657)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.894 (0.497–1.609)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.708\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eDFI (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e≤ 12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e\u0026gt; 12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.668 (1.164–2.390)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.635 (1.121–2.384)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/table\u003e\u003c/div\u003e\u003ch2\u003eProposal for future refinement of the M1 category in TNM-9 for mmNPC\u003c/h2\u003e\u003cp\u003eUsing the RPA algorithm (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA), we stratified the cohort into two distinctly prognostic subgroups: RPA-M1a (n = 76; ≤ 3 metastatic lesions and DFI \u0026gt; 12 months); and RPA-M1b (n = 142; \u0026gt; 3 lesions or DFI ≤ 12 months), which exhibited markedly distinct OS (mOS: not reached vs. 29 months; 3-year OS: 74.6% vs. 40.6%, P \u0026lt; 0.001) and PFS (mPFS: 45 vs. 10 months; 3-year PFS: 56.0% vs. 19.0%, P \u0026lt; 0.001) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eD, G). The Cox regression model, adjusting for age, sex, and specific organ involvement, confirmed that higher RPA groupings conferred a higher risk of death and disease progression (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and S3).\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab3\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate Cox regression analysis of OS in the PRA-M1 cohort.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAge, median (IQR), y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.015 (0.999–1.032)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.465 (0.886–2.423)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.137\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo. of metastatic organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSingle organ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMultiple organs (≥ 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.257 (0.630–2.508)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.516\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLocoregional recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.106 (0.681–1.797)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.638\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003ePRA-M1 subgroups\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRPA-M1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003ePRA-M1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e2.862 (1.768–4.632)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eBone involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.051 (0.573–1.927)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.873\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLiver involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.001 (0.541–1.854)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.997\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLung involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.850 (0.442–1.634)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.626\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eDistant LN involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.876 (0.482–1.595)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.666\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003eThe RPA model demonstrated superior prognostic discrimination for OS compared to the TNM-9 M1 stage. This was evidenced by a higher C-index (0.657 vs. 0.635), higher time-dependent AUC values (1-year: 0.660 vs. 0.635; 3-year: 0.708 vs. 0.672), and a lower AIC (1175.1 vs. 1186.7) (Table \u003cspan class=\"InternalRef\"\u003eS4\u003c/span\u003e).\u003c/p\u003e\u003ch2\u003eEfficacy of PCT, MDT and MT in the RPA-M1 subdivisions\u003c/h2\u003e\u003cp\u003eBaseline characteristics of the RPA-M1 subgroups are detailed in Tables S5 and S6. In the entire cohort, receipt of PCT (≥ 4 cycles), MDT, or MT was associated with significantly improved OS and PFS compared to non-receipt (all P \u0026lt; 0.05, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA-C and S3A-C). MVA confirmed PCT and MT as independent prognostic factors for OS (both P \u0026lt; 0.05), whereas MDT showed only a trend (P = 0.074; Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). All three modalities were independent prognostic factors for PFS (Table \u003cspan class=\"InternalRef\"\u003eS7\u003c/span\u003e). In the favorable RPA-M1a subgroup, MDT significantly improved both OS (mOS: not reached vs. 63 months; 3-year OS: 85% vs. 60%, P = 0.005; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eE) and PFS (P = 0.027; Figure \u003cspan class=\"InternalRef\"\u003eS3\u003c/span\u003eE). Notably, more intensive PCT failed to demonstrate significant improvements in either OS or PFS (all P \u0026gt; 0.05; Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eD and S3D). These findings were further validated after adjustment for potential confounders in MVA as detailed in Tables\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e and S7. MT was associated with a significant OS benefit in univariate analysis (mOS: not reached vs. 48 months; 3-year OS: 81.4% vs. 59.5%, P = 0.007; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eF). However, after adjusting for confounders in MVA, this effect was attenuated to a non-significant trend (P = 0.057; Tables\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Although MT yielded numerically higher PFS rates (mPFS: 49 vs. 29 months; 3-year PFS: 60.0% vs. 47.4%), this difference did not reach statistical significance in univariate analysis (P = 0.147; Figure \u003cspan class=\"InternalRef\"\u003eS3\u003c/span\u003eF), and MVA confirmed the absence of a significant independent effect on PFS (P \u0026gt; 0.05; Table \u003cspan class=\"InternalRef\"\u003eS7\u003c/span\u003e). Notably, despite these negative findings for conventional survival endpoints, MT did significantly prolong polymetastatic-free survival (median: not reached vs. 42 months; 3-year: 79.6% vs. 65.9%, P \u0026lt; 0.05; Figure \u003cspan class=\"InternalRef\"\u003eS4\u003c/span\u003e), underscoring its potential clinical value in delaying extensive metastatic dissemination beyond what is captured by standard PFS assessment.\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Tab4\" border=\"1\"\u003e \u003ccaption\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate analysis of OS in the whole cohort and each RPA-M1 subgroups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\"\u003e \u003cp\u003eWhole cohort\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\"\u003e \u003cp\u003eRPA-M1a cohort\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\"\u003e \u003cp\u003eRPA-M1b cohort\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eAge, median (IQR), y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.011 (0.994–1.028)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.998 (0.948–1.049)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.925\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.010 (0.992–1.028)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.293\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.491 (0.903–2.465)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.980 (0.428–9.160)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.382\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.305 (0.760–2.240)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.335\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo. of metastatic organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eSingle organ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMultiple organs (≥ 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.232 (0.606–2.505)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.564\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.647 (0.243–11.151)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.609\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.337 (0.610–2.933)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.469\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLocoregional recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.128 (0.680–1.872)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.641\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.439 (0.314–6.593)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.639\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.106 (0.613–1.995)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.737\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eBone involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.220 (0.666–2.236)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.519\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.574 (0.090–3.676)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.558\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.219 (0.621–2.3939)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.565\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLiver involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.058 (0.557–2.009)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.866\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.380 (0.039–3.666)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.403\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e1.186 (0.583–2.413)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.637\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eLung involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.738 (0.383–1.423)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.364\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.273 (0.027–2.797)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.831 (0.399–1.734)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.622\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eDistant LN involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.932 (0.502–1.733)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.825\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.660 (0.061–7.104)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.731\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.884 (0.450–1.734)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.719\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/table\u003e\u003c/div\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003c/div\u003e\u003ctable id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"9\"\u003e \u003c/colgroup\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\"\u003e \u003cp\u003ePCT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e\u0026lt; 4 cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e≥ 4 cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.589 (0.398–0.871)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.527 (0.202–1.374)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.190\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.526 (0.334–0.828)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMDT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.667 (0.428–1.040)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e0.074\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.252 (0.093–0.685)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.893 (0.533–1.498)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.699\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eMT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.382 (0.261–0.559)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.368 (0.131–1.030)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e0.388 (0.249–0.604)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRPA-M1 subgroups\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRPA-M1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\"\u003e \u003cp\u003eRPA-M1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e2.385 (1.437–3.958)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cem\u003eAbbreviations\u003c/em\u003e: CI, confidence interval;LN, lymph node; MDT, metastasis-directed therapy; MT, maintenance therapy; OS, overall survival; PCT, palliative chemotherapy; RPA, recursive-partitioning analysis.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003eIn the higher-risk RPA-M1b subgroup, both PCT (≥ 4 cycles) and MT were associated with significantly improved outcomes. Patients receiving ≥ 4 PCT cycles had superior OS (mOS: 36 vs. 24 months; 3-year OS: 49.5% vs. 34.6%, P = 0.011; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eG) and a trend toward better PFS (mPFS: 14 vs. 9 months; 3-year PFS: 19.7% vs. 18.6%, P = 0.081; Figure \u003cspan class=\"InternalRef\"\u003eS3\u003c/span\u003eG). Similarly, MT was associated with superior OS (mOS: 38 vs. 18 months; 3-year OS: 51.2% vs. 21.1%, P \u0026lt; 0.001; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eI) and PFS (mPFS: 13 vs. 8 months; 3-year PFS: 25.1% vs. 8%, P \u0026lt; 0.001; Figure \u003cspan class=\"InternalRef\"\u003eS3\u003c/span\u003eI). In contrast, MDT conferred no significant benefit in either OS or PFS in this subgroup (both P \u0026gt; 0.05; Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eH and S3H). These prognostic findings were further validated after adjustment for potential confounders as detailed in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e and S7.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, both mmNPC(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and M1-NPC(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) are highly heterogeneous diseases with considerable prognostic variability. Although TNM-9 subdivides M1-NPC into distinct categories, its applicability to mmNPC has remained uncertain. This study yielded several important findings. First, we demonstrated that the TNM-9 M1 category is applicable to mmNPC and that both this category and DFI independently predict prognosis. By integrating these factors via RPA, we developed a refined two-tier system: RPA-M1a (\u0026le;\u0026thinsp;3 metastases and DFI\u0026thinsp;\u0026gt;\u0026thinsp;12 months) and RPA-M1b (\u0026gt;\u0026thinsp;3 metastases or DFI\u0026thinsp;\u0026le;\u0026thinsp;12 months). This RPA-M1 system demonstrated robust discriminatory power, with 3-year OS rates of 74.6% versus 40.6% (mOS: not reached versus 29 months, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Moreover, it effectively stratified therapeutic benefit: MDT improved outcomes exclusively in the RPA-M1a subgroup, whereas intensified systemic therapy only improved outcomes in the RPA-M1b subgroup. This study represents the first validation of the prognostic utility of the TNM-9 M1 category in mmNPC and introduces an enhanced risk stratification model that integrates both metastatic burden and DFI.\u003c/p\u003e \u003cp\u003ePrior to TNM-9,(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) several subclassification systems were proposed for mmNPC.(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) The earliest and largest study to date, conducted by Shen et al. from Sun Yat-sen University Cancer Center (SYSUCC),(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) analyzed a multicenter cohort of 1,172 mmNPC patients and proposed a three-tiered system based on anatomic features: M1a (single lesion in a single organ), M1b (multiple lesions in a single organ), and M1c (metastases in multiple organs). With 86.3% of patients receiving PCT, median OS was 25.6 months. Another SYSUCC study(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) by Zheng et al. (n\u0026thinsp;=\u0026thinsp;817) stratified patients into four prognostic groups as follows: M1a (low EBV DNA\u0026thinsp;+\u0026thinsp;oligo lesion\u0026thinsp;\u0026le;\u0026thinsp;2), M1b (low EBV DNA\u0026thinsp;+\u0026thinsp;multiple lesions\u0026thinsp;\u0026gt;\u0026thinsp;2), M1c (high EBV DNA\u0026thinsp;+\u0026thinsp;no liver involvement), and M1d (high EBV DNA\u0026thinsp;+\u0026thinsp;liver involvement). With 65% of patients receiving chemotherapy, they reported a mOS of 17.7 months, with 1- and 3-year OS rates of 75.9% and 30.5%, respectively. In both studies, DFI was not identified as a significant prognostic factor.\u003c/p\u003e \u003cp\u003eDespite this, the prognostic value of DFI has been demonstrated in three SYSUCC studies(\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) focusing on liver-only(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) or bone-only(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) metastases, and a subsequent analysis from Fujian encompassing the full mmNPC spectrum.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) In 2022, Peng et al. from Jiangsu(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) developed a prognostic nomogram for mmNPC that incorporated DFI alongside metastatic burden and other clinical variables. The 1- and 3-year OS rates were 76.1% and 39.8%, respectively. Consistent with Peng et al\u0026rsquo;s study, the current series demonstrated that DFI retains independent prognostic significance beyond TNM-9 M1 category. The inconsistency in the prognostic value of DFI across studies likely reflects differences in study populations, particularly regarding inclusion criteria and treatment intensity. Both the study by Peng et al.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and our cohort had uniformly high rates of chemotherapy exposure\u0026mdash;all patients in Peng's study received at least one cycle of chemotherapy, while 100% of patients in our cohort received chemotherapy of at least two cycles and 23.9% of them received ICI during PCT phase. Our cohort demonstrated superior survival outcomes (mOS 42 months; 3-year OS 52.1%), suggesting that ensuring a minimum standard of treatment intensit\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ey\u003c/span\u003e is essential for elucidating the true prognostic impact of metastatic burden and temporal factors such as DFI.\u003c/p\u003e \u003cp\u003eSystemic therapy remains the cornerstone of treatment for metastatic NPC.(\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) However, the integration of comprehensive strategies, including MDT(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) and MT(\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) has substantially improved outcomes in recent years. Consistent with previous reports,(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) the present study confirmed that a higher number of PCT cycles (\u0026ge;\u0026thinsp;4) was associated with significantly improved OS in the overall cohort (HR, 0.589; 95% CI, 0.398\u0026ndash;0.871, P\u0026thinsp;=\u0026thinsp;0.008), corroborating findings from Zheng et al.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) and Peng et al.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Notably, none of the aforementioned studies performed subgroup analyses to explore whether the benefit of intensified PCT varied according to patient risk profiles. In the present study, subgroup analysis revealed that survival benefit of intensified PCT was confined to the RPA-M1b subgroup, with no significant benefit observed in the RPA-M1a subgroup. This finding suggests that for patients with low metastatic burden, enhancing PCT intensity may be unnecessary\u0026mdash;particularly in the immunotherapy era, where the optimal PCT duration remains to be defined. Moreover, the potential contribution of MDT and maintenance therapy in this population may further diminish the incremental value of intensified PCT. Our findings underscore the need for well-designed prospective studies to determine the optimal intensity of palliative chemotherapy within the context of multimodality treatment.\u003c/p\u003e \u003cp\u003eFollowing three landmark prospective phase III immunotherapy trials(\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and two pivotal non-immunotherapy studies(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) establishing capecitabine maintenance as a standard option, both immunotherapy and oral maintenance therapy have been widely adopted in real-world practice and are now recommended by treatment guidelines for metastatic NPC. However, whether all patients with metastatic NPC derive equivalent benefit from MT remains unclear, particularly given the limited data specifically addressing mmNPC. In the present study, MT was associated with improved survival in the overall cohort. Subgroup analysis further revealed that the survival benefit of MT was more pronounced in the RPA-M1b subgroup, whereas no significant benefit was observed in the RPA-M1a subgroup. This differential effect may be attributable to the confounding impact of effective prior PCT and MDT in the low-risk subgroup, potentially attenuating the incremental contribution of MT. These findings suggest that in the context of sufficiently intensive PCT and MDT, whether MT confers additional benefit\u0026mdash;and the optimal regimen and duration thereof\u0026mdash;warrants further investigation through well-designed prospective studies. Emerging evidence suggests that dynamic monitoring of EBV DNA may inform maintenance treatment strategies.(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e MDT is currently recommended as a treatment option for patients with oligometastatic disease by major clinical practice guidelines, including those of the National Comprehensive Cancer Network (NCCN). Multiple retrospective series have shown that MDT\u0026mdash;such as surgery or radiotherapy directed at limited metastatic lesions\u0026mdash;is associated with improved survival in selected low-risk mmNPC patients.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) Patient selection in these studies has typically been guided by metastatic burden, EBV-DNA level, DFI, and nomogram-based risk models. Aligning with these findings, the present study demonstrated that MDT significantly improved outcomes in the RPA-M1a subgroup, further corroborating prior evidence from multiple centers. However, our analysis also revealed that the survival benefit of MDT was limited in the RPA-M1b subgroup, suggesting that for patients with polymetastatic disease, treatment strategies should prioritize more effective systemic therapy, such as the combination of antibody-drug conjugates (ADCs)(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) and ICIs(\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), to achieve maximal tumor burden reduction. Notably, only 23.8% of patients in our cohort incorporated ICIs in the PCT phase.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eSeveral limitations should be considered when interpreting our findings. First, the retrospective, single-center design may introduce selection bias and limit the generalizability of the results. Second, the moderate sample size constrains statistical power for certain subgroup analyses and precluded a detailed evaluation of therapy efficacy across specific metastatic sites. Third, reflecting the real-world adoption curve of immunotherapy, only a subset of patients in this cohort received ICIs, which may affect the extrapolation of outcomes to the current treatment landscape. With the advent of more effective systemic regimens, including the integration of immune checkpoint inhibitors with chemotherapy for all patients, the net impact of MDT to metastatic lesions should be re-evaluated. Finally, our model did not incorporate plasma EBV DNA, a known prognostic biomarker in NPC. While this strategy enhances the model's practicality by avoiding inter-laboratory assay variability of EBV DNA detection,(\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) future iterations could be strengthened by including standardized biomarker data.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study validates the prognostic utility of the TNM-9 M1 subclassification in mmNPC and identifies DFI as an independent prognostic factor beyond anatomic metastatic burden. By integrating these two factors through RPA, we established a refined RPA-M1 classification that stratifies patients into two distinct prognostic subgroups: RPA-M1a (\u0026le;\u0026thinsp;3 metastases and DFI\u0026thinsp;\u0026gt;\u0026thinsp;12 months) and RPA-M1b (\u0026gt;\u0026thinsp;3 metastases or DFI\u0026thinsp;\u0026le;\u0026thinsp;12 months). This novel system demonstrates superior prognostic discrimination compared to the TNM-9 M1 category alone and, importantly, informs treatment decision-making. Our findings provide a practical, staging-aligned framework that addresses a critical gap left by prior classification systems and recent prospective trials. Prospective studies are warranted to validate this risk-stratified approach and to further refine prognostic precision and individualized therapeutic strategies making.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAIC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eakaike information criterion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003earea under receiver operating characteristic curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eADCs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eantibody-drug conjugates\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eC-index\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eharrell\u0026rsquo;s concordance index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDFI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edisease-free interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egemcitabine and platinum\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elymph node\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMDT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emetastasis-directed therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emaintenance therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eM1-NPC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ede novo metastatic NPC\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMVA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emultivariate analysis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emmNPC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emetachronous metastatic nasopharyngeal carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNCCN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enational comprehensive cancer network\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNPC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enasopharyngeal carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e 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class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRPA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erecursive partitioning analysis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICIs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmune checkpoint inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQRs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile ranges\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edocetaxel and platinum\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTPF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edocetaxel,platinum and 5-fluorouracil\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTPC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edocetaxel,platinum and capecitabine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003econsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Boards of Fujian Cancer Hospital.\u0026nbsp;The study was conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the other authors declare that he/she has no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was sponsored by the National Key Clinical Specialty Construction Program and Key Clinical Specialty Discipline Construction Program of Fujian, China. This research is also supported by Youth Talents Project of the Fujian Eagle Program, and Fujian Provincial Clinlical Research Center for Cancer Radiotherapy and Immunotherapy (Grant number 2020Y2012). Fujian Clinical Research Center for Radiation and Therapy of Digestive, Respiratory and Genitourinary Malignancies (2021Y2014), Natural Science Foundation of Fujian Province (Grant number 2023J011252 and 2025J01223), Fujian Cancer Hospital Program (2021YNDT02, 2023YNG05 and 202411002).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge the clinicians and research staff of Fujian Cancer Hospital for their assistance in data collection and management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDH, HX and XX contributed equally to this work. DH, HX and SL conceived and designed the study. DH, HX, XX, YYH, KL, YH, LZ, YZ and CH collected and curated the data. DH and HX performed the statistical analysis and interpreted the data. DH drafted the manuscript. HX, JP, YX, JW and QG critically revised the manuscript for important intellectual content. JP, SL, JW and QG supervised the study. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394(10192):64\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlanchard P, Lee A, Marguet S, Leclercq J, Ng WT, Ma J, et al. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol. 2015;16(6):645\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan JJ, Mai HQ, Ng WT, Hu CS, Li JG, Chen XZ, et al. 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Ann Transl Med. 2020;8(4):83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeng F, Ge Y, Wang R, Hu D, Cao X, Zhang Y, et al. Identifying nasopharyngeal carcinoma patients with metachronous metastasis sensitive to local treatment: a real-world study. J Biomed Res. 2022;36(4):221\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan R, Phua SKA, Soong YL, Oon LLE, Chan KS, Lucky SS, et al. Clinical utility of Epstein-Barr virus DNA and other liquid biopsy markers in nasopharyngeal carcinoma. Cancer Commun (Lond). 2020;40(11):564\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller JA, Huang C, Yamamoto F, Sahoo MK, Le QT, Pinsky BA. Comparison of Real-Time PCR and Digital PCR for Detection of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Carcinoma. 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J Clin Oncol. 2014;32(27):3059\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsu C, Lee SH, Ejadi S, Even C, Cohen RB, Le Tourneau C, et al. Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study. J Clin Oncol. 2017;35(36):4050\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, et al. Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial. JAMA. 2023;330(20):1961\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang Y, Qu S, Li J, Hu C, Xu M, Li W, et al. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2021;22(8):1162\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang Y, Pan J, Wang H, Zhao Y, Qu S, Chen N, et al. Tislelizumab plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer: A multicenter phase 3 trial (RATIONALE-309). Cancer Cell. 2023;41(6):1061\u0026ndash;72. e4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuckenberger M, Lievens Y, Bouma AB, Collette L, Dekker A, deSouza NM, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol. 2020;21(1):e18\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJin Y, Cai YC, Cao Y, Cai XY, Tan YT, Shi YX, et al. Radiofrequency ablation combined with systemic chemotherapy in nasopharyngeal carcinoma liver metastases improves response to treatment and survival outcomes. J Surg Oncol. 2012;106(3):322\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang H, Zhao Y, Deng Y, Zhan Z, Huang Y, Cao X, et al. Optimal therapeutic strategies for hepatic metachronous oligometastatic nasopharyngeal carcinoma: Insights from a retrospective study. Int J Cancer. 2025;156(1):174\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe S, Wang Y, Peng H, Yang L, Chen H, Liang S, et al. Pretreatment Alkaline Phosphatase and Epstein-Barr Virus DNA Predict Poor Prognosis and Response to Salvage Radiotherapy in Patients with Nasopharyngeal Carcinoma and Metachronous Bone-Only Metastasis. J Cancer. 2017;8(3):417\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng W, Zong J, Huang C, Chen J, Wu J, Chen C, et al. Multimodality Treatment May Improve the Survival Rate of Patients with Metastatic Nasopharyngeal Carcinoma with Good Performance Status. PLoS ONE. 2016;11(1):e0146771.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBossi P, Chan AT, Licitra L, Trama A, Orlandi E, Hui EP, et al. Nasopharyngeal carcinoma: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up(dagger). Ann Oncol. 2021;32(4):452\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBossi P, Chan AT, Even C, Machiels JP. [email protected] EGCEa. ESMO-EURACAN Clinical Practice Guideline update for nasopharyngeal carcinoma: adjuvant therapy and first-line treatment of recurrent/metastatic disease. Ann Oncol. 2023;34(3):247\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee AW, Ma BB, Ng WT, Chan AT. Management of Nasopharyngeal Carcinoma: Current Practice and Future Perspective. 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Anti-PD-1 antibody with or without capecitabine as maintenance therapy after first-line therapy of recurrent or metastatic nasopharyngeal carcinoma. Oncologist. 2025;30(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Zuo ZC, Zeng XY, Ma J, Ma CX, Chen RZ, et al. Establishing subdivisions of M1 stage nasopharyngeal carcinoma based on decision tree classification: A multicenter retrospective study. Oral Oncol. 2024;153:106834.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang Y, Zhou H, Tang L, Qiu S, Han Y, Ji D, et al. Izalontamab brengitecan, an EGFR and HER3 bispecific antibody-drug conjugate, versus chemotherapy in heavily pretreated recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 study in China. Lancet. 2025;406(10516):2235\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"metachronous metastatic nasopharyngeal carcinoma, M1 category, RPA-M1 classification, metastatic burden, disease-free interval","lastPublishedDoi":"10.21203/rs.3.rs-9310030/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9310030/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e To validate the prognostic value of the M1 category in version nine of the AJCC/UICC TNM staging system (TNM-9) in metachronous metastatic nasopharyngeal carcinoma (mmNPC) and to develop a refined M1 classification for improved risk stratification.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003ePatients with newly diagnosed mmNPC (2015–2024) were analyzed and restaged per TNM-9 M1 criteria. Independent prognostic factors from multivariate Cox analysis were integrated using recursive partitioning analysis (RPA) to establish an RPA-based M1 classification (RPA-M1). Model performance was assessed using Harrell's C-index, time-dependent AUC, and Akaike information criterion (AIC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong 218 patients, 111 (50.9%) were M1a and 107 (49.1%) M1b. The M1a subgroup demonstrated significantly higher 3-year overall survival (OS) than the M1b subgroup (63.2% vs. 40.8%, P \u0026lt; 0.001). Both the TNM-9 M1 category and disease-free interval (DFI) were independent prognostic factors for OS (both P \u0026lt; 0.05). The RPA model stratified patients into distinct prognostic groups: RPA-M1a (≤ 3 metastatic lesions and DFI \u0026gt; 12 months) and RPA-M1b (\u0026gt; 3 lesions or DFI ≤ 12 months), with 3-year OS rates of 74.6% and 40.6%, respectively (P \u0026lt; 0.001). The RPA-M1 classification showed superior prognostic discrimination compared with the TNM-9 M1 stage, evidenced by higher C-index, time-dependent AUCs, and lower AIC. Metastasis-directed therapy improved OS only in the RPA-M1a subgroup, while intensified systemic therapy primarily benefited the RPA-M1b subgroup.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe TNM-9 M1 category is applicable to mmNPC. The novel RPA-M1 classification, which integrates metastatic burden and DFI, offers superior risk stratification and enables more precise prognostication and individualized management.\u003c/p\u003e","manuscriptTitle":"Subdivision of metachronous metastatic nasopharyngeal carcinoma based on the framework of TNM-9: A recursive partitioning analysis of real-world data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 06:26:03","doi":"10.21203/rs.3.rs-9310030/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-03T09:00:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T13:01:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"148499163632636910066767679306225203083","date":"2026-05-02T10:08:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-01T06:00:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"256802345689129869566251035515567147497","date":"2026-05-01T04:40:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"85378383432015211139592914253135211506","date":"2026-04-29T22:28:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-29T13:59:13+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-06T06:46:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-06T05:52:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-06T05:51:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-04-03T07:18:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"82795215-b83f-4c74-955e-983053a70191","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-03T09:00:14+00:00","index":44,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T13:01:27+00:00","index":43,"fulltext":""},{"type":"reviewerAgreed","content":"148499163632636910066767679306225203083","date":"2026-05-02T10:08:58+00:00","index":42,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-01T06:00:30+00:00","index":40,"fulltext":""},{"type":"reviewerAgreed","content":"256802345689129869566251035515567147497","date":"2026-05-01T04:40:38+00:00","index":39,"fulltext":""},{"type":"reviewerAgreed","content":"85378383432015211139592914253135211506","date":"2026-04-29T22:28:39+00:00","index":37,"fulltext":""},{"type":"reviewersInvited","content":"15","date":"2026-04-29T13:59:13+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T06:26:03+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 06:26:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9310030","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9310030","identity":"rs-9310030","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}