An Exploratory Study of Refining TNM-8 M1 Categories and Prognostic Subgroups Using Plasma EBV DNA for Previously Untreated De Novo Metastatic Nasopharyngeal Carcinoma
(1) Background: NPC patients with de novo distant metastasis appears to be a heterogeneous group who demonstrate a wide range of survival, as suggested by growing evidence. Nevertheless, the current 8th edition of TNM staging (TNM-8) grouping all these patients into the M1 category is not able to id...
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| Format: | Article |
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MDPI AG
2022-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/8/1923 |
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| author | Sik-Kwan Chan Brian O’Sullivan Shao Hui Huang Tin-Ching Chau Ka-On Lam Sum-Yin Chan Chi-Chung Tong Varut Vardhanabhuti Dora Lai-Wan Kwong Chor-Yi Ng To-Wai Leung Mai-Yee Luk Anne Wing-Mui Lee Horace Cheuk-Wai Choi Victor Ho-Fun Lee |
| author_facet | Sik-Kwan Chan Brian O’Sullivan Shao Hui Huang Tin-Ching Chau Ka-On Lam Sum-Yin Chan Chi-Chung Tong Varut Vardhanabhuti Dora Lai-Wan Kwong Chor-Yi Ng To-Wai Leung Mai-Yee Luk Anne Wing-Mui Lee Horace Cheuk-Wai Choi Victor Ho-Fun Lee |
| author_sort | Sik-Kwan Chan |
| collection | DOAJ |
| description | (1) Background: NPC patients with de novo distant metastasis appears to be a heterogeneous group who demonstrate a wide range of survival, as suggested by growing evidence. Nevertheless, the current 8th edition of TNM staging (TNM-8) grouping all these patients into the M1 category is not able to identify their survival differences. We sought to identify any anatomic and non-anatomic subgroups in this study. (2) Methods: Sixty-nine patients with treatment-naive de novo M1 NPC (training cohort) were prospectively recruited from 2007 to 2018. We performed univariable and multivariable analyses (UVA and MVA) to explore anatomic distant metastasis factors, which were significantly prognostic of overall survival (OS). Recursive partitioning analysis (RPA) with the incorporation of significant factors from MVA was then performed to derive a new set of RPA stage groups with OS segregation (Set 1 Anatomic-RPA stage groups); another run of MVA was performed with the addition of pre-treatment plasma EBV DNA. A second-round RPA with significant prognostic factors of OS identified in this round of MVA was performed again to derive another set of stage groups (Set 2 Prognostic-RPA stage groups). Both sets were then validated externally with an independent validation cohort of 67 patients with distant relapses of their initially non-metastatic NPC (rM1) after radical treatment. The performance of models in survival segregation was evaluated by the Akaike information criterion (AIC) and concordance index (C-index) under 1000 bootstrapping samples for the validation cohort; (3) Results: The 3-year OS and median follow-up in the training cohort were 36.0% and 17.8 months, respectively. Co-existence of liver-bone metastases was the only significant prognostic factor of OS in the first round UVA and MVA. Set 1 RPA based on anatomic factors that subdivide the M1 category into two groups: M1a (absence of co-existing liver-bone metastases; median OS 28.1 months) and M1b (co-existing liver-bone metastases; median OS 19.2 months, <i>p</i> = 0.023). When pre-treatment plasma EBV DNA was also added, it became the only significant prognostic factor in UVA (<i>p</i> = 0.001) and MVA (<i>p</i> = 0.015), while co-existing liver-bone metastases was only significant in UVA. Set 2 RPA with the incorporation of pre-treatment plasma EBV DNA yielded good segregation (M1a: EBV DNA ≤ 2500 copies/mL and M1b: EBV DNA > 2500 copies/mL; median OS 44.2 and 19.7 months, respectively, <i>p</i> < 0.001). Set 2 Prognostic-RPA groups (AIC: 228.1 [95% CI: 194.8–251.8] is superior to Set 1 Anatomic-RPA groups (AIC: 278.5 [254.6–301.2]) in the OS prediction (<i>p</i> < 0.001). Set 2 RPA groups (C-index 0.59 [95% CI: 0.54–0.67]) also performed better prediction agreement in the validation cohort (vs. Set 1: C-index 0.47 [95% CI: 0.41–0.53]) (<i>p</i> < 0.001); (4) Conclusions: Our Anatomic-RPA stage groups yielded good segregation for de novo M1 NPC, and prognostication was further improved by incorporating plasma EBV DNA. These new RPA stage groups for M1 NPC can be applied to countries/regions regardless of whether reliable and sensitive plasma EBV DNA assays are available or not. |
| first_indexed | 2024-03-09T11:03:35Z |
| format | Article |
| id | doaj.art-cba2d0a0a7a447bc9b5d453ac647faba |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T11:03:35Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-cba2d0a0a7a447bc9b5d453ac647faba2023-12-01T01:05:53ZengMDPI AGCancers2072-66942022-04-01148192310.3390/cancers14081923An Exploratory Study of Refining TNM-8 M1 Categories and Prognostic Subgroups Using Plasma EBV DNA for Previously Untreated De Novo Metastatic Nasopharyngeal CarcinomaSik-Kwan Chan0Brian O’Sullivan1Shao Hui Huang2Tin-Ching Chau3Ka-On Lam4Sum-Yin Chan5Chi-Chung Tong6Varut Vardhanabhuti7Dora Lai-Wan Kwong8Chor-Yi Ng9To-Wai Leung10Mai-Yee Luk11Anne Wing-Mui Lee12Horace Cheuk-Wai Choi13Victor Ho-Fun Lee14Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2C1, CanadaDepartment of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2C1, CanadaDepartment of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Diagnostic Radiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaSchool of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China(1) Background: NPC patients with de novo distant metastasis appears to be a heterogeneous group who demonstrate a wide range of survival, as suggested by growing evidence. Nevertheless, the current 8th edition of TNM staging (TNM-8) grouping all these patients into the M1 category is not able to identify their survival differences. We sought to identify any anatomic and non-anatomic subgroups in this study. (2) Methods: Sixty-nine patients with treatment-naive de novo M1 NPC (training cohort) were prospectively recruited from 2007 to 2018. We performed univariable and multivariable analyses (UVA and MVA) to explore anatomic distant metastasis factors, which were significantly prognostic of overall survival (OS). Recursive partitioning analysis (RPA) with the incorporation of significant factors from MVA was then performed to derive a new set of RPA stage groups with OS segregation (Set 1 Anatomic-RPA stage groups); another run of MVA was performed with the addition of pre-treatment plasma EBV DNA. A second-round RPA with significant prognostic factors of OS identified in this round of MVA was performed again to derive another set of stage groups (Set 2 Prognostic-RPA stage groups). Both sets were then validated externally with an independent validation cohort of 67 patients with distant relapses of their initially non-metastatic NPC (rM1) after radical treatment. The performance of models in survival segregation was evaluated by the Akaike information criterion (AIC) and concordance index (C-index) under 1000 bootstrapping samples for the validation cohort; (3) Results: The 3-year OS and median follow-up in the training cohort were 36.0% and 17.8 months, respectively. Co-existence of liver-bone metastases was the only significant prognostic factor of OS in the first round UVA and MVA. Set 1 RPA based on anatomic factors that subdivide the M1 category into two groups: M1a (absence of co-existing liver-bone metastases; median OS 28.1 months) and M1b (co-existing liver-bone metastases; median OS 19.2 months, <i>p</i> = 0.023). When pre-treatment plasma EBV DNA was also added, it became the only significant prognostic factor in UVA (<i>p</i> = 0.001) and MVA (<i>p</i> = 0.015), while co-existing liver-bone metastases was only significant in UVA. Set 2 RPA with the incorporation of pre-treatment plasma EBV DNA yielded good segregation (M1a: EBV DNA ≤ 2500 copies/mL and M1b: EBV DNA > 2500 copies/mL; median OS 44.2 and 19.7 months, respectively, <i>p</i> < 0.001). Set 2 Prognostic-RPA groups (AIC: 228.1 [95% CI: 194.8–251.8] is superior to Set 1 Anatomic-RPA groups (AIC: 278.5 [254.6–301.2]) in the OS prediction (<i>p</i> < 0.001). Set 2 RPA groups (C-index 0.59 [95% CI: 0.54–0.67]) also performed better prediction agreement in the validation cohort (vs. Set 1: C-index 0.47 [95% CI: 0.41–0.53]) (<i>p</i> < 0.001); (4) Conclusions: Our Anatomic-RPA stage groups yielded good segregation for de novo M1 NPC, and prognostication was further improved by incorporating plasma EBV DNA. These new RPA stage groups for M1 NPC can be applied to countries/regions regardless of whether reliable and sensitive plasma EBV DNA assays are available or not.https://www.mdpi.com/2072-6694/14/8/1923nasopharyngeal carcinomametastaticM1 categoriesplasma EBV DNArecursive partitioning analysisTNM |
| spellingShingle | Sik-Kwan Chan Brian O’Sullivan Shao Hui Huang Tin-Ching Chau Ka-On Lam Sum-Yin Chan Chi-Chung Tong Varut Vardhanabhuti Dora Lai-Wan Kwong Chor-Yi Ng To-Wai Leung Mai-Yee Luk Anne Wing-Mui Lee Horace Cheuk-Wai Choi Victor Ho-Fun Lee An Exploratory Study of Refining TNM-8 M1 Categories and Prognostic Subgroups Using Plasma EBV DNA for Previously Untreated De Novo Metastatic Nasopharyngeal Carcinoma Cancers nasopharyngeal carcinoma metastatic M1 categories plasma EBV DNA recursive partitioning analysis TNM |
| title | An Exploratory Study of Refining TNM-8 M1 Categories and Prognostic Subgroups Using Plasma EBV DNA for Previously Untreated De Novo Metastatic Nasopharyngeal Carcinoma |
| title_full | An Exploratory Study of Refining TNM-8 M1 Categories and Prognostic Subgroups Using Plasma EBV DNA for Previously Untreated De Novo Metastatic Nasopharyngeal Carcinoma |
| title_fullStr | An Exploratory Study of Refining TNM-8 M1 Categories and Prognostic Subgroups Using Plasma EBV DNA for Previously Untreated De Novo Metastatic Nasopharyngeal Carcinoma |
| title_full_unstemmed | An Exploratory Study of Refining TNM-8 M1 Categories and Prognostic Subgroups Using Plasma EBV DNA for Previously Untreated De Novo Metastatic Nasopharyngeal Carcinoma |
| title_short | An Exploratory Study of Refining TNM-8 M1 Categories and Prognostic Subgroups Using Plasma EBV DNA for Previously Untreated De Novo Metastatic Nasopharyngeal Carcinoma |
| title_sort | exploratory study of refining tnm 8 m1 categories and prognostic subgroups using plasma ebv dna for previously untreated de novo metastatic nasopharyngeal carcinoma |
| topic | nasopharyngeal carcinoma metastatic M1 categories plasma EBV DNA recursive partitioning analysis TNM |
| url | https://www.mdpi.com/2072-6694/14/8/1923 |
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