Establishment of a prognostic nomogram for patients with locoregionally advanced nasopharyngeal carcinoma incorporating clinical characteristics and dynamic changes in hematological and inflammatory markers

Background This study aims to investigate the prognostic value of changes in hematological and inflammatory markers during induction chemotherapy (IC) and concurrent chemo-radiation (CCRT), thus construct nomograms to predict progression free survival (PFS) of patients with locally advanced nasopharyngeal carcinoma (LANPC). Methods 130 patients were included in this prospective analysis. Univariate and multivariate cox regression analyses were conducted to identify prognostic factors. Three multivariate analyses integrating different groups of variables were conducted independently. Concordance indexes (c-index), calibration plots and Kaplan-Meier curves were used to evaluate the nomograms. Bootstrap validation was performed to determine the accuracy of the nomogram using 1000 resamples. The performances of proposed nomograms and TNM staging system were compared to validate the prognostic value of hematological and inflammatory markers. Results Pretreatment gross tumor volume of nodal disease (GTVn), Δe/bHGB (hemoglobin count at end of treatment/baseline hemoglobin count), and stage were selected as predictors for 3-year PFS in first multivariate analysis of clinical factors. The second multivariate analysis of clinical factors and all hematological variables demonstrated that ΔminLYM (minimum lymphocyte count during CCRT/lymphocyte count post-IC), pretreatment GTVn and stage were associated with 3-year PFS. Final multivariate analysis, incorporating all clinical factors, hematological variables and inflammatory markers, identified the following prognostic factors: pretreatment GTVn, stage, ΔmaxPLR (maximum platelet-to-lymphocyte ratio (PLR) during CCRT/PLR post-IC), and ΔminPLT (minimum platelet count during CCRT/platelet count post-IC). Calibration plots showed agreement between the PFS predicted by the nomograms and actual PFS. Kaplan–Meier curves demonstrated that patients in the high-risk group had shorter PFS than those in the low-risk group (P ≤ 0.001). The c-indexes of the three nomograms for PFS were 0.742 (95% CI, 0.639-0.846), 0.766 (95% CI, 0.661-0.871) and 0.815 (95% CI,0.737-0.893) respectively, while c-index of current TNM staging system was 0.633 (95% CI, 0.531-0.736). Conclusion We developed and validated a nomogram for predicting PFS in patients with LANPC who received induction chemotherapy and concurrent chemo-radiation. Our study confirmed the prognostic value of dynamic changes in hematological and inflammatory markers. The proposed nomogram outperformed the current TNM staging system in predicting PFS, facilitating risk stratification and guiding individualized treatment plans.

[1]  Wei Jiang,et al.  Nomogram for distant metastasis-free survival in patients with locoregionally advanced nasopharyngeal carcinoma , 2022, Strahlentherapie und Onkologie.

[2]  Amrish Sharma,et al.  A systematic review and meta-analysis of the impact of radiation-related lymphopenia on outcomes in pancreatic cancer. , 2022, Future oncology.

[3]  Linlang Guo,et al.  Early onset of severe lymphopenia during definitive radiotherapy correlates with mean body dose and predicts poor survival in cervical cancer , 2022, Cancer biomarkers : section A of Disease markers.

[4]  U. Ricardi,et al.  The Impact of Pelvic Nodal Radiotherapy on Hematologic Toxicity: A Systematic Review with Focus on Leukopenia, Lymphopenia and Future Perspectives in Prostate Cancer Treatment. , 2021, Critical reviews in oncology/hematology.

[5]  D. Kwong,et al.  The Stromal and Immune Landscape of Nasopharyngeal Carcinoma and Its Implications for Precision Medicine Targeting the Tumor Microenvironment , 2021, Frontiers in Oncology.

[6]  B. O'Sullivan,et al.  Prognostic Factors for Overall Survival in Nasopharyngeal Cancer and Implication for TNM Staging by UICC: A Systematic Review of the Literature , 2021, Frontiers in Oncology.

[7]  Xiao-dong Zhu,et al.  Nomogram Based on Lactate Dehydrogenase-to-Albumin Ratio (LAR) and Platelet-to-Lymphocyte Ratio (PLR) for Predicting Survival in Nasopharyngeal Carcinoma , 2021, Journal of inflammation research.

[8]  Xiao-dong Zhu,et al.  Establishment of a Prognostic Nomogram for Patients With Locoregionally Advanced Nasopharyngeal Carcinoma Incorporating TNM Stage, Post-Induction Chemotherapy Tumor Volume and Epstein-Barr Virus DNA Load , 2021, Frontiers in Oncology.

[9]  Qin Wang,et al.  Changes in T Lymphocyte Subsets in Different Tumors Before and After Radiotherapy: A Meta-analysis , 2021, Frontiers in Immunology.

[10]  Jia-Lin Wang,et al.  Lymphopenia in Esophageal Cancer: What Have We Learned? , 2021, Frontiers in Oncology.

[11]  Zhiwei Chen,et al.  Comprehensive single-cell sequencing reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of nasopharyngeal carcinoma , 2021, Nature Communications.

[12]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[13]  R. Mohan,et al.  Prognostic impact of lymphopenia and neutrophil-lymphocyte ratio for patients with anal squamous cell carcinoma. , 2021, Journal of gastrointestinal oncology.

[14]  J. Shao,et al.  Development of a Nomogram Model for Treatment of Nonmetastatic Nasopharyngeal Carcinoma , 2020, JAMA network open.

[15]  Jeffrey W. Clark,et al.  Chemoradiation-related lymphopenia and its association with survival in patients with squamous cell carcinoma of the anal canal. , 2020, The oncologist.

[16]  Y. Mao,et al.  The evolution of the nasopharyngeal carcinoma staging system over a 10-year period: implications for future revisions , 2020, Chinese medical journal.

[17]  J. Seong,et al.  Significance of lymphocyte recovery from treatment-related lymphopenia in locally advanced pancreatic cancer. , 2020, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[18]  S. H. Cheng,et al.  Prognostic classification for patients with nasopharyngeal carcinoma based on American Joint Committee on cancer staging system T and N categories , 2020 .

[19]  Hui Wang,et al.  Radiation-induced lymphopenia correlates with survival in nasopharyngeal carcinoma: impact of treatment modality and the baseline lymphocyte count , 2020, Radiation Oncology.

[20]  J. Yun,et al.  Epstein–Barr Virus miRNA BART2-5p Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing RND3 , 2020, Cancer Research.

[21]  Xiao-dong Zhu,et al.  Prognostic Nomogram For Locoregionally Advanced Nasopharyngeal Carcinoma , 2020, Scientific Reports.

[22]  A. Garden,et al.  Lymphopenia during radiotherapy in patients with oropharyngeal cancer. , 2020, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[23]  H. Mai,et al.  Establishment and validation of two nomograms to predict the benefit of concurrent chemotherapy in stage II‐IVa nasopharyngeal carcinoma patients with different risk factors: Analysis based on a large cohort , 2020, Cancer medicine.

[24]  Melek Akcay Neutrophil/Lymphocyte Ratio and Prognosis in Patients with Non-Metastatic Nasopharyngeal Cancer: A Single-Center Experience , 2020 .

[25]  V. Grégoire,et al.  International Guideline on Dose Prioritization and Acceptance Criteria in Radiotherapy Planning for Nasopharyngeal Carcinoma. , 2019, International journal of radiation oncology, biology, physics.

[26]  Mengzhong Liu,et al.  Treatment-Related Lymphopenia Predicts Pathologic Complete Response and Recurrence in Esophageal Squamous Cell Carcinoma Undergoing Neoadjuvant Chemoradiotherapy , 2019, Annals of Surgical Oncology.

[27]  T. Showalter,et al.  Radiation-related Lymphopenia after Pelvic Nodal Irradiation for Prostate Cancer , 2019, Advances in radiation oncology.

[28]  Ying Sun,et al.  Prognostic value of neutrophil-to-lymphocyte ratio in advanced nasopharyngeal carcinoma: a large institution-based cohort study from an endemic area , 2019, BMC Cancer.

[29]  Jun Ma,et al.  Nasopharyngeal carcinoma , 2019, The Lancet.

[30]  L. Pączek,et al.  Radiotherapy and radiochemotherapy increase serum levels of pro-inflammatory interleukin-6 and C-reactive protein in patients with head and neck cancers , 2018 .

[31]  Yue Cai,et al.  Reduction of circulating lymphocyte count is a predictor of good tumor response after neoadjuvant treatment for rectal cancer , 2018, Medicine.

[32]  H. Ying,et al.  Prognostic values of hematological biomarkers in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy , 2018, European Archives of Oto-Rhino-Laryngology.

[33]  Jennifer R. Grandis,et al.  Targeting the IL-6/JAK/STAT3 signalling axis in cancer , 2018, Nature Reviews Clinical Oncology.

[34]  H. Sze,et al.  Treatment outcomes of nasopharyngeal carcinoma in modern era after intensity modulated radiotherapy (IMRT) in Hong Kong: A report of 3328 patients (HKNPCSG 1301 study). , 2018, Oral oncology.

[35]  Xiao-dong Zhu,et al.  Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in intensity modulated radiation therapy for nasopharyngeal carcinoma , 2018, Oncotarget.

[36]  Brian O'Sullivan,et al.  International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma. , 2017, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[37]  Ying Sun,et al.  The Prognostic Value of Treatment-Related Lymphopenia in Nasopharyngeal Carcinoma Patients , 2017, Cancer research and treatment : official journal of Korean Cancer Association.

[38]  Dan Li,et al.  Elevated pretreatment platelet distribution width and platelet count predict poor prognosis in nasopharyngeal carcinoma , 2017, Oncotarget.

[39]  Minzhong Tang,et al.  Prognostic Significance of Neutrophil to Lymphocyte Ratio, Lymphocyte to Monocyte Ratio, and Platelet to Lymphocyte Ratio in Patients with Nasopharyngeal Carcinoma , 2017, BioMed research international.

[40]  M. Chun,et al.  Minimum absolute lymphocyte count during radiotherapy as a new prognostic factor for nasopharyngeal cancer , 2016, Head & neck.

[41]  M. Brock,et al.  Survival in Patients With Severe Lymphopenia Following Treatment With Radiation and Chemotherapy for Newly Diagnosed Solid Tumors. , 2015, Journal of the National Comprehensive Cancer Network : JNCCN.

[42]  Yun-Fei Xia,et al.  Pretreatment platelet count improves the prognostic performance of the TNM staging system and aids in planning therapeutic regimens for nasopharyngeal carcinoma: a single-institutional study of 2,626 patients , 2015, Chinese journal of cancer.

[43]  Yun-Fei Xia,et al.  Pretreatment platelet count as a predictor for survival and distant metastasis in nasopharyngeal carcinoma patients , 2015, Oncology letters.

[44]  S. Grossman,et al.  Association between severe treatment‐related lymphopenia and progression‐free survival in patients with newly diagnosed squamous cell head and neck cancer , 2014, Head & neck.

[45]  C. Holmes,et al.  Platelets in Tumor Progression: A Host Factor That Offers Multiple Potential Targets in the Treatment of Cancer , 2014, Journal of cellular physiology.

[46]  K. Ang,et al.  An International Collaboration to Harmonize the Quantitative Plasma Epstein-Barr Virus DNA Assay for Future Biomarker-Guided Trials in Nasopharyngeal Carcinoma , 2013, Clinical Cancer Research.

[47]  Yun-Fei Xia,et al.  Increased platelet count is an indicator of metastasis in patients with nasopharyngeal carcinoma , 2013, Tumor Biology.

[48]  P. Zuk,et al.  Differential effect of ionizing radiation exposure on multipotent and differentiation‐restricted bone marrow mesenchymal stem cells , 2010, Journal of cellular biochemistry.

[49]  S. Demaria,et al.  Systemic effects of local radiotherapy. , 2009, The Lancet. Oncology.

[50]  D. Long,et al.  Inhibitory effect of mesenchymal stem cells on lymphocyte proliferation , 2008, Cell biochemistry and function.

[51]  F. Schmidt Meta-Analysis , 2008 .

[52]  K. Blum,et al.  Lymphocyte numbers and subsets in the human blood. Do they mirror the situation in all organs? , 2007, Immunology letters.

[53]  J. Sham,et al.  Prognostic impact of hemoglobin levels on treatment outcome in patients with nasopharyngeal carcinoma treated with sequential chemoradiotherapy or radiotherapy alone , 2004 .

[54]  K. Tanabe,et al.  The role of Fas ligand and transforming growth factor β in tumor progression , 2004 .

[55]  K. Münstedt,et al.  Hemoglobin levels during radiation therapy and their influence on local control and survival of patients with endometrial carcinoma. , 2004, Oncology reports.

[56]  Jiann-Jou Yang,et al.  IL-19 Induces Production of IL-6 and TNF-α and Results in Cell Apoptosis Through TNF-α1 , 2002, The Journal of Immunology.

[57]  A. Kakkar,et al.  Platelets and cancer. , 2002, The Lancet. Oncology.

[58]  S. Gabriel,et al.  Systematic Review of the Literature , 2021, Adherence to Antiretroviral Therapy among Perinatal Women in Guyana.

[59]  Jiann-Jou Yang,et al.  IL-19 induces production of IL-6 and TNF-alpha and results in cell apoptosis through TNF-alpha. , 2002, Journal of immunology.

[60]  C. Belka,et al.  Radiation-induced apoptosis in human lymphocytes and lymphoma cells critically relies on the up-regulation of CD95/Fas/APO-1 ligand. , 1998, Radiation research.