Prognostic Value Of ¹⁸F-fluorodeoxyglucose PET And Inflammatory Parameters In Patients With Nasopharyngeal Carcinoma

Background and objectiveNasopharyngeal carcinoma （NPC） is an endemic head and neck neoplasm in southern China, with high incidences of 20-30 per 100,000 populations reported in some areas of Guangdong province. Men are more likely to develop the disease than women, and peak age of disease occurrence is between 50 and 60 years. The cause of NPC has not been very clear. There may be some factors associated with NPC risk, such as Epstein-Barr virus （EB V） infection, family history of cancer, environmental risk factors （high salted fish intake, low fresh vegetables and fruits intake, tobacco smoking, and alcohol consumption）. Certain medical conditions in the ear, nose or throat （i.e., history of chronic rhinitis, sinusitis, nasal polyp, or otitis media） have also been proposed as risk factors for NPC. Clinical symptoms and signs of NPC are complex, with high malignant degree and high incidence of cervical lymph node metastasis and distant metastasis. Radiotherapy is the primary treatment modality for NPC, and concurrent chemo-radiotherapy with or without adjuvant chemotherapy is the recommended treatment regimen for locoregional advanced disease. Despite significant improvements in survival due to advances in imaging diagnosis, radiotherapy and combined modality treatments, local recurrence and distant metastasis remain the predominant mode of failure in patients with advanced NPC. Currently, the prognosis of NPC patients is evaluated based primarily on American Joint Cancer Committee （AJCC） Tumor-Node Metastasis （TNM） staging system. However, there is a discrepancy between actual clinical outcome and anatomically based TNM stage, indicating that the clinical staging is insufficient for precise prediction of the prognosis. It is therefore critical to explore valuable factors to predict outcome for NPC patients.¹⁸F-fluorodeoxy glucose positron emission tomography/computerized tomography (¹⁸F-FDG PET/CT), a synergistic combination of functional and anatomical imaging, based on the tracer principle and some unique metabolic characteristics of tumor, can be non-invasive, dynamic and quantitative reaction of the biological characteristics of metabolism in tumor tissue. It plays a growing role in the diagnosis, staging, and prognosis of NPC. FDG uptake using standardized uptake values （SUV） is a semi-quantitative indicator which represents the ratio of radioactivity of tumor uptake to the mean radioactivity of systemic injection. It has a certain malignant reference value for the identification of benign lesions. Maximum standardized uptake values （SUVmax） are correlated with tumor proliferation rates, metastatic potential, sensibility to radiotherapy/chemotherapy, and clinical outcomes. Recently, more and more studies addressed maximum standardized uptake values （SUVmax） as prognostic factors to predict short-term and long-term efficacy in head and neck cancer, lung cancer, breast cancer, and esophageal cancer. Furthermore, previous reports have shown that NPC patients with high maximum standardized uptake values （SUVmax） generally have less favorable outcomes.Cancer prognosis is not determined solely based on the local characteristics of tumor, but also the host systemic immune/inflammatory response. Inflammatory responses lead to chronic oxidative stress and generate oxygen free radicals, which have been shown to stimulate cancer initiation, promotion, and progression. Why is cancer-related inflammation especially important in NPC? First, inflammation is a key component of the tumor microenvironment. A consistent, massive leukocytic infiltration is present in virtually all primary tumors, and is suspected to enhance the malignant growth of NPC cells. Second, Epstein-Barr viral （EBV） infection is associated with NPC in the areas where NPC is endemic, and induces the consistent expression of viral immunogenic proteins that leads to a potent immune response. EBV-encoded RNAs （EBERs） cause a chronic inflammation, and play a pivotal role in inflammation-to-oncogenesis transition in NPC development. Finally, high levels of numerous cytokines and other inflammation-related factors are consistently detected in the peripheral blood of patients with NPC. Therefore, inflammation is closely related to the biological behavior of NPC. It has a certain molecular biology basis for inflammation associated factors to predict the prognosis of NPC.With the individual treatment - precision medical put forward, single prognostic indicators have been unable to meet the requirements of NPC risk stratification. Therefore, integration of tumor-associated factors （such as PET parameters） and host factors （such as inflammation associated markers） has important clinical significance for NPC. In addition, although it is reported that a substantial component of FDG uptake in tumor tissue is a result of activity localising to peri-tumoural inflammatory cells, studies on the relationship between ¹⁸F-FDG PET and inflammatory parameters are lacking. In this study, we investigated the association of PET SUVmax, peripheral inflammatory markers and TNM stage. We also assessed the prognostic power of SUVmax and peripheral inflammatory parameters for predicting different survival endpoints in patients with NPC. The combined use of PET parameters and blood inflammatory markers may eventually improve prognostic stratification and individually tailored treatment in NPC.MethodsFor the present study we included 121 patients who had been newly diagnosed with NPC from February 2009 to December 2013 at Nanfang Hospital of Southern Medical University. The inclusion criteria were:（1） biopsy-proven primary NPC, （2） pretreatment whole-body¹⁸F-FDG PET/CT and complete blood count （CBC） within two weeks, （3） non-disseminated NPC, and （4） receiving definitive radiotherapy at our institute. The exclusion criteria were:（1） simultaneous second primary tumors, （2） clinical evidence of infection or other systemic inflammatory conditions. Pretreatment maximum standardized uptake values （SUVmax） of PET and peripheral inflammatory factors （leukocyte, neutrophil, and monocyte counts） were recorded. All statistical analysis was performed using SPSS version 17.0 （SPSS, Chicago, IL）. The receiver operating characteristic （ROC） curve analysis was subjected to the selection of cut-off points for F-FDG PET maximum standardized uptake values （SUVmax） and peripheral inflammatory markers showing the best trade-off between sensitivity and specificity for progression. The spearman correlation test was applied to assess the relationship of F-FDG PET maximum standardized uptake values （SUVmax） and circulating inflammation makers. Kaplan-Meier analysis and log-rank test were used to compare the difference of survival rates. Multivariable Cox proportional hazards models were used to identify independent prognostic factors. Two-tailed values of P<0.05 were considered significant. The primary endpoint was progression-free survival （PFS）, and the secondary endpoints were overall survival （OS）, distant metastasis-free survival （DMFS）, and locoregional recurrence-free survival （LRFS）. PFS was calculated from the first day of treatment to the date of relapse at any site, death or last follow-up. OS was calculated from the first day of treatment to the date of death or last follow-up. DMFS was measured from the first day of treatment to the date of metastasis, death or last follow-up. LRFS was measured from the first day of treatment to the date of locoregional recurrence, death or last follow-up.ResultsA total of 121 patients with non-disseminated NPC were recruited. The time of last follow-up was June 2015, and the median follow-up duration was 37 months （range,4-74 months）. During the follow-up of 121 patients, distant metastasis developed in 19, locoregional recurrence in 7, both distant metastasis and locoregional recurrence in 3 and 12 died. The spearman correlation test revealed that SUVmax at the primary tumor （SUVmax-P） positively correlated with leukocytes （P=0.025）, neutrophils （P=0.009） and monocytes （P=0.043）. SUVmax at regional lymph nodes （SUVmax-N） was significantly associated with monocytes （P=0.024）. Higher T stage was significantly associated with increased SUVmax-P （r=0.526, P＜0.001）. Similarly, N stage positively correlated with SUVmax-N （r=0.622, P＜0.001）. Kaplan-Meier analysis showed that higher SUVmax at regional lymph nodes （SUVmax-N>10.15） significantly predicted poorer progression-free survival （3-year PFS rates 62.4% vs 86.4%, P=0.004） and distant metastasis-free survival （3-year DMFS rates 70.1% vs 89.2%, P=0.003）. In addition, compared with lower neutrophils （≤5.18×109/L）, higher neutrophils （>5.18×109/L） was significantly associated with poorer progression-free survival （3-year PFS rates 53.1% vs 85.7%, P=0.001）, distant metastasis-free survival （3-year DMFS rates 67.0% vs 86.8%, P=0.013） and locoregional recurrence-free survival （3-year LRFS rates82.4%vs 98.8%,P＜0.001）. As multivariate Cox regression analysis shows, higher values of SUVmax-N retained independent prognostic significance for poorer progression-free survival （Hazard Ratio:2.572,95%CI:1.121-5.898, P=0.026） and distant metastasis-free survival （Hazard Ratio:3.065,95%CI:1.145-8.201, P=0.026）. Neutrophils were independent predictive factors for progression-free survival （Hazard Ratio:3.684,95%CI:1.114-12.181, P=0.033） and distant metastasis-free survival （Hazard Ratio:2.888,95%CI:1.093-7.634, P=0.032）. Furthermore, when we stratified patients by both SUVmax-N and neutrophils, we found that patients with lower levels of both SUVmax-N and neutrophils （SUVmax-N<10.15 and neutrophils≤5.18×109/L） had significantly better prognosis in progression-free survival （3-year PFS rates 96.4% vs 58.5%, P＜0.001）, overall survival （3-year OS rates 95.7% vs 81.1%, P=0.044）, distant metastasis-free survival （3- year DMFS rates 96.4% vs 67.0%, P＜0.001） and locoregional recurrence-free survival （3- year LRFS rates 100% vs 90.2%, P=0.036） than those with SUVmax-N>10.15 or neutrophils>5.18 × 109/L.ConclusionsIn conclusion,¹⁸F-FDG PET maximum standardized uptake values （SUVmax） may be significantly associated with TNM stage and inflammatory factors in NPC. Both SUVmax at regional lymph nodes （SUVmax-N） and neutrophils were independent prognostic indicators for progression-free survival and distant metastasis-free survival. Combined assessment of SUVmax at regional lymph nodes （SUVmax-N） and neutrophils may lead to refinement of risk stratification and individual treatment in NPC.