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1.  Elevated expressions of survivin and VEGF protein are strong independent predictors of survival in advanced nasopharyngeal carcinoma 
Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China. The China 1992 TNM staging system has been widely used for prognosis prediction of NPC patients in China. Although NPC patients can be classified according to their clinical stage in this system, their prognosis may vary significantly.
280 cases of NPC with clinical follow-up data were collected and expressions of survivin and VEGF in tumor tissues were investigated by immunohistochemistry (IHC). Apoptosis index (AI) in 100 cases of NPC was detected by the TUNEL method.
Expression of survivin and VEGF were significantly associated with TNM stage, T-stage and metastasis of NPC. The patients with survivin and VEGF over-expression presented lower 5-year survival rate, as compared to those of low-expression (42.32% vs. 70.54%, 40.1% vs. 67.8%, respectively, P < 0.05), especially in advanced stage patients (36.51% vs. 73.41%, 35.03% vs. 65.22%, respectively, P < 0.05). The 5-year survival rate in NPC patients with survivin and VEGF dual over-expression was significantly lower than that of patients with dual low-expression (18.22% vs. 73.54%, respectively; P = 0.0003). Multivariate analysis indicated that both survivin and VEGF over-expression in NPC tumor tissues were strong independent factors of poor prognosis in NPC patients. The mean AI in the 39 survivin low-expression cases was 144.7 ± 39.9, which was significantly higher than that in 61 survivin over-expression cases (111.6 ± 39.8) (T test, P < 0.05).
Survivin and VEGF over-expression are independent prognostic factors for the patients with NPC. These results also suggest that tumor survivin and VEGF expressions are valuable prognostic markers for prognosis prediction in NPC patients.
PMCID: PMC2254380  PMID: 18171482
2.  Promising treatment outcomes of intensity-modulated radiation therapy for nasopharyngeal carcinoma patients with N0 disease according to the seventh edition of the AJCC staging system 
BMC Cancer  2012;12:68.
Intensity-modulated radiation therapy (IMRT) provides excellent locoregional control for nasopharyngeal carcinoma (NPC), and has gradually replaced two-dimensional conventional radiotherapy as the first-line radiotherapy technique. Furthermore, in the new seventh edition of the American Joint Committee on Cancer (AJCC) staging system, retropharyngeal lymph nodes were upgraded from N0 to N1 disease as a result of their negative impact on the distant metastasis-free survival (DMFS) rates of NPC. This retrospective study was conducted in order to review the treatment outcomes and patterns of failure in NPC patients with N0 disease after IMRT in order to effectively guide treatment in the future.
We retrospectively reviewed data from 506 biopsy-proven nonmetastatic NPC patients. There were 191 patients with negative cervical lymph node involvement. According to the seventh edition of the American Joint Committee on Cancer (AJCC) staging system, 110 patients (21.7%) were staged with N0 disease, and 81 patients (16.0%) were reclassified with N1 disease due to the presence of RLN metastasis. All patients received IMRT as the primary treatment.
In patients with negative cervical lymph node involvement, distant metastasis-free survival (DMFS) was significantly higher in patients without retropharyngeal lymph node (RLN) metastasis than those with RLN metastasis (95.9% vs. 88.1% respectively, P = 0.04). For N0 disease, the 5-year overall survival (OS), local relapse-free survival (LRFS), nodal relapse-free survival (NRFS) and DMFS rates were 93.8%, 97.1%, 99.1% and 95.9%, respectively. For T1N0, T2N0, T3N0 and T4N0, OS was 97.8%, 100%, 93.8% and 76.9%, LRFS was 100%, 92.9%, 100% and 88.9% and DMFS was 96.6%, 90.9%, 100% and 93.3%, respectively. OS and LRFS were higher in T1-3 N0 patients than T4N0 patients (P < 0.01 and P = 0.01, respectively).
The seventh edition of the AJCC N-staging system improves prognostic accuracy by upgrading RLN metastasis to N1 disease. IMRT produces excellent survival rates in T1-3 N0 disease; however, T4N0 disease remains a challenge and additional improvements are required to achieve a favorable prognosis for these NPC patients.
PMCID: PMC3332280  PMID: 22336097
3.  Involvement of both Cervical Lymph Nodes and Retropharyngeal Lymph Nodes has prognostic value for N1 patients with Nasopharyngeal Carcinoma 
The N1 definition of 2010 UICC/AJCC staging system for nasopharyngeal carcinoma (NPC) covers quite a large range of nodal pattern. The objective of this research is to investigate prognostic value of lymph nodes related factors including involvement of both cervical lymph nodes (CLNs) and retropharyngeal lymph nodes (RLNs) or not, size and number of cervical lymph nodes (CLNs) in N1 patients with NPC.
142 newly diagnosed non-metastatic N1 patients with NPC, staged according to the 2010 AJCC staging system for NPC were retrospectively enrolled. All patients had undergone contrast-enhanced magnetic resonance imaging (MRI), and received radiotherapy, with or without chemotherapy as their primary treatment.
The median follow-up was 48 months. The 5-year local recurrence-free survival (LFS), nodal recurrence-free survival (NFS), local-regional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) of the whole group were 82.3%, 83.0%, 81.0%, 82.1%, 75.3% and 89.8%, respectively. In univariate analysis, patients with both CLNs and RLNs involvement showed a significant lower DMFS, PFS and LRFS than the rest patients (p = 0.004 p = 0.003 and p = 0.034, respectively). Neither size nor number of CLNs affected the survival. In multivariate analysis, involvement of both CLNs and RLNs was an independent prognostic factor for DMFS and PFS (p = 0.019, p = 0.019), but there was no enough evidence confirming its prognostic value for LRFS (p = 0.051).
For N1 patients with NPC, involvement of both RLNs and CLNs may be a potentially prognostic factor for distant metastasis and disease progression. The N stage for N1 patients with involvement of both cervical lymph nodes and retropharyngeal lymph nodes might need to be deliberated.
PMCID: PMC3996203  PMID: 24393418
Nasopharyngeal carcinoma; Lymph nodes; Prognosis
4.  Clinical application of tumor volume in advanced nasopharyngeal carcinoma to predict outcome 
Current staging systems have limited ability to adjust optimal therapy in advanced nasopharyngeal carcinoma (NPC). This study aimed to delineate the correlation between tumor volume, treatment outcome and chemotherapy cycles in advanced NPC.
A retrospective review of 110 patients with stage III-IV NPC was performed. All patients were treated first with neoadjuvant chemotherapy, then concurrent chemoradiation, and followed by adjuvant chemotherapy as being the definitive therapy. Gross tumor volume of primary tumor plus retropharyngeal nodes (GTVprn) was calculated to be an index of treatment outcome.
GTVprn had a close relationship with survival and recurrence in advanced NPC. Large GTVprn (≧13 ml) was associated with a significantly poorer local control, lower distant metastasis-free rate, and poorer survival. In patients with GTVprn ≧ 13 ml, overall survival was better after ≧4 cycles of chemotherapy than after less than 4 cycles.
The incorporation of GTVprn can provide more information to adjust treatment strategy.
PMCID: PMC2842277  PMID: 20222940
5.  Treatment outcomes for different subgroups of nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy 
Chinese Journal of Cancer  2011;30(8):565-573.
Although many studies have investigated intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC), sample sizes in the reported studies are usually small and different in outcomes in different T and N subgroups are seldom analyzed. Herein, we evaluated the outcomes of NPC patients treated with IMRT and further explored treatment strategy to improve such outcome. We collected clinical data of 865 NPC patients treated with IMRT alone or in combination with chemotherapy, and classified all cases into the following prognostic categories according to different TNM stages: early stage group (T1–2N0–1M0), advanced local disease group (T3–4N0–1M0), advanced nodal disease group (T1–2N2–3M0), and advanced locoregional disease group (T3–4N2–3M0). The 5-year overall survival (OS), local relapse-free survival (LRFS), and distant metastases-free survival (DMFS) were 83.0%, 90.4%, and 84.0% respectively. The early disease group had the lowest treatment failure rate, with a 5-year OS of 95.6%. The advanced local disease group and advanced nodal disease group had similar failure pattern and treatment outcomes as well as similar hazard ratios for death (4.230 and 4.625, respectively). The advanced locoregional disease group had the highest incidence of relapse and death, with a 5-year DMFS and OS of 62.3% and 62.2%, respectively, and a hazard ratio for death of 10.402. Comparing with IMRT alone, IMRT in combination with chemotherapy provided no significant benefit to locoregionally advanced NPC. Our results suggest that the decision of treatment strategy for NPC patients should consider combinations of T and N stages, and that IMRT alone for early stage NPC patients can produce satisfactory results. However, for advanced local, nodal, and locoregional disease groups, a combination of chemotherapy and radiotherapy is recommended.
PMCID: PMC4013407  PMID: 21801605
Nasopharyngeal carcinoma; intensity-modulated radiation therapy; stratification treatment
6.  Randomized study of sinusoidal chronomodulated versus flat intermittent induction chemotherapy with cisplatin and 5-fluorouracil followed by traditional radiotherapy for locoregionally advanced nasopharyngeal carcinoma 
Chinese Journal of Cancer  2013;32(9):502-511.
Neoadjuvant chemotherapy plus radiotherapy is the most common treatment regimen for advanced nasopharyngeal carcinoma (NPC). Whether chronomodulated infusion of chemotherapy can reduce its toxicity is unclear. This study aimed to evaluate the toxic and therapeutic effects of sinusoidal chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) and 5-fluorouracil (5-FU) followed by radiotherapy in patients with locoregionally advanced NPC. Patients with biopsy-diagnosed untreated stages III and IV NPC (according to the 2002 UICC staging system) were randomized to undergo 2 cycles of sinusoidal chronomodulated infusion (Arm A) or flat intermittent constant rate infusion (Arm B) of DDP and 5-FU followed by radical radiotherapy. Using a “MELODIE” multi-channel programmed pump, the patients were given 12-hour continuous infusions of DDP (20 mg/m2) and 5-FU (750 mg/m2) for 5 days, repeated every 3 weeks for 2 cycles. DDP was administered from 10:00 am to 10:00 pm, and 5-FU was administered from 10:00 pm to 10:00 am each day. Chronomodulated infusion was performed in Arm A, with the peak deliveries of 5-FU at 4:00 am and DDP at 4:00 pm. The patients in Arm B underwent a constant rate of infusion. Radiotherapy was initiated in the fifth week, and both arms were treated with the same radiotherapy techniques and dose fractions. Between June 2004 and June 2006, 125 patients were registered, and 124 were eligible for analysis of response and toxicity. The major toxicity observed during neoadjuvant chemotherapy was neutropenia. The incidence of acute toxicity was similar in both arms. During radiotherapy, the incidence of stomatitis was significantly lower in Arm A than in Arm B (38.1% vs. 59.0%, P = 0.020). No significant differences were observed for other toxicities. The 1-, 3-, and 5-year overall survival rates were 88.9%, 82.4%, and 74.8% for Arm A and 91.8%, 90.2%, and 82.1% for Arm B. The 1-, 3-, and 5-year progression-free survival rates were 91.7%, 88.1%, and 85.2% for Arm A and 100%, 94.5%, and 86.9% for Arm B. The 1-, 3-, and 5-year distant metastasis-free survival rates were 82.5%, 79.1%, and 79.1% for Arm A and 90.2%, 85.2%, and 81.7% for Arm B. Chronochemotherapy significantly reduced stomatitis but was not superior to standard chemotherapy in terms of hematologic toxicities and therapeutic response.
PMCID: PMC3845560  PMID: 23816561
Chronochemotherapy; cisplatin; 5-fluorouracil; nasopharyngeal carcinoma; radiotherapy
7.  Role of chemotherapy in stage IIb nasopharyngeal carcinoma 
Chinese Journal of Cancer  2012;31(12):573-578.
The efficacy of neoadjuvant chemotherapy and adjuvant chemotherapy on stage IIb nasopharyngeal carcinoma (NPC) remains unclear. Conventional two-dimensional radiotherapy combined with concurrent chemotherapy can improve the overall survival, progression-free survival, recurrence-free survival, and distant metastasis-free survival of patients with stage IIb NPC. Intensity-modulated radiotherapy without concurrent chemotherapy also provides good outcomes for patients with stage IIb NPC. This article summarizes the features of stage IIb NPC and reviews the role of chemotherapy in this subgroup of NPC.
PMCID: PMC3777455  PMID: 22776232
Nasopharyngeal carcinoma; stage IIb; chemotherapy
8.  Evaluation of the new AJCC staging system for resectable hepatocellular carcinoma 
The aim of this study was to assess the validity of the 7th edition of the American Joint Committee on Cancer (AJCC) TNM system (TNM-7) for patients undergoing hepatectomy for hepatocellular carcinoma (HCC).
Partial hepatectomies performed for 879 patients from 1993 to 2005 were retrospectively reviewed. Clinicopathological factors, surgical outcome, overall survival (OS), and disease-free survival (DFS) were analyzed to evaluate the predictive value of the TNM-7 staging system.
According to the TNM-7 system, differences in five-year survival between stages I, II, and III were statistically significant. Subgroup analysis of stage III patients revealed that the difference between stages II and IIIA was not significant (OS, p = 0.246; DFS, p = 0.105). Further stratification of stages IIIA, IIIB and IIIC also did not reveal significant differences. Cox proportional hazard models of stage III analyses identified additional clinicopathological factors affecting patient survival: lack of tumor encapsulation, aspartate aminotransferase (AST) values > 68 U/L, and blood loss > 500 mL affected DFS whereas lack of tumor encapsulation, AST values > 68 U/L, blood loss > 500 mL, and serum α-fetoprotein (AFP) values > 200 ng/mL were independent factors impairing OS. Stage III factors including tumor thrombus, satellite lesions, and tumor rupture did not appear to influence survival in the stage III subgroup.
In terms of 5-year survival rates, the TNM-7 system is capable of stratifying post-hepatectomy HCC patients into stages I, II, and III but is unable to stratify stage III patients into stages IIIA, IIIB and IIIC. Lack of tumor encapsulation, AST values > 68 U/L, blood loss > 500 mL, and AFP values > 200 ng/mL are independent prognostic factors affecting long-term survival.
PMCID: PMC3200158  PMID: 21958080
American Joint Committee on Cancer; Tumor encapsulation; Hepatocellular carcinoma; Partial hepatectomy; TNM-7
9.  Comparing treatment outcomes of different chemotherapy sequences during intensity modulated radiotherapy for advanced N-stage nasopharyngeal carcinoma patients 
N-stage is related to distant metastasis of nasopharyngeal carcinoma (NPC) patients. We performed this study to compare the efficacy of different chemotherapy sequences in advanced N-stage (N2 and N3) NPC patients treated with intensity modulated radiotherapy (IMRT).
From 2001 to 2008, 198 advanced N-stage NPC patients were retrospectively analyzed. Thirty-three patients received IMRT alone. Concurrent chemoradiotherapy (CCRT) was delivered to 72 patients, neoadjuvant chemotherapy (NACT) + CCRT to 82 patients and CCRT + adjuvant chemotherapy (AC) to 11 patients.
The 5-year overall survival rate, recurrence-free survival rate, distant metastasis-free survival rate and progress-free survival rate were 47.7% and 73.1%(p<0.001), 74.5% and 91.3% (p = 0.004), 49.2% and 68.5% (p = 0.018), 37.5% and 63.8% (p<0.001) in IMRT alone and chemoradiotherapy group. Subgroup analyses indicated that there were no significant differences among the survival curves of CCRT, NACT + CCRT and CCRT + AC groups. The survival benefit mainly came from CCRT. However, there was only an improvement attendency in distant metastasis-free survival rate of CCRT group (p = 0.107) when compared with RT alone group, and NACT + CCRT could significantly improve distant metastasis-free survival (p = 0.017).
For advanced N-stage NPC patients, NACT + CCRT might be a reasonable treatment strategy.
PMCID: PMC3842780  PMID: 24219818
Nasopharyngeal carcinoma; Advanced N-stage; Intensity-modulated radiotherapy; Chemotherapy; Prognosis
10.  Imaging of nasopharyngeal inflammatory pseudotumours: differential from nasopharyngeal carcinoma 
The British Journal of Radiology  2010;83(985):8-16.
The purpose of this study was to describe the MRI findings of inflammatory pseudotumours (IPTs) involving the nasopharynx and to differentiate IPTs from nasopharyngeal carcinoma (NPC). The medical records and imaging studies of 7 patients (6 men, 1 woman; age range, 32–71 years; mean age, 52.4±18 years) with IPT involving the nasopharynx were reviewed retrospectively. The MRI findings were compared with those of seven patients with advanced NPC with skull base invasion. All patients with IPT involving the nasopharynx presented with single or multiple cranial neuropathies; six reported pain; and four patients had a recent history of otitis media. Three were initially misdiagnosed as having NPC according to MRI findings, and all underwent nasopharyngeal biopsy to exclude malignancy. 7/7 (100%) patients received systemic corticosteroid treatment; 7/7 (100%) showed initial rapid resolution of clinical symptoms or radiographical findings; 3/7 (42.9%) had resolution of all signs and symptoms; 3/7 (42.9%) still have limited residual symptoms; and 1/7 (14.3%) suffered recurrence 3 years after remission. The characteristic MR findings of IPT include an infiltrative growth pattern, minimal to mild mass effect, hypointensity on T2 weighted images, and moderate homogeneous enhancement after contrast administration. Intact nasopharyngeal mucosa, internal carotid artery encasement and narrowing, extensive pachymeningeal thickening and a relative paucity of associated neck lymphadenopathy are additional MR findings that favour the diagnosis of IPT rather than NPC. In conclusion, IPT involving the nasopharynx has characteristic MR findings which, together with clinical and laboratory presentations, are helpful in differentiating IPT from malignant tumours, especially NPC.
PMCID: PMC3487260  PMID: 19470567
11.  A Large Cohort Study Reveals the Association of Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio with Favorable Prognosis in Nasopharyngeal Carcinoma 
PLoS ONE  2013;8(12):e83069.
Nasopharyngeal carcinoma (NPC) is an endemic neoplasm in southern China. Although NPC sufferers are sensitive to radiotherapy, 20–30% of patients finally progress with recurrence and metastases. Elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with favorable prognosis in some hematology malignancies, but has not been studied in NPC. The aim of this study was to evaluate whether LMR could predict the prognosis of NPC patients.
A retrospective cohort of 1,547 non-metastatic NPC patients was recruited between January 2005 and June 2008. The counts for peripheral lymphocyte and monocyte were retrieved, and the LMR was calculated. Receiver operating characteristic curve analysis, univariate and multivariate COX proportional hazards analyses were applied to evaluate the associations of LMR with overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco-regional recurrence-free survival (LRRFS), respectively.
Univariate analysis revealed that higher LMR level (≥5.220) was significantly associated with superior OS, DFS and DMFS (P values <0.001). The higher lymphocyte count (≥2.145×109/L) was significantly associated with better OS (P = 0.002) and DMFS (P = 0.031), respectively, while the lower monocyte count (<0.475×109/L) was associated with better OS (P = 0.012), DFS (P = 0.011) and DMFS (P = 0.003), respectively. Multivariate Cox proportional hazard analysis showed that higher LMR level was a significantly independent predictor for superior OS (hazard ratio or HR  = 0.558, 95% confidence interval or 95% CI  = 0.417–0.748; P<0.001), DFS (HR  = 0.669, 95% CI  = 0.535–0.838; P<0.001) and DMFS (HR = 0.543, 95% CI  = 0.403–0.732; P<0.001), respectively. The advanced T and N stages were also independent indicators for worse OS, DFS, and DMFS, except that T stage showed borderline statistical significance for DFS (P = 0.053) and DMFS (P = 0.080).
The elevated pretreatment peripheral LMR level was a significant favorable factor for NPC prognosis and this easily accessed variable may serve as a potent marker to predict the outcomes of NPC patients.
PMCID: PMC3873908  PMID: 24386144
12.  Evaluation of the 7th AJCC TNM Staging System in Point of Lymph Node Classification 
Journal of Gastric Cancer  2011;11(2):94-100.
The 7th AJCC tumor node metastasis (TNM) staging system modified the classification of the lymph node metastasis widely compared to the 6th edition. To evaluate the prognostic predictability of the new TNM staging system, we analyzed the survival rate of the gastric cancer patients assessed by the 7th staging system.
Materials and Methods
Among 2,083 patients who underwent resection for gastric cancer at the department of surgery, Hanyang Medical Center from July 1992 to December 2009, This study retrospectively reviewed 5-year survival rate (5YSR) of 624 patients (TanyN3M0: 464 patients, TanyNanyM1: 160 patients) focusing on the number of metastatic lymph node and distant metastasis. We evaluated the applicability of the new staging system.
There were no significant differences in 5YSR between stage IIIC with more than 29 metastatic lymph nodes and stage IV (P=0.053). No significant differences were observed between stage IIIB with more than 28 metastatic lymph nodes and stage IV (P=0.093). Distinct survival differences were present between patients who were categorized as TanyN3M0 with 7 to 32 metastatic lymph nodes and stage IV. But patients with more than 33 metastatic lymph nodes did not show any significant differences compared to stage IV (P=0.055). Among patients with TanyN3M0, statistical significances were seen between patients with 7 to 30 metastatic lymph nodes and those with more than 31 metastatic lymph nodes.
In the new staging system, modifications of N classification is mandatory to improve prognostic prediction. Further study involving a greater number of cases is required to demonstrate the most appropriate cutoffs for N classification.
PMCID: PMC3204492  PMID: 22076209
Stomach neoplasms; Neoplasm staging; Lymph nodes
13.  Immunohistochemical consistency between primary tumors and lymph node metastases of gastric neuroendocrine carcinoma 
Gastric neuroendocrine carcinoma (G-NEC) is a rare, highly malignant tumor that exhibits aggressive growth leading to vascular invasion, distant metastasis and extremely poor prognosis. We studied the clinicopathological findings of seven patients at our institute to better under this disease.
Seven cases of G-NEC were identified among 1,027 cases of gastric carcinoma that underwent gastrectomy at Kansai Rousai Hospital between 2002 and 2010. We studied the pathological and immunohistochemical features of gastric neuroendocrine carcinomas at both the primary site and metastatic lymph nodes.
The mean patient age was 73 years (range 63 to 86 years). There were no females in this series. The final staging was Stage I in one case, Stage II in two, Stage III in two and Stage IV in two. A total of 31 metastatic lymph nodes were found in these patients. This study revealed that the ratio of neuroendocrine cells was similar between the primary and metastatic sites, which tended to show the same expression patterns of neuroendocrine markers.
Metastatic lymph nodes showed heterogeneous immunohistochemical expression patterns similar to the primary sites. G-NEC is far advanced at diagnosis and rapidly reaches the lymph nodes retaining its heterogeneity, carrying a worse prognosis than common gastric cancer.
Mini abstract
G-NEC grows rapidly and metastasizes to the lymph nodes, retaining its pathological and immunohistochemical heterogeneity even at the metastatic sites.
PMCID: PMC3475116  PMID: 22726317
Ki67; Immunohistochemistry; Heterogeneity
14.  Prognostic significance of maximum primary tumor diameter in nasopharyngeal carcinoma 
BMC Cancer  2013;13:260.
To evaluate the prognostic value of maximum primary tumor diameter (MPTD) in nasopharyngeal carcinoma (NPC).
Three hundred and thirty-three consecutive, newly-diagnosed NPC patients were retrospectively reviewed. Kaplan-Meier analysis and the log-rank test were used to estimate overall survival (OS), failure-free survival (FFS), distant metastasis-free survival (DMFS) and local relapse-free survival (LRFS). Cox proportional hazards regression analysis was used to assess the prognostic value of MPTD.
Median follow-up was 66 months (range, 2–82 months). Median MPTD in stage T1, T2, T3 and T4 was 27.9, 37.5, 45.0 and 61.3 mm, respectively. The proportion of T1 patients with a MPTD ≤ 30 mm was 62.3%; 72% and 62.9% of T2 and T3 patients had a MPTD > 30–50 mm, and 83.5% of T4 patients had a MPTD > 50 mm. For patients with a MPTD ≤ 30 mm, > 30–50 mm and > 50 mm, the 5-year OS, FFS, DMFS and LRFS rates were 85.2%, 74.2% and 56.3% (P < 0.001); 87%, 80.7% and 62.8% (P < 0.001); 88.7%, 86.4% and 72.5% (P = 0.003); and 98.2%, 93.2% and 86.3% (P = 0.012), respectively. In multivariate analysis, MPTD was a prognostic factor for OS, FFS and DMFS, and the only independent prognostic factor for LRFS. For T3-T4 patients with a MPTD ≤ 50 mm and > 50 mm, the 5-year OS, FFS and DMFS rates were 70.4% vs. 58.4% (P = 0.010), 77.5% vs. 65.2% (P = 0.013) and 83.6% vs. 73.6% (P = 0.047), respectively. In patients with a MPTD ≤ 30 mm, 5-year LRFS in T1, T2, T3 and T4 was 100%, 100%, 88.9% and 100% (P = 0.172).
Our data suggest that MPTD is an independent prognostic factor in NPC, and incorporation of MPTD might lead to a further refinement of T staging.
PMCID: PMC3668272  PMID: 23710879
Nasopharyngeal carcinoma; Magnetic resonance imaging; Maximum primary tumor diameter; TNM stage; Survival
15.  Radiological, pathological and DNA remission in recurrent metastatic nasopharyngeal carcinoma 
BMC Cancer  2006;6:259.
Circulating plasma Epstein Barr Virus DNA (EBV-DNA) is a sensitive and specific marker of nasopharyngeal carcinoma (NPC). The mainstay of treatment of metastatic NPC is systemic chemotherapy and resection for solitary metastasis. Despite high response rate to chemotherapy, complete remission is uncommonly seen.
Case Presentation
We report a case of recurrent metastatic NPC in a 43-year-old man, who achieved complete remission three times with chemotherapy and surgery. Serial plasma EBV-DNA levels were measured during the course of disease. The patient had three episodes of recurrences of NPC manifested as distant metastasis. Both time, rise in the plasma EBV-DNA level preceded detection of recurrences by imaging. Following systemic chemotherapy, he achieved complete remission each time, of which was confirmed by 18-flourodeoxyglucose positron emission tomography and hepatectomy pathology. The plasma EBV-DNA level dropped to zero copy/ml at the time of each remission.
This case highlights the high chemosensitivity of NPC by illustrating a rare occurrence of complete response of metastatic NPC to chemotherapy. This case also underscores the usefulness of EBV-DNA as a useful tool in monitoring NPC by its ability to detect early recurrence and excellent correlation with treatment response.
PMCID: PMC1634867  PMID: 17076893
16.  T4-Locally Advanced Nasopharyngeal Carcinoma: Prognostic Influence of Cranial Nerve Involvement in Different Radiotherapy Techniques 
The Scientific World Journal  2013;2013:439073.
Background. Cranial nerve involvement at disease presentation of nasopharyngeal carcinoma was not uncommon. We investigated the prognosis of patients with T4-locally advanced NPC, with or without cranial nerve involvement, and compared the outcome of patients treated using different radiotherapy techniques. Methods. In this retrospective study, 83 T4-locally advanced NPC patients were diagnosed according to the seventh edition of the American Joint Committee on Cancer staging system. All patients were treated using three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiation therapy (IMRT). The survival rate was analyzed using the Kaplan-Meier method. Results. The 5-year overall, locoregional-free, and disease-free survival rates of patients treated using IMRT were 88.9%, 75.2%, and 69.2%, respectively. The outcome in these patients was significantly better than that in patients treated using 3D-CRT, with survival rates of 58.2%, 54.4%, and 47.2%, respectively. There was no significant difference in the 5-year overall, locoregional-free, and disease-free survival rates of the patients with (64.2%, 60.5%, and 53.5%, resp.) and without (76.9%, 63.6%, and 57.6%, resp.) cranial nerve involvement. Conclusion. Locally advanced NPC patients treated using IMRT had significantly better outcomes than patients treated using 3D-CRT. Our results showed that the outcome of T4 NPC patients with or without cranial nerve involvement was not different.
PMCID: PMC3872400  PMID: 24385882
17.  Effectiveness and Toxicities of Intensity-Modulated Radiation Therapy for Patients with T4 Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(3):e91362.
To evaluate the effectiveness and toxicities in T4 nasopharyngeal carcinoma (NPC) using intensity-modulated radiotherapy (IMRT) combined with chemotherapy.
This is a retrospective analysis of 81 patients treated with intensity-modulated radiotherapy (IMRT). All the primary tumors were attributed to T4 stage according to the AJCC2010 staging system. And the distribution of disease by N stage was N0 in 13.6%, N1 in 30.9%, N2 in 37%, and N3 in 18.5%. Cisplatin-based chemotherapy was offered to all patients. Radiotherapy-related toxicities were graded according to the Acute and the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group (RTOG) scoring criteria. Chemotherapy-related toxicities were graded by National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0. Prognostic factors were assessed by univariate analysis.
With a median follow-up of 37 months, 12 patients experienced local regional failure and total distant metastasis occurred in 18 patients, representing the major mode of failure. Ten patients died. Among them, 70% died of distant metastasis. The 3-year actuarial rates of local failure–free survival (LFFS), regional failure–free survival (RFFS), distant failure–free survival (DFFS), overall survival (OS), and progression–free survival (PFS) were 83.8%, 97.4%, 81.3%, 90%, and 69.7%, respectively. Acute and late toxicities were mild or moderate.
IMRT provides excellent local-regional control for T4 NPC. Distant metastasis remains the major cause of treatment failure. Further explorations of the sequence and regimen of systemic therapy are needed in the future.
PMCID: PMC3946722  PMID: 24608637
18.  Detection of Stage I nasopharyngeal carcinoma by Serologic screening and clinical examination 
Chinese Journal of Cancer  2011;30(2):120-123.
In a prospective study, 42 048 adults residing in Zhongshan City, Guangdong, China, were followed for 16 years, and 171 of them developed nasopharyngeal carcinoma (NPC). Although Epstein-Barr virus (EBV) antibody levels of the cohort fluctuated, the antibody levels of 93% of the patients with NPC were raised and maintained at high levels for up to 10 years prior to diagnosis. This suggests that the Serologic window affords an opportunity to monitor tumor progression during the preclinical stage of NPC development, facilitating early NPC detection. We reviewed the clinical records of the 171 patients with NPC in the prospective study to assess the efficacy of early NPC detection by Serologic screening and clinical examination. Of the 171 patients, 51 had Stage I tumor (44 were among the 73 patients detected by clinical examination and 7 were among the 98 patients presented to outpatient department). Initial Serologic screening predicted 58 (95.1%) of the 61 patients detected within 2 years. The risk of the screened population (58/3093) raised 13 times relative to cohort (61/42 048) during this period. Clinical examination detected all the 58 predicted cases, and 35 (60.3%) of which were diagnosed with Stage I tumor. The Serologic prediction rate fell to 33.6% (37/110) 2 to 16 years after screening. The proportion of cases detected by clinical examination fell to 40.5% (15/37). The proportion of Stage I tumors among the cases detected by clinical examination during both periods remained at about 60%. We concluded that early detection of NPC can be accomplished by repeated Serologic screening to maintain high prediction rates and by promptly examining screened subjects to detect tumors before the symptoms develop.
PMCID: PMC4013341  PMID: 21272444
NPC; localized tumor; cancer screening; preclinical cancer
19.  Brain Metastasis of Nasopharyngeal Carcinoma: A Case Report and Literature Review 
Case Reports in Medicine  2012;2012:405917.
Central nervous system metastases from nasopharyngeal carcinoma (NPC) are uncommon. The patient presented was diagnosed with aggressive advanced NPC resistant to treatment and complicated by a solitary brain metastasis. A PubMed database search was conducted to review the existing literature regarding brain metastases of NPC, using the search terms “nasopharyngeal neoplasia,” “nasopharyngeal carcinoma,” “nasopharynx,” “radiotherapy,” “central nervous system,” and “brain” in section of “Title/Abstract.” The articles were first evaluated by title and then by abstract, and thereafter appropriate manuscripts were evaluated by full text. References of the published papers were also reviewed.
PMCID: PMC3295537  PMID: 22454646
20.  American Joint Committee on Cancer T Category for Eyelid Sebaceous Carcinoma Correlates with Nodal Metastasis and Survival 
Ophthalmology  2012;119(5):10.1016/j.ophtha.2011.11.006.
To determine whether T category of the American Joint Committee on Cancer (AJCC) TNM staging system for eyelid carcinoma, 7th edition, correlates with lymph node metastasis, distant metastasis, and survival in patients with sebaceous carcinoma of the eyelid.
Retrospective, cohort study.
Fifty consecutive patients treated by 1 author (BE) for eyelid sebaceous carcinoma between May 1999 and August 2010.
Each tumor was staged according to the AJCC 7th edition TNM criteria. The Kaplan-Meier method was used to determine associations between disease-specific survival and (1) T category at presentation, (2) lymph node metastasis, and (3) distant metastasis.
Main Outcome Measures
T category at presentation, nodal metastasis, survival.
The study included 37 women and 13 men (median age, 68.5 years; range, 44–86 years). Forty-four patients were white, 5 were Hispanic, and 1 was Asian. TNM designations were TXN0M0, 7 patients; T1N0M0, 4 patients; T2aN0M0, 12 patients; T2bN0M0, 11 patients; T2bN1M0, 2 patients; T2bN1M1, 1 patient; T3aN0M0, 2 patients; T3aN1M0, 5 patients; T3bN0M0, 1 patient; T3bN1M0, 1 patient; T3bN0M1, 2 patients; T4N0M0, 1 patient; and T4N0M1, 1 patient. T category at presentation was significantly associated with lymph node metastasis (P = 0.0079). No tumors with T category better than T2b or smaller than 9 mm in greatest dimension were associated with nodal metastasis. Five patients (10%) died of disease during follow-up. Their TNM designations were T2bN1M1, 1 patient; T3bN0M1, 2 patients; T4N0M0, 1 patient; and T4N0M1, 1 patient. No tumors smaller than 12 mm in greatest dimension were associated with distant metastasis or death. T category was significantly associated with disease-specific survival (P = 0.0009). Disease-specific survival was poorer among patients with T category of T3a or worse (P = 0.035).
T category in the 7th edition of the AJCC TNM staging system for eyelid carcinoma correlates with outcomes in patients with sebaceous carcinoma of eyelid. On the basis of the present findings, it seems reasonable to recommend sentinel lymph node biopsy or at least strict regional lymph node surveillance for patients with eyelid sebaceous carcinoma with tumors of T category T2b or worse or 10 mm or more in greatest dimension.
PMCID: PMC3869195  PMID: 22330966
21.  The Impact of Baseline Serum C-Reactive Protein and C-Reactive Protein Kinetics on the Prognosis of Metastatic Nasopharyngeal Carcinoma Patients Treated with Palliative Chemotherapy 
PLoS ONE  2013;8(10):e76958.
The aim of this study was to determine whether baseline C-reactive protein (CRP) levels and CRP kinetics predict the overall survival in metastatic nasopharyngeal carcinoma (mNPC) patients.
A total of 116 mNPC patients from January 2006 to July 2011 were retrospectively reviewed. Serum CRP level was measured at baseline and thereafter at the start of each palliative chemotherapy cycle for all patients.
Patients with higher values of baseline CRP (≥ 3.4 mg/L) had significantly worse survival than those with lower baseline CRP values (< 3.4 mg/L). Patients were divided into four groups according to baseline CRP and CRP kinetics: (1) patients whose CRP < 3.4 mg/L and never elevated during treatment; (2) patients whose CRP < 3.4 mg/L and elevated at least one time during treatment; (3) patients whose CRP ≥ 3.4 mg/L and normalized at least one time during treatment; and (4) patients whose CRP ≥ 3.4 mg/L and never normalized during treatment. The patients were further assigned to non-elevated, elevated, normalized, and non-normalized CRP groups. Overall survival rates were significantly different among the four groups, with three-year survival rates of 68%, 41%, 33%, and 0.03% for non-elevated, elevated, normalized, and non-normalized CRP groups respectively. When compared with the non-elevated group, hazard ratios of death were 1.69, 2.57, and 10.34 in the normalized, elevated, and non-normalized groups (P < 0.001).
Baseline CRP and CRP kinetics may be useful to predict the prognosis of metastatic NPC patients treated with palliative chemotherapy and facilitate individualized treatment. A prospective study to validate this prognostic model is still needed however.
PMCID: PMC3794978  PMID: 24130817
22.  Challenges in the Management of Nasopharyngeal Carcinoma: A Review 
Nasopharyngeal carcinoma (NPC) is a non-lymphomatous, squamous cell carcinoma that occurs in the epithelial lining of the nasopharynx, an area that shows varying degrees of differentiation. Although relatively rare worldwide, NPC has substantial incidence and mortality in populations in Southeast Asia and in people with Southern Chinese ancestry. In Malaysia, NPC is a leading cancer type. In the clinic, NPC presents on a very wide spectrum. Therefore, a high degree of suspicion on the part of the clinician and an increased awareness by the patient is essential for the recognition of an early lesion. Early detection of the cancer is important as it affects the patient’s prognosis and the mode of treatment. Managing patients with NPC is very challenging as patients usually present late when the cancer is already in an advanced stage. Here, we review the challenges in the management of NPC.
PMCID: PMC3216136  PMID: 22135512
nasopharyngeal carcinoma; management; challenges; medical sciences
23.  Locoregional radiotherapy in patients with distant metastases of nasopharyngeal carcinoma at diagnosis 
Chinese Journal of Cancer  2013;32(11):604-613.
Systemic chemotherapy is the basic palliative treatment for metastatic nasopharyngeal carcinoma (NPC); however, it is not known whether locoregional radiotherapy targeting the primary tumor and regional lymph nodes affects the survival of patients with metastatic NPC. Therefore, we aimed to retrospectively evaluate the benefits of locoregional radiotherapy. A total of 408 patients with metastatic NPC were included in this study. The mortality risks of the patients undergoing supportive treatment and those undergoing chemotherapy were compared with that of patients undergoing locoregional radiotherapy delivered alone or in combination with chemotherapy. Univariate and multivariate analyses were conducted. The contributions of independent factors were assessed after adjustment for covariates with significant prognostic associations (P < 0.05). Both locoregional radiotherapy and systemic chemotherapy were identified as significant independent prognostic factors of overall survival (OS). The mortality risk was similar in the group undergoing locoregional radiotherapy alone and the group undergoing systemic chemotherapy alone [multi-adjusted hazard ratio (HR) = 0.9, P = 0.529]; this risk was 60% lower than that of the group undergoing supportive treatment (HR = 0.4, P = 0.004) and 130% higher than that of the group undergoing both systemic chemotherapy and locoregional radiotherapy (HR = 2.3, P < 0.001). In conclusion, locoregional radiotherapy, particularly when combined with systemic chemotherapy, is associated with improved survival of patients with metastatic NPC.
PMCID: PMC3845550  PMID: 24206918
Nasopharyngeal carcinoma; distant metastases; overall survival; radiotherapy; systemic chemotherapy
24.  Validation of bidimensional measurement in nasopharyngeal carcinoma 
Our previous study showed a close relationship between computed tomography (CT)-derived bidimensional measurement of primary tumor and retropharyngeal nodes (BDMprn) and gross tumor volume of primary tumor and retropharyngeal nodes (GTVprn) in nasopharyngeal carcinoma (NPC) and better prognosis for NPC patients with smaller BDMprn. In this study, we report the results on of a study to validate the use of BDM in a separate cohort of NPC patients.
We retrospectively reviewed 103 newly diagnosed NPC cases who were treated with radiotherapy/concurrent chemoradiotherapy (CCRT) or CCRT with adjuvant chemotherapy from 2002 to 2009. We used magnetic resonance imaging (MRI) to measure BDMprn. We calculated overall survival, recurrence-free and distant metastasis-free survival curves and set a BDMprn cut off point to categorize patients into a high- or low-risk group. We then used Cox proportional hazard model to evaluate the prognostic influence of BDMprn after correcting age, gender and chemotherapy status.
After adjusting for age, gender, and chemotherapy status, BDMprn remained an independent prognostic factor for distant metastasis [Hazard ratio (HR) = 1.046; P = 0.042] and overall survival (HR = 1.012; P = 0.012). Patients with BDMprn < 15 cm2 had a greater 3-year overall survival rate than those with BDMprn ≧ 15 cm2 (92.3% vs. 73.7%; P = 0.009). They also had a greater 3-year distant metastasis-free survival (94% vs.75%; P = 0.034).
The predictive ability of BDMprn was validated in a separate NPC cohort. A BDMprn of 15 cm2 can be used to separate NPC patients into high- and low-risk groups and predict survival rates and metastasis potential. It can, therefore, be used as a reference to design clinical trials, predict prognosis, and make treatment decisions.
PMCID: PMC2930639  PMID: 20712871
25.  Long-term outcome and late toxicities of simultaneous integrated boost-intensity modulated radiotherapy in pediatric and adolescent nasopharyngeal carcinoma 
Chinese Journal of Cancer  2013;32(10):525-532.
The application of simultaneous integrated boost-intensity modulated radiotherapy (SIB-IMRT) in pediatric and adolescent nasopharyngeal carcinoma (NPC) is underevaluated. This study aimed to evaluate long-term outcome and late toxicities in pediatric and adolescent NPC after SIB-IMRT combined with chemotherapy. Thirty-four patients (aged 8–20 years) with histologically proven, non-disseminated NPC treated with SIB-IMRT were enrolled in this retrospective study. The disease stage distribution was as follows: stage I, 1 (2.9%); stage III, 14 (41.2%); and stage IV, 19 (55.9%). All patients underwent SIB-IMRT and 30 patients also underwent cisplatin-based chemotherapy. The prescribed dose of IMRT was 64–68 Gy in 29–31 fractions to the nasopharyngeal gross target volume. Within the median follow-up of 52 months (range, 9–111 months), 1 patient (2.9%) experienced local recurrence and 4 (11.8%) developed distant metastasis (to the lung in 3 cases and to multiple organs in 1 case). Four patients (11.8%) died due to recurrence or metastasis. The 5-year locoregional relapse–free survival, distant metastasis–free survival, disease-free survival, and overall survival rates were 97.1%, 88.2%, 85.3%, and 88.2%, respectively. The most common acute toxicities were grades 3–4 hematologic toxicities and stomatitis. Of the 24 patients who survived for more than 2 years, 16 (66.7%) and 15 (62.5%) developed grades 1–2 xerostomia and ototoxicity, respectively. Two patients (8.3%) developed grade 3 ototoxicity; no grade 4 toxicities were observed. SIB-IMRT combined with chemotherapy achieves excellent long-term locoregional control in pediatric and adolescent NPC, with mild incidence of late toxicities. Distant metastasis is the predominant mode of failure.
PMCID: PMC3845542  PMID: 24016394
Pediatric and adolescent; nasopharyngeal carcinoma; SIB-IMRT; outcome; late toxicity

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