Comparison the acute toxicity of two different induction chemotherapy schedules with cisplatin and fluorouracil in nasopharyngeal carcinoma patients.

PURPOSE: To compare the acute toxicity of two different induction chemotherapy (IndCT) regimen followed by the same IMRT in patients with advanced nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: From July 2015 to December 2016, 110 NPC patients with stage III-IV diseases were prospectively randomized to receive either a conventional triweekly cisplatin + 5-fluorouracil (PF) for 3 cycles or weekly P-F for 10 doses, followed by the same IMRT to both arms. The primary endpoints of this study were grade 3/4 and any grade acute toxicities during IndCT period. The secondary endpoints included tumor response and various survivals. RESULTS: Baseline patient characteristics were comparable in both groups. Patients who received weekly P-F experienced significant reduction of grade 3/4 acute toxicities, including neutropenia (12.7% vs. 40.0%, P = 0.0012), anorexia (0% vs. 14.6%, P = 0.0059), mucositis (0% vs. 14.6%, P = 0.0059), and hyponatremia (0% vs. 16.4%, P = 0.0027), compared with the triweekly PF group, resulting in fewer IndCT interruptions (1.8% vs. 16.4%, P = 0.0203), emergency room visits (0% vs. 12.7%, P = 0.0128), and additional hospitalizations (0% vs. 9.1%, P = 0.0568). The acute toxicities during IMRT period were similar. Weekly P-F arm had higher complete response rates (83.6% vs. 61.8%, P = 0.0152) and lower relapse rates (16.4% vs. 33.3%, P = 0.0402) after a median follow-up of 67 months. Kaplan-Meier survival analyses revealed a better trend of locoregional failure-free (P = 0.0892), distant metastasis failure-free (P = 0.0775), and progression-free (P = 0.0709) survivals, favoring the weekly P-F arm. CONCLUSION: IndCT of weekly schedule does reduce acute toxicities without compromised tumor response and survivals.

Comparison of radiotherapy combined with nimotuzumab vs. chemoradiotherapy for locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The present study compared the effectiveness and toxicity of two treatment modalities, namely radiotherapy combined with nimotuzumab (N) and chemoradiotherapy (CRT) in patients with locally recurrent nasopharyngeal carcinoma (LR-NPC). METHODS: Patients with LR-NPC who were treated with radiotherapy were retrospectively enrolled from January 2015 to December 2018. The treatment included radiotherapy combined with N or platinum-based induction chemotherapy and/or concurrent chemotherapy. The comparison of survival and toxicity between the two treatment modalities was evaluated using the log-rank and chi-squared tests. Overall survival (OS) was the primary endpoint. RESULTS: A total of 87 patients were included, of whom 32 and 55 were divided into the N group and the CRT group, respectively. No significant differences were noted in the survival rate between the N and the CRT groups (4-year OS rates, 37.1% vs. 40.7%, respectively; P = 0.735). Mild to moderate acute complications were common during the radiation period and mainly included mucositis and xerostomia. The majority of the acute toxic reactions were tolerated well. A total of 48 patients (55.2%) demonstrated late radiation injuries of grade ≥ 3, including 12 patients (37.5%) in the N group and 36 patients (66.5%) in the CRT group. The CRT group exhibited significantly higher incidence of severe late radiation injuries compared with that of the N group (P = 0.011). CONCLUSION: Radiotherapy combined with N did not appear to enhance treatment efficacy compared with CRT in patients with LR-NPC. However, radiotherapy combined with N may be superior to CRT due to its lower incidence of acute and late toxicities. Further studies are required to confirm the current findings.

Epstein-Barr virus-coded miR-BART13 promotes nasopharyngeal carcinoma cell growth and metastasis via targeting of the NKIRAS2/NF-κB pathway.

Based on analysis of Epstein-Barr virus (EBV) BART microRNA expression profiles, we previously reported that EBV-encoded miR-BART13 is upregulated in nasopharyngeal carcinoma (NPC) plasma specimens. However, the effects and molecular mechanisms of miR-BART13 in NPC remain largely unknown. We found that miR-BART13 was significantly upregulated in NPC tissue specimens. Ectopic expression of miR-BART13 promoted NPC cell proliferation, epithelial mesenchymal transition, and metastasis in vitro, and facilitated xenograft tumor growth and lung metastasis in vivo. Molecularly, NF-κB inhibitor interacting Ras-like 2 (NKIRAS2), a negative regulator of the NF-κB signaling, was identified to be a direct target of miR-BART13 in NPC cells, and NKIRAS2 mRNA and protein expression was inversely correlated with miR-BART13 in NPC tissues, respecitvely. Furthermore, the NF-κB signaling pathway was activated by miR-BART13. By rescued experiments, reconstitution of NKIRAS2 expression abrogated all the phenotypes upregulated by miR-BART13, and attenuated activity of NF-κB signaling pathway activated by miR-BART13 in NPC cells. Our findings indicated the newly identified miR-BART13/NKIRAS2/NF-κB signaling axis may provide further insights into better understanding of NPC initiation and development, and targeting of this pathway could be further studied as a therapeutic strategy for NPC patients.

Systemic immune-inflammation index as a prognostic marker in patients with newly diagnosed metastatic nasopharyngeal carcinoma: a propensity score-matched study.

BACKGROUND: Systemic immune-inflammation index (SII) is significantly associated with poor survival in variety of cancers. However, SII has not yet been investigated in patients with newly diagnosed metastatic nasopharyngeal carcinoma (mNPC). Thus, our aim is to explore the role of SII in metastatic Nasopharyngeal Carcinoma. METHODS: Two hundred and forty-three patients with newly diagnosed mNPC were retrospectively enrolled. The Kaplan-Meier analysis and Cox regression analysis was performed to evaluate the prognostic value of SII in overall survival (OS) and progression-free survival (PFS). Heterogeneity of factors was balanced by using propensity score-matched (PSM) analysis (1:1 for high SII versus low SII). RESULTS: Kaplan-Meier analysis showed that patients with high SII were associated with poor median OS (18.0 vs. 36.0 m, P<0.001) and PFS (10.0 vs. 22.0 m, P<0.001) in mNPC. The Cox regression analysis suggested that high SII was a prognostic factor for OS (HR 1.75, 95% CI: 1.22-2.52, P=0.001) and PFS (HR 1.69, 95% CI: 1.22-2.35, P=0.002). PSM analysis still confirmed that SII was an independent marker for OS (HR 1.86, 95% CI: 1.22-2.83, P=0.004) and PFS (HR 1.84, 95% CI: 1.23-2.77, P=0.003). CONCLUSIONS: SII is an independent prognostic biomarker for poor OS and PFS in patients with newly diagnosed mNPC and might be a promising tool for guiding treatment strategy decisions.

Prognostic nomogram for refining the prognostication of the proposed 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy.

BACKGROUND: The objective of this study was to develop a nomogram for refining prognostication for patients with nondisseminated nasopharyngeal cancer (NPC) staged with the proposed 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system. METHODS: Consecutive patients who had been investigated with magnetic resonance imaging, staged with the proposed 8th edition of the AJCC/UICC staging system, and irradiated with intensity-modulated radiotherapy from June 2005 to December 2010 were analyzed. A cohort of 1197 patients treated at Fujian Provincial Cancer Hospital was used as the training set, and the results were validated with 412 patients from Pamela Youde Nethersole Eastern Hospital. Cox regression analyses were performed to identify significant prognostic factors for developing a nomogram to predict overall survival (OS). The discriminative ability was assessed with the concordance index (c-index). A recursive partitioning algorithm was applied to the survival scores of the combined set to categorize the patients into 3 risk groups. RESULTS: A multivariate analysis showed that age, gross primary tumor volume, and lactate dehydrogenase were independent prognostic factors for OS in addition to the stage group. The OS nomogram based on all these factors had a statistically higher bias-corrected c-index than prognostication based on the stage group alone (0.712 vs 0.622, P <.01). These results were consistent for both the training cohort and the validation cohort. Patients with <135 points were categorized as low-risk, patients with 135 to <160 points were categorized as intermediate-risk, and patients with ≥160 points were categorized as high-risk. Their 5-year OS rates were 92%, 84%, and 58%, respectively. CONCLUSIONS: The proposed nomogram could improve prognostication in comparison with the TNM stage group. This could aid in risk stratification for individual NPC patients. Cancer 2016;122:3307-3315. © 2016 American Cancer Society.

Proposal for the 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy.

BACKGROUND: An accurate staging system is crucial for cancer management. Evaluations for continual suitability and improvement are needed as staging and treatment methods evolve. METHODS: This was a retrospective study of 1609 patients with nasopharyngeal carcinoma investigated by magnetic resonance imaging, staged with the 7th edition of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system, and irradiated by intensity-modulated radiotherapy at 2 centers in Hong Kong and mainland China. RESULTS: Among the patients without other T3/T4 involvement, there were no significant differences in overall survival (OS) between medial pterygoid muscle (MP) ± lateral pterygoid muscle (LP), prevertebral muscle, and parapharyngeal space involvement. Patients with extensive soft tissue involvement beyond the aforementioned structures had poor OS similar to that of patients with intracranial extension and/or cranial nerve palsy. Only 2% of the patients had lymph nodes > 6 cm above the supraclavicular fossa (SCF), and their outcomes resembled the outcomes of those with low extension. Replacing SCF with the lower neck (extension below the caudal border of the cricoid cartilage) did not affect the hazard distinction between different N categories. With the proposed T and N categories, there were no significant differences in outcome between T4N0-2 and T1-4N3 disease. CONCLUSIONS: After a review by AJCC/UICC preparatory committees, the changes recommended for the 8th edition include changing MP/LP involvement from T4 to T2, adding prevertebral muscle involvement as T2, replacing SCF with the lower neck and merging this with a maximum nodal diameter > 6 cm as N3, and merging T4 and N3 as stage IVA criteria. These changes will lead not only to a better distinction of hazards between adjacent stages/categories but also to optimal balance in clinical practicability and global applicability.

Potential surrogate endpoints for overall survival in locoregionally advanced nasopharyngeal carcinoma: an analysis of a phase III randomized trial.

The gold standard endpoint in trials of locoregionally advanced nasopharyngeal carcinoma (NPC) is overall survival (OS). Using data from a phase III randomized trial, we evaluated whether progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) or locoregional failure-free survival (LR-FFS) could be reliable surrogate endpoints for OS. Between July 2002 and September 2005, 316 eligible patients with stage III-IVB NPC were randomly assigned to receive either radiotherapy alone or chemoradiotherapy. 2- and 3-year PFS, FFS, D-FFS, and LR-FFS were tested as surrogate endpoints for 5-year OS using Prentice's four criteria. The Spearman's rank correlation coefficient was calculated to assess the strength of the associations. After a median follow-up time of 5.8 years, 2- and 3-year D-FFS and LR-FFS were not significantly different between treatment arms, in rejection of Prentice's second criterion. Being consistent with all Prentice's criteria, 2- and 3-year PFS and FFS were valid surrogate endpoints for 5-year OS; the rank correlation coefficient was highest (0.84) between 3-year PFS and 5-year OS. In conclusion, PFS and FFS at 2 and 3 years may be candidate surrogate endpoints for OS at 5 years; 3-year PFS may be more appropriate for early assessment of long-term survival.

Analysis on clinical characteristics and influencing factors of patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: To explore the independent prognostic factors for the recurrence/metastasis of patients with locoregionally advanced nasopharyngeal carcinoma (LANPC). MATERIALS AND METHODS: A total of 604 patients initially diagnosed as LANPC by pathohistology in Fujian Provincial Cancer Hospital were selected to analyze the relationship between the clinical pathological patterns, therapeutic protocols and clinical stages with the recurrence/metastasis of LANPC. RESULTS: The 1-, 3- and 5-year locoregionally recurrent rates of LANPC patients were 2.0%, 9.5% and 12.9% respectively, with average recurrent period being 78 months. Univariate analysis results indicated that clinical stages had certain influence on the recurrent period of LANPC patients. However, COX regression models showed that ages, genders and clinical stages were not the independent prognostic factors influencing the recurrence. The 1-, 3- and 5-year metastatic rates of LANPC patients were 6.6%, 17.5% and 18.8% respectively, with average metastatic period of 73 months. Univariate analysis results demonstrated that ages, N stages, clinical stages, locations of lymph node, retropharyngeal lymph node and extracapsular invasion of lymph node had certain influence on the metastatic period of LANPC patients. Additionally, further COX regression analysis results suggested that T stages, reduction protocols and extracapsular invasion of lymph node were the independent prognostic factors influencing the metastasis of patients with LANPC, in which T stages and extracapsular invasion of lymph node were the pestilent factors while reduction protocols the protective factor. CONCLUSIONS: Induction chemotherapy is beneficial to LANPC patients with initial treatment, and the metastatic rate decreases greatly after the application of reduction chemotherapy.

Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III to IVB nasopharyngeal carcinoma from endemic regions of China.

BACKGROUND: The objective of this study was to evaluate the long-term survival and late toxicities of concurrent-adjuvant chemotherapy in patients with stage III through IVB nasopharyngeal carcinoma (NPC) from endemic regions of China. METHODS: Patients with stage III to IVB NPC were assigned randomly to receive radiotherapy (RT) alone (the RT group) or RT plus concurrent adjuvant chemotherapy (the CRT group). CRT patients received concurrent cisplatin (40 mg/m2) weekly during RT followed by cisplatin (80 mg/m2) and fluorouracil (800 mg/m(2) daily for 5 days) every 4 weeks for 3 cycles. The primary endpoint was overall survival. RESULTS: In total, 316 patients underwent randomization, with 158 to each group. At a median follow-up of 70 months, the 5-year overall survival rate was 72% for the CRT group and 62% for the RT group (hazard ratio, 0.69; 95% confidence interval, 0.48-0.99; P = .043). Failure-free survival was significantly higher in the CRT group (P = .020). Most late toxicities were similar (33% vs. 26%; P = .089), except for cranial neuropathy (P = .042), peripheral neuropathy (P = .041), and ear damage (P = .048), which were significantly increased in the CRT group. CONCLUSIONS: The addition of concurrent adjuvant chemotherapy to RT provides survival benefits to patients with stage III through IVB NPC in endemic regions of China, and it does not increase most late toxicities apart from cranial neuropathy, peripheral neuropathy, and ear damage.

Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of china.

PURPOSE: A prospective randomized trial was performed to evaluate the efficacy of concurrent chemotherapy and adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) in endemic regions of China. METHODS AND MATERIALS: Between July 2002 and September 2005, 316 eligible patients were randomly assigned to receive either radiotherapy alone (RT) or chemoradiotherapy concurrent with adjuvant chemotherapy (CRT). All patients received 70 Gy in 7 weeks using standard RT portals and techniques. The CRT patients were given concurrent cisplatin (40 mg/m(2) on Day 1) weekly during RT, followed by cisplatin (80 mg/m(2) on Day 1) and fluorouracil (800 mg/m(2) on Days 1-5) every 4 weeks (Weeks 5, 9, and 13) for three cycles after completion of RT. All patients were analyzed by intent-to-treat analysis. RESULTS: The two groups were well-balanced in all prognostic factors and RT parameters. The CRT group experienced significantly more acute toxicity (62.6% vs. 32%, p = 0.000). A total of 107 patients (68%) and 97 patients (61%) completed all cycles of concurrent chemotherapy and adjuvant chemotherapy, with a median follow-up time of 29 months. The 2-year overall survival rate, failure-free survival rate, distant failure-free survival rate, and locoregional failure-free survival rate for the CRT and RT groups were 89.8% vs. 79.7% (p = 0.003), 84.6% vs. 72.5% (p = 0.001), 86.5% vs. 78.7% (p = 0.024), and 98.0% vs. 91.9% (p = 0.007), respectively. CONCLUSIONS: This trial demonstrated the significant survival benefits of concurrent chemotherapy plus adjuvant chemotherapy in patients with locoregionally advanced NPC in endemic regions of China.

Evaluation of sixth edition of AJCC staging system for nasopharyngeal carcinoma and proposed improvement.

PURPOSE: To evaluate the 6th edition of the International Union Against Cancer/American Joint Committee on Cancer staging system for nasopharyngeal carcinoma and to search for ways to improve the system. METHODS AND MATERIALS: We performed a retrospective review of data from 749 biopsy-proven nonmetastatic nasopharyngeal carcinoma patients. All patients had undergone contrast-enhanced computed tomography and had received radiotherapy as their primary treatment. RESULTS: The T stage, N stage, and stage group were significant, independent predictors for disease-specific death. No significant differences were found between Stage T2a and T1 in local failure-free survival or between Stage N3a and N2 in distant failure-free survival. Survival curves of the different T/N subsets showed a better segregation when T2a and N3a were downstaged to T1 and N2, respectively. The hazard ratio of disease-specific deaths for patients with T2N0 disease was similar to that of patients with T1N0 disease; the same result was found for the T3N0 and T4N0 subsets. Downstaging the T2N0 subset to Stage I, T3N0 to Stage II, and T4N0 to Stage III resulted in a more balanced patient distribution, better hazard consistency among subgroups, and improved hazard discrimination between overall stages. CONCLUSION: Using the 6th edition of the American Joint Committee on Cancer staging system produced an acceptable distribution of patient numbers and segregation of survival curves among the different stage groups. The prognostic accuracy of the staging system could be improved by recategorization of the T, N, and group stage criteria.

[The values of MRI, CT, and PET-CT in detecting retropharyngeal lymph node metastasis of nasopharyngeal carcinoma].

BACKGROUND & OBJECTIVE: Three-dimensional conformal and intensity-modulated radiotherapy is the direction of developing radiotherapy for nasopharyngeal carcinoma (NPC). The accuracy of target area outlines is especially important. This study was to explore the clinical diagnostic values of magnetic resonance imaging (MRI), computed tomography (CT), and 18-F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT in detecting retropharyngeal lymph node metastasis of NPC, and to provide references to the plan of radiotherapy. METHODS: MRI, enhanced spiral CT, and PET-CT reports of the nasopharynx and whole neck of 87 naive NPC patients, histologically diagnosed and treated in Cancer Center of Sun Yat-sen University between Jan. 2003 and Apr. 2005, were analyzed. The detection rates of retropharyngeal lymph node metastasis were compared among MRI, CT and PET-CT using Chi-square test. RESULTS: Among the 174 parapharyngeal spaces of the 87 patients, the detection rates of retropharyngeal lymph node metastasis by MRI and CT were significantly higher than that by PET-CT (44.8% and 33.9% vs. 24.1%, P < 0.001 and P = 0.002). As compared with CT, MRI played an advantage in detecting retropharyngeal lymph node metastasis of NPC (P = 0.037). The minimal axial diameter of retropharyngeal lymph node was positively correlated to the standard uptake value (SUV) of PET-CT (r = 0.832, P <0.001). CONCLUSIONS: MRI are better than CT and PET-CT in detecting retropharyngeal lymph node metastasis of NPC. The combination of MRI, CT, and PET-CT is useful for delineating targets accurately in 3-dimensional conformal intensity-modulated radiotherapy for NPC.

[The role of retropharyngeal lymph node metastasis in staging of nasopharyngeal carcinoma].

OBJECTIVE: The prevalence of retropharyngeal lymph node (RLN) metastasis in nasopharyngeal carcinoma (NPC) is high, but its role in '92 Fuzhou staging system for NPC is uncertain. This study was to identify the prognostic value of RLN metastasis in NPC, and to evaluate its role in the staging system. METHODS: Clinical data of 749 untreated patients with histologically diagnosed NPC, without metastasis, presented between Jan. 1999 and Dec. 1999 at the Department of Radiation Oncology of Cancer Center of Sun Yat-sen University, were reviewed. All patients received enhanced spiral CT scan on the nasopharynx and whole neck before treatment. Cox regression model was used to investigate the prognostic value of RLN metastasis. According to the principle of the staging system, the indices of hazard consistency, hazard discrimination, and distribution were evaluated to identify the role of RLN metastasis in the staging system for NPC. RESULTS: The occurrence rate of RLN metastasis was 51.5%; the occurrence rates were significantly higher in the patients in advanced T stage, N stage, and clinical stage than in the patients in early stages (57.8% vs. 45.2%, P=0.001; 60.3% vs. 47.6%, P=0.001; 57.9% vs. 38.9%, P<0.001). The 5-year overall survival rate and 5-year distant metastasis-freely survival rate were significantly lower in the patients with RLN metastasis than in the patients without RLN metastasis (58.7% vs. 72.2%, P<0.001; 74.5% vs. 84.9%, P<0.001). In multivariate analysis, RLN metastasis was not a prognostic factor for overall survival, but borderline significant difference was observed for distant metastasis-freely survival (P=0.053). The hazard ratios of death and distant metastasis for N0 stage with RLN metastasis were 0.540 and 0.411, respectively, which was similar to those for N1 stage (0.601 and 0.555, respectively). Classifying RLN metastasis to N1 stage improved the hazard consistency in the N classification, but the distribution was unsatisfactory, and the proportion of N1 stage patients was 50.2%. Classifying RLN metastasis to T2 stage improved the hazard discrimination, with good balances of distribution found in T classification, N classification, and clinical staging. CONCLUSIONS: Based on the enhanced CT image, RLN metastasis tends to affect distant metastasis-freely survival of NPC patients. According to the principle of '92 Fuzhou staging system and present patterns of radiotherapy for the primary tumor, classifying RLN metastasis to T2 stage is more reasonable.