Gemcitabine Plus Cisplatin Versus Fluorouracil Plus Cisplatin as First-Line Therapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: Final Overall Survival Analysis of GEM20110714 Phase III Study.

PURPOSE: GEM20110714 (ClinicalTrials.gov identifier: NCT01528618), the first randomized, phase III study of systemic chemotherapy in recurrent or metastatic nasopharyngeal carcinoma (NPC), reported significant progression-free survival improvement with gemcitabine plus cisplatin (GP) versus fluorouracil plus cisplatin (FP; hazard ratio, 0.55; 95% CI, 0.44 to 0.68; P < .001). Data from the final analysis of overall survival (OS) are presented here. METHODS: From February 2012 to October 2015, 362 patients were randomly assigned to receive either GP (gemcitabine 1 g/m2 once daily on days 1 and 8 and cisplatin 80 mg/m2 once daily on day 1; n = 181) or FP (fluorouracil 4 g/m2 in continuous intravenous infusion over 96 hours and cisplatin 80 mg/m2 once daily on day 1; n = 181) once every 21 days. The primary end point was progression-free survival, which has been previously reported; OS was a secondary end point. RESULTS: After a median follow-up time of 69.5 months with GP and 69.7 months with FP, 148 (81.8%) and 166 (91.7%) deaths occurred in the GP and FP arms, respectively. The estimated hazard ratio for OS was 0.72 (95% CI, 0.58 to 0.90; two-sided P = .004). The median OS was 22.1 months (95% CI, 19.2 to 25.0 months) with GP versus 18.6 months (95% CI, 15.4 to 21.7 months) with FP. The OS probabilities at 1, 3, and 5 years were 79.9% versus 71.8%, 31.0% versus 20.4%, and 19.2% versus 7.8%, respectively. Poststudy therapy was administered in 51.9% and 55.2% of patients in the GP and FP arms, respectively. CONCLUSION: Among patients with previously untreated advanced nasopharyngeal carcinoma, those who receive GP have longer OS than those receive FP. Gemcitabine plus cisplatin should be considered a preferred front-line option for these patients.

Randomized, Double-Blind, Placebo-Controlled Trial of Shuanghua Baihe Tablets to Prevent Oral Mucositis in Patients With Nasopharyngeal Cancer Undergoing Chemoradiation Therapy.

PURPOSE: Oral mucositis is a common unpreventable complication associated with chemoradiation therapy. Shuanghua Baihe tablets have been approved by the Chinese Food and Drug Administration for treating recurrent oral mucosa ulceration. This study assessed whether Shuanghua Baihe tablets could prevent oral mucositis during chemoradiation therapy for locally advanced nasopharyngeal carcinoma. METHODS AND MATERIALS: This multicenter, randomized, double-blind, placebo-controlled trial was conducted at 11 hospitals in China between January 22, 2014, and September 21, 2015. Eligible patients (N=240, 18-70 years old) with pathologically diagnosed locally advanced nasopharyngeal carcinoma were randomly assigned (computer-block randomization; 1:1) to receive Shuanghua Baihe tablets or a placebo (4 tablets, 3 times a day, for 7 weeks) at the initiation of chemoradiation therapy. Administration of Shuanghua Baihe tablets could be ended if grade 3 or higher oral mucositis developed and patients were unwilling to continue taking the drug. The primary endpoints were oral mucositis incidence and latency. RESULTS: The incidence of oral mucositis during this study was significantly lower in the Shuanghua Baihe group (85.0%; 95% confidence interval [CI], 78.6%-91.4%) than in the placebo group (96.6%; 95% CI, 93.4%-99.9%; P=.0028). The median latency period was 28 days in the Shuanghua Baihe group and 14 days in the placebo group (hazard ratio, 0.17; 95% CI, 0.12-0.23; P<.0001). Compared with placebo, Shuanghua Baihe tablets significantly reduced the oral mucositis severity scores recorded by the investigators (Oral Mucositis Score, 24.0 [range, 0.0-67.8] vs 57.5 [range, 0.0-98.0]; P<.0001), full-time nurses (Oral Assessment Guide score, 462.0 [range, 392.0-664.7] vs 520.4 [range, 392.0-714.0]; P<.0001), and patients (score for soreness of mouth and throat, 4.0 [range, 0-10] vs 6.0 [range, 0-10]; P<.0001). No serious adverse events were observed, and the incidence of mild or moderate gastrointestinal adverse events associated with Shuanghua Baihe tablets was 3.3%. The short-term response rate was similar in patients receiving Shuanghua Baihe tablets and those receiving placebo during chemoradiation therapy during this study. CONCLUSIONS: Shuanghua Baihe tablets reduced the occurrence, latency, and severity of oral mucositis in patients with nasopharyngeal cancer during chemoradiation therapy treatment.

PET/CT-guided dose-painting versus CT-based intensity modulated radiation therapy in locoregional advanced nasopharyngeal carcinoma.

BACKGROUND: The effect of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT)-guided dose-painting intensity-modulated radiation therapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) is unclear. This study aimed to assess the efficacy and toxicity of such combination. METHODS: From 2012 to 2014, 213 patients with stage III-IVB NPC received chemoradiotherapy by PET/CT-guided DP-IMRT (group A, n = 101) or CT-based IMRT (group B, n = 112). In group A, subvolume GTVnx-PET (gross tumor volume of nasopharynx in PET images) was defined within GTVnx (gross tumor volume of nasopharynx) as the SUV50%max isocontour; the dose to GTVnx-PET was escalated to DT 75.2 Gy/32 and 77.55 Gy/33 Fx, respectively, for patients with T1-2 and T3-4 disease, respectively. In group B, PGTVnx was irradiated at DT 70.4-72.6 Gy/32-33 Fx in 2.2 Gy per fraction. RESULTS: Complete response rates were 99.0% (100/101) and 92.9% (104/112) in groups A and B, respectively (P = 0.037). Compared with CT-based IMRT, FDG-PET/CT guided DP-IMRT significantly improved 3-year local failure-free survival (LFFS, 98.8% vs. 91.3%; P = 0.032), locoregional failure-free survival (LRFFS, 97.2 vs. 91.2%; P = 0.049), distant metastasis-free survival (DMFS, 92.9% vs. 87.4%; P = 0.041), disease free survival (DFS, 87.9% vs. 82.4%; P = 0.02), and overall survival (OS, 91.8% vs. 82.6%; P = 0.049). No statistically significant differences in acute and late toxic effects were observed. Multivariate analysis showed that dose painting (PET/CT-guided DP-IMRT vs CT-based IMRT without DP) was a significant independent prognostic factor for LFFS and DFS. CONCLUSION: FDG-PET/CT guided DP-IMRT plus chemotherapy is associated with a considerable survival benefit, without increasing toxicity in patients with locoregional advanced NPC. Further randomized trials are needed to fully assess the role of PET/CT-guided DP-IMRT.

Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Outcomes are poor for patients with recurrent or metastatic nasopharyngeal carcinoma and no well established first-line chemotherapy is available for the disease. We compared the efficacy and safety of gemcitabine plus cisplatin versus fluorouracil plus cisplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. METHODS: In this multicentre, randomised, open-label, phase 3 trial, patients with recurrent or metastatic nasopharyngeal carcinoma were recruited from 22 hospitals in China. Key inclusion criteria were Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and measurable lesions according to Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned in a 1:1 ratio to receive either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously on day 1), or fluorouracil (4 g/m2 in continuous intravenous infusion over 96 h) and cisplatin (80 mg/m2 on day 1 given intravenously) once every 3 weeks for a maximum of six cycles. The randomisation was done centrally via an interactive phone response system using block randomisation with a size of six. The primary endpoint was progression-free survival assessed by the independent image committee in the intention-to-treat population. Safety analyses were done in patients who received at least one cycle of study drug. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01528618. FINDINGS: Between Feb 20, 2012, and Oct 30, 2015, 362 patients were randomly assigned to a group (181 to the gemcitabine [plus cisplatin] group and 181 to the fluorouracil [plus cisplatin] group). Median follow-up time for progression-free survival was 19·4 months (IQR 12·1-35·6). The median progression-free survival was 7·0 months (4·4-10·9) in the gemcitabine group and 5·6 months (3·0-7·0) in the fluorouracil group (hazard ratio [HR] 0·55 [95% CI 0·44-0·68]; p<0·0001). A total of 180 patients in the gemcitabine group and 173 patients in the fluorouracil group were included in the safety analysis. Significantly different treatment-related grade 3 or 4 adverse events between the gemcitabine and fluorouracil groups were leucopenia (52 [29%] vs 15 [9%]; <0·0001), neutropenia (41 [23%] vs 23 [13%]; p=0·0251), thrombocytopenia (24 [13%] vs three [2%]; p=0·0007), and mucosal inflammation (0 vs 25 [14%]; <0·0001). Serious treatment-related adverse events occurred in seven (4%) patients in the gemcitabine group and ten (6%) in the fluorouracil group. Six (3%) patients in the gemcitabine group and 14 (8%) patients in the fluorouracil group discontinued treatment because of drug-related adverse events. No treatment-related deaths occurred in either group. INTERPRETATION: Gemcitabine plus cisplatin prolongs progression-free survival in patients with recurrent or metastatic nasopharyngeal carcinoma. The results establish gemcitabine plus cisplatin as the standard first-line treatment option for this population. FUNDING: Sun Yat-Sen University Clinical Research 5010 Programme, Chinese National Natural Science Foundation project (grant numbers 81372502 and 81201917), the National High Technology Research and Development Program of China (863 program numbers 2012AA02A501 and 2012AA02A502), and the Natural Science Foundation of Guangdong (grant number S2013010016564).

ERCC1 Cys8092Ala and XRCC1 Arg399Gln polymorphisms predict progression-free survival after curative radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in DNA repair genes can alter gene expression and activity and affect response to cancer treatment and, correspondingly, survival. The present study was designed to evaluate the utility of the XRCC1 Arg399Gln and ERCC1 Cys8092Ala SNPs, measured in pretreatment biopsy samples, as predictors of response to radiotherapy in patients with non-metastatic nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: The study included 75 consecutive patients with stage II-IVA-B NPC. XRCC1 Arg399Glu and ERCC1 Cys8092Ala SNPs were identified from paraffin-embedded biopsy specimens via Sanger sequencing. Expression of p53 and pAkt protein was analyzed by immunohistochemical staining. Potential relationships between genetic polymorphisms and progression-free survival (PFS) were analyzed by using a Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test. RESULTS: Multivariate analysis showed that carriers of the ERCC1 8092 Ala/Ala genotype [hazard ratio (HR) 1.882; 95% confidence interval (CI) 1.031-3.438; P = 0.039] and heavy smokers (≥20 pack-years) carrying the XRCC1 Arg/Arg genotype (HR 2.019; 95% CI 1.010-4.036; P = 0.047) had significantly lower PFS rates. Moreover, combined positive expression of p53 and pAkt led to significantly increased PFS in subgroups carrying the XRCC1 Gln allele (HR 7.057; 95% CI 2.073-24.021; P = 0.002) or the ERCC1 Cys allele (HR 2.568; 95% CI 1.056-6.248; P = 0.038). CONCLUSIONS: The ERCC1 Cys8092Ala polymorphism is an independent predictor of response to radiotherapy for NPC, and the XRCC1 Arg399Glu mutation combined with smoking status seems to predict PFS as well. Our results further suggest a possible correlation between these genetic polymorphisms and p53 protein status on survival.

Expression of pAkt affects p53 codon 72 polymorphism-based prediction of response to radiotherapy in nasopharyngeal carcinoma.

BACKGROUND: Codon 72 (Arg/Pro), the most frequently studied single nucleotide polymorphism (SNP) of p53 to date, is associated with the ability of the gene to induce cell apoptosis. The PI3K/Akt pathway plays an essential role in the transcriptional activation function of p53, and is an important factor in radiotherapy resistance. The present study was designed to evaluate the prediction of response to radiotherapy based on p53 codon 72 SNP and pAkt expression in biopsy specimens of locoregional nasopharyngeal carcinoma (NPC) before treatment. MATERIALS AND METHODS: In total, 75 consecutive patients with locoregional NPC were enrolled. The p53 codon 72 SNP was identified from retrospectively collected paraffin-embedded biopsy specimens using Sanger sequencing. Expression patterns of p53, p21, 14-3-3σ, and pAkt proteins were investigated using immunohistochemical analyses. The effects of genetic polymorphisms and protein expression on progression-free survival (PFS) were evaluated using the Cox proportional hazards model, Kaplan-Meier method, and log-rank test. RESULTS: The p53 codon 72 Pro/Pro carriers showed lower risk of disease progression (local recurrence and distant metastases) (HR: 0.300; 95% CI: 0.092-0.983; p=0.047). However, this association between the p53 codon 72 polymorphism and PFS was not significant in the pAkt-positive subgroup. No association was observed between protein expression of p53, p21 or 14-3-3σ and p53 codon72 polymorphisms. Notably, positive expression of p53 protein appeared to be correlated with poorer PFS among patients diagnosed as local regional lymph node metastasis (N+) before treatment (p=0.032). CONCLUSIONS: The p53 codon 72 Pro/Pro genotype may be an effective independent prognostic marker for better outcome in patients with locoregional NPC. Based on the current findings, we hypothesize that pAkt weakens the predictive value of p53 codon 72 SNP in NPC. A combination of positive p53 protein expression and local regional lymph node metastasis may additionally be predictive of high risk of disease progression.

Effects of magnetic induction hyperthermia and radiotherapy alone or combined on a murine 4T1 metastatic breast cancer model.

PURPOSE: The purpose of this study was to explore the effects of MIH and radiotherapy alone or combined on metastatic breast cancer and the underlying mechanisms. MATERIALS AND METHODS: A murine 4T1 metastatic breast cancer model was established and randomly assigned into four treatment groups: C (control), R (radiotherapy), MIH, and MIH+R. Tumour volume, lung metastasis, the expression of Bax and MMP-9, T cell subsets, serum cytokine levels, and mouse survival were evaluated. RESULTS: Group MIH + R showed significantly reduced tumour volume, lung metastasis, improved survival and increased Bax expression compared to group R or MIH (P<0.05). MMP-9 expression in the primary tumour tissue was significantly increased in group R compared to the other groups (P<0.05), which could be brought down by combined MIH treatment. Group MIH +R showed significantly higher CD4(+) T cell percentage as well as CD4(+)/CD8(+) cell ratio than group R (P<0.05). Group MIH+R showed significantly higher serum levels of TNF-α, IFN-γ and IL-2 than group R (P<0.05). CONCLUSIONS: MIH not only promotes the tumour-cell killing effect of radiotherapy through Bax-mediated cell death, but also improves cellular immunity in mice under radiotherapy and decreases the potential of radiotherapy to enhance MMP-9 expression, which leads to significant improvement in lung metastasis and overall survival of mice under combined treatment of MIH and R. This study is the first to have explored the effect of combined hyperthermia and radiotherapy on tumour metastasis and the underlying mechanisms. It provides insights into the application of MIH as an adjuvant to radiotherapy for metastatic breast cancer.

[Screening of molecular markers of lung squamous cell carcinoma by microarrays].

OBJECTIVE: To identify molecular markers of lung squamous cell carcinoma by cDNA microarray technique. METHODS: cDNA expression profiles were examined by microarrays of 6 surgical specimens of stage I lung squamous cell carcinomas. Those genes, either up-regulated or down-regulated in every specimen studied, were identified. The expression levels of nm23 and BRCA2 by the squamous cell carcinoma of the lung were further examined by immunohistochemical techniques. RESULTS: A total of 107 genes were identified, of which 26 were up-regulated and 81 were down-regulated in all six specimens. Immunohistochemical staining showed that, compared with normal lung tissues, the intensity of nm23 expression by the squamous cell carcinoma of lung was significantly increased while that of BRCA-2 was decreased. CONCLUSION: cDNA microarrays can be used to identify gene expression profile of lung cancer, some of which may be used as markers of lung squamous cell carcinoma.