Xiaomin Ou

Effect of dosimetric factors on occurrence and volume of temporal lobe necrosis following intensity modulated radiation therapy for nasopharyngeal carcinoma: A case-control study

PURPOSE To determine dosimetric risk factors for the occurrence of temporal lobe necrosis (TLN) among nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiation therapy (IMRT) and to investigate the impact of dose-volume histogram (DVH) parameters on the volume of TLN lesions (V-N). METHODS AND MATERIALS Forty-three NPC patients who had developed TLN following IMRT and 43 control subjects free of TLN were retrospectively assessed. DVH parameters included maximum dose (Dmax), minimum dose (Dmin), mean dose (Dmean), absolute volumes receiving specific dose (Vds) from 20 to 76 Gy (V20-V76), and doses covering certain volumes (Dvs) from 0.25 to 6.0 cm(3) (D0.25-D6.0). V-Ns were quantified with axial magnetic resonance images. RESULTS DVH parameters were ubiquitously higher in temporal lobes with necrosis than in healthy temporal lobes. Increased Vds and Dvs were significantly associated with higher risk of TLN occurrence (P<.05). In particular, Vds at a dose of ≥70 Gy were found with the highest odds ratios. A common increasing trend was detected between V-N and DVH parameters through trend tests (P for trend of <.05). Linear regression analysis showed that V45 had the strongest predictive power for V-N (adjusted R(2) = 0.305, P<.0001). V45 of <15.1 cm(3) was relatively safe as the dose constraint for preventing large TLN lesions with V-N of >5 cm(3). CONCLUSIONS Dosimetric parameters are significantly associated with TLN occurrence and the extent of temporal lobe injury. To better manage TLN, it would be important to avoid both focal high dose and moderate dose delivered to a large area in TLs.

Treatment outcomes and late toxicities of 869 patients with nasopharyngeal carcinoma treated with definitive intensity modulated radiation therapy: new insight into the value of total dose of cisplatin and radiation boost

This study was to report the long-term outcomes and toxicities of nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). From 2009 to 2010, 869 non-metastatic NPC patients treated with IMRT were retrospectively enrolled. With a median follow-up of 54.3 months, the 5-year estimated local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were 89.7%, 94.5%, 85.6%, 76.3%, 84.0%, respectively. In locally advanced NPC, gender, T, N, total dose of cisplatin more than 300 mg/m2 and radiation boost were independent prognostic factors for DMFS and DFS. Age, T, N and total dose of cisplatin were independent prognostic factors for OS. Radiation boost was an adverse factor for LRFS, RRFS, DMFS and DFS. Concurrent chemotherapy was not an independent prognostic factor for survival, despite marginally significant for DMFS in univariate analysis. Concurrent chemotherapy increased xerostomia and trismus, while higher total dose of cisplatin increased xerostomia and otologic toxicities. In conclusion, IMRT provided satisfactory long-term outcome for NPC, with acceptable late toxicities. Total dose of cisplatin was a prognostic factor for distant metastasis and overall survival. The role of concurrent chemotherapy and radiation boost in the setting of IMRT warrants further investigation.

Treatment outcome of nasopharyngeal carcinoma with retropharyngeal lymph nodes metastasis only and the feasibility of elective neck irradiation

OBJECTIVE To investigate the outcome of nasopharyngeal carcinoma (NPC) with retropharyngeal lymph nodes (RLNs) metastasis only and evaluate the feasibility of elective neck irradiation. MATERIALS AND METHODS This is a retrospective study of 119 newly diagnosed non-metastatic NPC patients with RLNs metastasis only. All of them received definitive radiotherapy. Eighty nine patients received elective neck irradiation to levels II, III, VA and the rest received whole neck irradiation, including levels II-V. RESULTS The median follow-up was 36.6 months. The 5-year local recurrence-free survival (LFS), nodal recurrence-free survival (NFS), distant metastasis-free survival (DMFS) and overall survival (OS) was 81.4%, 92.7%, 91.8%, and 93.6%, respectively. Four patients developed nodal relapse and only one was out-of-field relapse. No significant difference of nodal recurrence was observed between elective neck irradiation and whole neck irradiation. IMRT or three-dimensional conformal radiotherapy (3D-CRT) showed a trend of improving regional control, compared with conventional two-dimensional radiotherapy (2D-RT) (p=0.074). In 2D-RT, a higher dose (>5600 cGy) to the upper neck showed a benefit of regional control(p=0.006). Multivariate analysis demonstrated that only the dose of upper neck was an independent prognostic factor of NFS. CONCLUSIONS Elective irradiation to levels II, III, VA was not inferior to whole neck irradiation for NPC patients with RLNs metastasis only. However, more evidences are needed to confirm the result. IMRT showed a trend of improving regional control. A higher dose of prophylactic radiation may be required for upper neck region in patients with RLNs metastasis.

The role of adjuvant chemotherapy in nasopharyngeal carcinoma with bulky neck lymph nodes in the era of IMRT

Nasopharyngeal carcinoma (NPC) patients with N2–3 diseases are prone to develop distant metastasis even treated with standard concurrent chemoradiotherapy (CCRT). Our study is aim to determine the optimal treatment strategy of these patients. Patients with histologically proven NPC were retrospectively analyzed according to the AJCC 2002 stage classification system. A total of 547 patients who had N2–3 diseases were enrolled. They were all treated with Intensity-modulated radiation therapy (IMRT) combined with systemic treatments, including radiotherapy alone (RT alone), neoadjuvant chemotherapy followed by radiotherapy (NACT+RT), CCRT, NACT+CCRT, NACT followed by radiotherapy and adjuvant chemotherapy (NACT+RT+AC), CCRT+AC and NACT+CCRT+AC. A subgroup analysis was also conducted. With a median follow-up time of 53.8 months, adjuvant chemotherapy significantly decreased the risk of distant metastasis (HR 0.413, 95% CI 0.194–0.881, p = 0.022) as well as significantly increased the OS (HR 0.398, 95% CI 0.187–0.848, p = 0.017) in patients with N3 disease. The addition of adjuvant chemotherapy seemed to provide benefits to patients with N3 stage NPC and the current study may indicate the need for further randomized investigation.

Predictive single nucleotide polymorphism markers for acute oral mucositis in patients with nasopharyngeal carcinoma treated with radiotherapy

The aim of this study was to investigate the association between the susceptibility of severe oral mucositis (OM) in Chinese nasopharyngeal carcinoma (NPC) patients treated with radiotherapy and single nucleotide polymorphisms (SNPs) across the whole genome. SNPs were screened in a total of 24 patients with NPC and an additional 6 were subjected to mRNA expression analysis. Patients were subdivided into CTC 0-2 (CTC toxicity grade 0, 1, and 2) and CTC 3+ (CTC toxicity grade 3 and above) groups according to their CTC (common toxicity criteria) scores. The GTEx dataset was used to performed eQTL analyses and in-vitro functional assays were performed for eQTL-associated genes. Our data identified 7 functional SNPs associated with the development of OM. We observed that rs11081899-A, located in the 5′-UTR of the ZNF24 gene, was significantly correlated with a higher risk of severe mucositis (OR = 14.631, 95% CI = 2.61-105.46, p = 1.2 × 10−4), and positively associated with ZNF24 mRNA expression (p = 4.1 × 10−6) from GTEx dataset. In addition, high ZNF24 mRNA expression was associated with severe OM in patients with NPC (p = 0.02). Further functional assays revealed that ZNF24 knockdown reduced p65 expression and suppressed TNF-α-induced NF-κB activation and pro-inflammatory cytokines release. These findings suggested that rs11081899-A may be a genetic susceptibility factor for radiation-induced OM in patients with NPC, although its value in clinical application needs to be further verified in a large cohort. Also, we suggested that downregulation of ZNF24 may attenuate the development of mucositis by suppressing NF-κB activation.

Cetuximab in combination with chemoradiotherapy in the treatment of recurrent and/or metastatic nasopharyngeal carcinoma

The aim of the study was to assess the efficacy and toxicity of cetuximab in the combined treatment for patients with recurrent and/or metastatic nasopharyngeal carcinoma (R/M NPC). Between March 2007 and November 2011, a total of 30 R/M NPC patients treated with comprehensive therapy including cetuximab were retrospectively enrolled. Intensity-modulated radiation therapy was delivered in recurrent disease with a median dose of 60 Gy. Chemotherapy regimens included TP/TPF (docetaxel 60–75 mg/m2 d1+DDP 25 mg/m2 d1–3±5-FU 500 mg/m2/day with 120-h infusion), GP (gemcitabine 1.0 g/m2 d1, d8+DDP 25 mg/m2 d1–3), and PC (paclitaxel 60 mg/m2/week d1+carboplatin AUC 2/week d1). Acute and late toxicities were documented by the radiation oncologists. The median age of the patients was 44 years (range 26–62). A total of 21 patients (70%) achieved response (CR+PR). The median survival time, time to progression, and 2-year overall survival were 23.6, 12.2 months, and 53.3%, respectively. Cetuximab appears to be effective and well tolerated when combined with chemoradiation therapy for the treatment of R/M NPC.

EZH2 suppresses the nucleotide excision repair in nasopharyngeal carcinoma by silencing XPA gene

The enhancer of zeste homolog 2 (EZH2) is involved in a number of fundamental pathological processes of cancer. However, its role in DNA repair pathway is still unclear. Here, we have identified XPA as a novel target gene of EZH2 via a DNA repair pathway PCR array. XPA plays a pivot role in nucleotide excision repair (NER). The expression of XPA was significantly increased by EZH2 specific inhibitor GSK126 or lentiviral shEZH2 in nasopharyngeal carcinoma (NPC) CNE and 8F cell lines. Chromatin immunoprecipitation assay demonstrated that EZH2 catalyzes H3K27 trimethylation at the XPA promoters. Furthermore, we validated the negative correlation of EZH2 and XPA in a NPC tissue microarray by immunohistochemistry staining. We also found that high expression of EZH2 was positively correlated with advanced T, N, and AJCC stage of NPC; and low expression of XPA was positively correlated with advanced T and N stage. In NPC cell lines, increased XPA expression by EZH2 inhibition resulted in a more rapid removal of UVC induced 6‐4PP‐ and CPD‐DNA adducts, as well as enhanced efficiency of DNA repair after UVC irradiation as detected by the Comet assay and immunofluorescence staining of γH2Ax. Consistently, increased cell clonogenic survival, decreased apoptosis, and necrosis after UVC irradiation, and increased resistance to DNA damaging agent cisplatin was also observed in EZH2 inhibited cells. These results illustrate that EZH2 may promote carcinogenesis and cancer development of NPC by transcriptional repression of XPA gene and inactivation of NER pathway.

Who benefited most from higher cumulative dose of cisplatin among patients with locally advanced nasopharyngeal carcinoma treated by intensity-modulated radiation therapy? A retrospective study of 527 cases

Purpose: Our previous study demonstrated the benefit of cumulative dose of cisplatin during the whole treatment on locally advanced nasopharyngeal carcinoma (NPC) treated with various chemotherapy strategies. The purpose of this study is to identify the subgroup of locally advanced NPC who benefits from higher dose of cisplatin, and to clarify whether cumulative dose of cisplatin during the whole treatment brings survival benefit to those treated with concurrent chemoradiotherapy (CCRT). Materials and methods: This retrospective study enrolled 527 patients with locally advanced NPC treated with intensity-modulated radiation therapy (IMRT) and chemotherapy in our institution from 2009 to 2010. The median cumulative dose of cisplatin of 300mg/m2 was chose to be the cutoff value of low and high dose subgroups. Survival curves were estimated using the Kaplan-Meier method. Univariate analysis was conducted using the log-rank test. Multivariate analyses (MVA) were performed using Cox proportional hazards regression model. Results: With a median follow-up of 54.5 (1-76.7) months, high-dose subgroup had a significant higher distant metastasis-free survival (DMFS) (82.0% vs. 76.5%, p=0.029) and overall survival (OS) (84.1% vs. 74.0%, p=0.028). Cumulative dose of cisplatin were demonstrated an independent prognostic factors for DMFS (HR=0.524, 95% CI 0.340-0.806) and OS (HR=0.577, 95% CI 0.373-0.893) for the entire cohort upon MVA. As for T1-2N2-3, high-dose subgroup had a trend of better DMFS (85.7% vs. 76.3%, p=0.069) and a significant improvement in OS (87.8% vs. 76.3%, p=0.041). Similarly, in the subgroup of T3-4N2-3, higher dose of cisplatin was associated with higher OS (80.3% vs. 52.3%, p=0.032). Cumulative dose of cisplatin was an independent prognostic factor for DMFS (HR=0.483, 95%CI 0.292-0.798) and OS (HR=0.429, 95%CI 0.258-0.715) for patients with T1-4N2-3 disease upon MVA. However, the benefit of higher dose of cisplatin was not observed in the subgroup of T3-4N0-1. For patients receiving CCRT (n=278), those treated with higher dose of cisplatin had a significantly higher DMFS (87.7% vs. 75.4%, p=0.004). The benefit mainly derived from T3-4N2-3 patients treated with CCRT (5y DMFS: 87.9% vs. 58.2%, p=0.034). Cumulative dose of cisplatin was associated with a lower risk of distant metastasis (HR=0.427, 95% CI 0.228-0.801) for patients treated with CCRT upon MVA. Conclusions: Our study identified that patients with N2-3 disease were those benefited from higher cumulative dose. The benefit of higher cumulative dose maintained in those treated with CCRT. The intensity of chemotherapy may be tailored based on various stage subgroups in locally advanced NPC.

Patterns of local failures and suggestions for reduction of clinical target volume for nasopharyngeal carcinoma patients without cervical lymph node metastasis

Background To demonstrate the robustness of clinical target volume delineation for nasopharyngeal carcinoma (NPC) patients, this study makes a detailed analysis of the initial irradiated dose of the recurrent site and local failure patterns after intensity-modulated radiation therapy (IMRT). Based on this analysis, further improvement of delineation recommendations may be made in order to improve the quality-of-life in NPC, without decreasing the local control and survival rate. Methods In total, 382 newly diagnosed non-metastatic NPC patients were retrospectively enrolled, receiving elective neck irradiation to levels II, III, and VA. For patients with local failure, the location and extent of local failures were transferred to the pretreatment planning computed tomography (CT) for dosimetric analysis. The dose of radiation received by GTVr (gross tumor volume of recurrence) was calculated and analyzed with dose-volume histogram (DVH). Failures were classified as: “in field” if 95% of GTVr was within the 95% isodose, “marginal” if 20%–95% of GTVr was within the 95% isodose, or “outside” if less than 20% of GTVr was inside the 95% isodose. Results With a median follow-up time of 61.3 months, 12 patients developed local recurrence (10 cases available). The 5-year overall survival, local relapse–free survival, regional relapse–free survival, distant metastasis failure–free survival, and disease–free survival were 87.8%, 95.2%, 99.1%, 93.3%, and 82.5%, respectively. Dose conformity with IMRT was excellent, and the recurrence was mainly within 3 years after the first treatment. The dosimetric analysis showed that seven failures were classified as “in-field”, two failures as “marginal”, and only one failure as “out-field”. Most local relapse sites located just the same site of primary tumor and most anatomic sites were at low risk of concurrent bilateral tumor invasion. Conclusions IMRT with elective neck irradiation provides excellent local control for NPC patients without cervical lymph node metastasis. In-field failures are the main patterns for local recurrence, and the radioresistant subvolumes within the gross tumor volume are needed to be identified. This study proposed suggestions for reduction of target volume during IMRT treatment for NPC patients.

Interplay of Tumor Spread, Volume and Epstein-Barr Virus DNA in Nasopharyngeal Carcinoma: Feasibility of An Integrative Risk Stratification Scheme

Purpose: To investigate the inter-correlation of tumor spread, volume and quantitative plasma Epstein-Barr virus DNA level (pEBV DNA), and to further assess the prognostic efficacy of a novel risk stratification combining anatomic, volumetric and biological features in nasopharyngeal carcinoma (NPC). Methods and Materials: One hundred and twelve patients with non-metastatic NPC were prospectively enrolled. Correlation of pEBV DNA with tumor invasiveness, lymph node (LN) metastasis, tumor volume and classification was tested by univariate and multivariate analyses. 5-year distant metastasis free survival (DMFS) was evaluated using Kaplan-Meier method and Cox proportional hazards model. Results: Tumor volume, TNM stage and pEBV DNA were strongly inter-correlated to each other. Nodal volume, skull base invasion and LN metastasis to supraclavicular fossa were determined to be independent predictors for pEBV DNA level. To exclude collinearity, a risk stratification based on combination of EBV DNA, nodal volume and anatomic features was established, offering significant distinguishing ability in 5-year DMFS. Further multivariate Cox regression analysis found the novel stratification to be independent predictor of DMFS. Conclusions: Both anatomic spread and tumor volume contribute to pEBV DNA level, leading to strong inter-correlation between NPC stage, volume and EBV DNA. The proposed risk stratification combining anatomic, volumetric and biological features showed potential in refining DMFS prediction.