Staging nodal metastases in nasopharyngeal carcinoma: which method should be used to measure nodal dimension on MRI?

AIM: To investigate four methods to measure the maximum dimension (MD) of metastatic neck nodes and correlate with clinical outcome in nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Magnetic resonance imaging (MRI) examinations of 712 NPC patients were analysed. MD measurements using methods 1, 2, 3, and 4 were obtained from a single node in the axial plane; a single node in the axial/coronal plane; a single and/or confluent nodes in the axial/coronal plane; and a single and/or confluent and/or contiguous nodes in the axial/coronal plane, respectively. MDs obtained from the four methods were correlated with nodal volume (NV) using Pearson's correlation test. MDs obtained from the four methods, T and N stages, age, gender, and treatment were correlated with overall survival (OS), disease-specific survival (DSS), distant metastases free survival (DMFS), and regional relapse-free survival (RRFS) using cox regression. RESULTS: Method 4 (R: 0.84) had the strongest correlation with NV followed by method 3 (R: 0.77), method 2 (R: 0.70) and method 1(R: 0.69). Method 4 was the only independent nodal measurement of OS, DSS, and DMFS (p-values = 0.008, <0.001 and <0.001, respectively). None of the MD methods was an independent measurement of RRFS. CONCLUSIONS: The best method to obtain the MD for staging incorporates not only single and confluent, but also contiguous metastatic nodes measured in the plane with the MD.

Multicenter phase II study of the AKT inhibitor MK-2206 in recurrent or metastatic nasopharyngeal carcinoma from patients in the mayo phase II consortium and the cancer therapeutics research group (MC1079).

BACKGROUND: This study investigated the activity of MK-2206, an AKT inhibitor, in metastatic or recurrent nasopharyngeal carcinoma (NPC). METHOD: Oral MK-2206 at a dose of 200 mg was administered on days 1, 8, 15 and 22 of a 28-day cycle until progression. Plasma EBV DNA clearance during the first month of treatment was measured, and archived tumors were analyzed for the expression of AKT and PIK3CA mutation and PIK3CA amplification. The dual primary endpoint was objective response rate and 6-month progression-free survival (PFS) rate. RESULTS: 21 patients were enrolled and one patient achieved a partial response (5 %) and 11 had stable disease (52 %), with a median PFS of 3.5 months (95 % confidence interval, CI: 0.9-7.3). The 6-month PFS rate was 43 % (95 % CI: 22-66 %) and the median OS was 10 months (95 % CI: 5.9 months-not reached). Seven patients (33 %) experienced grade 3 toxicities which could be related to MK-2206. Macular-papular rash was the most common (n = 6), followed by hyperglycemia (n = 2) and fatigue (n = 1). In the 12 tumor samples analyzed, PIK3CA amplification was detected in one patient's primary NPC, who had SD lasting over 12 months. Patients with decreasing EBV DNA values over time were more likely to be alive and progression-free for at least 6 months than those without a decrease (p = 0.001). CONCLUSION: The study was terminated due to the limited activity observed in this heavily pre-treated group of patients. Further studies are needed to elucidate the optimal way of selecting patients for AKT inhibitors.

Efficacy and toxicity of intensity-modulated radiation therapy for prostate cancer in Chinese patients.

OBJECTIVE: To report the treatment efficacy and toxicity profile of intensitymodulated radiation therapy in Chinese patients with clinically localised prostate cancer. DESIGN: Historical cohort study. SETTING: Oncology unit in a university teaching hospital in Hong Kong. PATIENTS: Patients with clinically localised prostate cancer undergoing intensity-modulated radiation therapy in our institution between May 2001 and November 2009 were reviewed. MAIN OUTCOME MEASURES: The 5-year biochemical failure­free survival, 5-year overall survival, as well as acute/late gastro-intestinal toxicities and genito-urinary toxicities. RESULTS: A total of 182 patients were treated with prostate intensitymodulated radiation therapy with or without whole-pelvic radiotherapy. The median follow-up was 44 months. The median patient age was 72 years. Overall survival of the cohort was 92% after 5 years. The favourable, intermediate, and unfavourable risk category distributions of the National Comprehensive Cancer Network were 21 (12%), 42 (23%), and 119 (65%), respectively. The 5-year actuarial biochemical failure­free survival rates for patients in these categories were 95%, 82%, and 80%, respectively. Multivariate analysis identified early tumour stage, low pre-treatment prostate-specific antigen levels, and the use of adjuvant androgen deprivation as independent prognostic factors for better biochemical failure­free survival. Grade 2 and 3 late gastro-intestinal/genito-urinary toxicities occurred in 8%/3% and 4%/3% of the patients, respectively. CONCLUSION: Intensity-modulated radiation therapy for prostate cancer is feasible and safe in the Chinese population. These data are consistent with the results of other series in Caucasian populations.

A phase II study of concurrent cetuximab-cisplatin and intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: Based on our previous work on the clinical activity of cetuximab in recurrent nasopharyngeal carcinoma (NPC), we evaluated the feasibility of adding cetuximab to concurrent cisplatin and intensity-modulated radiotherapy (IMRT) in locoregionally advanced NPC. PATIENTS AND METHODS: Patients with American Joint Committee on Cancer stage III-IVB NPC were given an initial dose of cetuximab (400 mg/m(2)) 7-10 days before receiving concurrent IMRT, weekly cisplatin (30 mg/m(2)/week) and cetuximab (250 mg/m(2)/week). RESULTS: Thirty patients (median age of 45 years) with stage III (67%), IVA (30%) and IVB (3%) nonkeratinizing NPC were enrolled. Grade 3-4 oropharyngeal mucositis occurred in 26 (87%) patients and 10 (33%) patients required short-term nasogastric feeding. Grade 3 radiotherapy-related dermatitis occurred in six patients (20%) and three patients (10%) had grade 3 cetuximab-related acneiform rash. These grade 3-4 skin and mucosal toxic effects were manageable and reversible. At a median follow-up of 31.8 months [95% confidence interval (CI) 26.2-32.1 months], the 2-year progression-free survival was 86.5% (95% CI 74.3% to 98.8%). CONCLUSIONS: Concurrent administration of cetuximab, weekly cisplatin and IMRT is a feasible strategy against locoregionally advanced NPC. Preliminary survival data compare favorably with historic data and further follow-up is warranted.

Hemorrhagic complications in a phase II study of sunitinib in patients of nasopharyngeal carcinoma who has previously received high-dose radiation.

BACKGROUND: We aimed to evaluate the safety and efficacy of single-agent sunitinib in nasopharyngeal carcinoma (NPC). METHODS: Eligible patients had progressive disease after prior platinum-based chemotherapy. Sunitinib was given as continuous once-daily dosing of 37.5 mg in 4-week cycles until progression. RESULTS: Thirteen patients were enrolled. Recruitment was stopped after two patients died of hemorrhagic events. All patients had previously received curative radiotherapy (RT) to nasopharynx/neck (including nine patients who had chemoradiotherapy). Patients received a median of three cycles of sunitinib. One patient was still on sunitinib with stable disease after 24 cycles. Hemorrhagic events occurred in nine patients (64%), including epistaxis in six, hemoptyses in three and hematemesis in two patients. Prior RT to thorax was significantly associated with hemoptyses (P = 0.03). Two patients with local tumor invasion into the carotid sheath developed fatal epistaxis/hematemesis within the first cycle of sunitinib, likely due to internal carotid blowout after tumor shrinkage. CONCLUSIONS: Sunitinib demonstrated modest clinical activity in heavily pretreated NPC patients. However, the high incidence of hemorrhage from the upper aerodigestive tract in NPC patients who received prior high-dose RT to the region is of concern. Direct vascular invasion by tumors appeared to increase the risk of serious bleeding.

A split-organ delineation approach for dose optimisation for intensity-modulated radiotherapy for advanced T-stage nasopharyngeal carcinoma.

AIMS: To assess the dosimetric effect of using a split-organ delineation approach during intensity-modulated radiotherapy (IMRT) treatment planning for advanced T-stage nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Twenty NPC patients with T3-4 tumours were studied. A reference (REF) IMRT plan was generated based on a standard treatment planning protocol, with a set of user-defined dose constraints for optimisation. An investigative (INV) IMRT plan was then generated based on the same protocol, but treating several organs at risk (OARs; parotid glands, temporal lobes, cochlea, auditory nerves and planning organ at risk volume [PRV] of the brainstem) as split organs consisting of target-overlapping and non-target-overlapping sub-segments. These sub-segments were assigned independent dose constraints. The REF and INV plans were compared with respect to target coverage and OAR sparing. Target coverage was evaluated by the Dmin (minimum dose), V66/V60 (percentage volume of gross target volume [GTV]/planning target volume [PTV] receiving 66 Gy/60 Gy), target conformity index (CI), and tumour control probability (TCP). The sparing of OARs was evaluated by the commonly used dose end points for the respective OAR, and normal tissue complication probability (NTCP). RESULTS: For PTV coverage, the INV plan was superior to the REF plan in terms of Dmin (P=0.000), CI (P=0.005) and TCP (P=0.002). This is attributed to an increase in dose to the PTV-OAR overlapping sub-segments. Regarding the sparing of OARs, there was a significant reduction in the mean dose of the parotid glands (P=0.002), and a slight, but non-significant, increase in NTCP of the temporal lobes, cochlea and brainstem. CONCLUSIONS: Using a split-organ delineation approach in IMRT treatment planning for advanced T-stage NPC, a significant improvement in the target coverage and TCP could be achieved, whereas the mean dose of the parotid was reduced significantly. There was insignificant change in the NTCP of the temporal lobe, parotid gland, cochlea and brainstem, but a significant change in the NTCP of the auditory nerve. The approach provides the planner extra room to manipulate the dose constraints during optimisation, and to obtain the desired result in less attempts. This approach also has the potential to be used in a broader context for IMRT planning for other tumour sites.

Diffusion-Weighted Imaging of Nasopharyngeal Carcinoma: Can Pretreatment DWI Predict Local Failure Based on Long-Term Outcome?

BACKGROUND AND PURPOSE: Pretreatment prediction of patients with nasopharyngeal carcinoma who will fail conventional treatment would potentially allow these patients to undergo more intensive treatment or closer posttreatment monitoring. The aim of the study was to determine the ability of pretreatment DWI to predict local failure in patients with nasopharyngeal carcinoma based on long-term clinical outcome. MATERIALS AND METHODS: One hundred fifty-eight patients with pretreatment DWI underwent analysis of the primary tumor to obtain the ADC mean, ADC skewness, ADC kurtosis, volume, and T-stage. Univariate and multivariate analyses using logistic regression were performed to compare the ADC parameters, volume, T-stage, and patient age in primary tumors with local failure and those with local control, by using a minimum of 5-year follow-up to confirm local control. RESULTS: Local control was achieved in 131/158 (83%) patients (range, 60.3-117.7 months) and local failure occurred in 27/158 (17%) patients (range, 5.2-79.8 months). Compared with tumors with local control, those with local failure showed a significantly lower ADC skewness (ADC values with the greatest frequencies were shifted away from the lower ADC range) (P = .006) and lower ADC kurtosis (curve peak broader) (P = .024). The ADC skewness remained significant on multivariate analysis (P = .044). There was a trend toward higher tumor volumes in local failure, but the volume, together with T-stage and ADC mean, were not significantly different between the 2 groups. CONCLUSIONS: Pretreatment DWI of primary tumors found that the skewness of the ADC distribution curve was a predictor of local failure in patients with nasopharyngeal carcinoma, based on long-term clinical outcome.

Perturbation of Hoxb5 signaling in vagal and trunk neural crest cells causes apoptosis and neurocristopathies in mice.

Neural crest cells (NCCs) migrate from different regions along the anterior-posterior axis of the neural tube (NT) to form different structures. Defective NCC development causes congenital neurocristopathies affecting multiple NCC-derived tissues in human. Perturbed Hoxb5 signaling in vagal NCC causes enteric nervous system (ENS) defects. This study aims to further investigate if perturbed Hoxb5 signaling in trunk NCC contributes to defects of other NCC-derived tissues besides the ENS. We perturbed Hoxb5 signaling in NCC from the entire NT, and investigated its impact in the development of tissues derived from these cells in mice. Perturbation of Hoxb5 signaling in these NCC resulted in Sox9 downregulation, NCC apoptosis, hypoplastic sympathetic and dorsal root ganglia, hypopigmentation and ENS defects. Mutant mice with NCC-specific Sox9 deletion also displayed some of these phenotypes. In vitro and in vivo assays indicated that the Sox9 promoter was bound and trans-activated by Hoxb5. In ovo studies further revealed that Sox9 alleviated apoptosis induced by perturbed Hoxb5 signaling, and Hoxb5 induced ectopic Sox9 expression in chick NT. This study demonstrates that Hoxb5 regulates Sox9 expression in NCC and disruption of this signaling causes Sox9 downregulation, NCC apoptosis and multiple NCC-developmental defects. Phenotypes such as ENS deficiency, hypopigmentation and some of the neurological defects are reported in patients with Hirschsprung disease (HSCR). Whether dysregulation of Hoxb5 signaling and early depletion of NCC contribute to ENS defect and other neurocristopathies in HSCR patients deserves further investigation.

The impact of 18F-FDG PET/CT on assessment of nasopharyngeal carcinoma at diagnosis.

The aim of this study was to determine whether the use of whole-body (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography (PET)/CT alters staging and management of nasopharyngeal carcinoma (NPC) when compared with current staging practice. 52 patients with Stage III-IV NPC without distant metastases on chest X-ray/CT, abdominal ultrasound or bone scan were recruited for the study. Whole-body (18)F-FDG PET/CT and MRI of the head and neck were performed. The scans were compared for extent of the primary tumour (PT), cervical nodal metastases (CNM) and distant metastases (DM). Any discordance in results was assessed with respect to staging and impact on management. MRI and (18)F-FDG PET/CT scans were discordant in 28 (54%) patients. There was discordance in the extent of PT at 28 sites; in all sites, MRI showed more extensive tumour involving the nasopharynx (n = 8), skull base (n = 14), brain (n = 4) and orbit (n = 2). There was also variation among the extent of CNM in four nodes of the retropharyngeal region, with the nodes being positive on MRI. (18)F-FDG PET /CT did not identify any additional distant metastases but did identify a second primary tumour in the colon. The additional use of (18)F-FDG PET/CT did not "up-stage" the overall stage or change management in any patient. In conclusion, there is discordance between MRI and (18)F-FDG PET/CT, and the additional use of (18)F-FDG PET/CT for the current assessment of NPC at diagnosis does not appear to be justified in this cohort of patients.