S. F. Leung

Multicenter prospective randomized trial comparing standard esophagectomy with chemoradiotherapy for treatment of squamous esophageal cancer: early results from the Chinese University Research Group for Esophageal Cancer (CURE).

We conducted a prospective randomized trial to compare the efficacy and survival outcome by chemoradiation with that by esophagectomy as a curative treatment. From July 2000 to December 2004, 80 patients with potentially resectable squamous cell carcinoma of the mid or lower thoracic esophagus were randomized to esophagectomy or chemoradiotherapy. A two-or three-stage esophagectomy with two-field dissection was performed. Patients treated with chemoradiotherapy received continuous 5-.uorouracil infusion (200 mg/m2/day) from day 1 to 42 and cisplatin (60 mg/m2) on days 1 and 22. The tumor and regional lymphatics were concomitantly irradiated to a total of 50–60 Gy.Tumor response was assessed by endoscopy, endoscopic ultrasonography, and computed tomography scan. Salvage esophagectomy was performed for incomplete response or recurrence. Forty-four patients received standard esophagectomy, whereas 36 were treated with chemoradiotherapy. Median follow-up was 16.9 months. The operative mortality was 6.8%. The incidence of postoperative complications was 38.6%. No difference in the early cumulative survival was found between the two groups (RR = 0.89; 95% confidence interval, 0.37-2.17; log-rank test P =0.45). There was no difference in the disease-free survival. Patients treated with surgery had a slightly higher proportion of recurrence in the mediastinum, whereas those treated with chemoradiation sustained a higher proportion of recurrence in the cervical or abdominal regions. Standard esophagectomy or chemoradiotherapy offered similar early clinical outcome and survival for patients with squamous cell carcinoma of the esophagus. The challenge lies in the detection of residue disease after chemoradiotherapy.

Phase II study of neoadjuvant carboplatin and paclitaxel followed by radiotherapy and concurrent cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: Therapeutic monitoring with plasma Epstein-Barr virus DNA

PURPOSEnTo assess the efficacy of neoadjuvant paclitaxel and carboplatin (TC) followed by concurrent cisplatin and radiotherapy (RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and to monitor treatment response with plasma Epstein-Barr virus (EBV) DNA.nnnPATIENTS AND METHODSnThirty-one patients with International Union Against Cancer stages III and IV undifferentiated NPC had two cycles of paclitaxel (70 mg/m2 on days 1, 8, and 15) and carboplatin (area under the curve 6 mg/mL/min on day 1) on a 3-weekly cycle, followed by 6 to 8 weeks of cisplatin (40 mg/m2 weekly) and RT at 66 Gy in 2-Gy fractions. Plasma EBV DNA was measured serially using the real-time quantitative polymerase chain reaction method. Results All patients completed planned treatment. Response to neoadjuvant TC was as follows: 12 patients (39%) achieved partial response (PR) and 18 achieved (58%) complete response (CR) in regional nodes; five patients (16%) achieved PR and no patients achieved CR in nasopharynx. At 6 weeks after RT, one patient (3%) achieved PR and 30 patients (97%) achieved CR in regional nodes, and 31 patients (100%) achieved CR in nasopharynx; 29 patients (93%) had EBV DNA level of less than 500 copies/mL. Neoadjuvant TC was well tolerated, and the most common acute toxicity of cisplatin plus RT was grade 3 mucositis (55%). At median follow-up of 33.7 months (range, 7 to 39.3 months), six distant and three locoregional failures occurred. Plasma EBV DNA level increased significantly in eight of nine patients who experienced treatment failure but did not increase in those who did not. The 2-year overall and progression-free survival rates were 91.8% and 78.5%, respectively. CONCLUSION This strategy was feasible and resulted in excellent local tumor control. Serial plasma EBV DNA provides a noninvasive method of monitoring response in NPC.

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

BACKGROUNDnBased 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.nnnPATIENTS AND METHODSnPatients with American Joint Committee on Cancer stage III-IVB NPC were given an initial dose of cetuximab (400 mg/m2) 7-10 days before receiving concurrent IMRT, weekly cisplatin (30 mg/m2/week) and cetuximab (250 mg/m2/week).nnnRESULTSnThirty 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%).nnnCONCLUSIONSnConcurrent 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.BACKGROUNDnBased 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.nnnPATIENTS AND METHODSnPatients 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).nnnRESULTSnThirty 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%).nnnCONCLUSIONSnConcurrent 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.

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.

Multicenter phase II study of gemcitabine and oxaliplatin in advanced nasopharyngeal carcinoma—correlation with excision repair cross-complementing-1 polymorphisms

BACKGROUNDnNasopharyngeal carcinoma (NPC) is a platinum-sensitive cancer and excision repair cross-complementing group 1 (ERCC1) polymorphisms have been shown to predict survival in several cancers following platinum therapy.nnnPATIENTS AND METHODSnThis multicenter study evaluated the activity of oxaliplatin and prolonged infusion of gemcitabine (GEMOX regimen) in recurrent NPC. Baseline blood samples were genotyped for the presence of ERCC1-118 gene polymorphisms.nnnRESULTSnForty-two patients were recruited, of whom most (61%) had metastatic disease. Of the 40 patients evaluated for response, the respective overall response and disease control rates were 56.1% and 90.2%. At a median follow-up of 14.8 months, the respective median overall survival and time to progression were 19.6 months [95% confidence interval (CI) = 12.8-22 months] and 9 months (95% CI = 7.3-10 months). Grade 3-4 toxic effects were uncommon. The distribution of ERCC1-118 genotypes from 29 patients was C/C (n = 17, 40.5%), C/T (n = 10, 23.8%) and T/T (n = 2, 4.8%). No differences in survival or response rates were found between genotypes.nnnCONCLUSIONSnGEMOX is active in the treatment of recurrent NPC. Detection of single-nucleotide gene polymorphisms from genomic DNA in peripheral blood is feasible in NPC and further studies are warranted.

Early Swallowing Problems in a Cohort of Patients With Nasopharyngeal Carcinoma: Symptomatology and Videofluoroscopic Findings

Objective: To study the incidence and the degree of swallowing dysfunction in patients with nasopharyngeal carcinoma (NPC) who underwent radiation therapy treatment.

Concurrent Chemoradiotherapy or Endoscopic Stenting for Advanced Squamous Cell Carcinoma of Esophagus: A Case-Control Study

We evaluated the role of chemoradiotherapy (CRT) for patients with inoperable squamous esophageal cancer. Patients with locally advanced or metastatic squamous esophageal carcinoma who received CRT were recruited. The CRT consists of continuous infusion of 5-fluorouracil at 200 mg/m2/day, and cisplatin at 60 mg/m2 on days 1 and 22, with concurrent radiotherapy for a total of 50 to 60 Gy in 25 to 30 fractions over 6 weeks. Efficacy was assessed by endoscopy and computed tomographic scan before and 8 weeks after completion of the treatment program. Median survival and the need for palliative esophageal stenting were compared with another group of patients who received endoscopic stenting. From 1996 to 2003, a total of 36 consecutive patients (33 male, mean ± SD age 63.2 ± 9.5 years) with T4 disease (81%) with or without cervical nodal metastasis (50%) received CRT, while 36 patients treated with endoscopic stenting alone were recruited as controls. Both groups were comparable in demographics, pretreatment dysphagia score, comorbidities, and tumor characteristics. CRT was completed in 32 patients (89%). There was no treatment-related mortality. Tumor volume was greatly reduced after CRT in 19 patients. Four patients (11%) received salvage esophagectomy 9 to 42 months after CRT. Compared with the stenting group, CRT statistically significantly improved 5-year survival (15% vs. 0%, P = .01), median survival (10.8 months vs. 4.0 months, P < .005), and need for stenting (22% vs. 100%, P = .005). Palliative CRT can effectively improve the symptoms of dysphagia in patients with inoperable squamous esophageal carcinoma. It results in better survival compared with endoscopic stenting in these patients.

Angiographic Features, Collaterals, and Infarct Topography of Symptomatic Occlusive Radiation Vasculopathy A Case-Referent Study

Background and Purpose— Occlusive radiation vasculopathy (ORV) predisposes head-and-neck cancer survivors to ischemic strokes. Methods— We analyzed the digital subtraction angiography acquired in 96 patients who had first-ever transient ischemic attack or ischemic strokes attributed to ORV. Another age-matched 115 patients who had no radiotherapy but symptomatic high-grade (>70%) carotid stenoses were enrolled as referent subjects. Digital subtraction angiography was performed within 2 months from stroke onset and delineated carotid and vertebrobasilar circulations from aortic arch up to intracranial branches. Two reviewers blinded to group assignment recorded all vascular lesions, collateral status, and infarct pattern. Results— ORV patients had less atherosclerotic risk factors at presentation. In referent patients, high-grade stenoses were mostly focal at the proximal internal carotid artery. In contrast, high-grade ORV lesions diffusely involved the common carotid artery and internal carotid artery and were more frequently bilateral (54% versus 22%), tandem (23% versus 10%), associated with complete occlusion in one or both carotid arteries (30% versus 9%), vertebral artery (VA) steno-occlusions (28% versus 16%), and external carotid artery stenosis (19% versus 5%) (all P<0.05). With comparable rates of vascular anomaly, ORV patients showed more established collateral circulations through leptomeningeal arteries, anterior communicating artery, posterior communicating artery, suboccipital/costocervical artery, and retrograde flow in ophthalmic artery. In terms of infarct topography, the frequencies of cortical or subcortical watershed infarcts were similar in both groups. Conclusions— ORV angiographic features and corresponding collaterals are distinct from atherosclerotic patterns at initial stroke presentation. Clinical decompensation, despite more extensive collateralization, may precipitate stroke in ORV.

Final results of a phase III randomized study of concurrent weekly cisplatin-RT versus RT alone in locoregionally advanced nasopharyngeal carcinoma (NPC)

5523 Background/Objective: NPC is highly radiosensitive and chemosensitive. 3 cycles of 3-weekly chemotherapy concurrent with RT followed by 3 cycles of adjuvant chemotherapy has improved survival over RT alone in a previous randomized study. The regimen was associated with significant toxicities. This randomized phase III study compared concurrent weekly cisplatin-RT with RT alone in patients with locoregionally advanced NPC.nnnMETHODSnPatients with Hos N2 or N3 stage or N1 stage with nodal size ≥ 4 cm were randomized to receive cisplatin 40 mg/m2 weekly up to 8 weeks concurrently with RT (CRT) or RT alone. The primary endpoints are progression-free survival (PFS) and overall survival (OS).nnnRESULTSn350 eligible patients were randomized. Baseline patient characteristics, treatment toxicities and PFS analysis at median follow up of 2.71 years have been published previously. At a median follow up of 5.5 years where 58 and 73 deaths were found out of 174 CRT and 176 RT patients respectively (95th and 5th percentiles ranging from 3.8 to 8.7 years respectively), the 5 year PFS was 62% for the CRT arm and 52% for the RT arm (p=0.0764 with a hazards ratio of 1.33 and a 95% C.I. 0.97 to 1.84). The 5 year OS was 72% for the CRT arm and 59% for the RT arm (p=0.0479) with a hazards ratio of 1.41 (95% C.I. 1.00 to 2.00). Using Cox regression analysis, male sex (p=0.0284), advanced Hos T (p=0.0002) and advanced age (p=0.0019) had poorer prognoses. The treatment-by-covariate interaction effect was not significant under the Cox model (p=0.1122, 3 d.f.). The treatment effect on OS remains borderline significant in favor of CRT (p=0.0586, with hazards ratio of 1.40 with 95% C.I. 0.99 to 1.97) after adjusting for significant covariates. There were no treatment-related deaths. In the CRT arm, 4.6% of patients had grade 4 mucositis and 12.6% of patients had grade 3 leukopenia.nnnCONCLUSIONnWeekly cisplatin-RT is well tolerated in patients with advanced NPC in endemic areas and is associated with clinically significant improvement in PFS and OS. This regime can be offered as standard treatment in locoregionally advanced NPC. No significant financial relationships to disclose.

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)

SummaryBackground 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 200xa0mg 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 (5xa0%) and 11 had stable disease (52xa0%), with a median PFS of 3.5xa0months (95xa0% confidence interval, CI: 0.9–7.3). The 6-month PFS rate was 43xa0% (95xa0% CI: 22–66xa0%) and the median OS was 10xa0months (95xa0% CI: 5.9xa0months–not reached). Seven patients (33xa0%) experienced grade 3 toxicities which could be related to MK-2206. Macular-papular rash was the most common (nu2009=u20096), followed by hyperglycemia (nu2009=u20092) and fatigue (nu2009=u20091). In the 12 tumor samples analyzed, PIK3CA amplification was detected in one patient’s primary NPC, who had SD lasting over 12xa0months. Patients with decreasing EBV DNA values over time were more likely to be alive and progression-free for at least 6xa0months than those without a decrease (pu2009=u20090.001). 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.