Yan Ping Mao

Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial

BACKGROUND The effect of the addition of adjuvant chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to assess the contribution of adjuvant chemotherapy to concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone. METHODS We did an open-label phase 3 multicentre randomised controlled trial at seven institutions in China. Randomisation was by a computer-generated random number code. Patients were stratified by treatment centre and randomly assigned in blocks of four. Treatment allocation was not masked. We randomly assigned patients with non-metastatic stage III or IV (except T3-4N0) nasopharyngeal carcinoma to receive concurrent chemoradiotherapy plus adjuvant chemotherapy or concurrent chemoradiotherapy alone. Patients in both groups received 40 mg/m(2) cisplatin weekly up to 7 weeks, concurrently with radiotherapy. Radiotherapy was given as 2·0-2·27 Gy per fraction with five daily fractions per week for 6-7 weeks to a total dose of 66 Gy or greater to the primary tumour and 60-66 Gy to the involved neck area. The concurrent chemoradiotherapy plus adjuvant chemotherapy group subsequently received 80 mg/m(2) adjuvant cisplatin and 800 mg/m(2) per day fluorouracil for 120 h every 4 weeks for three cycles. Our primary endpoint was failure-free survival. We did efficacy analyses in our intention-to-treat population. Our trial is ongoing; in this report we present the 2 year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT00677118. FINDINGS 251 patients were assigned to the concurrent chemoradiotherapy plus adjuvant chemotherapy group and 257 to the concurrent chemoradiotherapy alone group. After a median follow-up of 37·8 months (range 1·3-61·0), the estimated 2 year failure-free survival rate was 86% (95% CI 81-90) in the concurrent chemoradiotherapy plus adjuvant chemotherapy group and 84% (78-88) in concurrent chemoradiotherapy only group (hazard ratio 0·74, 95% CI 0·49-1·10; p=0·13). Stomatitis was the most commonly reported grade 3 or 4 adverse event during both radiotherapy (76 of 249 patients in the concurrent chemoradiotherapy plus adjuvant chemotherapy group and 82 of 254 in the concurrent chemoradiotherapy alone group) and adjuvant chemotherapy (43 [21%] of 205 patients treated with adjuvant chemotherapy). INTERPRETATION Adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve failure-free survival after concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma. Longer follow-up is needed to fully assess survival and late toxic effects, but such regimens should not, at present, be used outside well-designed clinical trials. FUNDING Sun Yat-sen University Clinical Research 5010 Programme (No 2007037), Science Foundation of Key Hospital Clinical Programme of Ministry of Health PR China (No 2010-178), and Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2010).

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.

How Does Magnetic Resonance Imaging Influence Staging According to AJCC Staging System for Nasopharyngeal Carcinoma Compared With Computed Tomography

PURPOSE To analyze the degree and pattern of influence of magnetic resonance imaging (MRI) on staging according to the 6th edition of the American Joint Committee on Cancer staging system compared with computed tomography (CT). METHODS AND MATERIALS The MRI and CT scans and medical records of 420 consecutive patients with newly diagnosed nasopharyngeal carcinoma (NPC) were analyzed retrospectively. The tumors of all patients were staged according to the 6th edition of the American Joint Committee on Cancer staging system. RESULTS A significant difference (p <0.05) was found between CT and MRI in demonstrating involvement in the oropharynx (CT, 25.0% vs. MRI, 14.5%), prevertebral muscle (CT, 18.4% vs. MRI, 36.0%), parapharyngeal space (CT, 82.6% vs. MRI, 68.8%), skull base (CT, 31.0% vs. MRI, 52.6%), sphenoid sinus (CT, 13.6% vs. MRI, 16.7%), ethmoid sinus (CT, 7.1% vs. MRI, 3.3%), intracranial area (CT, 4.8% vs. MRI, 16.0%), and retropharyngeal lymph nodes (CT, 52.1% vs. MRI, 69.0%). The incidence of cervical lymph node metastasis and lymph node metastasis at each level was similar according to CT and MRI. MRI resulted in changes in 49.8% of T stage cases, 10.7% of N stage cases, and 38.6% of clinical stage cases. CONCLUSION MRI demonstrated early primary tumor involvement more precisely and deep primary tumor infiltration more easily. The use of MRI caused dramatic changes in the results of the T stage and clinical staging and should be preferred to CT in staging NPC. Patients would benefit from changes in treatment strategies resulting from the use of MRI.

Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial

BACKGROUND The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial. METHODS We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III-IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18-59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m2 cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m2 on day 1), intravenous cisplatin (60 mg/m2 on day 1), and continuous intravenous fluorouracil (600 mg/m2 per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT01245959. FINDINGS Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38-49), 3-year failure-free survival was 80% (95% CI 75-85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66-78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48-0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 [42%] vs 17 [7%]), leucopenia (98 [41%] vs 41 [17%]), and stomatitis (98 [41%] vs 84 [35%]). INTERPRETATION Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities. FUNDING Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000).

Is primary tumor volume still a prognostic factor in intensity modulated radiation therapy for nasopharyngeal carcinoma

BACKGROUND AND PURPOSE To evaluate the prognostic value of gross primary tumor volume (GTV-P) in nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiotherapy (IMRT). METHODS AND MATERIALS A total of 694 nonmetastatic and histologically proven NPC patients who underwent IMRT were retrospectively reviewed. Samples were split randomly into a training set (n=232) and a test set (n=462) to analysis. The receiver operating characteristic (ROC) curves were calculated to identify the cut-off point and test the prognostic validity of the GTV-P. The correlations between GTV-P and the American Joint Committee on Cancer (AJCC) disease stages were also analyzed. RESULTS The 5-year disease-free survival (DFS), overall survival (OS), local relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) rates for NPC patients with GTV-P<19 vs. ≥19 ml were 94.9% vs. 64.8%, 97.0% vs. 76.4%, 98.2% vs. 92.5% and 97.1% vs. 75.2%, respectively (all P<0.05) in all patients. Multivariate analysis indicated GTV-P was an independent prognostic factor. The ROC curve verified that the predictive ability of T classifications was improved when combined with GTV-P (P<0.001). CONCLUSIONS GTV-P is an independent prognostic indicator for treatment outcome after IMRT, and significantly improves the prognostic validity of T classifications in NPC.

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.

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.

Re-Evaluation of 6th Edition of AJCC Staging System for Nasopharyngeal Carcinoma and Proposed Improvement Based on Magnetic Resonance Imaging

PURPOSE To use magnetic resonance imaging to re-evaluate and improve the 6th edition of the International Union Against Cancer/American Joint Committee on Cancer staging system for nasopharyngeal carcinoma. METHODS AND MATERIALS We performed a retrospective review of the data from 924 biopsy-proven nonmetastatic nasopharyngeal carcinoma cases. All patients had undergone magnetic resonance imaging examinations and received radiotherapy as their primary treatment. RESULTS The T classification, N classification, and stage group were independent predictors. No significant differences in the local failure hazards between adjacent T categories were observed between Stage T2b and T1, Stage T2b and T2a, and Stage T2b and T3. Although the disease failure hazards for Stage T1 were similar to those for Stage T2a, those for Stage T2b were similar to those for Stage T3. Survival curves of the different T/N subsets showed a better segregation when Stage T2a was downstaged to T1, T2b and T3 were incorporated into T2, and the nodal greatest dimension was rejected. The disease failure hazard for T3N0-N1 subsets were similar to those of the T1-T2N1 subsets belonging to Stage II; the same result was found for the T4N0-N2 subsets in the sixth American Joint Committee on Cancer staging system. However, the staging system we propose shows more consistent hazards within the same stage group and better survival discrimination among T categories, N categories, and overall stages. CONCLUSION Using the 6th American Joint Committee on Cancer staging system produces 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 recategorizing the T, N, and group stage criteria.

The seventh edition of the UICC/AJCC staging system for nasopharyngeal carcinoma is prognostically useful for patients treated with intensity-modulated radiotherapy from an endemic area in China

PURPOSE To evaluate the 7th edition of the International Union against Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system for nasopharyngeal carcinoma (NPC) in patients treated with intensity-modulated radiotherapy. METHODS AND MATERIALS We performed a retrospective data review from 512 patients with biopsy-proven, nonmetastatic NPC in our cancer center (South China) between January 2003 and December 2006. RESULTS The local relapse-free survival rates (LRFS) and disease failure-free survival rates (DFS) in the 6th edition system T1 and T2a stages were not significantly different (P=0.629 and P=0.820), while the LRFS and DFS of T1 and T2 using the 7th edition system were significantly different (P=0.019 and P=0.009). The LRFS and DFS between T2 and T3 in the 7th edition systems were lack of significance (P=0.874 and P=0.589). The total difference in distant metastasis-free survival rate and DFS between N0 and N3 was slightly larger using the 7th edition system than the 6th edition. The nodal dimension of a cervical lymph node was not a significant prognostic factor. CONCLUSIONS We observed a better segregation of survival curves by using the 7th edition system. It seems reasonable to downstage T3 as T2 and reject nodal greatest dimension from the N-staging system in the future revised edition.

Extension of Local Disease in Nasopharyngeal Carcinoma Detected by Magnetic Resonance Imaging: Improvement of Clinical Target Volume Delineation

PURPOSE To define by MRI the local extension patterns in patients presenting with nasopharyngeal carcinoma (NPC) and to improve clinical target volume delineation. METHODS AND MATERIALS Consecutive patients (N = 943) with newly diagnosed and untreated NPC were included in this study. All patients underwent MRI of the nasopharynx and neck, which was reviewed by two radiologists. RESULTS According to the incidence rates of tumor invasion, the anatomic sites surrounding the nasopharynx were initially classified into three risk grades: high risk (> or = 35%), medium risk (> or = 5-35%), and low risk (< 5%). Incidence rates of tumor invasion into anatomic sites at medium risk were increased, reaching 55.2%, when adjacent high-risk anatomic sites were involved. However, the rates were substantially lower, mostly < 10%, when adjacent high-risk sites were not involved. The incidence rates of concurrent tumor invasion into bilateral sites were < 10%, except in the case of prevertebral muscle involvement (13.1%). Among the 178 incidences of cavernous sinus invasion, there were often two or more simultaneous infiltration routes (60.6%); when only one route was involved, the foramen ovale was the most common (26.4%). CONCLUSIONS In patients presenting with NPC, local disease spreads stepwise from proximal sites to more distal sites. Tumors extend quickly through privileged pathways such as neural foramina. The anatomic sites surrounding the nasopharynx are at low risk of concurrent bilateral tumor invasion. Selective radiotherapy of the local disease in NPC may be feasible.

Baseline serum lactate dehydrogenase levels for patients treated with intensity-modulated radiotherapy for nasopharyngeal carcinoma: a predictor of poor prognosis and subsequent liver metastasis.

PURPOSE To evaluate the prognostic value of baseline serum lactate dehydrogenase (LDH) levels in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS Cases of NPC (n = 465) that involved treatment with IMRT with or without chemotherapy were retrospectively analyzed. RESULTS The mean (±SD) and median baseline serum LDH levels for this cohort were 172.77 ± 2.28 and 164.00 IU/L, respectively. Levels of LDH were significantly elevated in patients with locoregionally advanced disease (p = 0.016). Elevated LDH levels were identified as a prognostic factor for rates of overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS), with p values <0.001 in the univariate analysis and p < 0.001, p = 0.004, and p = 0.003, respectively, in the multivariate analysis. Correspondingly, the prognostic impact of patient LDH levels was found to be statistically significant for rates of OS, DFS, and DMFS (p = 0.028, 0.024, and 0.020, respectively). For patients who experienced subsequent liver failure after treatment, markedly higher pretreatment serum LDH levels were detected compared with patients experiencing distant metastasis events at other sites (p = 0.032). CONCLUSIONS Elevated baseline LDH levels are associated with clinically advanced disease and are a poor prognosticator for OS, DFS, and DMFS for NPC patients. These results suggest that elevated serum levels of LDH should be considered when evaluating treatment options.