Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Comparison of Epstein-Barr virus DNA level in plasma, peripheral blood cell and tumor tissue in nasopharyngeal carcinoma.

BACKGROUND: The plasma Epstein-Barr virus DNA (EBV-DNA) level has been found to be an indicator for staging and prognosis of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: The EBV-DNA level in plasma, peripheral blood cells (PBC) and neoplastic tissues was quantitatively analyzed and potential associations with clinical parameters of NPC were investigated. RESULTS: The plasma EBV-DNA detecting rate and level in NPC (92%, 82,500 copies/ml) was significantly higher than that in NPC after treatment (19%, 0 copy/ml) and in controls (12%, 0 copy/ml) (p < 0.001); while there was no significance of the PBC EBV-DNA detecting rate and EBV-DNA load in NPC before (24%, 0 copy/actin) and after treatment (14%, 0 copy/actin), and in controls (16%, 0 copy/actin). The plasma EBV-DNA level was not correlated to the PBC EBV-DNA load in NPC before (p = 0.92) and after treatment (p = 0.267), and in controls (p = 0.735). The EBV-DNA level in NPC tumor (27.8 copies/actin) was significantly higher than that in nasopharyngitis and was positively correlated to the ratio of EBER1-positive cells on the NPC section (p = 0.001). The plasma EBV-DNA level was significantly increased in TNM stages I, II, III and IV NPC, whereas there was no significant difference of PBC EBV-DNA load in different stage NPC. CONCLUSION: Our results indicate that plasma EBV-DNA is a more sensitive and reliable biomarker than PBC EBV-DNA for diagnosis, staging and therapeutic effect evaluation at a molecular level in NPC clinical practice. Plasma EBV-DNA may derive from the cancer cells and PBC EBV-DNA from circulating mononuclear cells in NPC patients.

[Quantitative analysis of Epstein-Barr virus DNA in plasma and peripheral blood cells in patients with nasopharyngeal carcinoma].

OBJECTIVE: To quantitative analysis of Epstein-Barr virus (EBV) DNA levels in plasma, peripheral blood cells (PBCs) and tumor tissue in nasopharyngeal carcinoma (NPC), to investigate the relationship between EBV-DNA levels and clinical parameters. METHODS: Blood of 150 primary NPC and 49 corresponding tumor tissues, 47 nasopharyngitis tissues and blood of 75 controls were entered this investigation. Plasma and PBCs were isolated for quantitative detection of EBV-DNA by using real-time quantitative PCR (RQ-PCR). The paraffin-embedded tissue sections were conducted to quantitative detection of EBV-DNA, and EBER1 in situ hybridization (ISH) for calculating the percentage of positive cells on the tissue section. RESULTS: Plasma EBV-DNA levels and detecting rate in NPC before treatment (median 82 500 copies/ml, 92%) were significantly higher than that in NPC after treatment (median 0 copy/ml, 19%) and in controls (median 0 copy/ml, 12%) (P < 0.05), whereas there was no significant difference between NPC after treatment and controls (P > 0.05). There was no significant difference of PBCs EBV-DNA load and detecting rate in NPC before (0 copy/actin, 24%) and after treatment (0 copy/actin, 14%), as well as in controls (0 copy/actin, 16%) (P > 0.05). Plasma EBV-DNA level was not correlated to PBCs EBV-DNA load in NPC before (P = 0.92) and after treatment (P = 0.27), and controls (P = 0.74). EBV-DNA level (27.8 copies/actin) in NPC tumor tissues was significantly higher than that in nasopharyngitis (0 copy/actin) (P < 0.05), and was positively correlated to the ratio of EBER1 positive cells to total cells on the NPC section. In NPC patients, plasma EBV-DNA level was significantly increased in TNM stage I (2500 copies/ml), II (32 590 copies/ml), III (86 000 copies/ml) and IV (166 200 copies/ml), whereas there was no significantly difference of PBCs EBV-DNA loads in difference stages of NPC. CONCLUSION: Plasma EBV-DNA level is a more sensitive and reliable biomarker than PBCs EBV-DNA loads for reflection the tumor volumes in NPC patients. Plasma EBV-DNA detection will improve TNM staging in NPC clinical practice on molecular level.

Toxicity of concurrent chemoradiotherapy with cetuximab for locoregionally advanced nasopharyngeal carcinoma.

Overexpression of the epidermal growth factor receptor can be found in 80 % of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and is associated with shorter survival. In this work, we evaluated the feasibility of adding cetuximab to concurrent cisplatin and radiotherapy (RT) in locoregionally advanced NPC. Twenty-eight patients with locoregionally advanced NPC who received the combination therapy were retrospectively reviewed and short-term efficacy was evaluated. Grade 3-4 oral mucositis occurred in 20 (71.4 %) patients. Grade 3 radiotherapy-related dermatitis occurred in seven patients (25 %). Three patients (14.3 %) had grade 3 and one patient (3.6 %) had grade 4 cetuximab-related acneiform rashes. These grade 3-4 skin and mucosal toxic effects were manageable and reversible. At a median follow-up of 33.4 months (95 % CI 29.2-38.1 months), the 2-year progression-free survival was 89.3 % (95 % CI 76.4-98.1 %). In conclusion, concurrent administration of cetuximab, cisplatin and RT is a feasible strategy against locoregionally advanced NPC. Preliminary survival data compare favorably with historic data and further follow-up is warranted.

Transdermal fentanyl for pain due to chemoradiotherapy-induced oral mucositis in nasopharyngeal cancer patients: evaluating efficacy, safety, and improvement in quality of life.

This study evaluated the efficacy, safety, and quality of life (QoL) measure of transdermal fentanyl (TDF) for moderate-to-severe pain due to oral mucositis caused by chemoradiotherapy in patients with advanced nasopharyngeal carcinoma (NPC). Patients with NPC who experienced moderate-to-severe oral mucosal pain during chemoradiotherapy (n = 78) received TDF for pain relief. Pain relief and QoL were compared before and after treatment. The mean numeric rating scale score was reduced from 7.41 ± 0.96 before treatment to 5.54 ± 0.86, 3.27 ± 0.73, 2.88 ± 0.62, and 2.82 ± 0.68 on days 1, 4, 7, and 10, respectively, after treatment (P < 0.001). Karnofsky performance status and SPAASMS (Score for pain, Physical activity levels, Additional pain medication, Additional physician/emergency room visits, Sleep, Mood, and Side effects) scores showed significant improvement after treatment, indicating an improved QoL of patients (both P<0.001). The most common adverse reactions were nausea and vomiting (10.26%). No serious life-threatening adverse events and no symptoms of drug withdrawal were observed. TDF is effective, safe, and improves QoL in treating pain due to oral mucositis caused by chemoradiotherapy in NPC patients.

Mepilex Lite dressings for managing acute radiation dermatitis in nasopharyngeal carcinoma patients: a systematic controlled clinical trial.

More than 60% nasopharyngeal carcinoma patients receiving the radical radiotherapy treatment will develop moist desquamation skin reaction at some time during the course of treatment. The purpose of this study was to compare the effectiveness of Mepilex Lite dressings and the usual care in the healing of postirradiation dermatitis in nasopharyngeal carcinoma patients. This was a randomized controlled trial, and a sample of 88 nasopharyngeal carcinoma patients who had developed radiation dermatitis was assessed. Comparisons were made regarding parameters related to wound healing, including healing time and wound pain, and also regarding the impact of wound on the patient, including restriction of neck movement, sleep problem, and disturbance in body image. The results showed that radiation-induced dermatitis in the study group (Mepilex Lite, 43 patients) healed in a median of 16 days, which was significantly different from the healing time in the control group (median 23 days, 45 patients; P = 0.009). No statistically significant differences were detected between the 2 groups with respect to neck mobility and appearance disturbance. However, Mepilex significantly improved patients' sleep (P = 0.005). The researchers conclude that Mepilex Lite dressing provides a promising alternative to radiation dermatitis of nasopharyngeal carcinoma patients and is worthy of further research.