Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of ...tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.
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.
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.
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.
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.
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.
For the Chinese translation of the abstract see Supplementary Materials section.
•Current advances in radiation technology and introduction of chemotherapy potentially provides great value to reinvestigate clinical features and survival outcomes in patients with different NPC ...subtypes.•Type D NPC is an aggressive NPC subtype, and HR for death following disease recurrence in patients with type D NPC was 1.6 compared with type A NPC.•Annual HR in type A patients increased peaking at 12–18 months after initial treatment, and downward thereafter. Similar trend also occurred in type D during the first 5 years following treatment. Notably, a minor peak was also observed 7–8 years post treatment.•Alcohol consumption, absence of family history of cancer, and elevated EBV DNA and LDH were attributed to the development of type D tumors.
To compare clinical features and survival outcomes in patients with ascending type (type A) and descending type (type D) nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era.
A total of 5194 patients with type A and type D NPC treated at Sun Yat-sen University Cancer Center were randomly selected. Tumors that were mainly advanced local disease (T3-4 stage) with early stage cervical lymph node involvement (N0-1 stage) were determined as type A, while tumors with advanced lymph node disease (N2-3 stage) but early stage local invasion (T1-2 stage) were classified as type D NPC. Kaplan–Meier’s analysis was used to evaluate survival rates, and log-rank test survival curves were used for comparison. In the multivariate analysis Cox proportional hazard models were developed.
There was a larger proportion of type A tumors (82%) than type D tumors (18%). Compared to patients with type A tumors, those with type D tumors had increased likelihood of distant metastasis, regional recurrence, disease recurrence, and death (P < 0.001 for all), however, not for local recurrence (P < 0.001). The HR (hazard ratio) for death following recurrence of disease for type D tumors were 1.6 compared to type A tumors. Multivariate analysis revealed that elevated EBV DNA, elevated lactate dehydrogenase, alcohol consumption, and no family history of cancer attributed to the development of type D tumors. Annual hazard rate in type A patients increased, peaking at 12–18 months after initial treatment and downward thereafter. Similar trend also occurred in type D during the first 5 years following treatment. Notably, a minor peak was also observed 7–8 years post treatment.
In the IMRT era, recurrence patterns differed across tumor types. Type D NPC had a more aggressive clinical course and worse outcomes compared with type A NPC.
Cancer nanomedicine is one of the most promising domains that has emerged in the continuing search for cancer diagnosis and treatment. The rapid development of nanomaterials and nanotechnology ...provide a vast array of materials for use in cancer nanomedicine. Among the various nanomaterials, covalent organic frameworks (COFs) are becoming an attractive class of upstarts owing to their high crystallinity, structural regularity, inherent porosity, extensive functionality, design flexibility, and good biocompatibility. In this comprehensive review, recent developments and key achievements of COFs are provided, including their structural design, synthesis methods, nanocrystallization, and functionalization strategies. Subsequently, a systematic overview of the potential oncotherapy applications achieved till date in the fast-growing field of COFs is provided with the aim to inspire further contributions and developments to this nascent but promising field. Finally, development opportunities, critical challenges, and some personal perspectives for COF-based cancer therapeutics are presented.
We outline the latest developments in COF-based nanomedicines for use in oncotherapy, including material synthesis, nanocrystallization, and functionalization strategies, as well as their therapeutics applications.
Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the ...role of chemotherapy with use of intensity-modulated radiation therapy (IMRT).
To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT.
This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022.
Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m2 every 3 weeks for 3 cycles n = 169).
The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms).
Among 341 randomized patients (mean SD age, 48 10 years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, -1.4%; 1-sided 95% CI, -7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, -29% 95% CI, -39% to -20%), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation.
Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy.
ClinicalTrials.gov Identifier: NCT02633202.
Abstract Background and purpose To recommend contouring methods and atlas of organs at risk (OARs) for nasopharyngeal carcinoma (NPC) patients receiving intensity-modulated radiotherapy, in order to ...help reach a consensus on interpretations of OARs delineation. Methods and materials Two to four contouring methods for the middle ear, inner ear, temporal lobe, parotid gland and spinal cord were identified via systematic literature review; their volumes and dosimetric parameters were compared in 41 patients. Areas under the receiver operating characteristic curves for temporal lobe contouring were compared in 21 patients with unilateral temporal lobe necrosis (TLN). Results Various contouring methods for the temporal lobe, middle ear, inner ear, parotid gland and spinal cord lead to different volumes and dosimetric parameters ( P < 0.05). For TLN, D1 of PRV was the most relevant dosimetric parameter and 64 Gy was the critical point. We suggest contouring for the temporal lobe, middle ear, inner ear, parotid gland and spinal cord. A CT–MRI fusion atlas comprising 33 OARs was developed. Conclusions Different dosimetric parameters may hinder the dosimetric research. The present recommendation and atlas, may help reach a consensus on subjective interpretation of OARs delineation to reduce inter-institutional differences in NPC patients.
•The relationship between physical performance and hip fracture is point out.•Participants with hip fractures had poorer physical performance than those without hip fractures.•After adjustment for ...potential confounding factors, a significant risk gradient for hip fracture was associated with the SPPB score and repeated chair stands.•No modification effect of cognition function was found on the relationship between physical performance and hip fracture.
This study aims to evaluate the association between the risk of hip fracture and score on the Short Physical Performance Battery (SPPB) and handgrip strength in community-dwelling elderly people in China.
A total of 5,958 community-dwelling Chinese people aged 60 years or more from the China Health and Retirement Longitudinal Study (CHARLS) were surveyed in 2011 (baseline) and followed through to 2016. Score on the SPPB (which comprises tests of balance, walking speed, and repeated chair stands) and handgrip strength were determined at baseline. Binary logistic regression models were used to estimate the risk ratio (RR) and 95 % CI.
During an average of approximately 4 years of follow-up, 180 (3.0 %) participants experienced incident hip fracture. After multivariate adjustment, the overall SPPB score and repeated chair stands alone distinguished a gradient of hip fracture risks. The risk of hip fracture was 1.65-fold higher in poor SPPB performers (score 0−6) than in good SPPB performers (score 10−12). Participants unable to complete repeated chair stands, and those who took ≥16.7 s or 13.7–16.6 s to complete them, had a higher risk than those who took ≤ 11.1 s to complete them, with RRs of 2.45, 2.12, and 1.93, respectively. Participants unable to complete the balance tests had a higher hip fracture risk than those with scores of 4, with an RR of 2.16. Walking speed and handgrip strength were not associated with increased hip fracture risk.
Among community-dwelling elderly Chinese people, overall SPPB score, as well as performance on repeated chair stands and balance tests within the SPPB, were significantly and independently associated with increased hip fracture risk. These indicators could be used to predict hip fracture in clinical settings.
Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated efficacy in nasopharyngeal carcinoma (NPC). Thyroid dysfunction is among the most common immune-related adverse events. ...This study aimed to explore the clinical pattern of thyroid dysfunction and its relationship with survival marker in nonmetastatic NPC after immunotherapy.
From January 1, 2019, to December 31, 2021, 165 pairs of nonmetastatic NPC patients (165 with and 165 without anti-PD-1 immunotherapy) matched by the propensity score matching method were included in this study. Thyroid function was assessed retrospectively before the first treatment and during each immunotherapy cycle.
The spectrum of thyroid dysfunction was different between the immunotherapy and control groups (P < 0.001). Compared with the control group, patients in the immunotherapy group developed more hypothyroidism (14.545% vs. 7.273%), less hyperthyroidism (10.909% vs. 23.636%), and a distinct pattern, biphasic thyroid dysfunction (3.030% vs. 0%). Immunotherapy also accelerates the onset of hypothyroidism, which was earlier with a median onset time difference of 32 days (P < 0.001). Patients who acquired thyroid dysfunction during immunotherapy had better complete biological response to treatment (OR, 10.980; P = 0.042).
For nonmetastatic NPC, thyroid dysfunction was associated with better response to treatment in immunotherapy but not in routine treatment. Thyroid function could be used as a predictor for survival and should be under regular and intensive surveillance in clinical practice of anti-PD-1 immunotherapy for nonmetastatic NPC.
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