To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.
Systematic review and network meta-analysis.
...Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018.
Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group.
36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer.
Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events.
PROSPERO CRD42017082553.
Background： The prognostic values of staging parameters require continual re-assessment amid changes in diag-nostic and therapeutic methods. This study aimed to identify the prognostic factors and ...failure patterns of non-meta-static nasopharyngeal carcinoma（NPC） in the intensity-modulated radiotherapy（IMRT） era.Methods： We reviewed the data from 749 patients with newly diagnosed, biopsy-proven, non-metastatic NPC in our cancer center（South China, an NPC endemic area） between January 2003 and December 2007. All patients under-went magnetic resonance imaging（MRI） before receiving IMRT. The actuarial survival rates were estimated using the Kaplan–Meier method, and survival curves were compared using the log-rank test. Multivariate analyses with the Cox proportional hazards model were used to test for the independent prognostic factors by backward eliminating insigniicant explanatory variables.Results： The 5-year occurrence rates of local failure, regional failure, locoregional failure, and distant failure were 5.4, 3.0, 7.4, and 17.4%, respectively. The 5-year survival rates were as follows： local relapse-free survival, 94.6%; nodal relapse-free survival, 97.0%; distant metastasis-free survival, 82.6%; disease-free survival, 75.1%; and overall survival, 82.0%. Multivariate Cox regression analysis revealed that orbit involvement was the only signiicant prognostic fac-tor for local failure（P = 0.011）. Parapharyngeal tumor extension, retropharyngeal lymph node involvement, and the laterality, longest diameter, and Ho＇s location of the cervical lymph nodes were signiicant prognostic factors for both distant failure and disease failure（all P 〈 0.05）. Intracranial extension had signiicant prognostic value for distant failure（P = 0.040）.Conclusions： The key failure pattern for NPC was distant metastasis in the IMRT era. With changes in diagnostic and therapeutic technologies as well as treatment modalities, the signiicant prognostic parameters for local control have also been altered substantially.
We aimed to evaluate the value of deep learning on positron emission tomography with computed tomography (PET/CT)-based radiomics for individual induction chemotherapy (IC) in advanced nasopharyngeal ...carcinoma (NPC).
We constructed radiomics signatures and nomogram for predicting disease-free survival (DFS) based on the extracted features from PET and CT images in a training set (
= 470), and then validated it on a test set (
= 237). Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were applied to evaluate the discriminatory ability of radiomics nomogram, and compare radiomics signatures with plasma Epstein-Barr virus (EBV) DNA.
A total of 18 features were selected to construct CT-based and PET-based signatures, which were significantly associated with DFS (
< 0.001). Using these signatures, we proposed a radiomics nomogram with a C-index of 0.754 95% confidence interval (95% CI), 0.709-0.800 in the training set and 0.722 (95% CI, 0.652-0.792) in the test set. Consequently, 206 (29.1%) patients were stratified as high-risk group and the other 501 (70.9%) as low-risk group by the radiomics nomogram, and the corresponding 5-year DFS rates were 50.1% and 87.6%, respectively (
< 0.0001). High-risk patients could benefit from IC while the low-risk could not. Moreover, radiomics nomogram performed significantly better than the EBV DNA-based model (C-index: 0.754 vs. 0.675 in the training set and 0.722 vs. 0.671 in the test set) in risk stratification and guiding IC.
Deep learning PET/CT-based radiomics could serve as a reliable and powerful tool for prognosis prediction and may act as a potential indicator for individual IC in advanced NPC.
We analyzed the number of circulating tumor cells (CTCs) and Epstein–Barr virus DNA (EBV DNA) for diagnosis, monitoring and prognosis of patients with metastatic nasopharyngeal carcinoma (mNPC). The ...levels of CTCs and EBV DNA were measured at baseline and after first‐line chemotherapy in 148 mNPC patients prospectively enrolled between December 2014 and August 2016. We also collected 122 non‐mNPC cases within the same time frame for examining CTCs and EBV DNA at baseline. In 270 NPC patients, we observed improved specificity (86.0% vs. 41.0%) and inferior sensitivity (42.3% vs. 81.3%) of CTCs as compared to EBV DNA for diagnosis of distant metastasis. mNPC patients were stratified into unfavorable and favorable prognostic groups, respectively, based on CTC of 12 at baseline and 1 after first‐line chemotherapy and EBV DNA of 10,000 at baseline and 4,000 after first‐line chemotherapy. Conversion of baseline unfavorable CTCs and EBV DNA to favorable after first‐line chemotherapy was associated with significantly longer progression‐free survival (PFS) and overall survival (OS) compared to patients with unfavorable CTCs and EBV DNA at both time points. Among patients with a complete/partial response as per imaging evaluation, favorable CTCs and EBV DNA levels after first‐line chemotherapy were associated with significantly longer PFS and OS. In conclusion, our data demonstrated the number of CTCs and EBV DNA before, after and during first‐line chemotherapy were strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.
What's new?
Endemic nasopharyngeal carcinoma (NPC) is associated with latent infection of the oncogenic Epstein‐Barr virus (EBV) and frequently metastasizes to distant lymph nodes and organs. Metastatic NPC is treated by serial administration of cytotoxic or targeted therapies and treatment response is generally assessed with serial imaging, which often fails to detect changes in tumor burden. Here, the authors show that the number of circulating tumor cells (CTCs) and EBV DNA levels before, after, and during first‐line chemotherapy are strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.
To compare the results of intensity-modulated radiotherapy (IMRT) with those of two-dimensional conventional radiotherapy (2D-CRT) in the treatment of patients with nasopharyngeal carcinoma (NPC).
A ...retrospective review of data from 1,276 patients with biopsy-proven, nonmetastatic NPC was performed. All patients had undergone magnetic resonance imaging and were staged according to the sixth edition of the American Joint Committee on Cancer staging criteria. Radiotherapy was the primary treatment for all patients.
Of the 1,276 patients, 512 were treated with IMRT and 764 with 2D-CRT. The 5-year actuarial local relapse-free survival (LRFS), the nodal relapse-free survival (NRFS), the distant metastasis-free survival (DMFS), and the disease-free survival (DFS) rates were 92.7%, 97.0%, 84.0%, and 75.9%, respectively, for the IMRT group, and 86.8%, 95.5%, 82.6%, and 71.4%, respectively, for the 2D-CRT group. In stage T1 patients, improvement of LRFS in the IMRT group was even significantly higher than in the 2D-CRT group (100% vs. 94.4%; p = 0.016). A trend of improvement of DFS was observed in the IMRT group compared with the 2D-CRT group but without reaching statistical significance. NRFS and DMFS rates were similar in the two groups.
A greater improvement of treatment results with IMRT than with 2D-CRT was demonstrated primarily by achieving a higher local tumor control rate in NPC patients, especially in the early T stage patients. The goal of better control of both local failure in advanced, nonmetastatic NPC patients and of distant failure should be addressed in future studies.
Low serum albumin is predictive of poor survival in nasopharyngeal carcinoma (NPC). We evaluated the ability of the pretreatment albumin/globulin ratio (AGR) to predict long-term mortality in ...patients with NPC.
This retrospective study examined an unselected cohort of 694 patients with NPC who had documented pretreatment total serum protein and serum albumin levels (ALB). AGR was calculated as AGR = ALB/(total serum protein--ALB). Survival analysis was used to evaluate the predictive value of AGR.
Multivariate analysis demonstrated that a low pretreatment serum AGR (<1.4) was an independent predictor of poor OS (P = 0.029) and DMFS (P = 0.033). A low AGR was significantly associated with advanced stage disease (P<0.001), high white blood cell count (P = 0.033), high neutrophil count (P = 0.047), high total serum protein (P<0.001) and low ALB (P<0.001).
The pretreatment AGR may represent a simple, potentially useful predictive biomarker for evaluating the long-term prognosis of patients with undifferentiated NPC.
To clarify the optimal cumulative cisplatin dose (CCD) in locoregionally‐advanced nasopharyngel carcinoma (NPC) patients receiving induction chemotherapy (IC) plus concurrent chemoradiotherapy ...(CCRT). Using the NPC‐specific database from the established big‐data intelligence platform at Sun Yat‐Sen University Cancer Center, 583 non‐disseminated, locoregionally‐advanced NPC patients receiving IC plus CCRT were enrolled. Propensity score matching (PSM) analysis was conducted to control for confounding factors. The median CCD was 160 mg/m2 after IC (range, 40‐300 mg/m2); only 74 patients (12.7%) achieved CCD >200 mg/m2. Patients receiving >200 mg/m2 CCD did not show significantly improved 5‐year overall survival (OS) (HR = 1.19; 95% confidence intervals CI 0.69‐2.06, P = .53) and progression‐free survival (PFS) (HR = 1.03; 95% CI: 0.63‐1.68, P = .92) compared with patients receiving <200 mg/m2 CCD. Further investigations of the potential of median CCD (160 mg/m2) to yield survival benefits revealed that there were no significant differences in survival endpoints between patients receiving CCD >160 mg/m2 and CCD < 160 mg/m2 in both the original and PSM cohorts. In addition, subgroup analysis indicated a favorable PFS, but not OS, with higher cisplatin administration in patients with pretreatment Epstein–Barr virus deoxyribonucleic acid (EBV DNA) <1000 copies/mL (HR = 0.26, 95% CI: 0.07‐0.93, P = .03) and receiving <3 IC cycles (HR = 0.59, 95% CI 0.33‐1.07, P = .08). Our analysis of real world data provided references for the optimal CCD in locoregionally‐advanced NPC receiving additional IC. The causal relationship between 200 mg/m2 CCD and improved survival was not defined; 160 mg/m2 CCD might be enough. However, for patients with EBV DNA <1000 copy/mL and receiving <3 IC cycles, a higher dose might be necessary.
Our analysis of real world data provided references for the optimal CCD in locoregionally‐advanced NPC receiving IC plus CCRT. The causal relationship between 200 mg/m2 CCD and improved survival was not defined; 160 mg/m2 CCD might be enough. However, for patients with EBV DNA < 1000 copy/mL, and receiving<3 IC cycles, higher dose might be necessary.
The effect of socioeconomic factors on receipt of definitive treatment and survival outcomes in non‐metastatic head and neck squamous cell carcinoma (HNSCC) remains unclear. Eligible patients (n = 37 ...995) were identified from the United States Surveillance, Epidemiology and End Results (SEER) database between 2007 and 2012. Socioeconomic factors (i.e., median household income, education level, unemployment rate, insurance status, marital status and residence) were included in univariate/multivariate Cox regression analysis; validated factors were used to generate nomograms for cause‐specific survival (CSS) and overall survival (OS), and a prognostic score model for risk stratification. Low‐ and high‐risk groups were compared for all cancer subsites. Impact of race/ethnicity on survival was investigated in each risk group. Marital status, median household income and insurance status were included in the nomograms for CSS and OS, which had higher c‐indexes than the 6th edition TNM staging system (all P < 0.001). Based on three disadvantageous socioeconomic factors (i.e., unmarried status, uninsured status, median household income <US $65 394), the prognostic score model generated four risk subgroups with scores of 0, 1, 2 or 3, which had significantly separated CSS/OS curves (all P < 0.001). Low‐risk patients (score 0–1) were more likely to receive definitive treatment and obtain better CSS/OS than high‐risk patients (score 2–3). Chinese and non‐Hispanic black patients with high‐risk socioeconomic status had best and poorest CSS/OS, respectively. Therefore, marital status, median household income and insurance status have significance for predicting survival outcomes. Low‐risk socioeconomic status and Chinese race/ethnicity confer protective effects in HNSCC.
We built nomograms for CSS/OS and a prognostic score model for risk stratification based on validated socioeconomic factors, such as marital status, median household income and insurance status. Both nomograms had higher efficacies than the 6th edition TNM staging system, and the prognostic score model generated four risk subgroups with separated CSS/OS. Low‐risk socioeconomic status and Chinese race/ethnicity confer protective effects on patients with non‐matastatic HNSCC.
Because of the uneven geographic distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in ...nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC + CCRT in locoregionally advanced NPC.
Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively.
Median follow-up was 5.0 years. The HR for PFS was 0.70 95% confidence interval (CI), 0.56-0.86;
= 0.0009; 9.3% absolute benefit at 5 years in favor of IC + CCRT versus CCRT alone. IC + CCRT also improved OS (HR = 0.75; 95% CI, 0.57-0.99;
= 0.04) and reduced distant failure (HR = 0.68; 95% CI, 0.51-0.90;
= 0.008). IC + CCRT had a tendency to improve locoregional control compared with CCRT alone (HR = 0.70; 95% CI, 0.48-1.01;
= 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected.
This IPD pooled analysis demonstrates the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control.
.
Background.
The objective of this study was to evaluate the prognostic value of the cumulative cisplatin dose (CCD) for long‐term survival outcomes after concurrent chemoradiotherapy (CCRT) in ...locoregionally advanced nasopharyngeal carcinoma (NPC).
Methods.
Patients were included in an open‐label phase III multicenter randomized controlled trial performed at seven institutions in China, and the 298 patients receiving CCRT only were assessed. Patient survival between different CCD groups were compared.
Results.
Median CCD for the 298 patients was 240 mg/m2 (range, 40–320 mg/m2); 113 (37.9%) patients received a CCD of <240 (≤200) mg/m2, and 185 (62.1%) received a CCD of ≥240 mg/m2. For CCD of ≥240 mg/m2 vs. <240 mg/m2, the estimated 5‐year overall survival, disease‐free survival, locoregional relapse‐free survival, and distant metastasis‐free survival rates were 83.2% vs. 76.2% (p = .403), 73.5% vs. 67.8% (p = .461), 90.4% vs. 86.8% (p = .551), and 82.6% vs. 79.7% (p = .632), respectively. Multivariate analysis demonstrated that CCD (240 mg/m2) was not an independent prognostic factor in either the entire cohort or stage III/IV subgroup.
Conclusion.
A CCD of ≥240 mg/m2 was not an independent prognostic factor in patients with locoregionally advanced NPC at high risk of distant metastasis, and 200 mg/m2 cisplatin may be adequate to achieve a survival benefit.
Implications for Practice:
The current standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin‐based concurrent chemoradiotherapy (CCRT), and the cisplatin is delivered every 3 weeks (100 mg/m2) for three cycles. However, the prognostic value of cumulative cisplatin dose (CCD) delivered during CCRT is controversial. The present study investigated the prognostic value of CCD and demonstrated that a CCD of 200 mg/m2 during CCRT is adequate to achieve satisfactory survival outcomes for patients with locoregionally advanced NPC. This finding is of great importance to clinicians because it could allow patients to avoid excessive treatment and toxicities.
摘要
背景. 本研究旨在评价顺铂累积剂量(CCD)对局部晚期鼻咽癌(NPC)患者同步放化疗(CCRT)后长期生存转归的预后价值。
方法. 在中国的7家机构开展了一项开放标签的III期多中心、随机对照临床试验, 本研究仅评估其中298例仅接受CCRT治疗的患者。比较不同CCD组的患者的生存。
结果. 298例患者的中位CCD为240 mg/m2(范围40∼320 mg/m2), 113例(37.9%)患者接受的CCD < 240(≤200)mg/m2, 而185例(62.1%)接受的CCD≥240 mg/m2。CCD≥240 mg/m2和<240 mg/m2患者的估算5年总生存率、无疾病生存率、局部无复发生存率和无远处转移生存率分别为83.2% vs. 76.2%(P=0.403)、73.5% vs. 67.8%(P=0.461)、90.4% vs. 86.8%(P=0.551)和82.6% vs. 79.7%(P=0.632)。多变量分析证实CCD(240 mg/m2)不是总队列或III/IV期亚组的独立预后因素。
结论. CCD≥240 mg/m2不是具有远处转移高风险的局部晚期NPC患者的独立预后因素, 顺铂200 mg/m2可能足以达到生存获益。The Oncologist 2016;21:1369–1376
对临床实践的提示: 目前局部晚期鼻咽癌(NPC)的标准治疗是含顺铂的同步放化疗(CCRT), 顺铂每3周给药一次(100 mg/m2), 共3周期。但CCRT治疗过程中顺铂累积剂量(CCD)的预后价值仍有争议。本研究调查了CCD的预后价值, 并证实局部晚期NPC患者的CCRT中给予CCD 200 mg/m2足以达到满意的生存转归。本研究结果对临床医生意义重大, 因为这些结果使得患者得以避免过度治疗及毒性。
This study evaluated the prognostic value of the cumulative cisplatin dose (CCD) for long‐term survival outcomes after concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma (NPC). A CCD of ≥240 mg/m2 was not an independent prognostic factor in patients with locoregionally advanced NPC at high risk of distant metastasis, and 200 mg/m2 cisplatin may be adequate to achieve a survival benefit.
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