Long-term Survival with 18-Fluorodeoxyglucose Positron Emission Tomography-directed Therapy in Non-small Cell Lung Cancer with Synchronous Solitary Brain Metastasis

AimsAt diagnosis, <1% of patients with non-small cell lung cancer (NSCLC) have synchronous solitary brain metastasis (SSBM). In prior cohorts without 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) staging, definitive treatment to intracranial and intrathoracic disease showed a 5-year overall survival (OS) of 11–21%. We investigated the long-term survival outcomes for patients with SSBM NSCLC, diagnosed in the FDG-PET/CT era and treated definitively with local therapies to both intracranial and intrathoracic sites of disease.Materials and methodsThis retrospective study assessed patients staged with FDG-PET/CT who received definitive lung and SSBM treatment from February 1999 to December 2017. A lung-molecular graded prognostic assessment (lung-molGPA) score was assigned for each patient using age, performance status score, and, where carried out, molecular status. Overall survival and progression-free survival (PFS) were calculated using Kaplan–Meier methods. Cox proportional hazard models determined OS and PFS prognostic factors.ResultsForty-nine patients newly diagnosed with NSCLC and SSBM had a median age of 63 years (range 34–76). The median follow-up of all patients was 3.9 years. Thirty-three patients (67%) had ≥T2 disease, 23 (47%) had ≥N2. At 2 years, 45% of first failures were intracranial only (95% confidence interval 30–59). At 3 and 5 years, OS was 45% (95% confidence interval 32–63) and 30% (95% confidence interval 18–51), respectively. In ≥N1 disease, 5-year OS was 34% (95% confidence interval 18–63). The 3- and 5-year PFS was 8% (95% confidence interval 3–22) and 0%, respectively. Higher lung-molGPA was associated with longer OS (hazard ratio 0.26, 95% confidence interval 0.11–0.61, P = 0.002). Higher lung-molGPA (hazard ratio 0.33, 95% confidence interval 0.15–0.71, P = 0.005) and lower N-stage (hazard ratio 1.56, 95% confidence interval 1.13–2.15, P = 0.007) were associated with longer PFS.ConclusionsDefinitive treatment of patients with NSCLC and SSBM staged with FDG-PET/CT can result in 5-year survivors, including those with ≥N1 disease.     

早发型非转移性结直肠癌患者预后预测模型的构建及外部验证

目的:探讨影响早发型非转移性结直肠癌（early-onset non-metastatic colorectal cancer,EONCRC）患者预后的相关独立危险因素,并构建列线图预测EONCRC患者预后。方法:从美国监测、流行病学和结果数据库SEER数据库中收集了9 097例EONCRC患者的数据,患者按照7∶3比例随机分配到训练集(6 369例)和验证集(2 728例)。通过单变量、多变量COX比例风险回归分析确定独立的预后因素,并构建列线图。 使用C指数、ROC曲线和校准曲线评价列线图的区分度、预测效能和校准度。使用新疆军区总医院收治的EONCRC患者临床资料(n=171)对列线图进行了外部验证并对其预后影响因素进行了分析。结果:多因素分析确定了与总生存期有关的8个独立风险因素,分别是组织学分化程度、组织学类型、神经浸润、分期、T分期、手术、化疗和放疗,并将它们纳入列线图。SEER训练集、SEER验证集、外部验证集的C指数值分别为0.765(95%置信区间,0.749~0.781)、0.785(95%置信区间,0.763~0.807)、0.766(95%置信区间,0.713~0.819),校准曲线表明了列线图预测总生存率与实际总生存率具有良好的一致性。ROC曲线显示,列线图可以准确预测EONCRC患者1年(AUC=0.834 9)、3年(AUC=0.794 7)和5年(AUC=0.771 2)的生存率。根据列线图的风险评分将患者分为高风险、中风险和低风险组,在SEER训练集、SEER验证集、外部验证集中,低风险组的5年生存率均最高,其次是中风险组和高危组。结论:本研究确定了EONCRC患者预后相关的8个独立危险因素,列线图能准确预测中国及美国EONCRC患者1年、3年、5年总生存率,对EONCRC患者进行个体化的分层及预后评估,为临床的诊疗提供科学依据。     

Prognostic factors in young ovarian cancer patients: An analysis of four prospective phase III intergroup trials of the AGO Study Group,GINECO and NSGO

ObjectivesWe evaluated in a large study meta-database of prospectively randomised phase III trials the prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients < and >40 years of age with advanced epithelial ovarian cancer.MethodsA total of 5055 patients of the AGO, GINECO, NSGO intergroup studies AGO-OVAR 3, 5, 7 and 9 were merged to identify 294 patients <40 years and 4761 patients ≥40 years. We conducted survival analyses and Cox proportional hazard regression models and additionally analysed a very homogeneous subcohort of 405 patients with serous epithelial ovarian cancer, excellent performance status, who had received complete macroscopic upfront cytoreduction and ≥5 chemotherapy cycles.ResultsFor patients <40 years, the median PFS was 28.9 months and the median OS was 75.3 months, while the median PFS for patients ≥40 years was 18.1 months and the median OS was 45.7 months. Independent prognostic factors were similar in both age groups. In a multivariate analysis including prognostic factors potentially leading to confounding, young age appeared to improve PFS (hazard ratio [HR], 0.86; 95% confidence interval [CI]: 0.72–1.03) and OS (HR, 0.73; 95% CI: 0.59–0.91). The observed effect was even stronger in the subcohort of optimally treated patients with SEOC: PFS (HR, 0.34; 95% CI: 0.19–0.59) and OS (HR, 0.23; 95% CI: 0.09–0.56).DiscussionPrognostic factors were similar in both age groups. Young age appeared a strong independent protective prognostic factor for PFS and OS in the subcohort.     

Gender Differences and Their Effects on Survival Outcomes in Lung Cancer Patients Treated With PD-1/PD-L1 Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

AimsProgrammed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors have had a major impact on the approach to care of patients with lung cancer. An important issue that is not known is whether they benefit men and women the same. We conducted a meta-analysis of all randomised controlled trials evaluating PD-1/PD-L1 inhibition in patients with non-small cell lung cancer (NSCLC) to determine if clinical response and survival are influenced by gender.Materials and methodsA PubMed search was carried out to identify all randomised controlled trials evaluating PD-1/PD-L1 inhibitors compared with conventional chemotherapy in NSCLC. Random-effects meta-analysis and meta-regression were performed to assess overall survival and progression-free survival (PFS) and whether there were differences in these outcomes between men and women.ResultsIn total, 12 studies with data for overall survival and 11 studies with data for PFS were included. Immunotherapy showed a statistically significant benefit over chemotherapy for overall survival (pooled hazard ratio = 0.72, 95% confidence interval = 0.65–0.81, P < 0.001) and progression-free survival (pooled hazard ratio = 0.62, 95% confidence interval = 0.54–0.72, P < 0.001). We did not find a statistically significant difference between men and women in terms of overall survival (males versus females: pooled hazard ratio = 0.74, 95% confidence interval = 0.66–0.83 versus pooled hazard ratio = 0.72, 95% confidence interval = 0.63–0.82, P = 0.709) or progression-free survival (males versus females: pooled hazard ratio = 0.63, 95% confidence interval = 0.53–0.75 versus pooled hazard ratio = 0.72, 95% confidence interval = 0.58–0.88, P = 0.372).ConclusionThis is the first systematic review and meta-analysis investigating the effect of gender and response to PD-1/PD-L1 checkpoint inhibitors in patients solely with NSCLC. We examined 9270 and 6193 patients in terms of overall survival and PFS, respectively. Although there are significant biological differences between men's and women's immune responses, we have shown that these drugs offer the same survival benefit in patients with NSCLC regardless of gender.     

Neoadjuvant Chemotherapy in Locally Advanced Cervical Carcinoma – a Role in Patients with Para-aortic Lymph Node Involvement? A 10-year Institutional Experience

AimsOverall survival and progression-free survival with concomitant chemoradiotherapy for locally advanced cervical carcinoma have been described as 66% and 58%, respectively, at 5 years. Para-aortic lymph node involvement significantly increases the risk of relapse and death. The role of additional chemotherapy in these patients is as yet undefined. This aim of the present study was to determine the outcome of a cohort of para-aortic lymph node-positive patients treated with neoadjuvant chemotherapy followed by extended-field chemoradiation compared with patients treated with extended-field chemoradiation without neoadjuvant chemotherapy.Materials and methodsWe reviewed patients with International Federation of Gynaecology and Obstetrics (FIGO) 2014 stage IB1–IVA cervical carcinoma who received extended-field radiotherapy in addition to standard pelvic chemoradiotherapy with or without neoadjuvant chemotherapy, at University College London Hospital (January 2007 to January 2018). Patients in open clinical trials were excluded.ResultsOverall, 47 patients (15.8% of 298 eligible patients) with pelvic and/or para-aortic lymph node-positive cervical carcinoma received extended-field radiotherapy. Nineteen patients (40.4%) had both neoadjuvant chemotherapy (all received six cycles) and extended-field radiotherapy (median 44 days); 28 (59.6%) patients received extended-field radiotherapy alone (median 43 days). All patients completed radical radiotherapy within 49 days. We observed evidence that patients receiving neoadjuvant chemotherapy and extended-field radiotherapy had a lower risk of death (median follow-up 4.8 years, three deaths) compared with extended-field radiotherapy alone (median follow-up 3.0 years, 11 deaths; hazard ratio = 0.27, 95% confidence interval 0.08–1.00; P = 0.05). Three-year overall survival rates were 83.3% (95% confidence interval 66.1–100) and 64.6% (95% confidence interval 44.6–84.6), respectively. A PFS benefit was seen (hazard ratio 0.25, 95% confidence interval 0.08–0.77; P = 0.02), with 3-year PFS rates of 77.8% (95% confidence interval 58.6–97.0) and 35.0% (95% confidence interval 14.0–56.0), respectively.ConclusionsOur institutional experience suggests that the use of additional systemic therapy before chemoradiotherapy benefits patients with locoregionally advanced (FIGO 2018 IIIC2) cervical cancer. Neoadjuvant chemotherapy was associated with longer overall survival and PFS, without compromising definitive extended-field chemoradiation.     

Long-Term Outcomes of Cervical Cancer Patients Treated With Definitive Chemoradiation Following a Complete Metabolic Response

AimsA complete metabolic response (CMR) on early post-treatment ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a positive prognostic factor for cervical cancer patients treated with definitive chemoradiation, but long-term outcomes of this group of patients are unknown. Patterns of failure and risk subgroups are identified.Materials and methodsPatients who received curative-intent chemoradiation from 1998 to 2018 for International Federation of Gynecology and Obstetrics (FIGO) stage IB1–IVA cervical cancer and had a CMR on post-treatment FDG-PET within 5 months of treatment completion were included. Cox proportional hazards models determined factors associated with locoregional and distant failure. Kaplan–Meier estimates of freedom from any recurrence (FFR) of patient subgroups were compared with Log-rank tests.ResultsThere were 402 patients with a CMR after chemoradiation on FDG-PET. Initial T stage was T1 (38%)/T2 (40%)/T3 (20%)/T4 (2%); initial FDG-avid nodal status was no nodes (50%)/pelvic lymph nodes (40%)/pelvic and para-aortic lymph nodes (10%). After a median follow-up of 6 years, 109 (27%) recurred. The pattern of recurrence was locoregional (27%), distant (61%) or both (12%). No factors were associated with locoregional failure. Distant recurrence was more likely in patients with T3–4 lesions (hazard ratio = 2.4, 95% confidence interval 1.5–3.8) and involvement of pelvic (hazard ratio = 1.6, 95% confidence interval 1.0–2.7) or para-aortic lymph nodes (hazard ratio = 2.7, 95% confidence interval 1.4–5.0) at diagnosis. The 5-year FFR rates for T1–2 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 85, 76 and 62%, respectively (P = 0.04, none versus para-aortic nodes). The 5-year FFR for T3–4 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 68, 56 and 25%, respectively (P = 0.09, none versus para-aortic nodes).ConclusionsT3–4 tumours and para-aortic nodal involvement at diagnosis are poor prognostic factors, even after a CMR following chemoradiation.     

Clinical features and prognostic factors for extracranial oligometastatic breast cancer in China

Evidence of an oligometastatic state in metastatic breast cancer (MBC) is relatively limited. The aim of our study was to investigate the clinical features and prognostic factors for extracranial oligometastatic breast cancer and to identify the best treatment approaches in this select population. Fifty postoperative inpatients diagnosed with extracranial oligometastatic breast cancer at the National Cancer Center in China between 2009 and 2014 were consecutively enrolled. Oligometastatic breast cancer was defined as MBC with three or fewer metastatic lesions confined to one organ; de novo Stage IV disease and local-regional recurrence were excluded. The median progression-free survival (PFS) and overall survival (OS) times were 15.2 and 78.9 months, respectively, and the 2-year PFS and 5-year OS rates were 40% and 58%, respectively. First-line treatment approach with standard systemic treatment + surgical resection for all metastatic lesions was an independent prognostic factor for prolonged PFS (hazard ratio = 0.32; 95% confidence interval [CI], 0.14-0.73; P = .006) and OS (hazard ratio = 0.35; 95% CI, 0.14-0.86; P = .022). Subgroup analysis showed that patients with a disease-free interval (DFI) ≥24 months, one metastatic lesion or the hormone receptor (HR) + subtype were more likely to get benefit from resection. Patients with oligometastatic breast cancer have a relatively good prognosis. Surgical resection for metastatic lesions could significantly improve PFS and OS. Further prospective research is warranted to confirm the results and to develop biomarkers for better patient selection.     

Consolidative Radiotherapy in Oligometastatic Lung Cancer: Patient Selection With a Prediction Nomogram

BackgroundPatients with stage IV oligometastatic (≤ 3 sites) non–small-cell lung cancer have a progression-free survival (PFS) and overall survival benefit when all sites of metastatic disease and the primary tumor are treated radically with consolidative radiotherapy (cRT). However, the optimal selection of patients most likely from cRT is yet to be defined.Patients and MethodsPatients with metastatic non–small-cell lung cancer treated with definitive radiotherapy to all metastatic sites and primary tumor (2008-2019) were retrospectively identified. Univariable Cox proportional-hazards model was used to compare outcomes with demographic and clinical characteristics. A predictive nomogram model for selection of patients most likely to benefit from cRT was constructed.ResultsThere were 91 patients identified with a total of 114 metastases treated. Median PFS from the start of cRT was 10.9 months (95% confidence interval [CI], 8.1-16.6), while the median survival time was 37.0 months (95% CI, 31.3-NR). On univariable modeling, patients with squamous histology (hazard ratio, 4.16; 95% CI, 1.99-8.71; P < .001) and those treated with non–stereotactic body radiotherapy hypofractionated therapy (hazard ratio, 5.43; 95% CI, 2.10-14.01; P < .001) had worse overall survival, while patients with targetable mutations (hazard ratio, 0.49; 95% CI, 0.25-0.98; P = .04) had a longer survival. Using a predictive nomogram model, patients with a solitary site of metastasis, targetable mutations, intracranial disease, and metachronous timing of oligometastases had a larger PFS benefit from cRT.ConclusioncRT is associated with favorable outcomes in PFS and overall survival. These results may aid in patient counseling, selection for aggressive local therapy, and stratification in future prospective clinical trials.     

Hyperglycaemia and Survival in Solid Tumours: A Systematic Review and Meta-analysis

AimsDiabetes is associated with adverse cancer outcomes. However, the effect of hyperglycaemia in non-diabetic cancer patients is unclear.Materials and methodsA systematic search of electronic databases identified publications exploring the effect of hyperglycaemia on overall survival, disease-free survival (DFS) or progression-free survival (PFS). Data from studies reporting a hazard ratio and 95% confidence interval and/or a P-value were pooled in a meta-analysis using generic inverse-variance and random effects modelling. Subgroup analyses were conducted based on method of hyperglycaemia measurement (HbA1c, other) and stage (early, advanced, mixed). Meta-regression was performed to evaluate the influence of clinical characteristics including baseline diabetes status on the hazard ratio for overall survival.ResultsTwelve studies comprising a total of 9872 patients were included. All studies reported hazard ratios for overall survival. Three studies reported DFS; two reported PFS outcomes. Definitions of hyperglycaemia and cut-offs varied between studies. Hyperglycaemia was associated with worse overall survival (hazard ratio 2.05, 95% confidence interval 1.67–2.51; P < 0.001) and DFS (hazard ratio 1.98, 95% confidence interval 1.20–3.27; P = 0.007), but did not affect PFS (hazard ratio 1.08, 95% confidence interval 0.72–1.62; P = 0.71). The association with worse overall survival was maintained in subgroups based on method of hyperglycaemia measurement (subgroup difference P = 0.46) and stage (P = 0.14). Meta-regression showed a significantly greater magnitude of association between hyperglycaemia and decreased overall survival in studies with higher proportions of women and diabetic patients.ConclusionsHyperglycaemia is associated with adverse overall survival and DFS in patients with cancer. The therapeutic role of glycaemic control in cancer patients warrants further investigation.     

Circulating tumor cells predict progression-free and overall survival in Chinese patients with metastatic breast cancer,HER2-positive or triple-negative (CBCSG004): a multicenter,double-blind,prospective trial

BackgroundThe aim of this multicenter, double-blind, prospective study was to evaluate the potential utility of circulating tumor cell (CTC) measurements in predicting responses to anticancer therapies, including response to human epidermal growth factor receptor-2 (HER-2)-targeted agents, progression-free survival (PFS), and overall survival (OS) in Chinese women with metastatic breast cancer (MBC).Patients and methodsThree hundred MBC patients planned to complete three CTC blood draws and two imaging studies.ResultsA total of 294 of the 300 MBC patients enrolled from six leading Chinese cancer centers were assessable. In multivariate Cox regression analyses, the baseline CTC number remained an independent prognostic factor for PFS [hazard ratio (HR) = 1.93; 95% confidence interval (CI) = 1.39–2.69; P < 0.001) and OS (HR = 3.76; 95% CI = 2.35–6.01; P < 0.001). Similar results were observed for CTC counts at the first follow-up visit for both PFS (P = 0.049) and OS (P < 0.001).ConclusionsEnumeration of CTCs in Chinese MBC patients provides substantial prognostic information and is an independent factor associated with PFS and OS. Moreover, we demonstrated the prognostic value in the various disease subtypes, including HER-2-positive disease irrespective of therapy.     

New prognostic index to predict survival in patients with cancer of unknown primary site with unfavourable prognosis

AimsTo identify independent prognostic factors in patients with cancer of unknown primary site (CUP) who do not belong to prognostically favourable subsets, and to develop a prognostic index for predicting survival in these patients.Materials and methodsIn this prospective study, univariate and multivariate analyses of prognostic factors were conducted in a population of 145 patients with CUP in two clinical institutions. Subsets of patients with favourable prognostic features and those requiring well-defined treatment were excluded.ResultsThe 1-year overall survival rate for all patients was 42% and the median overall survival was 330 days. Overall survival was significantly related to the following pre-treatment prognostic factors: poor Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, presence of liver metastasis, elevated serum lactate dehydrogenase (LDH), high white blood cell count, anaemia, age ≥ 63 years, and prolonged QTc interval in electrocardiography (ECG). In multivariate analysis, four independent adverse prognostic parameters were retained: elevated LDH (hazard ratio 2.21; 95% confidence interval 1.41–3.47; P = 0.001), prolonged QTc interval (hazard ratio 2.10; 95% confidence interval 1.28–3.44; P = 0.003), liver metastasis (hazard ratio 1.77; 95% confidence interval 1.11–2.81; P = 0.016) and ECOG PS ≥ 2 (hazard ratio 1.69; 95% confidence interval 1.05–2.73; P = 0.03). We developed a prognostic index for overall survival based on the following subgroups: good prognosis (no or one adverse factor), intermediate prognosis (two adverse factors) and poor prognosis (three or four adverse factors). The median overall survival for the three subgroups was 420, 152 and 60 days, respectively, P < 0.0001.ConclusionsThis study validated previously identified important prognostic factors for survival in patients with CUP. Prolonged QTc was additionally identified as a strong adverse prognostic factor. We developed a simple prognostic index using performance status, LDH, presence of liver metastasis and QTc interval in ECG, which allowed assignment of patients into three subgroups with divergent outcome.     

T-category Remains an Important Prognostic Factor for Oropharyngeal Carcinoma in the Era of Human Papillomavirus

AimsTo determine prognostic factors for locoregional relapse (LRR), distant relapse and all-cause death in a contemporary cohort of locoregionally advanced oropharyngeal squamous cell carcinoma (OSCC) treated with definitive chemoradiotherapy or radiotherapy alone.Materials and methodsOSCC patients treated with definitive radiotherapy between 2005 and 2010 were identified from a prospective head and neck database. Patient age, gender, smoking history, human papillomavirus (HPV) status, T- and N-category, lowest involved nodal level and gross tumour volume of the primary (GTV-p) and nodal (GTV-n) disease were analysed in relation to LRR, distant relapse and death by way of univariate and multivariate analysis.ResultsIn total, 130 patients were identified, 88 HPV positive, with a median follow-up of 42 months. On multivariate analysis HPV status was a significant predictor of LRR (hazard ratio 0.15; 95% confidence interval 0.05–0.51) and death (hazard ratio 0.29; 95% confidence interval 0.14–0.59) but not distant relapse (hazard ratio 0.53, 95% confidence interval 0.22–1.27). Increasing T-category was associated with a higher risk of LRR (hazard ratio 1.80 for T3/4 versus T1/2; 95% confidence interval 1.08–2.99), death (hazard ratio 1.37, 95% confidence interval 1.06–1.77) and distant relapse (hazard ratio 1.35; 95% confidence interval 1.00–1.83). Increasing GTV-p was associated with increased risk of distant relapse and death. N3 disease and low neck nodes were significant for LRR, distant relapse and death on univariate analysis only.ConclusionTumour HPV status was the strongest predictor of LRR and death. T-category is more predictive of distant relapse and may provide additional prognostic value for LRR and death when accounting for HPV status.     

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy

BackgroundOptimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear.Patients and methodsWe examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses.ResultsPTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I–II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34–0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22–0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14–0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17–0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission.ConclusionsThis analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.     

First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients

BackgroundBevacizumab has consistently demonstrated improved progression-free survival (PFS) and response rate when combined with first-line chemotherapy for HER2-negative metastatic breast cancer (mBC). However, the lack of a significant overall survival (OS) difference continues to attract debate, and identification of patients deriving greatest benefit from bevacizumab remains elusive.Patients and methodsIndividual patient data from three randomised phase III trials in the first-line HER2-negative mBC setting were analysed, focusing specifically on efficacy in poor-prognosis patients.ResultsThe meta-analysis (n = 2447) demonstrated a PFS hazard ratio (HR) of 0.64 (95% confidence interval [CI] 0.57–0.71; median 9.2 months with bevacizumab versus 6.7 months with non-bevacizumab therapy) and response rate of 49% versus 32%, respectively. The OS HR was 0.97 (95% CI 0.86–1.08); median 26.7 versus 26.4 months, respectively. In patients with triple-negative mBC, the HRs for PFS and OS were 0.63 (95% CI 0.52–0.76) and 0.96 (95% CI 0.79–1.16), respectively. Median PFS was 8.1 months with bevacizumab versus 5.4 months with chemotherapy alone, median OS was 18.9 versus 17.5 months, respectively, and 1-year OS rates were 71% versus 65%.ConclusionsBevacizumab improves efficacy, including 1-year OS rates, both overall and in subgroups of poor-prognosis patients with limited treatment options.     

Brain Metastasis Growth Kinetics: A Novel Prognosticator for Stereotactic Radiotherapy

AimsThe rate of size change in brain metastasis may have clinical implications on tumour biology and prognosis for patients who receive stereotactic radiotherapy (SRT). We analysed the prognostic value of brain metastasis size kinetics and propose a model for patients with brain metastases treated with linac-based SRT in predicting overall survival.Materials and methodsWe analysed the patients receiving linac-based SRT between 2010 and 2020. Patient and oncological factors, including the changes in sizes of brain metastasis between the diagnostic and stereotactic magnetic resonance imaging, were collected. The associations between prognostic factors and overall survival were assessed using Cox regression with least absolute selection and shrinkage operator (LASSO) checked by 500 bootstrap replications. Our prognostic score was calculated by evaluating the most statistically significant factors. Patients were grouped and compared according to our proposed score, Score Index for Radiosurgery in Brain Metastases (SIR) and Basic Score for Brain Metastases (BS-BM).ResultsIn total, 85 patients were included. We developed the prognostic model based on the most important predictors of overall survival: growth kinetics, i.e. percentage change in brain metastasis size per day between the diagnostic and stereotactic magnetic resonance imaging (hazard ratio per 1% increase, 1.32; 95% confidence interval 1.06–1.65), extracranial oligometastatic diseases (≤5 involvements) (hazard ratio 0.28; 95% confidence interval 0.16–0.52) and the presence of neurological symptoms (hazard ratio 2.99; 95% confidence interval 1.54–5.81). Patients with scores 0, 1, 2 and 3 had a median overall survival of 44.4 (95% confidence interval 9.6–not reached), 20.4 (95% confidence interval 15.6–40.8), 12.0 (95% confidence interval 7.2–22.8) and 2.4 (95% confidence interval 1.2–not reached) years, respectively. The optimism-corrected c-indices for our proposed model, SIR and BS-BM were 0.65, 0.58 and 0.54, respectively.ConclusionsBrain metastasis growth kinetics is a valuable metric for survival outcomes of SRT. Our model is useful in identifying patients with brain metastasis treated with SRT with different overall survival.     

A prospective,multicenter validation study of a prognostic index composed of S-phase fraction,progesterone receptor status,and tumour size predicts survival in node-negative breast cancer patients: NNBC,the node-negative breast cancer trial

BackgroundIn a retrospective study on node-negative breast cancer, a prognostic index consisting of a proliferation factor, S-phase fraction (SPF), progesterone receptor status (PR), and tumour size identified one-third of patients as high risk, with a sixfold increased risk of breast cancer death. This prospective multicenter cohort study was set up to validate the index.Patients and methodsIn 576 T1-2N0 patients <60 years, prospective analyses of PR and SPF were carried out. High risk was defined as ≥2 of the following: size >20 mm, PR-negativity, and high SPF (in the absence of SPF, Bloom–Richardson grade 3). Median follow-up was 17.8 years.ResultsThirty-one percent were high risk. In univariate analysis, the index was prognostic for breast cancer-specific survival after 5 years [hazard ratio (HR) = 4.7, 95% confidence interval (95% CI) 2.5–8.9], 10 years (HR = 2.2, 95% CI 1.5–3.3), and 15 years (HR = 1.7, 95% CI 1.2–2.5), and remained significant after adjustment for adjuvant medical treatment and age. In the 37% of patients with no risk factors, only one patient died of breast cancer the first 5 years.ConclusionsThis prospective study validates a prognostic index consisting of a proliferation factor, PR-status, and tumour size. The index may be helpful for prognostic considerations and for selection of patients in need of adjuvant therapy.     

Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014

BackgroundBased on the risk stratification from the International Germ Cell Cancer Collaborative Group (IGCCCG), only 14% of patients with metastatic germ-cell tumors (GCT) had poor-risk disease with a 5-year progression-free survival (PFS) rate of 41% and a 5-year overall survival (OS) rate of only 48%. This analysis attempts to identify prognostic factors for patients with poor-risk disease.Patients and methodsWe conducted a retrospective analysis of all patients with GCT diagnosed and treated at Indiana University from 1990 to 2014. Clinical and pathological characteristics were available for all patients and all of them were treated with cisplatin–etoposide-based chemotherapy. Cox proportional hazards models were used to target significant predictors of disease progression and mortality. A significance level of 5% was used in the analysis.ResultsWe identified 273 consecutive patients with poor-risk GCT (PRGCT). Median follow-up time was 8 years (range 0.03–24.5). The 5-year PFS and OS rates were 58% [95% confidence interval (CI) 51% to 63%] and 73% (95% CI 67% to 78%), respectively. In multivariate survival analyses, multiple risk factors were associated with disease progression, including liver metastasis, brain metastasis, primary mediastinal nonseminomatous GCT (PMNSGCT), and elevation in logarithmic β-hCG. Significant predictors of mortality were PMNSGCT [hazard ratio (HR) 4.63, 95% CI 2.25–9.56; P < 0.001], brain metastasis (HR 3.30, 95% CI 1.74–6.23; P < 0.001), and increasing age (HR 1.03, 95% CI 1.01–1.06; P = 0.02).ConclusionsPatients with PMNSGCT, brain metastasis, or with increasing age are at higher risk of death than their counterparts. This contemporary cohort (1990–2014) of 273 patients with PRGCT had improved PFS and OS outcomes than those from the historical IGCCCG group of patients (1975–1990).     

Prognostic significance of E-cadherin protein expression in pathological stage I-III endometrial cancer.

PURPOSE: Decreased expression of E-cadherin in endometrial cancer cells is associated with adverse prognostic features. This study aimed to evaluate the prognostic significance of decreased E-cadherin expression in patients with endometrial cancer. EXPERIMENTAL DESIGN: Between 1992 and 1999, 102 endometrial cancer patients with stage I-III disease underwent primary surgery at the University of Chicago. Representative tissue specimens were immunostained with a monoclonal antibody to E-cadherin. A semiquantitative evaluation scale was developed based on the percentage of endometrial cancer cells with membranous E-cadherin staining. Tissue sections were scored as "3" if >75%, "2" if 25-75%, "1" if 5-25%, and "0" if <5% of cells stained. E-Cadherin staining was correlated with overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and extrapelvic progression. Multivariate Cox proportional hazards modeling was used to estimate hazard ratios, controlling for clinicopathological characteristics and adjuvant treatment. Median follow-up for the study group was 58.5 months. RESULTS: E-Cadherin staining was scored as 0, 1, 2, and 3 in 29.4%, 18.6%, 26.5%, 25.5% of cases, respectively. E-Cadherin expression was positively correlated with myometrial invasion (Kendall tau: 0.30, P < 0.01), and negatively correlated with grade (Kendall tau: -0.13, P = 0.15) and papillary serous or clear cell histology (Kendall tau: -0.14, P = 0.12). Five-year actuarial OS, CSS, PFS, and extrapelvic recurrence rates for negative (score = 0), heterogeneous (score = 1-2), and positive (score = 3) staining were as follows: OS, 69.2 versus 75.7 versus 81.0% (P = 0.64); CSS, 78.8 versus 91.2 versus 95.5% (P = 0.19); PFS, 69.1 versus 88.6 versus 92.2% (P = 0.079), and extrapelvic progression, 20.8 versus 7.3 versus 4.0% (P = 0.17). On multivariate Cox regression, a higher E-cadherin expression score was associated with decreased overall mortality [hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.34-1.03; P = 0.066), and statistically significant decreases in endometrial cancer mortality (HR, 0.23; 95% CI, 0.055-0.94; P = 0.040), disease progression (HR, 0.28; 95% CI, 0.10-0.77; P = 0.014), and extrapelvic recurrence (HR, 0.24; 95% CI, 0.062-0.97; P = 0.045). CONCLUSIONS: Decreased E-cadherin expression is an independent prognostic factor for disease progression and mortality in pathological stage I-III endometrial cancer. Evaluation of E-cadherin expression may aid in the selection of patients for more aggressive adjuvant therapy.     

Prognostic factors for progression-free and overall survival in advanced biliary tract cancer

BackgroundBiliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease.MethodsMultivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset.ResultsA total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.20–2.02]} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival [HR 2.24 (95% CI 1.53–3.28)]. In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57–68); 1-year OS: AUC 64% (95% CI 58–69)].ConclusionThese data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers.     

Metronomic Temozolomide in Heavily Pretreated Patients With Recurrent Isocitrate Dehydrogenase Wild-type Glioblastoma: A Large Real-Life Mono-Institutional Study

AimsGlioblastoma (GBM) is the most common primary malignant brain tumour in adults and frequently relapses. The aim of this study was to assess the efficacy and safety of metronomic temozolomide (TMZ) in the recurrent GBM population.Materials and methodsAll patients treated at our centre between September 2013 and March 2021 were retrospectively reviewed. The main inclusion criteria were first-line therapy with the Stupp protocol, relapse after the first or subsequent line of therapy, treatment with a metronomic TMZ schedule (50 mg/m² continuously) and histological diagnosis of isocitrate dehydrogenase wild-type GBM according to World Health Organization 2016 classification.ResultsIn total, 120 patients were enrolled. The median follow-up was 15.6 months, the median age was 59 years, Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0–2 in 107 patients (89%). O⁶-methylguanine-DNA-methyltransferase (MGMT) was methylated in 66 of 105 (62%) evaluable patients. The median number of prior lines of treatment was 2 (range 1–7). Three (2%) patients showed a partial response; 48 (40%) had stable disease; 69 (57%) had progressive disease. The median overall survival from the start of metronomic TMZ was 5.4 months (95% confidence interval 4.3–6.4), whereas the median progression-free survival (PFS) was 2.6 months (95% confidence interval 2.3–2.8). At univariate analysis, MGMT methylated and unmethylated patients had a median PFS of 2.9 and 2.1 months (P = 0.001) and a median overall survival of 5.6 and 4.4 months (P = 0.03), respectively. At multivariate analysis, the absence of MGMT methylation (hazard ratio = 2.3, 95% confidence interval 1.3–3.9, P = 0.004) and ECOG-PS ≤ 2 (hazard ratio = 0.5, 95% confidence interval 0.3–0.9, P = 0.017) remained significantly associated with PFS, whereas ECOG-PS ≤ 2 (hazard ratio = 0.4, 95% confidence interval 0.3–07, P = 0.001) was the only factor associated with overall survival. The most common grade 3–4 toxicities were haematological (lymphopenia 10%, thrombocytopenia 3%).ConclusionsRechallenge with metronomic TMZ is a well-tolerated option for recurrent GBM, even in pretreated patients. Patients with methylated MGMT disease and good ECOG-PS seem to benefit the most from this treatment.