Eligibility criteria in clinical trials limit the study population for safety and scientific purposes. The American Society of Clinical Oncology and The Friends of Cancer Research collaboration ...reconsidered common eligibility criteria in cancer trials and found many to be unnecessarily restrictive. The current recommendations further their efforts to facilitate accrual and improve the generalizability of research results to practice.
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Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated ...metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer.
Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity.
The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively (P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting.
The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal.
Background & Aims Approximately 50% of all patients with pancreatic ductal adenocarcinoma (PDA) develop diabetes mellitus before their cancer diagnosis. Screening individuals with new-onset diabetes ...might allow earlier diagnosis of PDA. We sought to develop and validate a PDA risk prediction model to identify high-risk individuals among those with new-onset diabetes. Methods We conducted a retrospective cohort study in a population representative database from the United Kingdom. Individuals with incident diabetes after the age of 35 years and 3 or more years of follow-up after diagnosis of diabetes were eligible for inclusion. Candidate predictors consisted of epidemiologic and clinical characteristics available at the time of diabetes diagnosis. Variables with P values <.25 in the univariable analyses were evaluated using backward stepwise approach. Model discrimination was assessed using receiver operating characteristic curve analysis. Calibration was evaluated using the Hosmer−Lemeshow test. Results were internally validated using a bootstrapping procedure. Results We analyzed data from 109,385 patients with new-onset diabetes. Among them, 390 (0.4%) were diagnosed with PDA within 3 years. The final model (area under the curve, 0.82; 95% confidence interval, 0.75−0.89) included age, body mass index, change in body mass index, smoking, use of proton pump inhibitors, and anti-diabetic medications, as well as levels of hemoglobin A1C, cholesterol, hemoglobin, creatinine, and alkaline phosphatase. Bootstrapping validation showed negligible optimism. If the predicted risk threshold for definitive PDA screening was set at 1% over 3 years, only 6.19% of the new-onset diabetes population would undergo definitive screening, which would identify patients with PDA with 44.7% sensitivity, 94.0% specificity, and a positive predictive value of 2.6%. Conclusions We developed a risk model based on widely available clinical parameters to help identify patients with new-onset diabetes who might benefit from PDA screening.
Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require ...tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection.
A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence.
Of 103 patients, 84 stage I (9.5%), II (23.8%), III (47.6%), IV (19%) had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (
= 39) or completion of adjuvant therapy (
= 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred positive predictive value (PPV), 100%; HR, 11.28 (
< 0.0001). Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence HR, 1.84 (
= 0.18); PPV = 53.9%.
Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.
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Purpose.
This analysis pooled individual patient data from randomized controlled trials (RCTs) to more thoroughly examine clinical outcomes when adding bevacizumab to chemotherapy for patients with ...metastatic colorectal cancer (mCRC).
Patients and Methods.
Patient data were pooled from the first‐line AVF2107, NO16966, ARTIST, AVF0780, AVF2192, and AGITG MAX RCTs and the second‐line E3200 RCT. All analyses were based on the intent‐to‐treat population. To assess differences in time‐to‐event variables by treatment (chemotherapy with or without placebo vs. chemotherapy plus bevacizumab), stratified random‐effects (overall) and fixed‐effects (subgroup comparisons) models were used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs).
Results.
The analysis population comprised 3,763 patients (1,773 chemotherapy with or without placebo; 1,990 chemotherapy plus bevacizumab). The addition of bevacizumab to chemotherapy was associated with statistically significant increases in overall survival (OS; HR, 0.80; 95% CI, 0.71–0.90) and progression‐free survival (PFS; HR, 0.57; 95% CI, 0.46–0.71). The effects on OS and PFS across subgroups defined by chemotherapy backbone (oxaliplatin‐based, irinotecan‐based), extent of disease (liver metastases only, extensive disease), age (<65, ≥65 years), Eastern Cooperative Oncology Group performance status (0, ≥1), and KRAS status (wild‐type, mutant) were consistent with the overall analysis. Incidence rates of grade ≥3 hypertension, proteinuria, bleeding, wound‐healing complications, gastrointestinal perforations, and thromboembolic events were increased with bevacizumab treatment.
Conclusion.
The use of bevacizumab with chemotherapy resulted in statistically significant increases in OS and PFS for patients with mCRC. The PFS benefit extended across the clinically relevant subgroups examined. The observed safety profile of bevacizumab was consistent with that reported in individual trials.
摘要
目的 本分析将来自随机对照试验（RCT）的贝伐珠单抗联合化疗治疗的转移性结直肠癌（mCRC）患者数据汇总至更彻底的临床结果检验中。。
患者和方法 汇总的患者数据来自一线AVF2107、NO16966、ARTIST、AVF0780、AVF2192和AGITG MAX RCT，以及二线E3200 RCT。所有分析基于意向治疗人群。按照治疗（化疗±安慰剂 vs.化疗+贝伐珠单抗）评估时间至事件变量的差异，采用分层随机效应（全体）和固定效应（亚组比较）模型估计汇总风险比（HR）和95%可信区间（CI）。
结果 分析人群包含3763例患者（化疗±安慰剂组1773例，化疗+贝伐珠单抗组1990例）。化疗+贝伐珠单抗治疗与总生存（OS；HR，0.80；95% CI，0.71 ∼ 0.90）和无进展生存（PFS；HR，0.57；95% CI，0.46 ∼ 0.71）的显著改善相关。根据基础化疗（以奥沙利铂为基础和以伊立替康为基础）定义的亚组间OS和PFS、疾病范围（仅肝转移、广泛性疾病）、年龄（<65、≥65岁）、东部肿瘤协作组体能状态（0，≥1），和KRAS状态（野生型、突变）的效应和总分析相一致。贝伐珠单抗治疗≥3级高血压、蛋白尿、出血、伤口愈合并发症、胃肠道穿孔和血栓栓塞事件的发生率升高。
结论 化疗联合贝伐珠单抗可使mCRC患者的OS和PFS显著延长。在检测的临床相关亚组中观察到广泛的PFS获益。本研究观察到的贝伐珠单抗安全性特征和单个临床研究中报告的相一致。The Oncologist 2013;18:1004‐1012
This analysis examined clinical outcomes when adding bevacizumab to chemotherapy for patients with metastatic colorectal cancer (mCRC). The use of bevacizumab with chemotherapy resulted in statistically significant increases in overall and progression‐free survival for patients with mCRC, and the observed safety profile of bevacizumab was consistent with that reported in individual trials.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
IMPORTANCE Difference in breast cancer survival by race is a recognized problem among Medicare beneficiaries. OBJECTIVE To determine if racial disparity in breast cancer survival is primarily ...attributable to differences in presentation characteristics at diagnosis or subsequent treatment. DESIGN, SETTING, AND PATIENTS Comparison of 7375 black women 65 years and older diagnosed between 1991 to 2005 and 3 sets of 7375 matched white control patients selected from 99 898 white potential controls, using data for 16 US Surveillance, Epidemiology and End Results (SEER) sites in the SEER-Medicare database. All patients received follow-up through December 31, 2009, and the black case patients were matched to 3 white control populations on demographics (age, year of diagnosis, and SEER site), presentation (demographics variables plus patient comorbid conditions and tumor characteristics such as stage, size, grade, and estrogen receptor status), and treatment (presentation variables plus details of surgery, radiation therapy, and chemotherapy). MAIN OUTCOMES AND MEASURES 5-Year survival. RESULTS The absolute difference in 5-year survival (blacks, 55.9%; whites, 68.8%) was 12.9% (95% CI, 11.5%-14.5%; P < .001) in the demographics match. This difference remained unchanged between 1991 and 2005. After matching on presentation characteristics, the absolute difference in 5-year survival was 4.4% (95% CI, 2.8%-5.8%; P < .001) and was 3.6% (95% CI, 2.3%-4.9%; P < .001) lower for blacks than for whites matched also on treatment. In the presentation match, fewer blacks received treatment (87.4% vs 91.8%; P < .001), time from diagnosis to treatment was longer (29.2 vs 22.8 days; P < .001), use of anthracyclines and taxols was lower (3.7% vs 5.0%; P < .001), and breast-conserving surgery without other treatment was more frequent (8.2% vs 7.3%; P = .04). Nevertheless, differences in survival associated with treatment differences accounted for only 0.81% of the 12.9% survival difference. CONCLUSIONS AND RELEVANCE In the SEER-Medicare database, differences in breast cancer survival between black and white women did not substantially change among women diagnosed between 1991 and 2005. These differences in survival appear primarily related to presentation characteristics at diagnosis rather than treatment differences.
While societal acceptance for sexual and gender minority (SGM) individuals is increasing, this group continues to face barriers to quality healthcare. Little is known about clinicians' experiences ...with SGM patients in the oncology setting. To address this, a mixed method survey was administered to members of the ECOG-ACRIN Cancer Research Group.
We report results from the open-ended portion of the survey. Four questions asked clinicians to describe experiences with SGM patients, reservations in caring for them, suggestions for improvement in SGM cancer care, and additional comments. Data were analyzed using content analysis and the constant comparison method.
The majority of respondents noted they had no or little familiarity with SGM patients. A minority of respondents noted experience with gay and lesbian patients, but not transgender patients; many who reported experience with transgender patients also noted difficulty navigating the correct use of pronouns. Many respondents also highlighted positive experiences with SGM patients. Suggestions for improvement in SGM cancer care included providing widespread training, attending to unique end-of-life care issues among SGM patients, and engaging in efforts to build trust.
Clinicians have minimal experiences with SGM patients with cancer but desire training. Training the entire workforce may improve trust with, outreach efforts to, and cancer care delivery to the SGM community.
Lessons Learned
Palbociclib monotherapy demonstrated minimal clinical activity in patients with previously treated gastroesophageal cancers.
Further clinical evaluation of palbociclib monotherapy is ...not warranted in gastroesophageal cancers, but improved understanding of resistance mechanisms may permit rational combination approaches.
Background
Dysregulation of the cell cycle is a hallmark of cancer. Progression through the G1/S transition requires phosphorylation of retinoblastoma (RB) by cyclin‐dependent kinases (CDKs) 4 and 6, which are regulated by cyclins D and E. Amplifications of cyclin D loci and activating mutations in CDKs are frequent molecular aberrations in gastroesophageal malignancies. We conducted a phase II trial of the CDK4/6 inhibitor palbociclib as an initial test of efficacy.
Methods
Patients with previously treated metastatic gastroesophageal cancers with intact RB nuclear expression by immunohistochemistry were treated with 125 mg daily of palbociclib for days 1–21 of 28‐day cycles. The primary endpoint was overall response rate.
Results
We screened 29 patients and enrolled 21 patients: 5 with gastric adenocarcinoma, 3 with gastroesophageal junction adenocarcinoma, 8 with esophageal adenocarcinoma, and 5 with esophageal squamous cell carcinoma. All 29 tumors screened had intact nuclear RB expression, and four treated patients tested positive for CCND1 overexpression. No objective responses were seen. Median progression‐free survival was 1.8 months, and median overall survival was 3.0 months. All recurrent grade 3 or 4 toxicities were hematologic, with neutropenia in eight patients (38%), anemia in four patients (19%), and thrombocytopenia in two patients (10%).
Conclusion
Palbociclib has limited single‐agent activity in gastroesophageal tumors.
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Early detection of pancreatic ductal adenocarcinoma (PDA) may improve survival. We previously developed a clinical prediction model among patients with new-onset diabetes to help identify PDAs 6 ...months prior to the clinical diagnosis of the cancer. We developed and internally validated a new model to predict PDA risk among those newly diagnosed with impaired fasting glucose (IFG).
We conducted a retrospective cohort study in The Health Improvement Network (THIN) (1995-2013) from the UK. Eligible study patients had newly diagnosed IFG during follow-up in THIN. The outcome was incident PDA diagnosed within 3 years of IFG diagnosis. Candidate predictors were factors associated with PDA, glucose metabolism or both.
Among the 138 232 eligible patients with initial IFG diagnosis, 245 (0.2%) were diagnosed with PDA within 3 years. The median time from IFG diagnosis to clinical PDA diagnosis was 326 days (IQR 120-588). The final prediction model included age, BMI, proton pump inhibitor use, total cholesterol, low-density lipoprotein, alanine aminotransferase and alkaline phosphatase. The model achieved good discrimination area under the curve 0.71 (95% CI, 0.67-0.75) and calibration (Hosmer and Lemeshow goodness-of-fit test P > 0.05 in 17 of the 20 imputed data sets) with optimism of 0.0012662 (95% CI, -0.00932 to 0.0108771).
We developed and internally validated a sequential PDA prediction model based on clinical information routinely available at the initial appearance of IFG. If externally validated, this model could significantly extend our ability to detect PDAs at an earlier stage.
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