To evaluate whether capecitabine plus oxaliplatin (XELOX) is noninferior to fluorouracil. folinic acid, and oxaliplatin (FOLFOX-4) as first-line therapy in metastatic colorectal cancer (MCRC).
The ...initial design of this trial was a randomized, two-arm, noninferiority, phase III comparison of XELOX versus FOLFOX-4. After patient accrual had begun, the trial design was amended in 2003 after bevacizumab phase III data became available. The resulting 2 x 2 factorial design randomly assigned patients to XELOX versus FOLFOX-4, and then to also receive either bevacizumab or placebo. We report here the results of the analysis of the XELOX versus FOLFOX-4 arms. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately. The prespecified primary end point for the noninferiority analysis was progression-free survival.
The intent-to-treat population comprised 634 patients from the original two-arm portion of the study, plus an additional 1,400 patients after the start of the amended 2 x 2 design, for a total of 2,034 patients. The median PFS was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4-containing arms (hazard ratio HR, 1.04; 97.5% CI, 0.93 to 1.16). The median overall survival was 19.8 months with XELOX versus 19.6 months with FOLFOX-4 (HR, 0.99; 97.5% CI, 0.88 to 1.12). FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhea and grade 3 hand-foot syndrome than FOLFOX-4.
XELOX is noninferior to FOLFOX-4 as a first-line treatment for MCRC, and may be considered as a routine treatment option for appropriate patients.
Liquid biopsy offers a minimally invasive alternative to tissue-based evaluation of mutational status in cancer. The goal of the present study was to evaluate the aggregate performance of OncoBEAM ...RAS mutation analysis in plasma of colorectal cancer (CRC) patients at 10 hospital laboratories in Spain where this technology is routinely implemented.
Circulating cell-free DNA from plasma was examined for RAS mutations using the OncoBEAM platform at each hospital laboratory. Results were then compared to those obtained from DNA extracted from tumour tissue from the same patient.
The overall percentage agreement between plasma-based and tissue-based RAS mutation testing of the 236 participants was 89% (210/236; kappa, 0.770 (95% CI: 0.689-0.852)). Re-analysis of tissue from all discordant cases by BEAMing revealed two false negative and five false positive tumour tissue RAS results, with a final concordance of 92%. Plasma false negative results were found more frequently in patients with exclusive lung metastatic disease.
In this first prospective real-world RAS mutation performance comparison study, a high overall agreement was observed between results obtained from plasma and tissue samples. Overall, these findings indicate that the plasma-based BEAMing assay is a viable solution for rapid delivery of RAS mutation status to determine mCRC patient eligibility for anti-EGFR therapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
This work proposes a discrete‐time output feedback controller to stabilize an integrator chain system in the presence of measurement noise and external disturbances. Besides, two structural ...systems are considered, the first one is a system with a saturation in the control input. The second one is a system with an unbounded input. Since the system output is supposed to be periodically sampled and noisy, a discrete‐time filtering observer is designed. Hence, using the output of the observer, a discrete‐time controller is derived. The closed‐loop system convergence and robustness analysis are also presented. Simulation results are performed, aiming to illustrate the main characteristics of the proposal, including comparisons between the closed‐loop system with an explicit and implicit discrete‐time observer. Finally, having proved the features of the implicit realization, the controller with an implicit differentiator is implemented to control a DC–DC buck converter.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary Background Patients with peritoneal metastatic colorectal cancer have reduced overall survival compared with patients with metastatic colorectal cancer without peritoneal involvement. Here we ...further investigated the effect of the number and location of metastases in patients receiving first-line systemic chemotherapy. Methods We analysed individual patient data for previously untreated patients enrolled in 14 phase 3 randomised trials done between 1997 and 2008. Trials were included if protocols explicitly pre-specified and solicited for patients with peritoneal involvement in the trial data collection process or had done a formal peritoneum-focused review of individual pre-treatment scans. We used stratified multivariable Cox models to assess the prognostic associations of peritoneal metastatic colorectal cancer with overall survival and progression-free survival, adjusting for other key clinical-pathological factors (age, sex, Eastern Cooperative Oncology Group (ECOG) performance score, primary tumour location colon vs rectum, previous treatment, and baseline BMI). The primary endpoint was difference in overall survival between populations with and without peritoneal metastases. Findings Individual patient data were available for 10 553 patients. 9178 (87%) of 10 553 patients had non-peritoneal metastatic colorectal cancer (4385 with one site of metastasis, 4793 with two or more sites of metastasis), 194 (2%) patients had isolated peritoneal metastatic colorectal cancer, and 1181 (11%) had peritoneal metastatic colorectal cancer and other organ involvement. These groups were similar in age, ethnic origin, and use of targeted treatment. Patients with peritoneal metastatic colorectal cancer were more likely than those with non-peritoneal metastatic colorectal cancer to be women (565 41% of 1371 vs 3312 36% of 9169 patients; p=0·0003), have colon primary tumours (1116 84% of 1334 patients vs 5603 66%; p<0·0001), and have performance status of 2 (136 10% vs 521 6%; p<0·0001). We recorded a higher proportion of patients with mutated BRAF in patients with peritoneal-only (eight 18% of 44 patients with available data) and peritoneal metastatic colorectal cancer with other sites of metastasis (34 12% of 289), compared with patients with non-peritoneal metastatic colorectal cancer (194 9% of 2230; p=0·028 comparing the three groups). Overall survival (adjusted HR 0·75, 95% CI 0·63–0·91; p=0·003) was better in patients with isolated non-peritoneal sites than in those with isolated peritoneal metastatic colorectal cancer. Overall survival of patients with two of more non-peritoneal sites of metastasis (adjusted HR 1·04, 95% CI 0·86–1·25, p=0.69) and those with peritoneal metastatic colorectal cancer plus one other site of metastasis (adjusted HR 1·10, 95% CI 0·89–1·37, p=0·37) was similar to those with isolated peritoneal metastases. Compared with patients with isolated peritoneal metastases, those with peritoneal metastases and two or more additional sites of metastasis had the shortest survival (adjusted HR 1·40; CI 1·14–1·71; p=0·0011). Interpretation Patients with peritoneal metastatic colorectal cancer have significantly shorter overall survival than those with other isolated sites of metastases. In patients with several sites of metastasis, poor survival is a function of both increased number of metastatic sites and peritoneal involvement. The pattern of metastasis and in particular, peritoneal involvement, results in prognostic heterogeneity of metastatic colorectal cancer. Funding None.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
This article presents explicit and implicit discrete‐time realizations for a class of homogeneous sliding mode‐based differentiators. The proposed approach relies on the method of exact ...discretization for linear systems with a zero‐order holder. The two discrete‐time schemes present the homogeneity property and, after a finite time, the accuracy of its continuous‐time counterpart, even in the presence of bounded noise. In comparison to the explicit realization, which makes it possible to determine the state of the system later from the state at present, for this case, the implicit method requires finding a solution by solving generalized equations that involve the current state of the system and two support variables. Therefore, this document proves that the polynomial's unique positive root defines the required solution as part of the main results. Hence, it is possible to introduce a non‐anticipative method to implement the implicit discrete‐time realization, including an appropriate root‐finding method for the polynomial. Finally, the simulation results include comparisons between the proposed implicit and explicit discrete methods with other existing schemes. Numerical studies clearly show that the implicit method supersedes the explicit one, consistent with the implicit and explicit time discretization of other continuous‐time algorithms.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose.
The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment ...following induction chemotherapy with XELOX plus bevacizumab in the first‐line treatment of patients with metastatic colorectal cancer (mCRC).
Patients and Methods.
Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression‐free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety.
Results.
The intent‐to‐treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow‐up was 29.0 months (range, 0–53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand–foot syndrome, and neuropathy.
Conclusion.
Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single‐agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients.
摘要
目的 本项 III 期试验旨在比较一线卡培他滨+奥沙利铂（ XELOX ）+贝伐珠单抗诱导化疗后贝伐珠单抗单药与贝伐珠单抗 +XELOX 维持治疗对转移性结直肠癌（ mCRC ）患者的疗效和安全性。
患者与方法 患者随机接受6个周期的贝伐珠单抗+卡培他滨+奥沙利铂（每3周），继以 XELOX+ 贝伐珠单抗或贝伐珠单抗单药，直至进展。主要终点为无进展生存（PFS）时间；次要终点为总生存（OS）时间、客观缓解率（RR）、至缓解时间、缓解持续时间和安全性。
结果 意向性治疗人群包含480例患者（XELOX+贝伐珠单抗，n=239；贝伐珠单抗，n =241）；基线特征方面无显著差异。中位随访时间为29.0个月（范围，0~53.2个月）。两组的中位PFS或OS时间或RR无显著差异。 XELOX+ 贝伐珠单抗组vs.贝伐珠单抗组最常见的3级或4级毒性为腹泻、手足综合征和神经病变。
结论 尽管无法证实贝伐珠单抗是否不劣于 XELOX+ 贝伐珠单抗，但>3周的中位PFS损害能可靠排除。本研究提示，单药贝伐珠单抗维持治疗可能是 mCRC 患者继 XELOX+ 贝伐珠单抗诱导治疗后的适宜选择。
This phase III trial compared the efficacy and safety of bevacizumab alone with that of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first‐line treatment of patients with metastatic colorectal cancer. Noninferiority could not be confirmed, but the median progression‐free survival detriment was >3 weeks.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this work we study the time series of annual and seasonal streamflow for 44 rivers in southern Chile, spanning the ecoregion between 34°S and 45°S for the 1952–2003 period. We analyze spatial ...variability using a clustering process to define regional streamflow averages. We find two main regions, divided approximately by parallel 37.5°S. The analysis includes application of the multitaper (MTM) and maximum entropy (MEM) methods to find periodicities or interannual and decadal cycles. Singular spectral analysis (SSA) is applied in order to augment the signal‐to‐noise ratio. Significant correlation with climatic indexes was found at different spatial and temporal scales, with El Niño–Southern Oscillation (ENSO) influence being stronger at the northern subregion, and notably the Antarctic Oscillation (AAO) and the Pacific Decadal Oscillation (PDO) showing strong correlation with summer flows in the southern subregion. Also, we found significant decreasing trends affecting a region between 37.5°S and 40°S. These are coherent with decreasing trends observed in precipitation in the area, and also with a decreasing trend observed in the Southern Oscillation Index (SOI). These findings provide, for the first time, a comprehensive view of the streamflow variability in a sensitive ecoregion in South America. We expect that these results will inform decision making in a context of increasing water demands for diverse uses as well as contribute to the general understanding of climatic patterns of variability in the Pacific Rim.
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BFBNIB, CEKLJ, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the ...last decade with extended OS, this surrogacy requires re-examination.
Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti-epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R(2) statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.
Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R(2), 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.
In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.
One drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyperpermeability of the tumor vasculature. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme ...usually repressed in the tumor milieu. Here we show that specific SOD3 re-expression in tumor-associated endothelial cells (ECs) increases doxorubicin (Doxo) delivery into and chemotherapeutic effect on tumors. Enhanced SOD3 activity fostered perivascular nitric oxide accumulation and reduced vessel leakage by inducing vascular endothelial cadherin (VEC) transcription. SOD3 reduced HIF prolyl hydroxylase domain protein activity, which increased hypoxia-inducible factor-2α (HIF-2α) stability and enhanced its binding to a specific VEC promoter region. EC-specific HIF-2α ablation prevented both the SOD3-mediated increase in VEC transcription and the enhanced Doxo effect. SOD3, VEC, and HIF-2α levels correlated positively in primary colorectal cancers, which suggests a similar interconnection of these proteins in human malignancy.
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