Cetuximab for the treatment of colorectal cancer Jonker, Derek J; O'Callaghan, Chris J; Karapetis, Christos S ...
New England journal of medicine/The New England journal of medicine,
11/2007, Letnik:
357, Številka:
20
Journal Article
Recenzirano
Odprti dostop
Cetuximab, an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor (EGFR), has activity against colorectal cancers that express EGFR.
From December 2003 to August 2005, 572 ...patients who had colorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin or had contraindications to treatment with these drugs underwent randomization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care (287 patients) or best supportive care alone (285 patients). The primary end point was overall survival.
In comparison with best supportive care alone, cetuximab treatment was associated with a significant improvement in overall survival (hazard ratio for death, 0.77; 95% confidence interval CI, 0.64 to 0.92; P=0.005) and in progression-free survival (hazard ratio for disease progression or death, 0.68; 95% CI, 0.57 to 0.80; P<0.001). These benefits were robust after adjustment in a multivariable Cox proportional-hazards model. The median overall survival was 6.1 months in the cetuximab group and 4.6 months in the group assigned to supportive care alone. Partial responses occurred in 23 patients (8.0%) in the cetuximab group but in none in the group assigned to supportive care alone (P<0.001); the disease was stable in an additional 31.4% of patients assigned to cetuximab and in 10.9% of patients assigned to supportive care alone (P<0.001). Quality of life was better preserved in the cetuximab group, with less deterioration in physical function and global health status scores (both P<0.05). Cetuximab treatment was associated with a characteristic rash; a rash of grade 2 or higher was strongly associated with improved survival (hazard ratio for death, 0.33; 95% CI, 0.22 to 0.50; P<0.001). The incidence of any adverse event of grade 3 or higher was 78.5% in the cetuximab group and 59.1% in the group assigned to supportive care alone (P<0.001).
Cetuximab improves overall survival and progression-free survival and preserves quality-of-life measures in patients with colorectal cancer in whom other treatments have failed. (ClinicalTrials.gov number, NCT00079066 ClinicalTrials.gov.).
Patients with advanced incurable cancer face complex physical, psychological, social, and spiritual consequences of disease and its treatment. Care for these patients should include an individualized ...assessment of the patient's needs, goals, and preferences throughout the course of illness. Consideration of disease-directed therapy, symptom management, and attention to quality of life are important aspects of quality cancer care. However, emerging evidence suggests that, too often, realistic conversations about prognosis, the potential benefits and limitations of disease-directed therapy, and the potential role of palliative care, either in conjunction with or as an alternative to disease-directed therapy, occur late in the course of illness or not at all. This article addresses the American Society of Clinical Oncology's (ASCO's) vision for improved communication with and decision making for patients with advanced cancer. This statement advocates an individualized approach to discussing and providing disease-directed and supportive care options for patients with advanced cancer throughout the continuum of care. Building on ASCO's prior statements on end-of-life care (1998) and palliative care (2009), this article reviews the evidence for improved patient care in advanced cancer when patients' individual goals and preferences for care are discussed. It outlines the goals for individualized care, barriers that currently limit realization of this vision, and possible strategies to overcome these barriers that can improve care consistent with the goals of our patients and evidence-based medical practice.
Recent data have suggested that disease biology and outcome of colon cancer may differ between right-sided and left-sided tumors. However, the literature on the prognostic value of tumor laterality ...is conflicting.
To explore differences in laterality based on disease characteristics and outcomes in a population-based cohort of early-stage colon cancer.
This investigation was a population-based retrospective cohort study of patients with early-stage colon cancer from the province of Ontario, Canada. Electronic records of treatment were linked to the Ontario Cancer Registry to identify all patients with colon cancer who underwent resection between January 1, 2002, and December 31, 2008. The date of the final analysis was October 20, 2016. The study population included a 25% random sample of all patients with resected stage I to III disease. Right-sided colon cancer was defined as any tumor arising in the cecum, ascending colon, hepatic flexure, or transverse colon. Left-sided colon cancer was defined as any tumor arising in the splenic flexure, descending colon, sigmoid colon, or rectosigmoid colon.
Overall survival (OS) and cancer-specific survival (CSS) measured from the time of resection.
This study identified 6365 patients with early-stage colon cancer (48.7% 3098 of 6365 female). Their median age was 72 years, and 51.7% (3291 of 6365) had right-sided disease. Stage distribution was 18.3% (1163 of 6365) stage I, 38.4% (2446 of 6365) stage II, and 43.3% (2756 of 6365) stage III. Patients with right-sided colon cancer were more likely to be older (median age, 73 vs 70 years; P < .001) and female (54.4% 1790 of 3291 vs 42.6% 1308 of 3074, P < .001) and have greater comorbidity. Right-sided cancers were more likely to be T4 (19.2% 631 of 3291 vs 15.9% 490 of 3074, P < .001) and poorly differentiated (21.1% 695 of 3291 vs 9.6% 295 of 3074, P < .001) but less likely to be node positive (42.0% 1383 of 3291 vs 44.7% 1373 of 3074, P = .03) compared with left-sided disease. In adjusted analyses, there was no difference in long-term survival for right-sided compared with left-sided colon cancer: the hazard ratios were 1.00 (95% CI, 0.92-1.08) for OS and 1.00 (95% CI, 0.91-1.10) for CSS. These results were consistent when the survival analyses were restricted to stage III disease: the hazard ratios were 1.03 (95% CI, 0.93-1.14) for OS and 1.10 (95% CI, 0.97-1.24) for CSS.
In this population-based cohort of early-stage resected colon cancer, disease laterality was not associated with long-term OS or CSS.
Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H).
To ...evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC.
A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease.
We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio.
The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB).
Of 180 patients enrolled (121 men 67.2% and 59 women 32.8%; median range age, 65 36-87 years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio HR, 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 64% patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 20% in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004).
This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted.
ClinicalTrials.gov Identifier: NCT02870920.
Given the high levels of sedentary time and treatment-related side effects in prostate cancer survivors (PCS), interventions targeting sedentary behavior (SED) may be more sustainable compared to ...physical activity (PA).
To examine the feasibility of a web-based intervention (RiseTx) for reducing SED and increasing moderate-to-vigorous physical activity (MVPA) among PCS undergoing ADT. Secondary outcomes include changes in SED, MVPA, light intensity PA, and quality of life.
Forty-six PCS were recruited from two cancer centres in Toronto, Ontario, Canada between July 2015-October 2016. PCS were given an activity tracker (Jawbone), access to the RiseTx website program, and provided with a goal of increasing walking by 3000 daily steps above baseline levels over a 12-week period. A range of support tools were progressively released to reduce SED time (e.g., self-monitoring of steps) during the five-phase program. Objective measures of SED, MVPA, and daily steps were compared across the 12-week intervention using linear mixed models.
Of the 46 PCS enrolled in the study, 42 completed the SED intervention, representing a 9% attrition rate. Measurement completion rates were 97 and 65% at immediately post-intervention and 12-week follow-up for all measures, respectively. Overall adherence was 64% for total number of logins (i.e., > 3 visits each week). Sample mean age was 73.2 ± 7.3 years, mean BMI was 28.0 ± 3.0 kg/m
, mean number of months since diagnosis was 93.6 ± 71.2, and 72% had ADT administered continuously. Significant reductions of 455.4 weekly minutes of SED time were observed at post-intervention (p = .005). Significant increases of + 44.1 for weekly minutes of MVPA was observed at immediately post-intervention (p = .010). There were significant increases in step counts of + 1535 steps from baseline to post-intervention (p < .001).
RiseTx was successful in reducing SED and increasing MVPA in PCS. PCS were satisfied with the intervention and its components. Additional strategies may be needed though for maintenance of behavior change. The next step for RiseTx is to replicate these findings in a larger, randomized controlled trial that will have the potential for reducing sedentary time among PCS.
NCT03321149 (ClinicalTrials.gov Identifier).
Background
In Ontario, FOLFIRINOX (FFX) and gemcitabine + nab‐paclitaxel (GnP) have been publicly funded for first‐line unresectable locally advanced pancreatic cancer (uLAPC) or metastatic ...pancreatic cancer (mPC) since April 2015. We examined the real‐world effectiveness and safety of FFX vs GnP for advanced pancreatic cancer, and in uLAPC and mPC.
Methods
Patients receiving first‐line FFX or GnP from April 2015 to March 2017 were identified in the New Drug Funding Program database. Baseline characteristics and outcomes were obtained through the Ontario Cancer Registry and other population‐based databases. Overall survival (OS) was assessed using Kaplan‐Meier and weighted Cox proportional hazard models, weighted by the inverse propensity score adjusting for baseline characteristics. Weighted odds ratio (OR) for hospitalization and emergency department visits (EDV) were estimated from weighted logistic regression models.
Results
For 1130 patients (632 FFX, 498 GnP), crude median OS was 9.6 and 6.1 months for FFX and GnP, respectively. Weighted OS was improved for FFX vs GnP (HR = 0.77, 0.70‐0.85). Less frequent EDV and hospitalization were observed in FFX (EDV: 67.8%; Hospitalization: 49.2%) than GnP (EDV: 77.7%; Hospitalization: 59.3%). More frequent febrile neutropenia‐related hospitalization was observed in FFX (5.8%) than GnP (3.3%). Risk of EDV and hospitalization were significantly lower for FFX vs GnP (EDV: OR = 0.68, P = .0001; Hospitalization: OR = 0.76, P = .002), whereas the risk of febrile neutropenia‐related hospitalization was significantly higher (OR = 2.12, P = .001). Outcomes for uLAPC and mPC were similar.
Conclusion
In the real world, FFX had longer OS, less frequent all‐cause EDV and all‐cause hospitalization, but more febrile neutropenia‐related hospitalization compared to GnP.
In the real world, implementation of universal public funding of FOLFIRINOX for metastatic pancreatic cancer was associated with improved overall survival, less frequent all‐cause emergency department visits, less frequent all‐cause hospitalization, but increased febrile neutropenia‐related hospitalization compared to patients treated with gemcitabine + nab‐paclitaxel. Expanding funding to include unresectable locally advanced pancreatic cancer was associated with a similar trend in benefits, but with improved absolute survival.
Although quality of life (QOL) is an important clinical end point, cancer drugs are often approved based on overall survival (OS) or putative surrogate end points such as progression-free survival ...(PFS) without QOL data.
To ascertain whether cancer drug trials that show improvement in OS or PFS also improve global QOL of patients with cancer compared with the control treatment, as well as to assess how unchanged or detrimental QOL outcomes are reported in trial publications.
This retrospective cohort study included all patients with cancer in the advanced setting who were enrolled into phase 3 randomized clinical trials (RCTs) of cancer drugs reporting QOL data and published in English language in a PubMed-indexed journal in the calendar year 2019. The systematic search of PubMed was conducted in July 2020.
Association of QOL outcomes with OS and PFS, framing of unchanged QOL outcomes in trial publications, and the association of favorable framing with industry funding of the trials.
A total of 45 phase 3 RCTs enrolling 24 806 participants (13 368 in the experimental arm and 11 438 in the control arm) met the inclusion criteria and were included in the study analyses. Improvement in global QOL with the experimental agent was reported in 11 (24%) RCTs. The RCTs with improved QOL were more likely to also show improved OS vs trials with unimproved QOL (7 of 11 64% trials vs 10 of 34 29% trials; χ2 = 4.13; P = .04); there was no such association observed for PFS (6 of 11 55% trials vs 17 of 34 50% trials, χ2 = 0.03; P = .87). Six trials reported worsening QOL, of which 3 (50%) were trials of targeted drugs, and 11 trials reported improvement in QOL, of which 6 (55%) were trials of immunotherapy drugs. Of the 34 trials in which QOL was not improved compared with controls, 16 (47%) reported these results in a positive frame, an observation statistically significantly associated with industry funding (χ2 = 6.35; P = .01).
In this cohort study, a small proportion of RCTs of cancer drugs showed benefit in global QOL with the experimental agent. These results showed an association between QOL benefit and OS benefit but no such association with PFS benefit. Trials that failed to show improved QOL often reported their QOL outcomes more favorably. Non-immunotherapy-targeted drugs led to worse QOL more often than did cytotoxic agents.
During the past two decades clinical and research efforts have led to increasingly sophisticated and effective methods and instruments designed to detect exaggeration or fabrication of ...neuropsychological dysfunction, as well as somatic and psychological symptom complaints. A vast literature based on relevant research has emerged and substantial portions of professional meetings attended by clinical neuropsychologists have addressed topics related to malingering (Sweet, King, Malina, Bergman, & Simmons,
2002
). Yet, despite these extensive activities, understanding the need for methods of detecting problematic effort and response bias and addressing the presence or absence of malingering has proven challenging for practitioners. A consensus conference, comprised of national and international experts in clinical neuropsychology, was held at the 2008 Annual Meeting of the American Academy of Clinical Neuropsychology (AACN) for the purposes of refinement of critical issues in this area. This consensus statement documents the current state of knowledge and recommendations of expert clinical neuropsychologists and is intended to assist clinicians and researchers with regard to the neuropsychological assessment of effort, response bias, and malingering.
The pantropical response of soil moisture to El Niño Solander, Kurt C.; Newman, Brent D.; Carioca de Araujo, Alessandro ...
Hydrology and earth system sciences,
05/2020, Letnik:
24, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The 2015–2016 El Niño event ranks as one of the most severe on record in terms of the magnitude and extent of sea surface temperature (SST) anomalies generated in the tropical Pacific Ocean. ...Corresponding global impacts on the climate were expected to rival, or even surpass, those of the 1997–1998 severe El Niño event, which had SST anomalies that were similar in size. However, the 2015–2016 event failed to meet expectations for hydrologic change in many areas, including those expected to receive well above normal precipitation. To better understand how climate anomalies during an El Niño event impact soil moisture, we investigate changes in soil moisture in the humid tropics (between ±25∘) during the three most recent super El Niño events of 1982–1983, 1997–1998 and 2015–2016, using data from the Global Land Data Assimilation System (GLDAS). First, we use in situ soil moisture observations obtained from 16 sites across five continents to validate and bias-correct estimates from GLDAS (r2=0.54). Next, we apply a k-means cluster analysis to the soil moisture estimates during the El Niño mature phase, resulting in four groups of clustered data. The strongest and most consistent decreases in soil moisture occur in the Amazon basin and maritime southeastern Asia, while the most consistent increases occur over eastern Africa. In addition, we compare changes in soil moisture to both precipitation and evapotranspiration, which showed a lack of agreement in the direction of change between these variables and soil moisture most prominently in the southern Amazon basin, the Sahel and mainland southeastern Asia. Our results can be used to improve estimates of spatiotemporal differences in El Niño impacts on soil moisture in tropical hydrology and ecosystem models at multiple scales.
PDF
