Novel medicines are entering the market rapidly and are increasingly being used alone or in combination to treat illnesses of every sort. While transforming the lives of many patients, these new ...therapies have also forced us to reconsider the way we evaluate, use and fund medicines. This article offers a primer to help practitioners understand how the therapeutic landscape is changing and how this might impact the evidence generation, access to interventions, patient experience and quality of care.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Measuring patient reported outcomes can improve the quality and effectiveness of healthcare interventions. The aim of this study was to identify the final set of items that can be included in a ...patient-reported outcome measure to assess recovery of patients following percutaneous coronary interventions.
A consecutive sample of 200 patients registered in the Victorian Cardiac Outcomes Registry participated in a telephone survey 30 days following their percutaneous cardiac procedure. Rasch analysis was used to select the best set of items to form a concise and psychometrically sound patient-reported outcome measure. Key measurement properties assessed included overall fit to the Rasch measurement model, unidimensionality, response formats (thresholds), targeting, internal consistency and measurement invariance.
Five items were identified as being reliable and valid measures of patient-reported outcomes: pain or discomfort, shortness of breath, confidence in performing usual activities, feeling unhappy and having trouble sleeping. Data showed overall fit to a Rasch model of expected item functioning (χ2 16.99; p = 0.07) and all items demonstrated unidimensionality (t-test less than 0.05 threshold value). Internal consistency was acceptable (equivalent Cronbach's α 0.65) given there are only five items, but there was a ceiling effect (mean logit score -1.24) with compromised score precision for patients with better recovery.
We identified a succinct set of items that can be used in a patient-reported outcome measure following percutaneous coronary interventions. This patient-report outcome measure has good structural validity and acceptable internal consistency. While further psychometric evaluations are recommended, the items identified capture the patient's perspective of their recovery following a percutaneous coronary intervention.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for ...advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501).
Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by
/
mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures.
Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat ITT, n = 226;
exon 11 ITT, n = 163) or sunitinib (ITT, n = 227;
exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib (
exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16;
= .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal
= .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the
exon 11 ITT population (23.9%
14.6%, nominal
= .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3%
65.6%, nominal
< .0001), and better scores on patient-reported outcome measures of tolerability.
Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.
Accurate pre-operative imaging plays a vital role in patient selection for surgery and in allocating stage-appropriate therapies to patients diagnosed with pancreatic cancer (PC). This study aims to: ...(1) understand the current diagnosis and staging practices for PC; and (2) explore the factors (barriers and enablers) that influence the use of a pancreatic protocol computed tomography (PPCT) or magnetic resonance imaging (MRI) to confirm diagnosis and/or accurately stage PC.
Semi-structured interviews were conducted with radiologists, surgeons, gastroenterologists, medical and radiation oncologists from the states of New South Wales (NSW) and Victoria, Australia. Interviews were conducted either in person or via video conferencing. All interviews were recorded, transcribed verbatim, de-identified and data were thematically coded according to the 12 domains explored within the Theoretical Domains Framework (TDF). Common belief statements were generated to compare the variation between participant responses.
In total, 21 clinicians (5 radiologists, 10 surgeons, 2 gastroenterologists, 4 medical and radiation oncologists) were interviewed over a four-month-period. Belief statements relevant to the TDF domains were generated. Across the 11 relevant domains, 20 themes and 30 specific beliefs were identified. All TDF domains, with the exception of social influences were identified by participants as relevant to protocol-based imaging using either a PPCT or MRI, with the domains of knowledge, skills and environmental context and resources being offered by most participants as being relevant in influencing their decisions.
To maximise outcomes and personalise therapy it is imperative that diagnosis and staging investigations using the most appropriate imaging modalities are conducted in a timely, efficient and effective manner. The results provide an understanding of specialists' opinion and behaviour in relation to a PPCT or MRI and should be used to inform the design of future interventions to improve compliance with this practice.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of ...brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity.
Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m(2) intravenous loading dose followed by weekly maintenance of 250 mg/m(2) plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS).
A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio HR, 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively.
Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.
Abstract The 1st St. Gallen EORTC Gastrointestinal Cancer Conference 2012 Expert Panel clearly differentiated treatment and staging recommendations for the various gastroesophageal cancers. For ...locally advanced gastric cancer (⩾T3N+), the preferred treatment modality was pre- and postoperative chemotherapy. The majority of panel members would also treat T2N+ or even T2N0 tumours with a similar approach mainly because pretherapeutic staging was considered highly unreliable. It was agreed that adenocarcinoma of the gastroesophageal junction (AEG) is classified best according to Siewert et al. Preoperative radiochemotherapy (RCT) is the preferred treatment for AEG type I and II tumours. For AEG type III, i.e. tumours which may be considered as gastric cancer, perioperative chemotherapy is the majority approach. For resectable squamous cell cancer of the oesophagus a clear majority recommended radiochemotherapy followed by surgery as optimal approach, irrespective of tumour size. In contrast, definitive RCT was judged appropriate for advanced tumours with extended lymph node involvement (N2) or for cancers of the upper oesophagus. Additional recommendations are presented on the use of endosonography, PET-CT scan and laparoscopy for staging and on the preferred approach to surgery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery patients with localized, high- or intermediate-risk GI stromal tumor (GIST).
...Patients were randomly assigned to 2 years of imatinib 400 mg daily or no further therapy after surgery. The primary end point was overall survival; relapse-free survival (RFS), relapse-free interval, and toxicity were secondary end points. In 2009, given the concurrent improvement in prognosis of patients with advanced GIST, we changed the primary end point to imatinib failure-free survival (IFFS), with agreement of the independent data monitoring committee. We report on a planned interim analysis.
A total of 908 patients were randomly assigned between December 2004 and October 2008: 454 to imatinib and 454 to observation. Of these, 835 patients were eligible. With a median follow-up of 4.7 years, 5-year IFFS was 87% in the imatinib arm versus 84% in the control arm (hazard ratio, 0.79; 98.5% CI, 0.50 to 1.25; P = .21); RFS was 84% versus 66% at 3 years and 69% versus 63% at 5 years (log-rank P < .001); and 5-year overall survival was 100% versus 99%, respectively. Among 528 patients with high-risk GIST by local pathologist, 5-year IFFS was 79% versus 73%; among 336 centrally reviewed high-risk patients, it was 77% versus 73%, respectively.
This study confirms that adjuvant imatinib has an overt impact on RFS. No significant difference in IFFS was observed, although in the high-risk subgroup there was a trend in favor of the adjuvant arm. IFFS was conceived as a potential end point in the adjuvant setting because it is sensitive to secondary resistance, which is the main adverse prognostic factor in patients with advanced GIST.
Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in
and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to ...refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across
mutation subgroups.
Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by
mutations and correlation of clinical outcomes and
mutational status was assessed.
Overall, 129 patients enrolled (ripretinib 150 mg once daily,
= 85; placebo,
= 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in
exon 11 (ripretinib, 61.2%; placebo, 77.3%) and
exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan-Meier PFS analysis (exon 11,
< 0.0001; exon 9,
= 0.0023; exon 13,
< 0.0001; exon 17,
< 0.0001). Among patients with wild-type
by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo.
Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of
mutations in patients with advanced GIST who were previously treated with three or more TKIs.
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