Background
Improvements in cancer treatment have increased the number of cancer survivors, but also increased the long-term and late effects from cancer therapy. Patient reported “side effect bother” ...could be used to measure the burden of treatment, and the risk for negative outcomes such as dose reduction, treatment delay or discontinuation. The current study addresses the psychometric properties of a single item, determines what represents a “meaningful change”, and evaluates the correlation to safety endpoints and functioning.
Methods
Results from 5911 patients enrolled in 8 clinical trials representing 5 disease types in oncology and hematology who completed either the Functional Assessment of Cancer Therapy (FACT) GP5 item or a modified bother item (MBI) were assessed.
Results
Patients ranged in age from 18 to 93 years, with all cancer stages represented and approximately equal numbers of males and females. Test–retest reliability was acceptable, as were convergent and known groups validity. The GP5 and MBI effectively demonstrated sensitivity to change over time and established meaningful thresholds.
Conclusions
The results indicate that these single-items are psychometrically sound, capable of distinguishing known groups, responsive to change and can identify meaningful change over time in terms of treatment-related symptoms. It extends the findings of recent scientific groups by providing analyses not included in prior studies, and further supports the FDA’s recommendation to include a single item question in clinical trials.
To investigate the efficacy and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 in patients with metastatic renal cell ...carcinoma (mRCC) refractory to prior therapies that included, but were not limited to, sorafenib.
In this multicenter, open-label, phase II study, patients with sorafenib-refractory mRCC received a starting dose of axitinib 5 mg orally twice daily. A one-arm, single-stage design was used to estimate the primary end point of objective response rate (ORR), defined by RECIST (Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival (PFS), overall survival (OS), and patient-reported outcomes.
Of 62 patients recruited, 100% had received prior sorafenib, and 74.2% had received two or more prior systemic treatments. The axitinib dose was titrated to greater than 5 mg twice daily in 53.2% of patients, and 35.5% of patients had the dose modified to less than 5 mg twice daily. In 62 patients evaluable for response, the ORR was 22.6%, and the median duration of response was 17.5 months. Median PFS and OS times were 7.4 months (95% CI, 6.7 to 11.0 months) and 13.6 months (95% CI, 8.4 to 18.8 months), respectively. All-causality grade 3 to 4 adverse events included hand-foot syndrome (16.1%), fatigue (16.1%), hypertension (16.1%), dyspnea (14.5%), diarrhea (14.5%), dehydration (8.1%), and hypotension (6.5%).
Axitinib has antitumor activity in patients with mRCC refractory to prior VEGF-targeted therapy, including sorafenib. Toxicities were mild to moderate and were manageable. A randomized, phase III trial to compare axitinib with sorafenib in patients who have mRCC refractory to one prior first-line therapy regimen is underway.
Summary Background Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in ...advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. Methods In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m2 intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov , number NCT00471146. Findings Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9–9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9–10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786–1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 7% and 5 2% events, respectively), abdominal pain (20 7% and 17 6%), fatigue (27 9% and 21 7%), and anorexia (19 6% and 11 4%). Interpretation The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. Funding Pfizer.
Summary Background Axitinib (AG-013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We aimed to assess the activity and safety of axitinib ...in patients with metastatic renal-cell cancer who had failed on previous cytokine-based treatment. Methods Between Oct 3, 2003, and April 7, 2004, 52 patients were enrolled. All patients who had at least one measurable target lesion received axitinib orally (starting dose 5 mg twice daily). The primary endpoint was objective response (ie, percentage of patients with confirmed complete response or partial response by use of Response Evaluation Criteria In Solid Tumors RECIST criteria. Secondary endpoints were duration of response, time to progression, overall survival, safety, pharmacokinetics, and patient-reported health-related quality of life. This trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00076011. Findings In an intention-to-treat analysis, two complete and 21 partial responses were noted, for an objective response rate of 44·2% (95% CI 30·5–58·7). Median response duration was 23·0 months (20·9–not estimable; range 4·2–29·8). However, 12 of 23 initial responders progressed with response duration ranging from 4·2 months to 26·5 months. Additionally, 22 patients showed stable disease for longer than 8 weeks, including 13 patients with stable disease for 24 weeks or longer. Four patients had early disease progression. Three patients had missing response data. Median time to progression was 15·7 months (8·4–23·4, range 0·03–31·5) and median overall survival was 29·9 months (20·3–not estimable; range 2·4–35·8). Treatment-related adverse events included diarrhoea, hypertension, fatigue, nausea, and hoarseness. Treatment-related hypertension occurred in 30 patients and resolved with antihypertensive treatment in all but eight patients, of whom seven patients had a history of hypertension at baseline. Interpretation Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.
In this hypothesis-generating analysis, we examined whether longitudinal changes in patient-reported outcomes (PROs), such as symptoms, over time would be prognostic for progression-free survival ...(PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who were newly treated with obinutuzumab (G) in combination with CHOP (G-CHOP) or rituximab (R) with CHOP (R-CHOP), in the GOYA Phase 3 trial (NCT01287741). Our results show that from the study baseline to cycle 3 day 1, every 1-point increase (worsening) in fever symptoms was associated with a 41% higher risk of death (hazard ratio HR, 1.41;
P
= 0.01). Every 1-point increase (worsening) in lumps or swelling symptoms was associated with a 27% higher risk of disease progression or death (PFS events) (HR, 1.27;
P
= 0.01) and a 29% higher risk of death (OS events) (HR, 1.29;
P
= 0.02). No significant associations were observed between survival and changes in other symptoms, such as itching. Our study suggests that changes in some PROs are related to survival in DLBCL patients.
As new cancer treatment regimens demonstrate increased potential to improve patients’ survival, more focus is directed toward the quality of that extension of life and to obtaining additional ...information from patients regarding their experience with treatment. The utility of capturing patient-reported treatment-related symptoms to complement traditional clinician-rated symptomatic adverse event reporting is well-documented. The National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events is an item library aimed at capturing patient-reported symptoms to inform the patient perspective on a treatment’s tolerability. The U.S. Food and Drug Administration has recommended using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events in clinical trials. A practical guideline is needed to inform a priori selection of specific Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items for use in any given industry-sponsored oncology clinical trial. Standardizing this selection process will foster systematic and consistent data collection as part of drug development and enhance our knowledge on how to use patient-relevant information as part of a treatment’s risk/benefit assessment. This article presents methods and consensus recommendations for selecting specific Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items to include in early-phase and late-phase oncology clinical trials.
It is widely known that depression exists in patients with cancer. The prevalence, however, varies widely by study and is often attributable to differences in assessment procedures. Attempts to ...identify accurate methods of assessing depression in cancer patients have employed different diagnostic approaches, assessment methods (e.g., self-report versus interview), and inclusion criteria. Unfortunately, all of these variables affect conclusions that can be drawn regarding the presence of depression in cancer patients. Other variables that can further affect the assessment of depression in cancer patients include individual differences such as the patient’s age, gender, race/ethnicity, hospitalization status, and type and stage of cancer. Finally, the specific assessor and the timing of the assessment also likely affect conclusions about depression in cancer patients. This review was designed to succinctly address all of the above issues and identify several areas for future research, including refining diagnostic criteria for depression in cancer patients; creating cancer-specific depression measures with appropriate cutoffs; focusing on the issues of age, race, ethnicity, subculture, and type and stage of cancer in creating depression assessment tools; and exploring the issues of clinical versus subclinical depression, who and when to assess, and timely and cost-effective ways to assess.
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