Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy

Trametinib, a selective inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) and MEK2, significantly improves progression-free survival compared with chemotherapy in patients with BRAF V600E/K mutation–positive advanced or metastatic melanoma (MM). However, the pivotal clinical trial permitted randomized chemotherapy control group patients to switch to trametinib after disease progression, which confounded estimates of the overall survival (OS) advantage of trametinib. Our purpose was to estimate the switching-adjusted treatment effect of trametinib for OS and assess the suitability of each adjustment method in the primary efficacy population. Of the patients randomized to chemotherapy, 67.4% switched to trametinib. We applied the rank-preserving structural failure time model, inverse probability of censoring weights, and a two-stage accelerated failure time model to obtain estimates of the relative treatment effect adjusted for switching. The intent-to-treat (ITT) analysis estimated a 28% reduction in the hazard of death with trametinib treatment (hazard ratio [HR], 0.72; 95% CI, 0.52–0.98) for patients in the primary efficacy population (data cut May 20, 2013). Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first-line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation–positive advanced melanoma or MM. Adjusting for switching resulted in lower HRs than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method

Quality of Life in Hormone Receptor–Positive HER-2+ Metastatic Breast Cancer Patients During Treatment with Letrozole Alone or in Combination with Lapatinib

This paper presents analyses evaluating quality of life in patients with hormone receptor–positive human epidermal growth factor receptor 2–positive tumors receiving letrozole alone or in combination with lapatinib in clinical trial EGF30008

Q-TWiST analysis of lapatinib combined with capecitabine for the treatment of metastatic breast cancer

The addition of lapatinib (Tykerb/Tyverb) to capecitabine (Xeloda) delays disease progression more effectively than capecitabine monotherapy in women with previously treated HER2+ metastatic breast cancer (MBC). The quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) method was used to compare treatments. The area under survival curves was partitioned into health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse period until death or end of follow-up (REL). Average times spent in each state, weighted by utility, were derived and comparisons of Q-TWiST between groups performed with varying combinations of the utility weights. Utility weights of 0.5 for both TOX and REL, that is, counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 7-week difference in quality-adjusted survival favouring combination therapy (P=0.0013). The Q-TWiST difference is clinically meaningful and was statistically significant across an entire matrix of possible utility weights. Results were robust in sensitivity analyses. An analysis with utilities based on EQ-5D scores was consistent with the above findings. Combination therapy of lapatinib with capecitabine resulted in greater quality-adjusted survival than capecitabine monotherapy in trastuzumab-refractory MBC patients

Health-related quality of life in patients treated with pembrolizumab for microsatellite instability–high/mismatch repair–deficient advanced solid tumours: Results from the KEYNOTE-158 study

Background: In the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite instability−high (MSI-H)/mismatch repair‒deficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K). Patients and methods: Eligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score. Results: At data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean [95% CI] change, 3.07 [0.19–5.94]), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 [6.36–15.35]). Patients with CR/PR showed improvements in physical (5.58 [1.91–9.25]), role (9.88 [3.80–15.97]), emotional (5.62 [1.56–9.68]), and social (8.33 [2.70–13.97]) functioning, and stable cognitive functioning (1.74 [−1.45 to 4.94]). Conclusions: Pembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours

Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study

We report the first quality-of-life assessment of a MEK inhibitor in metastatic melanoma from a phase III study. Trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. Less functional impairment, smaller declines in health status, and less exacerbation of symptoms were observed with trametini

Psychometric evaluation of the Osteoporosis Patient Treatment Satisfaction Questionnaire (OPSAT-Q™), a novel measure to assess satisfaction with bisphosphonate treatment in postmenopausal women

BACKGROUND: The Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q) is a new measure of patient satisfaction with bisphosphonate treatment for osteoporosis. The objective of this study was to evaluate the psychometric characteristics of the OPSAT-Q. METHODS: The OPSAT-Q contains 16 items in four subscales: Convenience, Confidence with Daily Activities, Side Effects, and Overall Satisfaction. All four subscale scores and an overall composite satisfaction score (CSS) can be computed. The OPSAT-Q, Osteoporosis Targeted Quality of Life (OPTQoL), and sociodemographic/clinical questionnaires, including 3 global items on convenience, functioning and side effects, were self-administered to women with osteoporosis or osteopenia recruited from four US clinics. Analyses included item and scale performance, internal consistency reliability, reproducibility, and construct validity. Reproducibility was measured using the intraclass correlation coefficient (ICC) via a follow-up questionnaire completed by participants 2 weeks post baseline. RESULTS: 104 women with a mean age of 65.1 years participated. The majority were Caucasian (64.4%), living with someone (74%), and not currently employed (58.7%). 73% had osteoporosis and 27% had osteopenia. 80% were taking weekly bisphosphonates and 18% were taking daily medication (2% missing data). On a scale of 0–100, individual patient subscale scores ranged from 17 to 100 and CSS scores ranged from 44 to 100. All scores showed acceptable internal consistency reliability (Cronbach's alpha > 0.70) (range 0.72 to 0.89). Reproducibility ranged from 0.62 (Daily Activities) to 0.79 (Side Effects) for the subscales; reproducibility for the CSS was 0.81. Significant correlations were found between the OPSAT-Q subscales and conceptually similar global measures (p < 0.001). CONCLUSION: The findings from this study confirm the validity and reliability of the OPSAT-Q and support the proposed composition of four subscales and a composite score. They also support the use of the OPSAT-Q to examine the impact of bisphosphonate dosing frequency on patient satisfaction

Relationship between effects on time-to-disease progression and overall survival in studies of metastatic breast cancer

The relationship between overall survival (OS) and disease progression end points has been demonstrated in colorectal, colon, and non-small cell lung cancers. We assessed the association between OS and time-to-progression (TTP) or progression-free survival (PFS) in metastatic breast cancer (MBC) studies. A literature search retrieved all randomised controlled trials since 1994 in patients with MBC in which OS and either TTP or PFS were reported. Summary data on trial and patient characteristics were abstracted. Study effect sizes were derived as the ratio of median progression (or survival) times, which approximates the hazard ratio. Effects were centred at zero for regression analyses weighted by sample size. Numerous treatments were represented in 67 studies (17 081 patients). Modeling showed a positive association between outcomes for progression and survival (R2=0.30) with a slope of 0.32 (P<0.001) and a non-significant intercept. Thus, a treatment effect on TTP/PFS translated into a concordant effect on OS, but with attenuated effect size. Similar results were found in models of subsets and sensitivity analyses. These results demonstrate that treatment effects on progression end points in MBC trials are expected to result in treatment differences on OS that are smaller yet consistently in the same direction

Usporedba dugotrajne primjene triju intrakanalnih lijekova na mikrotvrdoću i otpornost na lom korijenskog dentina: in vitro istraživanje

Objectives: The aim of this research was to evaluate the effect of long-term use of three intracanal medicaments on the radicular dentin microhardness and fracture resistance. Material and methods: A chemomechanical preparation was done using the Protaper rotary instruments up to F3. The teeth were stored in an incubator at 37°C at 100% humidity and were categorized in three groups by random allocation, namely: Triple Antibiotic Paste (TAP), Calcium hydroxide paste (Apexcal) and Ledermix. Following medicament application, the access openings of all teeth were sealed with 4 mm thickness of cavit. The samples were stored for periods of 1 week, 1 month and 3months. Two dentin cylinders measuring 5mm and 3mm were obtained from each sample. The cervical third was used for fracture resistance and the middle third was used for micro hardness evaluation. The microhardness testing was done using a Knoop microhardness tester, and the fracture resistance testing was done using the universal testing machine. Results: Calcium hydroxide showed maximally negative effect on the physical properties of radicular dentin compared to TAP (p= 0.0100 at one month and Ledermix (p=0.0001 at one month ). With an increase in the application time, there was an increased deterioration in the physical properties of radicular dentin. Conclusion: Long-term placement of calcium hydroxide, Triple Antibiotic Paste, and Ledermix (p= 0.0001at 3 months) significantly affects the microhardness and fracture resistance of radicular dentin.Cilj rada: Željelo se procijeniti kako dugotrajna upotreba triju intrakanalnh lijekova utječe na mikrotvrdoću i otpornost na lom radikularnog dentina.Materijal i metode: Kemomehanička preparacija obavljena Protaperovim rotirajućim instrumentima do F3. Zubi su zatim stavljeni u inkubator i čuvani na temperaturi od 37 °C u 100 posto vlažnom okružju te su slučajnim odabirom podijeljeni u tri skupine: trostruka antibiotička pasta (TAP), pasta od kalcijeva hidroksida (Apexcal), Ledermix. Nakon primjene lijekova svi su ulazni otvori zabrtvljeni 4 mm debelim slojem Cavita. Uzorci su zatim uskladišteni tjedan dana, mjesec dana i tri mjeseca. Od svakog uzorka uzeta su po dva dentinska cilindra debljine 3 i 5 mm. Za otpornost na lom korištena je cervikalna trećina, a za procjenu mikrotvrdoće srednja trećina. Mikrotvrdoća je ispitana testerom Knoop Microhardness, a otpornost na lom univerzalnim ispitnim uređajem. Rezultati: Kalcijev hidroksid najsnažnije je negativno djelovao na fizička svojstva radikularnog dentina u usporedbi s TAP-om (p = 0,0100 nakon mjesec dana) i Ledermixom (p = 0,0001 nakon mjesec dana). Kako se povećavalo razdoblje djelovanja, tako su se pogoršavala fizička obilježja radikularnog dentina. Zaključak: Dugotrajno korištenje kalcijeva hidroksida, TAP-a i Ledermixa (p = 0,0001 nakon 3 mjeseca) znatno utječe na mikrotvrdoću i otpornost na lom radikularnog dentina

Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine

Background: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18–0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. Methods: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. Results: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. Conclusions: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. Clinical Trials.gov identifier NCT01227889

Performance of a multianalyte test as an aid for the diagnosis of ovarian cancer in symptomatic women

Background: Concomitant with the development of in vitro diagnostic multivariate index assays (IVDMIAs) to improve the diagnostic efficiency of ovarian cancer detection is the need to identify appropriate biostatistical approaches to assess improvements in risk predication. In this study, we assessed the utility of three different approaches for comparing diagnostic efficiency of an ovarian cancer multivariate assay in a retrospective case control phase 2 biomarker trial. The control cohort included both disease-free women and women with benign gynecological conditions to more accurately reflect the target population of symptomatic women