Peggy L. Lin

Interpreting score differences in the SF-36 Vitality scale: using clinical conditions and functional outcomes to define the minimally important difference

ABSTRACT Objective: To propose the minimally important difference (MID) for the SF-36 Vitality (VT) scale by evaluating the association of score differences with clinical conditions and functional outcomes. Methods: Analyses were performed on data from the Medical Outcomes Study (n = 3445). The first analyses regressed VT scores (0–100 scale) on chronic conditions that cause fatigue in order to determine the impact of each condition on VT. The second set of analyses examined the relationship between baseline VT scores and other outcomes at baseline, 1‑year, and 7‑year follow-up. Results: VT scores were significantly reduced in patients with anemia [5 points (95% CI 2–9 points)], CHF [6 (3–9) points], and COPD [6 (3–9) points]. Decreases in VT score were significantly associated with increased odds of negative outcomes, including inability to work due to health at baseline [OR (5 points) = 1.27 (95% CI 1.24–1.31), OR (10 points) = 1.62 (1.54–1.71)], job loss at 1 year [OR (5) = 1.13 (1.08–1.19), OR (10) = 1.28 (1.17–1.41)], hospitalization at 1 year [OR (5) = 1.08 (1.05–1.11), OR (10) = 1.17 (1.10–1.23)], short-term mortality [0–18 months–Hazard Ratio (HR) (5) = 1.10–1.71, HR (10) = 1.21–2.39, depending on VT level] and long-term mortality [19+ months–HR (5) = 1.05–1.31, HR (10) = 1.10–1.54]. The mortality risk increase was largest at low VT levels. Conclusions: VT decrements of 5–10 points were seen for diseases known to cause fatigue. Further, differences of 5–10 points in the VT score were associated with significant increased risk of negative outcomes. We recommend an MID of 5 points for analyses of groups with VT scores below average. For follow-up of individual patients, we recommend a 10-point difference as important.

Functionality and health-status benefits associated with reduction of osteoarthritis pain

ABSTRACT Objective: To evaluate the association between pain intensity improvement and improvements in functionality and health status in patients with chronic osteoarthritis pain of the hip or knee. Methods: Data were obtained from a 12-week, randomized, double-blind, placebo-controlled study of tramadol ER 100 mg, 200 mg, 300 mg, or 400 mg once daily. Patients reported pain intensity with a 100-mm visual analog scale (0 = no pain, 100 = extreme pain) and functionality and health status with the disease-specific Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire and the generic Short-Form-36 Health Survey (SF‑36). Pain intensity improvement from baseline was categorized as < 0%, 0–14%, 15–29%, 30–49%, 50–69%, and ≥ 70%, and mean changes in WOMAC and SF‑36 scores were determined for patients in each category. Results: A total of 1011 patients received placebo (n = 205) or tramadol ER 100 mg (n = 202), 200 mg (n = 201), 300 mg (n = 201), or 400 mg (n = 202). The degree of pain intensity improvement was correlated with the degree of improvement in WOMAC and SF‑36 scores; as little as 15% reduction of pain intensity was associated with notable improvements in function and health status. Potential limitations included the lack of established thresholds to assess clinically meaningful changes in these outcomes. Conclusions: Pain intensity improvement is associated with corresponding improvements in function and health status. While large improvements in pain intensity are associated with large improvements in health status and functionality, modest pain reductions are also associated with improvement of certain health status parameters.

Treatment patterns in metastatic renal cell carcinoma: a retrospective review of medical records from US community oncology practices

Abstract Background: Vascular endothelial growth factor (VEGF) inhibitors, including targeted therapy with tyrosine kinase inhibitors (TKIs) and the angiogenesis inhibitor bevacizumab, and mammalian target of rapamycin (mTOR) inhibitors are now the standard of care for metastatic renal cell carcinoma (mRCC). However, real-world treatment patterns are not well characterized. Objective: To describe treatment patterns during the first, second, and third lines of targeted therapies for mRCC among community oncologists in the US. Methods: Participating physicians recruited from a nationwide panel each identified up to 15 adult mRCC patients who initiated a second therapy after January 2010. Information extracted from medical records included types of targeted therapies, reasons for treatment choices, patterns of treatment discontinuation, and dose adjustments. Results: Thirty-six physicians contributed charts from 433 mRCC patients. Seventy-seven percent of patients received a VEGF inhibitor as first targeted therapy; 23% received an mTOR inhibitor. Among first-line VEGF users, second-line treatments were 66% mTOR and 34% VEGF inhibitors. Among first-line mTOR users, second-line treatments were 94% VEGF and 6% mTOR inhibitors. Sunitinib followed by everolimus was the most commonly used treatment sequence. Estimated median duration for second targeted therapy was 8.6 months, and median overall survival (OS) and progression-free survival (PFS) were 27.4 and 10.8 months, respectively. Efficacy, treatment guidelines and mechanism of action were the most important considerations for treatment choice. Limitations: Limitations include no adjustment for baseline characteristics, possible difference between physician-defined progression and central review in the clinical trial setting, and limited data availability for axitinib during the study period. Conclusion: In this large retrospective chart review among community oncologists, VEGF–mTOR–VEGF was the most common treatment sequence for mRCC. The most common drugs were sunitinib in the first line and everolimus in the second line.

Treatment patterns and duration in post-menopausal women with HR+/HER2− metastatic breast cancer in the US: a retrospective chart review in community oncology practices (2004–2010)

Abstract Background: Clinical guidelines prefer endocrine therapy (ET) as initial treatment for post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer (mBC). Chemotherapy (CT) should be reserved for patients who develop symptomatic visceral disease or have no clinical benefit after three sequential ET regimens. It is unclear if real-world clinical practice reflects these guidelines. Objective: To describe treatment patterns and treatment durations by lines of therapy for ET and CT among post-menopausal HR+/HER2− mBC patients. Methods: Charts were reviewed from a network of community-based oncology practices of eligible patients who had progressed after initiating adjuvant or first-line treatment for mBC between 1 January 2004 and 30 September 2010. Extracted chart data included demographics, treatment histories, and outcomes. Treatment duration was estimated using Kaplan–Meier estimators. Results: A total of 144 patients were studied. Patients received a median of two lines of ET, and <10% had three or more lines of ET before receiving CT. From first line to second line, the median treatment duration was 11.6 to 4.9 months for ET overall; 13.8 to 10.5 months for anastrozole; 18.6 to 7.0 months for letrozole; and 5.1 to 2.9 months for fulvestrant. For CT, the median duration was 5.1 months in the first line and 3.7 months and below in subsequent lines. Conclusion: During the study period (1 January 2004 – 30 September 2012), most patients received <3 lines of ET before receiving CT. The drop in median duration of ET from first to second line suggests that single agent ETs might not be as effective beyond the first line. A key limitation of this study was the small sample size. In addition, more research is needed to further investigate the short treatment duration of fulvestrant across early lines of therapy (which could indicate lack of efficacy).

Everolimus-Based Therapy versus Chemotherapy among Patients with HR+/HER2− Metastatic Breast Cancer: Comparative Effectiveness from a Chart Review Study

Objective. To compare the real-world effectiveness of everolimus-based therapy and chemotherapy in postmenopausal women with hormone-receptor-positive/human-epidermal-growth-factor-receptor-2-negative (HR+/HER2−) metastatic breast cancer (mBC). Methods. This retrospective chart review examined a nationwide sample of postmenopausal HR+/HER2− mBC women in community-based oncology practices. Patients received everolimus-based therapy or chemotherapy for mBC between 07/01/2012 and 04/15/2013, after failure of a non-steroidal aromatase inhibitor. Overall survival (OS), progression-free survival (PFS), and time on treatment (TOT) were compared using Kaplan-Meier analysis and Cox proportional hazards models adjusting for line of therapy and baseline characteristics. Results. 234 and 137 patients received everolimus-based therapy and chemotherapy. Patients treated with everolimus-based therapy tended to have less aggressive mBC than patients treated with chemotherapy. Multivariate-adjusted Cox models showed that everolimus-based therapy was associated with significantly longer OS [hazard ratio (HR) = 0.37, 95% confidence interval (CI): 0.22–0.63], PFS (HR = 0.70, 95% CI = 0.50–0.97), and TOT (HR = 0.34, 95% CI: 0.25–0.45) than chemotherapy. Adjusted comparative effectiveness results were generally consistent across lines of therapy. Conclusion. In this retrospective chart review of postmenopausal HR+/HER2− mBC patients, treatment with everolimus-based therapy was associated with longer OS, PFS, and TOT than chemotherapy.

Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: synthesis of findings from two multi-practice chart reviews in the United States

Abstract Background: Second-line targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors (TKIs). This study compares the effectiveness of these therapies in a multi-practice chart review and synthesizes the findings with those of a similarly designed study. Methods: Medical oncologists/hematologists (N = 36) were recruited to review charts for patients aged ≥18 years, received a first-line TKI and initiated second-line targeted therapy in 2010 or later. The primary outcome was time from second-line initiation to treatment failure (TTF; discontinuation, physician-assessed progression, or death, whichever occurred first). TTF was compared among patients receiving second-line everolimus (EVE), temsirolimus (TEM), or TKI as a class, using a Cox proportional hazards model adjusting for type of initial TKI and response, histological subtype, performance status, and sites of metastasis. Hazard ratios (HRs) for TTF were pooled, in a meta-analysis, with previously reported HRs for progression-free survival from a chart review with a similar design. Results: A total of 138, 64 and 79 patients received second-line therapy with EVE, TEM or a TKI, respectively. Adjusting for baseline characteristics, EVE was associated with numerical, but not statistically significant, reductions of 28% (HR = 0.72; 95% CI [0.45–1.16]) and 26% (HR = 0.74; 95% CI [0.48–1.15]) in the hazard of TTF compared to TEM and TKI, respectively. After pooling the HRs from both studies, EVE was associated with significantly reduced hazards of TTF compared to TEM and TKI (HR = 0.73; 95% CI [0.57–0.93]; and HR = 0.75; 95% CI [0.57–0.98], respectively). Limitations: Limitations include retrospective analyses with possible missing or erroneous chart data, confounding of unobserved factors due to non-randomization, and limited data for axitinib during the study period. Conclusions: In pooled results from two independent multi-practice chart reviews of second-line mRCC treatment, EVE was associated with significantly reduced hazards of treatment failure compared to TEM and to TKIs as a class.

Comparative effectiveness of everolimus-based therapy versus endocrine monotherapy among postmenopausal women with HR+/HER2− metastatic breast cancer: a retrospective chart review in community oncology practices in the US

Abstract Background: Everolimus-based therapy and endocrine monotherapy are used among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2−) metastatic breast cancer (mBC) whose disease progressed or recurred on a non-steroidal aromatase inhibitor (NSAI). However, limited evidence exists regarding the real-world comparative effectiveness of these agents. Methods: This retrospective chart review examined postmenopausal HR+/HER2− mBC patients in community-based oncology practices who received everolimus-based therapy or endocrine monotherapy (index therapy) as any line of therapy for mBC between 1 July 2012 and 15 April 2013 after NSAI failure. Time on treatment (TOT), progression-free survival (PFS), and time to chemotherapy (TTC) from index therapy initiation were compared using Kaplan–Meier analyses and Cox proportional hazards models adjusting for baseline characteristics. Results: A total of 243 and 270 patients received everolimus-based therapy or endocrine monotherapy in a quota-based sample. Patients treated with everolimus-based therapy had a higher proportion of visceral metastases, high tumor burden, and use of prior chemotherapies for mBC. After adjusting for baseline characteristics, everolimus-based therapy was associated with significantly longer TOT (HR = 0.67, 95% CI: 0.51–0.87) and PFS (HR = 0.75, 95% CI: 0.57–0.98) than endocrine monotherapy. No significant difference was found between everolimus-based therapy and endocrine monotherapy in TTC (HR = 0.81, 95% CI: 0.52–1.27). Results stratified by line of therapy were generally consistent with the overall results. Limitations: Limitations include recall and information bias with potentially absent or erroneous chart data, unobserved factors due to non-randomization, inability to measure outcome assessments paired with measuring outcomes prior to exposures, and potential patient selection bias associated with chart review. Conclusions: Among a nationwide sample of postmenopausal HR+/HER2− mBC patients treated in community oncology settings, treatment with everolimus-based therapy was associated with significantly longer TOT and PFS compared to endocrine monotherapy.

Prognostic factors for survival following initiation of second-line treatment with everolimus for metastatic renal cell carcinoma: evidence from a nationwide sample of clinical practice in the United States

Objective: Comparing prognostic factors for overall survival (OS) in community-practice metastatic renal cell carcinoma (mRCC) patients receiving second-line everolimus with those previously reported in clinical trials. Research design and methods: Two separate chart sets (2009 – 2012) were used to develop and validate a prognostic model for patients initiating second-line everolimus after first-line tyrosine kinase inhibitor (TKI). Main outcome measures: Prognostic factors for OS have been identified and validated in separate samples. Results: One-year OS probabilities in the study (n = 220) and validation (n = 97) samples were 68 and 67%; median OS was 19 and 23 months – higher than the 1-year OS of 60% and median OS of 14.8 months of RECORD-1. Karnofsky performance score < 80%, duration of mRCC < 1 year, progression on first-line TKI, liver metastasis and clear cell histology were significant prognostic factors for shorter survival. One-year OS estimates were 84% for validation sample patients with 0 – 2 risk factors, 63% for 3 risk factors and 22% for 4 – 5 risk factors (log-rank p < 0.001). Conclusion: Real-world prognostic factors for OS following second-line everolimus for mRCC were largely consistent with those previously identified in trial data; however, OS was longer in the practice setting than in clinical trials and was not associated with type of first-line TKI.

Sequential use of targeted therapies for metastatic renal cell carcinoma: A physician survey and chart review of community oncology practices in the United States.

418 Background: Multiple targeted agents are available to treat metastatic renal cell carcinoma (mRCC) and no consensus has been reached for optimal treatment sequencing. This study describes physician-reported treatment preferences, reasons for treatment choices, and current treatment patterns for mRCC in the community setting. METHODS A physician survey and retrospective chart review was conducted during May and June 2012 among community-based oncologists or hematologists who had ≥5 mRCC patients under their care in 2011. Charts were reviewed for adult mRCC patients initiated on 2nd-targeted therapy after January 2010 to collect information on current treatment sequence in mRCC patients and reasons for treatment choices. A parallel survey collected physician treatment preferences for 1st-, 2nd-, and 3rd-targeted therapies for mRCC patients with good or poor prognosis. RESULTS The study included surveys from 36 physicians and charts from 433 mRCC patients. The majority of patients (77%) received a tyrosine kinase inhibitor (TKI) and the rest (23%) received a mammalian target of rapamycin inhibitor (mTOR) as the 1st-targeted therapy. Sunitinib was the most common TKI and temsirolimus was the most common mTOR in the 1st-line setting. Among patients receiving 1st-line TKI, 34% received TKI (pazopanib was most used TKI) and 66% received mTOR (everolimus was most used mTOR) in the 2nd-line. Among 1st-line mTOR users, 94% used TKI (sunitinib was most used) and 6% mTOR (everolimus was most used) for 2nd-line. TKI-mTOR-TKI was the most commonly observed treatment sequence. Physician-stated preferences for 1st and 2nd targeted therapies were largely consistent with the results from the chart review, though actual mTOR use in the 2nd-line was greater than expected. Treatment guidelines and evidence from clinical trials were the top-ranked factors impacting treatment choices. CONCLUSIONS In this large, retrospective chart review, TKI-mTOR-TKI was the most commonly observed treatment sequence for mRCC in the community setting.

Real-world effectiveness of everolimus-based therapy versus endocrine monotherapy and chemotherapy in patients of HR+/HER2- breast cancer with liver metastasis in the USA

Objective: This study investigated the comparative effectiveness of everolimus-based therapy (EVE) versus endocrine monotherapy (ET) and chemotherapy (CT) in the treatment of hormone-receptor-positive human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients with liver metastasis. Methods: Medical charts of patients treated by community oncologists were examined. Eligible patients included postmenopausal women with HR+/HER2- mBC with liver metastasis who received EVE, ET or CT between 1 July 2012 and 15 April 2013 after non-steroidal aromatase inhibitor use. Time on treatment (TOT) and progression-free survival (PFS) were compared between EVE and ET or CT using Kaplan–Meier analyses and Cox proportional hazards models. Results: Among the 202 patients in the study, 82 received EVE, 49 ET, and 71 CT. After adjusting for baseline characteristics, EVE was associated with significantly longer TOT than ET (hazard ratio [HR]: 0.49; 95% CI: 0.28 – 0.86) or CT (HR: 0.35; 95% CI: 0.22 – 0.55), and significantly longer PFS than ET (HR: 0.48; 95% CI: 0.27 – 0.87). PFS was not significantly different with EVE versus CT (HR: 0.76; 95% CI: 0.44 – 1.32). Conclusions: EVE had significantly longer TOT and PFS than ET and longer TOT than CT among postmenopausal HR+/HER2- mBC patients with liver metastasis.