Michael S. Wolf

Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

PURPOSE Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. PATIENTS AND METHODS KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. RESULTS KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. CONCLUSION Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer

PURPOSE Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR). We compared the activity of panitumumab plus best supportive care (BSC) to that of BSC alone in patients with metastatic colorectal cancer who had progressed after standard chemotherapy. PATIENTS AND METHODS We randomly assigned 463 patients with 1% or more EGFR tumor cell membrane staining, measurable disease, and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC (n = 231) or BSC alone (n = 232). Tumor assessments by blinded central review were scheduled from week 8 until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included objective response, overall survival (OS), and safety. BSC patients who progressed could receive panitumumab in a cross-over study. RESULTS Panitumumab significantly prolonged PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66, [P < .0001]). Median PFS time was 8 weeks (95% CI, 7.9 to 8.4) for panitumumab and 7.3 weeks (95% CI, 7.1 to 7.7) for BSC. Mean (standard error) PFS time was 13.8 (0.8) weeks for panitumumab and 8.5 (0.5) weeks for BSC. Objective response rates also favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10% for panitumumab and 0% for BSC (P < .0001). No difference was observed in OS (HR, 1.00; 95% CI, 0.82 to 1.22), which was confounded by similar activity of panitumumab after 76% of BSC patients entered the cross-over study. Panitumumab was well tolerated. Skin toxicities, hypomagnesaemia, and diarrhea were the most common toxicities observed. No patients had grade 3/4 infusion reactions. CONCLUSION Panitumumab significantly improved PFS with manageable toxicity in patients with chemorefractory colorectal cancer.

Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study

PURPOSE Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. PATIENTS AND METHODS In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. RESULTS KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. CONCLUSION This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.

Low Literacy Impairs Comprehension of Prescription Drug Warning Labels

AbstractBACKGROUND: Adverse events resulting from medication error are a serious concern. Patients’ literacy and their ability to understand medication information are increasingly seen as a safety issue. OBJECTIVE: To examine whether adult patients receiving primary care services at a public hospital clinic were able to correctly interpret commonly used prescription medication warning labels. DESIGN: In-person structured interviews with literacy assessment. SETTING: Public hospital, primary care clinic. PARTICIPANTS: A total of 251 adult patients waiting for an appointment at the Louisiana State University Health Sciences Center in Shreveport (LSUHSC-S) Primary Care Clinic. MEASUREMENTS: Correct interpretation, as determined by expert panel review of patients’ verbatim responses, for each of 8 commonly used prescription medication warning labels. RESULTS: Approximately one-third of patients (n=74) were reading at or below the 6th-grade level (low literacy). Patient comprehension of warning labels was associated with one’s literacy level. Multistep instructions proved difficult for patients across all literacy levels. After controlling for relevant potential confounding variables, patients with low literacy were 3.4 times less likely to interpret prescription medication warning labels correctly (95% confidence interval: 2.3 to 4.9). CONCLUSIONS: Patients with low literacy had difficulty understanding prescription medication warning labels. Patients of all literacy levels had better understanding of warning labels that contained single-step versus multiple-step instructions. Warning labels should be developed with consumer participation, especially with lower literate populations, to ensure comprehension of short, concise messages created with familiar words and recognizable icons.

Health Literacy and Health Actions: A Review and a Framework From Health Psychology

The association between performance on health literacy measures and health outcomes is well established. The next step is to understand the processes through which health literacy affects health. This review introduces a framework drawing on ideas from health psychology and proposing that associations between health literacy and health outcomes could be mediated by a range of health actions involving access and use of health care, patient—provider interactions, and the management of health and illness. The framework outlines routes through which health literacy might affect either health actions themselves or the motivational and volitional determinants that have been identified in social cognition models. The implications of the framework for future research and intervention strategies are discussed.

Development and validation of a short-form, Rapid Estimate of Adult Literacy in Medicine

Background:Although prior studies used the 66-item Rapid Estimate of Adult Literacy in Medicine (REALM instrument) for literacy assessment, researchers may require a shorter, validated instrument when designing interventions for clinical contexts. Objective:To develop and validate a very brief literacy assessment tool, the REALM-Short Form (REALM-SF). Patients:The model development, validation, and field testing validation samples included 1336, 164, and 50 patients, respectively. Setting:General medicine and subspecialty clinics and medicine inpatient wards. Design:For development and validation samples, indicator variables for REALM instrument items were evaluated as potential predictors of REALM instrument score by stepwise multiple regression analysis with subsequent bootstrap and confirmatory factor analysis of selected items. Pearson correlations compared REALM-SF and REALM instrument scores and kappa analyses compared grade level assignments. For the field testing validation sample, Pearson correlations compared Wide Range Achievement Test and REALM-SF scores. Results:The REALM-SF included 7 items with stable model coefficients and 1 underlying linear factor. REALM-SF and REALM instrument scores were highly correlated in development (r = 0.95, P < 0.001) and validation (r = 0.94, P < 0.001) samples. There was excellent agreement between REALM-SF and REALM instrument grade-level assignments when dichotomized at the 6th grade (development: 97% agreement, K = 0.88, P < 0.001; validation: 88% agreement, K = 0.75, P < 0.001) and 8th grade levels (development: 94% agreement, K = 0.78, P < 0.001; validation: 84% agreement, K = 0.67, P < 0.001). REALM-SF and Wide Range Achievement Test scores were highly correlated (r = 0.83, P < 0.001) in field testing validation. Conclusions:The REALM-SF provides researchers a brief, validated instrument for assessing patient literacy in diverse research settings.

The mechanisms linking health literacy to behavior and health status

OBJECTIVE To examine the mechanisms linking health literacy to physical activity and self-reported health. METHODS From 2005-2007, patients (N = 330) with hypertension were recruited from safety net clinics. Pathanalytic models tested the pathways linking health literacy to physical activity and self-reported health. RESULTS There were significant paths from health literacy to knowledge (r = 0.22, P < 0.001), knowledge to self-efficacy (r = 0.13, P < 0.01), self-efficacy to physical activity (r = 0.17, P < 0.01), and physical activity to health status (r = 0.17, P < 0.01). CONCLUSIONS Health education interventions should be literacy sensitive and aim to enhance patient health knowledge and self-efficacy to promote self-care behavior and desirable health outcomes.

Readability, suitability, and characteristics of asthma action plans: examination of factors that may impair understanding.

OBJECTIVE: Recognition of the complexity of asthma management has led to the development of asthma treatment guidelines that include the recommendation that all pediatric asthma patients receive a written asthma action plan. We assessed the readability, suitability, and characteristics of asthma action plans, elements that contribute to the effectiveness of action plan use, particularly for those with limited literacy. METHODS: This was a descriptive study of 30 asthma action plans (27 state Department of Health (DOH)–endorsed, 3 national action plans endorsed by 6 states). Outcome measures: (1) readability (as assessed by Flesch Reading Ease, Flesch-Kincaid, Gunning Fog, Simple Measure of Gobbledygook, Forcast), (2) suitability (Suitability Assessment of Materials [SAM], adequate: ≥0.4; unsuitable: <0.4), (3) action plan characteristics (peak flow vs symptom-based, symptoms, recommended actions). RESULTS: Mean (SD) overall readability grade level was 7.2 (1.1) (range = 5.7–9.8); 70.0% were above a sixth-grade level. Mean (SD) suitability score was 0.74 (0.14). Overall, all action plans were found to be adequate, although 40.0% had an unsuitable score in at least 1 factor. The highest percent of unsuitable scores were found in the categories of layout/typography (30.0%), learning stimulation/motivation (26.7%), and graphics (13.3%). There were no statistically significant differences between the average grade level or SAM score of state DOH developed action plans and those from or adapted from national organizations. Plans varied with respect to terms used, symptoms included, and recommended actions. CONCLUSIONS: Specific improvements in asthma action plans could maximize patient and parent understanding of appropriate asthma management and could particularly benefit individuals with limited literacy skills.

Limited health literacy is a barrier to medication reconciliation in ambulatory care.

BackgroundLimited health literacy may influence patients’ ability to identify medications taken; a serious concern for ambulatory safety and quality.ObjectiveTo assess the relationship between health literacy, patient recall of antihypertensive medications, and reconciliation between patient self-report and the medical record.DesignIn-person interviews, literacy assessment, medical records abstraction.ParticipantsAdults with hypertension at three community health centers.MeasurementWe measured health literacy using the short-form Test of Functional Health Literacy in Adults. Patients were asked about the medications they took for blood pressure. Their responses were compared with the medical record.ResultsOf 119 participants, 37 (31%) had inadequate health literacy. Patients with inadequate health literacy were less able to name any of their antihypertensive medications compared to those with adequate health literacy (40.5% vs 68.3%, p = 0.005). After adjusting for age and income, this difference remained (adjusted odds ratio [OR] = 2.9, 95% confidence interval [95%CI] = 1.3–6.7). Agreement between patient reported medications and the medical record was low: 64.9% of patients with inadequate and 37.8% with adequate literacy had no medications common to both lists.ConclusionsLimited health literacy was associated with a greater number of unreconciled medications. Future studies should investigate how this may impact safety and hypertension control.

Health Literacy, Cognitive Abilities, and Mortality Among Elderly Persons

BackgroundLow health literacy and low cognitive abilities both predict mortality, but no study has jointly examined these relationships.MethodsWe conducted a prospective cohort study of 3,260 community-dwelling adults age 65 and older. Participants were interviewed in 1997 and administered the Short Test of Functional Health Literacy in Adults and the Mini Mental Status Examination. Mortality was determined using the National Death Index through 2003.Measurements and Main ResultsIn multivariate models with only literacy (not cognition), the adjusted hazard ratio was 1.50 (95% confidence of interval [CI] 1.24–1.81) for inadequate versus adequate literacy. In multivariate models without literacy, delayed recall of 3 items and the ability to serial subtract numbers were associated with higher mortality (e.g., adjusted hazard ratios [AHR] 1.74 [95% CI 1.30–2.34] for recall of zero versus 3 items, and 1.32 [95% CI 1.09–1.60] for 0–2 vs 5 correct subtractions). In multivariate analysis with both literacy and cognition, the AHRs for the cognition items were similar, but the AHR for inadequate literacy decreased to 1.27 (95% CI 1.03 – 1.57).ConclusionsBoth health literacy and cognitive abilities independently predict mortality. Interventions to improve patient knowledge and self-management skills should consider both the reading level and cognitive demands of the materials.