Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine-Induced Hand-Foot Syndrome: A Randomized Clinical Trial.

IMPORTANCE: Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. OBJECTIVE: To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. DESIGN, SETTING, AND PARTICIPANTS: This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. INTERVENTIONS: Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. MAIN OUTCOMES AND MEASURES: Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. RESULTS: In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10-8), including a novel DPYD variant (rs75267292; P = 1.57 × 10-10), and variants in the MACF1 (rs183324967, P = 4.80 × 10-11; rs148221738, P = 5.73 × 10-10) and SPRY2 (rs117876855, P < 1.01 × 10-8; rs139544515, P = 1.30 × 10-8) genes involved in wound healing. CONCLUSIONS AND RELEVANCE: Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00486213.

Minimal clinically important difference (MCID) for the functional assessment of cancer therapy: cognitive function (FACT-Cog) in breast cancer patients.

OBJECTIVES: This is the first reported study to determine the minimal clinically important difference (MCID) of Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), a validated subjective neuropsychological instrument designed to evaluate cancer patients' perceived cognitive deterioration. STUDY DESIGN AND SETTING: Breast cancer patients (n = 220) completed FACT-Cog and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) at baseline and at least 3 months later. Anchor-based approach used the validated EORTC-QLQ-C30-Cognitive Functioning scale (EORTC-CF) as the anchor for patients who showed minimal deterioration and a receiver operating characteristic (ROC) curve to identify the optimal MCID cutoff for deterioration. Distribution-based approach used one-third standard deviation (SD), half SD, and one standard error of measurement (SEM) of the total FACT-Cog score (148 points). RESULTS: There was a moderate correlation between changes in FACT-Cog and EORTC-CF scores (r = 0.43; P < 0.001). The EORTC-CF-anchored MCID was 9.6 points (95% confidence interval: 4.4, 14.8). The MCID from the ROC method was 7.5 points (area under the curve: 0.75; sensitivity: 75.6%; specificity: 68.8%). For the distribution-based approach, the MCIDs corresponding to one-third SD, half SD, and one SEM were 6.9, 10.3, and 10.6 points, respectively. Combining the approaches, the MCID identified for FACT-Cog ranged from 6.9 to 10.6 points (4.7-7.2% of the total score). CONCLUSION: The estimates of 6.9-10.6 points as MCID can facilitate the interpretation of patient-reported cognitive deterioration and sample size estimates in future studies.

Measurement properties of the eight-item abbreviated functional assessment of cancer therapy--breast symptom index and comparison with its 37-item parent measure.

CONTEXT: The Functional Assessment of Cancer Therapy--Breast Symptom Index (FBSI) is an eight-item instrument extracted from the Functional Assessment of Cancer Therapy--Breast (FACT-B). There has been no formal assessment of this eight-item version. OBJECTIVES: This study aimed to examine the measurement properties of and comparability between the English and the Chinese versions of the FBSI and to compare it with its parent instrument, the FACT-B, in breast cancer patients in Singapore. METHODS: This was an observational study of 271 breast cancer patients. Known-group validity of FBSI scores was assessed using four health indicators. Convergent and divergent validity was examined by correlation coefficients between the FBSI and the FACT-B. Responsiveness was assessed in relation to longitudinal changes in performance status. Test-retest reliability was evaluated by the intraclass correlation coefficient. Multiple regression analyses were performed to compare the scores on the two language versions. Receiver operating characteristic curve analyses were used for comparison between the FBSI and the FACT-B. RESULTS: For both language versions, the FBSI demonstrated known-group validity, convergent and divergent validity, and sufficient test-retest reliability (intraclass correlation coefficient = 0.75-0.77). The English version was responsive to changes in performance status. The Chinese version was responsive to decline in performance status, but there was no conclusive evidence about its responsiveness to improvement in performance status. No practical significant difference was found in the outcomes between the two language versions despite minor difference in one item. The FBSI performed comparably with the FACT-B. CONCLUSION: The English and Chinese versions of the FBSI are valid and reliable and provide comparable FBSI scores. The English version is responsive to change, whereas the responsiveness of the Chinese version warrants further study.

The English and Chinese versions of the five-level EuroQoL Group's five-dimension questionnaire (EQ-5D) were valid and reliable and provided comparable scores in Asian breast cancer patients.

OBJECTIVE: To examine the measurement properties of and comparability between the English and Chinese versions of the five-level EuroQoL Group's five-dimension questionnaire (EQ-5D) in breast cancer patients in Singapore. METHODS: This is an observational study of 269 patients. Known-group validity and responsiveness of the EQ-5D utility index and visual analog scale (VAS) were assessed in relation to various clinical characteristics and longitudinal change in performance status, respectively. Convergent and divergent validity was examined by correlation coefficients between the EQ-5D and a breast cancer-specific instrument. Test-retest reliability was evaluated. The two language versions were compared by multiple regression analyses. RESULTS: For both English and Chinese versions, the EQ-5D utility index and VAS demonstrated known-group validity and convergent and divergent validity, and presented sufficient test-retest reliability (intraclass correlation = 0.72 to 0.83). The English version was responsive to changes in performance status. The Chinese version was responsive to decline in performance status, but there was no conclusive evidence about its responsiveness to improvement in performance status. In the comparison analyses of the utility index and VAS between the two language versions, borderline results were obtained, and equivalence cannot be definitely confirmed. CONCLUSION: The five-level EQ-5D is valid, responsive, and reliable in assessing health outcome of breast cancer patients. The English and Chinese versions provide comparable measurement results.

Comparison of the measurement properties between a short and generic instrument, the 5-level EuroQoL Group's 5-dimension (EQ-5D-5L) questionnaire, and a longer and disease-specific instrument, the Functional Assessment of Cancer Therapy-Breast (FACT-B), in Asian breast cancer patients.

PURPOSE: To compare the measurement precision and related properties between the 5-level EuroQoL Group's 5-dimension (EQ-5D-5L) questionnaire and the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire in assessing breast cancer patients. METHODS: An observational study of 269 Singaporean breast cancer patients. To compare discriminative ability and responsiveness, the effect sizes (in standard deviation) of the EQ-5D-5L and the FACT-B in relation to health indicators and the change in performance status or quality of life were estimated. Test-retest reliability was examined using the intraclass correlation (ICC). RESULTS: Using performance status, evidence of disease, and treatment status as the criteria, the differences (FACT-B minus EQ-5D-5L) in the effect size for discriminative ability were negative or closed to zero, and the 90% confidence intervals totally fell within the zone that indicated the non-inferiority of the EQ-5D-5L. For responsiveness and test-retest reliability, the confidence intervals of the differences in effect size and ICC overlapped the non-inferiority margin; thus, non-inferiority in these two aspects could neither be confirmed nor rejected. CONCLUSIONS: The EQ-5D-5L was non-inferior to the FACT-B in discriminating breast cancer patients with different health conditions cross-sectionally. The EQ-5D-5L serves as a reasonable alternative or supplementary instrument to the FACT-B in assessing breast cancer patients' health outcomes.

Effects of chemotherapy and psychosocial distress on perceived cognitive disturbances in Asian breast cancer patients.

BACKGROUND: There is conflicting evidence on the effect of chemotherapy and psychosocial distress on perceived cognitive changes in cancer patients. OBJECTIVE: To compare the severity of perceived cognitive disturbance in Asian breast cancer patients receiving chemotherapy and those not receiving chemotherapy, and identify clinical characteristics associated with perceived cognitive disturbances. METHODS: A cross-sectional, observational study was conducted at the largest cancer center in Singapore. Breast cancer patients receiving chemotherapy and not receiving chemotherapy completed the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30), and Beck Anxiety Inventory to assess their perceived cognitive functioning, health-related quality of life, and anxiety, respectively. Multiple regression was conducted to delineate the factors associated with perceived cognitive disturbances. RESULTS: A total of 85 breast cancer patients receiving chemotherapy and 81 not receiving chemotherapy were recruited. Chemotherapy patients experienced more fatigue (QLQ-C30 fatigue scores: 33.3 vs 22.2 points; p = 0.005) and moderate-to-severe anxiety (21.9% vs 8.6%; p = 0.002) compared to non-chemotherapy patients. Non-chemotherapy patients reported better perceived cognitive functioning than those who received chemotherapy (FACT-Cog scores: 124 vs 110 points, respectively; p < 0.001). Chemotherapy and endocrine therapy were strongly associated with perceived cognitive disturbances (p < 0.001 and 0.021, respectively). The interacting effect between anxiety and fatigue was moderately associated with perceived cognitive disturbances (ß = -0.29; p = 0.037). CONCLUSIONS: Chemotherapy and endocrine treatment were associated with significant cognitive disturbances among Asian breast cancer patients. Psychosocial factors could be used to identify cancer patients who are more susceptible to cognitive disturbances in the clinical setting.

Measurement properties of the English and Chinese versions of the Functional Assessment of Cancer Therapy-Breast (FACT-B) in Asian breast cancer patients.

The objective of the study was to examine the measurement properties of and comparability between the English and Chinese versions of the Functional Assessment of Cancer Therapy-Breast (FACT-B) in breast cancer patients in Singapore. This is an observational study of 271 Singaporean breast cancer patients. The known-group validity of FACT-B total score and Trial Outcome Index (TOI) were assessed in relation to performance status, evidence of disease, and treatment status cross-sectionally; responsiveness to change was assessed in relation to change in performance status longitudinally. Internal consistency and test-retest reliability were evaluated by the Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. Multiple regression analyses were performed to compare the scores on the two language versions, adjusting for covariates. The FACT-B total score and TOI demonstrated known-group validity in differentiating patients with different clinical status. They showed high internal consistency and test-retest reliability, with Cronbach's alpha ranging from 0.87 to 0.91 and ICC ranging from 0.82 to 0.89. The English version was responsive to the change in performance status. The Chinese version was shown to be responsive to decline in performance status but the sample size of Chinese-speaking patients who improved in performance status was too small (N = 6) for conclusive analysis about responsiveness to improvement. Two items concerning sexuality had a high item non-response rate (50.2 and 14.4%). No practically significant difference was found in the total score and TOI between the two language versions despite minor differences in two of the 37 items. The English and Chinese versions of the FACT-B are valid, responsive, and reliable instruments in assessing health-related quality of life in breast cancer patients in Singapore. Data collected from the English and Chinese versions can be pooled and either version could be used for bilingual patients.