Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 13, 2018
Purpose To provide evidence-based consensus recommendations on choice of end points for clinical ... more Purpose To provide evidence-based consensus recommendations on choice of end points for clinical trials in metastatic breast cancer, with a focus on biologic subtype and line of therapy. Methods The National Cancer Institute Breast Cancer Steering Committee convened a working group of breast medical oncologists, patient advocates, biostatisticians, and liaisons from the Food and Drug Administration to conduct a detailed curated systematic review of the literature, including original reports, reviews, and meta-analyses, to determine the current landscape of therapeutic options, recent clinical trial data, and natural history of four biologic subtypes of breast cancer. Ongoing clinical trials for metastatic breast cancer in each subtype also were reviewed from ClinicalTrials.gov for planned primary end points. External input was obtained from the pharmaceutic/biotechnology industry, real-world clinical data specialists, experts in quality of life and patient-reported outcomes, and com...
Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induc... more Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus <grade 3 in CALGB 40101 assuming a fixed effects model. The percentage of ≥grade 3 TIPN in 1269 European Americans and 139 African Americans in S0221, was 11.6 and 22.3%, respectively. CALGB 40101 ≥grade 3 TOPN was 7.2%. The most significant association with ≥grade 3 TIPN was the G allele of rs1858826 in GNGT1 (Pmeta=1.1×10), which showed a decrease in risk of ≥grade 3 TIPN (odds ratio=0.29, 95%...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2013
CRA1008 Background: S0221 is a SWOG-coordinated phase III adjuvant chemotherapy intergroup trial ... more CRA1008 Background: S0221 is a SWOG-coordinated phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer which hypothesized that 1) the weekly AC+G regimen is superior to ddAC x 6 and 2) 12 weeks of weekly paclitaxel (wP) is superior to q 2 week paclitaxel x 6 (ddP). Between December 2003 and November 2010, 2,716 patients were randomized in a 2 x 2 factorial design to 1) AC+G vs ddAC and 2) P 80 mg/m(2)/week x 12 vs P 175 mg/m(2) q 2 weeks x 6. If there was no significant interaction between the factors, the trial was powered to find a disease-free survival hazard ratio (HR) ≤ 0.82 for weekly vs q 2 week for each factor. At the first interim analysis, the AC randomization was halted for futility, and S0221 was closed to accrual 10 November 2010. S0221 reopened 15 December 2010, after which time all patients received 4 cycles of ddAC and randomization to P weekly x 12 and ddP x 6 continued. Accrual halted at a total of 3,294...
About half of U.S. states currently have legislation requiring radiology facilities to disclose m... more About half of U.S. states currently have legislation requiring radiology facilities to disclose mammographic breast density information to women, often with language recommending discussion of supplemental screening options for women with dense breasts. To examine variation in breast density assessment across radiologists in clinical practice. Cross-sectional and longitudinal analyses of prospectively collected observational data. 30 radiology facilities within the 3 breast cancer screening research centers of the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. Radiologists who interpreted at least 500 screening mammograms during 2011 to 2013 (n = 83). Data on 216 783 screening mammograms from 145 123 women aged 40 to 89 years were included. Mammographic breast density, as clinically recorded using the 4 Breast Imaging Reporting and Data System categories (heterogeneously dense and extremely dense categories were considered "den...
British journal of clinical pharmacology, Jun 9, 2016
In the SWOG S0226 trial the combination of anastrozole plus fulvestrant (n=349) was superior to a... more In the SWOG S0226 trial the combination of anastrozole plus fulvestrant (n=349) was superior to anastrozole alone (n=345) in hormone receptor (HR)-positive metastatic breast cancer. Here we report a pharmacokinetic subset analysis investigating a possible drug interaction between anastrozole and fulvestrant. Post-menopausal patients with HR-positive metastatic breast cancer were randomized to anastrozole with or without concurrent fulvestrant. Blood samples were collected at 2, 4, 6, and 8 months, just prior to receiving the next dose of anastrozole and fulvestrant. Drug concentrations were measured via LC/MS-MS. Anastrozole concentration was compared in patients on anastrozole alone vs. patients on concomitant fulvestrant. Comparisons were made at each time point using parametric tests and over time using a linear mixed effects model. A total of 483 anastrozole concentration measurements, 224 samples from 64 patients on the anastrozole alone arm and 259 from 73 patients on the comb...
To compare treatment patterns and the ten-year survival of prostate cancer patients in two large,... more To compare treatment patterns and the ten-year survival of prostate cancer patients in two large, nonprofit, group/staff HMOs to those of patients receiving care in the fee-for-service health setting. A cohort of men age 65 and over diagnosed with prostate cancer between 1985 and the end of 1992 and followed through 1994. Subjects (n = 21,741) were ascertained by two population-based tumor registries covering the greater San Francisco-Oakland and Seattle-Puget Sound areas. Linkage of registry data with Medicare claims data and with HMO inpatient utilization data allowed the determination of health plan enrollment and the measurement of comorbid conditions. Multivariate regression models were used to examine HMO versus FFS treatment and survival differences adjusting for sociodemographic and clinical characteristics. Among cases with non-metastatic prostate cancer, HMO patients were more likely than FFS patients to receive aggressive therapy (either prostatectomy or radiation) in San...
Study Design Low back pain patients seen in primary care were allocated randomly to one of two ed... more Study Design Low back pain patients seen in primary care were allocated randomly to one of two educational interventions or to usual care. Objective To evaluate educational interventions designed to improve the outcomes of primary care for low back pain. Summary of Background Data Patients with back pain are frequently dissatisfied with their medical care and identify lack of information as the most insufficient aspect. Methods In a large Health Maintenance Organization clinic, 293 subjects were allocated randomly to receive usual care, an educational booklet, or a 15-minute session with a clinic nurse, including the booklet and a follow-up telephone call. Outcome measures included satisfaction with care, perceived knowledge, participation in exercise, functional status, symptom relief, and health care use. Outcomes were assessed 1, 3, 7, and 52 weeks after the intervention. Results The nurse intervention resulted in higher patient satisfaction than usual care (P < 0.001) and higher perceived knowledge (P < 0.001). Self-reported exercise participation was also higher in the nurse intervention group after a 1-week follow-up period (97% vs. 65% in the other groups; P < 0.0001). There were no significant differences among the three groups in worry, symptoms, functional status, or health care use at any follow-up interval. Differences in self-reported exercise and perceived knowledge were no longer significant after 7 weeks. Conclusions These findings challenge the value of purely educational approaches in reducing functional impact or health care use related to back pain and also challenge the value of fitness exercise in the most acute phase of back pain.
The current study compares treatment use and long-term survival in colorectal cancer patients bet... more The current study compares treatment use and long-term survival in colorectal cancer patients between Medicare beneficiaries enrolled in two large prepaid group/staff health maintenance organizations (HMOs) and the fee-for-service (FFS) setting. The study is based on 15,352 colorectal cancer cases diagnosed between 1985 and 1992 and followed through 1995. Survival differences between the HMO and FFS cases were assessed using Cox regression. Treatment differences were evaluated using logistic regression. HMO cases had a lower overall mortality than did FFS cases but not a significantly lower colorectal cancer-specific mortality. Use of surgical resection was similar between HMO and FFS cases. However, rectal cancer cases in the HMOs were more likely to receive postsurgical radiation therapy than FFS cases. Superior overall survival in the HMOs may be the result of increased colorectal cancer screening, greater use of adjuvant therapies, and selection of healthier individuals.
Purpose: We determined the risk of breast cancer and tumor characteristics among current postmeno... more Purpose: We determined the risk of breast cancer and tumor characteristics among current postmenopausal hormone therapy users compared with nonusers, by duration of use. Methods: From January 1996 to December 2000, data were collected prospectively on 374,465 postmenopausal women aged 50 to 79 years who underwent screening mammography. We calculated the relative risk (RR) of breast cancer (invasive or ductal carcinoma-in-situ) and type of breast cancer within 12 months of postmenopausal therapy use among current hormone users with a uterus (proxy for estrogen and progestin use) and without a uterus (proxy for estrogen use), compared with nonusers. Results: Compared with nonusers, women using estrogen and progestin for ≥ 5 years were at increased risk of breast tumors of stage 0 or I (RR, 1.51; 95% CI, 1.37 to 1.66), stage II or higher (RR, 1.46; 95% CI, 1.30 to 1.63), size ≤ 20 mm (RR, 1.59; 95% CI, 1.43 to 1.76), size greater than 20 mm (RR, 1.24; 95% CI, 1.09 to 1.42), grade 1 or ...
Purpose: There are no established genetic markers for prediction of outcomes after cyclophosphami... more Purpose: There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a SWOG (Southwest Oncology Group) trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematologic toxicity and disease-free survival (DFS). Experimental Design: Germline DNA was available from 458 women who were at high risk of relapse and was randomized to CAF (CP, intravenous doxorubicin, and 5-fluorouracil) versus CMF (CP, intravenous methotrexate, and 5-fluorouracil) ± tamoxifen, and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematologic toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6CYP3A4GSTA1and GSTP1were estimated by logistic regression and Cox proportional hazard regression. Results: Compared wit...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 13, 2018
Purpose To provide evidence-based consensus recommendations on choice of end points for clinical ... more Purpose To provide evidence-based consensus recommendations on choice of end points for clinical trials in metastatic breast cancer, with a focus on biologic subtype and line of therapy. Methods The National Cancer Institute Breast Cancer Steering Committee convened a working group of breast medical oncologists, patient advocates, biostatisticians, and liaisons from the Food and Drug Administration to conduct a detailed curated systematic review of the literature, including original reports, reviews, and meta-analyses, to determine the current landscape of therapeutic options, recent clinical trial data, and natural history of four biologic subtypes of breast cancer. Ongoing clinical trials for metastatic breast cancer in each subtype also were reviewed from ClinicalTrials.gov for planned primary end points. External input was obtained from the pharmaceutic/biotechnology industry, real-world clinical data specialists, experts in quality of life and patient-reported outcomes, and com...
Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induc... more Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus <grade 3 in CALGB 40101 assuming a fixed effects model. The percentage of ≥grade 3 TIPN in 1269 European Americans and 139 African Americans in S0221, was 11.6 and 22.3%, respectively. CALGB 40101 ≥grade 3 TOPN was 7.2%. The most significant association with ≥grade 3 TIPN was the G allele of rs1858826 in GNGT1 (Pmeta=1.1×10), which showed a decrease in risk of ≥grade 3 TIPN (odds ratio=0.29, 95%...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2013
CRA1008 Background: S0221 is a SWOG-coordinated phase III adjuvant chemotherapy intergroup trial ... more CRA1008 Background: S0221 is a SWOG-coordinated phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer which hypothesized that 1) the weekly AC+G regimen is superior to ddAC x 6 and 2) 12 weeks of weekly paclitaxel (wP) is superior to q 2 week paclitaxel x 6 (ddP). Between December 2003 and November 2010, 2,716 patients were randomized in a 2 x 2 factorial design to 1) AC+G vs ddAC and 2) P 80 mg/m(2)/week x 12 vs P 175 mg/m(2) q 2 weeks x 6. If there was no significant interaction between the factors, the trial was powered to find a disease-free survival hazard ratio (HR) ≤ 0.82 for weekly vs q 2 week for each factor. At the first interim analysis, the AC randomization was halted for futility, and S0221 was closed to accrual 10 November 2010. S0221 reopened 15 December 2010, after which time all patients received 4 cycles of ddAC and randomization to P weekly x 12 and ddP x 6 continued. Accrual halted at a total of 3,294...
About half of U.S. states currently have legislation requiring radiology facilities to disclose m... more About half of U.S. states currently have legislation requiring radiology facilities to disclose mammographic breast density information to women, often with language recommending discussion of supplemental screening options for women with dense breasts. To examine variation in breast density assessment across radiologists in clinical practice. Cross-sectional and longitudinal analyses of prospectively collected observational data. 30 radiology facilities within the 3 breast cancer screening research centers of the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. Radiologists who interpreted at least 500 screening mammograms during 2011 to 2013 (n = 83). Data on 216 783 screening mammograms from 145 123 women aged 40 to 89 years were included. Mammographic breast density, as clinically recorded using the 4 Breast Imaging Reporting and Data System categories (heterogeneously dense and extremely dense categories were considered "den...
British journal of clinical pharmacology, Jun 9, 2016
In the SWOG S0226 trial the combination of anastrozole plus fulvestrant (n=349) was superior to a... more In the SWOG S0226 trial the combination of anastrozole plus fulvestrant (n=349) was superior to anastrozole alone (n=345) in hormone receptor (HR)-positive metastatic breast cancer. Here we report a pharmacokinetic subset analysis investigating a possible drug interaction between anastrozole and fulvestrant. Post-menopausal patients with HR-positive metastatic breast cancer were randomized to anastrozole with or without concurrent fulvestrant. Blood samples were collected at 2, 4, 6, and 8 months, just prior to receiving the next dose of anastrozole and fulvestrant. Drug concentrations were measured via LC/MS-MS. Anastrozole concentration was compared in patients on anastrozole alone vs. patients on concomitant fulvestrant. Comparisons were made at each time point using parametric tests and over time using a linear mixed effects model. A total of 483 anastrozole concentration measurements, 224 samples from 64 patients on the anastrozole alone arm and 259 from 73 patients on the comb...
To compare treatment patterns and the ten-year survival of prostate cancer patients in two large,... more To compare treatment patterns and the ten-year survival of prostate cancer patients in two large, nonprofit, group/staff HMOs to those of patients receiving care in the fee-for-service health setting. A cohort of men age 65 and over diagnosed with prostate cancer between 1985 and the end of 1992 and followed through 1994. Subjects (n = 21,741) were ascertained by two population-based tumor registries covering the greater San Francisco-Oakland and Seattle-Puget Sound areas. Linkage of registry data with Medicare claims data and with HMO inpatient utilization data allowed the determination of health plan enrollment and the measurement of comorbid conditions. Multivariate regression models were used to examine HMO versus FFS treatment and survival differences adjusting for sociodemographic and clinical characteristics. Among cases with non-metastatic prostate cancer, HMO patients were more likely than FFS patients to receive aggressive therapy (either prostatectomy or radiation) in San...
Study Design Low back pain patients seen in primary care were allocated randomly to one of two ed... more Study Design Low back pain patients seen in primary care were allocated randomly to one of two educational interventions or to usual care. Objective To evaluate educational interventions designed to improve the outcomes of primary care for low back pain. Summary of Background Data Patients with back pain are frequently dissatisfied with their medical care and identify lack of information as the most insufficient aspect. Methods In a large Health Maintenance Organization clinic, 293 subjects were allocated randomly to receive usual care, an educational booklet, or a 15-minute session with a clinic nurse, including the booklet and a follow-up telephone call. Outcome measures included satisfaction with care, perceived knowledge, participation in exercise, functional status, symptom relief, and health care use. Outcomes were assessed 1, 3, 7, and 52 weeks after the intervention. Results The nurse intervention resulted in higher patient satisfaction than usual care (P < 0.001) and higher perceived knowledge (P < 0.001). Self-reported exercise participation was also higher in the nurse intervention group after a 1-week follow-up period (97% vs. 65% in the other groups; P < 0.0001). There were no significant differences among the three groups in worry, symptoms, functional status, or health care use at any follow-up interval. Differences in self-reported exercise and perceived knowledge were no longer significant after 7 weeks. Conclusions These findings challenge the value of purely educational approaches in reducing functional impact or health care use related to back pain and also challenge the value of fitness exercise in the most acute phase of back pain.
The current study compares treatment use and long-term survival in colorectal cancer patients bet... more The current study compares treatment use and long-term survival in colorectal cancer patients between Medicare beneficiaries enrolled in two large prepaid group/staff health maintenance organizations (HMOs) and the fee-for-service (FFS) setting. The study is based on 15,352 colorectal cancer cases diagnosed between 1985 and 1992 and followed through 1995. Survival differences between the HMO and FFS cases were assessed using Cox regression. Treatment differences were evaluated using logistic regression. HMO cases had a lower overall mortality than did FFS cases but not a significantly lower colorectal cancer-specific mortality. Use of surgical resection was similar between HMO and FFS cases. However, rectal cancer cases in the HMOs were more likely to receive postsurgical radiation therapy than FFS cases. Superior overall survival in the HMOs may be the result of increased colorectal cancer screening, greater use of adjuvant therapies, and selection of healthier individuals.
Purpose: We determined the risk of breast cancer and tumor characteristics among current postmeno... more Purpose: We determined the risk of breast cancer and tumor characteristics among current postmenopausal hormone therapy users compared with nonusers, by duration of use. Methods: From January 1996 to December 2000, data were collected prospectively on 374,465 postmenopausal women aged 50 to 79 years who underwent screening mammography. We calculated the relative risk (RR) of breast cancer (invasive or ductal carcinoma-in-situ) and type of breast cancer within 12 months of postmenopausal therapy use among current hormone users with a uterus (proxy for estrogen and progestin use) and without a uterus (proxy for estrogen use), compared with nonusers. Results: Compared with nonusers, women using estrogen and progestin for ≥ 5 years were at increased risk of breast tumors of stage 0 or I (RR, 1.51; 95% CI, 1.37 to 1.66), stage II or higher (RR, 1.46; 95% CI, 1.30 to 1.63), size ≤ 20 mm (RR, 1.59; 95% CI, 1.43 to 1.76), size greater than 20 mm (RR, 1.24; 95% CI, 1.09 to 1.42), grade 1 or ...
Purpose: There are no established genetic markers for prediction of outcomes after cyclophosphami... more Purpose: There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a SWOG (Southwest Oncology Group) trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematologic toxicity and disease-free survival (DFS). Experimental Design: Germline DNA was available from 458 women who were at high risk of relapse and was randomized to CAF (CP, intravenous doxorubicin, and 5-fluorouracil) versus CMF (CP, intravenous methotrexate, and 5-fluorouracil) ± tamoxifen, and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematologic toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6CYP3A4GSTA1and GSTP1were estimated by logistic regression and Cox proportional hazard regression. Results: Compared wit...
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Papers by William Barlow