Publications by authors named "Bernard Cole"

89 Publications

A Peer-Based Strategy to Overcome HPV Vaccination Inequities in Rural Communities: A Physical Distancing-Compliant Approach.

Crit Rev Eukaryot Gene Expr 2021 ;31(1):61-69

KM Consulting, New Jersey, USA.

The human papilloma virus (HPV) vaccine is the world's first proven and effective vaccine to prevent cancers in males and females when administered pre-exposure. Like most of the US, barely half of Vermont teens are up-to-date with the vaccination, with comparable deficits in New Hampshire and Maine. The rates for HPV vaccine initiation and completion are as low as 33% in rural New England. Consequently, there is a compelling responsibility to communicate its importance to unvaccinated teenagers before their risk for infection increases. Messaging in rural areas promoting HPV vaccination is compromised by community-based characteristics that include access to appropriate medical care, poor media coverage, parental and peer influence, and skepticism of science and medicine. Current strategies are predominantly passive access to literature and Internet-based information. Evidence indicates that performance-based messaging can clarify the importance of HPV vaccination to teenagers and their parents in rural areas. Increased HPV vaccination will significantly contribute to the prevention of a broadening spectrum of cancers. Reducing rurality-based inequities is a public health priority. Development of a performance-based peer-communication intervention can capture a window of opportunity to provide increasingly effective and sustained HPV protection. An effective approach can be partnering rural schools and regional health teams with a program that is nimble and scalable to respond to public health policies and practices compliant with COVID-19 pandemic-related modifications on physical distancing and interacting in the foreseeable future.
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http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2021036945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128079PMC
March 2021

Taking the message to the rural patient: evidence-based PTSD care.

J Behav Med 2021 Jan 2. Epub 2021 Jan 2.

Department of Mathematics and Statistics, University of Vermont, Burlington, VT, USA.

The Department of Veterans Affairs and Department of Defense (VA/DoD) Clinical Practice Guideline for PTSD recommends against the use of benzodiazepines. Despite the recommendation, clinicians continue potentially inappropriate benzodiazepine prescribing practices for veterans with PTSD. We designed an educational product aimed at decreasing benzodiazepine use in PTSD care. Using VA data, the booklet was mailed to over 1300 New England veterans. Veterans were advised to discuss the booklet's information with their medical provider on their next appointment. The intervention resulted in a significant decrease in benzodiazepine use in veterans with PTSD, with 66% of the sample showing a dose reduction from pre- to post-booklet time points. Longitudinal analyses noted that rural veterans were significantly more likely to reduce benzodiazepine use than those in urban settings. Direct to consumer education appears to be an effective strategy to empower rural veterans to improve benzodiazepine prescribing safety and quality.
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http://dx.doi.org/10.1007/s10865-020-00194-7DOI Listing
January 2021

Clinical behavior of recurrent hormone receptor-positive breast cancer by adjuvant endocrine therapy within the Breast International Group 1-98 clinical trial.

Cancer 2021 Mar 8;127(5):700-708. Epub 2020 Dec 8.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Endocrine therapy resistance is a major cause of distant recurrence (DR) in hormone receptor-positive breast cancer. This study evaluated differences in survival after DR in patients treated with different adjuvant endocrine therapy regimens in the Breast International Group (BIG) 1-98 trial.

Methods: BIG 1-98 compared 5 years of adjuvant treatment among 4 arms: tamoxifen (T), letrozole (L), tamoxifen followed by letrozole (TL), and letrozole followed by tamoxifen (LT). After a median follow-up of 8.1 years, 911 of 8010 patients (T, 302; L, 285; TL, 170; and LT, 154) had DR as the site of first recurrence. Univariate and multivariate Cox analyses were performed to determine features associated with post-DR survival.

Results: The median follow-up time after DR was 59 months (interquartile range, 29-88 months). Among all patients with DR, 38.1% were 65 years old or older at enrollment, 61.9% had tumors larger than 2 cm, and 69.7% were node positive. Neoadjuvant or adjuvant chemotherapy was administered to 35.6% of the patients. There was no difference in post-DR survival by treatment arm (median survival, 20.8 months for T, 17.9 months for L, 17.3 months for TL, and 20.8 months for LT; P = .21). In multivariate analysis, older patients (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.15-1.59) and patients with tumors larger than 2 cm (HR, 1.19; 95% CI, 1.00-1.41), 4 or more positive nodes (HR, 1.31; 95% CI, 1.05-1.64), progesterone receptor (PR)-negative tumors (HR, 1.25; 95% CI, 1.02-1.52), or shorter disease-free survival (DFS) had significantly worse post-DR survival.

Conclusions: Treatment with adjuvant T, L, or their sequences was not associated with differences in survival after DR. Significant differences in survival were observed by age, primary tumor size, nodal and PR status, and DFS, and this suggests that traditional baseline high-risk features remain prognostic in the metastatic setting.
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http://dx.doi.org/10.1002/cncr.33318DOI Listing
March 2021

Tumor density is associated with response to endobronchial ultrasound-guided transbronchial needle injection of cisplatin.

J Thorac Dis 2020 Sep;12(9):4825-4832

Division of Pulmonary and Critical Care, University of Florida, Gainesville, FL, USA.

Background: Endobronchial ultrasound-guided transbronchial needle injection of cisplatin (EBUS-TBNI cisplatin) is a therapeutic option for patients with recurrent lung cancer. However, the tumor characteristics that influence the distribution of the agent following intratumoral delivery remain largely unknown.

Methods: We performed a retrospective evaluation of EBUS-TBNI cisplatin cases performed at two centers. Semi-automated tumor segmentation from CT scans was performed while blinded to the outcome of response. Twenty-four algorithmic radiomics features from two categories, Morphology (i.e., shape, volume) and Intensity (i.e., density), were extracted, and feature selection performed via least absolute shrinkage and selection operator (LASSO) regression. Models were constructed from clinicoepidemiologic variables and selected radiomics features and evaluated using the likelihood ratio chi-square assessment and Akaike's information criterion (AIC).

Results: Thirty-eight patients with available imaging data were analyzed. Based on RECIST criteria, 27 of 38 treated sites demonstrated complete or partial remission (71%). The top three features identified by LASSO regression were variance, energy, and kurtosis. All three are measures of intensity, a surrogate for tumor density. Two logistic regression models with the outcome of response were created, each with the top 3 categorical features: (I) an Intensity model including variance, energy, and kurtosis, and (II) a Morphology model including surface-to-volume ratio, spherical disproportion, and maximum 3-dimensional (3D) diameter. Only the Intensity model met criteria for significance (P=0.024), and it resulted in a lower AIC and higher pseudo R square value vs. the Morphology model.

Conclusions: Measures of tumor density are more highly associated with response to EBUS-TBNI cisplatin than measures of morphology.
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http://dx.doi.org/10.21037/jtd-20-674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578514PMC
September 2020

Evidence for Expanding Invasive Mediastinal Staging for Peripheral T1 Lung Tumors.

Chest 2020 11 26;158(5):2192-2199. Epub 2020 Jun 26.

Division of Pulmonary and Critical Care, University of Vermont Medical Center, Burlington, VT. Electronic address:

Background: Guidelines recommend invasive mediastinal staging for patients with non-small cell lung cancer and a "central" tumor. However, there is no consensus definition for central location. As such, the decision to perform invasive staging largely remains on an empirical foundation.

Research Question: Should patients with peripheral T1 lung tumors undergo invasive mediastinal staging?

Study Design And Methods: All participants with a screen-detected cancer with a solid component between 8 and 30 mm were identified from the National Lung Screening Trial. After translation of CT data, cancer location was identified and the X, Y, Z coordinates were determined as well as distance from the main carina. A multivariable logistic regression model was constructed to evaluate for predictors associated with lymph node metastasis.

Results: Three hundred thirty-two participants were identified, of which 69 had lymph node involvement (20.8%). Of those with lymph node metastasis, 39.1% were N2. There was no difference in rate of lymph node metastasis based on tumor size (OR, 1.03; P = .248). There was also no statistical difference in rate of lymph node metastasis based on location, either by distance from the carina (OR, 0.99; P = .156) or tumor coordinates (X: P = .180; Y: P = .311; Z: P = .292). When adjusted for age, sex, histology, and smoking history, there was no change in the magnitude of the risk, and tests of significance were not altered.

Interpretation: Our data indicate a high rate of N2 metastasis among T1 tumors and no significant relationship between tumor diameter or location. This suggests that patients with small, peripheral lung cancers may benefit from invasive mediastinal staging.
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http://dx.doi.org/10.1016/j.chest.2020.05.607DOI Listing
November 2020

Folic acid supplementation and risk of colorectal neoplasia during long-term follow-up of a randomized clinical trial.

Am J Clin Nutr 2019 10;110(4):903-911

Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.

Background: The Aspirin/Folate Polyp Prevention Study previously found folic acid increased risk of advanced and multiple colorectal adenomas during a surveillance colonoscopy interval starting about 3 y after randomization.

Objective: We conducted secondary analyses to evaluate folic acid effects with additional follow-up after treatment was stopped.

Methods: In total, 1021 participants recently diagnosed with colorectal adenomas were randomly assigned to 1 mg/d of folic acid (n = 516) or placebo (n = 505), with or without aspirin, beginning 6 July 1994. The original 3-y treatment period was extended into a subsequent colonoscopy interval, but eventually stopped prematurely on 1 October 2004. With additional post-treatment follow-up, a total of 663 participants who extended treatment completed a second colonoscopic surveillance interval after the initial 3-y follow-up. In addition, 490 participants provided information regarding a subsequent surveillance colonoscopy occurring before completion of follow-up on 31 May 2012, including 325 who had agreed to extended treatment. Study endpoints included conventional adenomas, sessile serrated adenomas/polyps (SSA/Ps), or colorectal cancer, and RRs with 95% CIs were adjusted for baseline characteristics associated with availability of follow-up.

Results: Among those who extended treatment, any colorectal neoplasia was found in 118 (36%) participants assigned to placebo and 146 (43%) assigned to folic acid during the second surveillance interval (RR: 1.21; 95% CI: 0.99, 1.47; P = 0.06). Increased risk of SSA/P with extended folic acid supplementation was statistically significant during the second surveillance interval (RR: 1.94; 95% CI: 1.02, 3.68; P = 0.04). There was no evidence of post-treatment effects for any colorectal neoplasia (RR: 1.01; 95% CI: 0.80, 1.28; P = 0.94), and the post-treatment effect for SSA/P was no longer statistically significant (RR: 1.38; 95% CI: 0.59, 3.19; P = 0.46).

Conclusions: Delayed treatment effects were not observed, but folic acid may increase SSA/P risk. This trial was registered at clinicaltrials.gov as NCT00272324.
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http://dx.doi.org/10.1093/ajcn/nqz160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766439PMC
October 2019

Phthalate Exposure and Breast Cancer Incidence: A Danish Nationwide Cohort Study.

J Clin Oncol 2019 07 17;37(21):1800-1809. Epub 2019 Apr 17.

2 University of Southern Denmark, Odense, Denmark.

Purpose: Phthalate exposure is ubiquitous and especially high among users of drug products formulated with phthalates. Some phthalates mimic estradiol and may promote breast cancer. Existing epidemiologic studies on this topic are small, mostly not prospective, and have given inconsistent results. We estimated associations between longitudinal phthalate exposures and breast cancer risk in a Danish nationwide cohort, using redeemed prescriptions for phthalate-containing drug products to measure exposure.

Methods: We ascertained the phthalate content of drugs marketed in Denmark using an internal Danish Medicines Agency ingredient database. We enrolled a Danish nationwide cohort of 1.12 million women at risk for a first cancer diagnosis on January 1, 2005. By combining drug ingredient data with the Danish National Prescription registry, we characterized annual, cumulative phthalate exposure through redeemed prescriptions. We then fit multivariable Cox regression models to estimate associations between phthalate exposures and incident invasive breast carcinoma according to tumor estrogen receptor status.

Results: Over 9.99 million woman-years of follow-up, most phthalate exposures were not associated with breast cancer incidence. High-level dibutyl phthalate exposure (≥ 10,000 cumulative mg) was associated with an approximately two-fold increase in the rate of estrogen receptor-positive breast cancer (hazard ratio, 1.9; 95% CI, 1.1 to 3.5), consistent with in vitro evidence for an estrogenic effect of this compound. Lower levels of dibutyl phthalate exposure were not associated with breast cancer incidence.

Conclusion: Our results suggest that women should avoid high-level exposure to dibutyl phthalate, such as through long-term treatment with pharmaceuticals formulated with dibutyl phthalate.
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http://dx.doi.org/10.1200/JCO.18.02202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351345PMC
July 2019

Applications of Noninferiority Trials in Interventional Pulmonology.

J Bronchology Interv Pulmonol 2019 Jan;26(1):6-9

Division of Pulmonary and Critical Care, University of Vermont Medical Center, Burlington, VT.

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http://dx.doi.org/10.1097/LBR.0000000000000554DOI Listing
January 2019

Axillary dissection versus no axillary dissection in patients with breast cancer and sentinel-node micrometastases (IBCSG 23-01): 10-year follow-up of a randomised, controlled phase 3 trial.

Lancet Oncol 2018 10 5;19(10):1385-1393. Epub 2018 Sep 5.

IBCSG and European Institute of Oncology, Milan, Italy.

Background: We previously reported the 5-year results of the phase 3 IBCSG 23-01 trial comparing disease-free survival in patients with breast cancer with one or more micrometastatic (≤2 mm) sentinel nodes randomly assigned to either axillary dissection or no axillary dissection. The results showed no difference in disease-free survival between the groups and showed non-inferiority of no axillary dissection relative to axillary dissection. The current analysis presents the results of the study after a median follow-up of 9·7 years (IQR 7·8-12·7).

Methods: In this multicentre, randomised, controlled, open-label, non-inferiority, phase 3 trial, participants were recruited from 27 hospitals and cancer centres in nine countries. Eligible women could be of any age with clinical, mammographic, ultrasonographic, or pathological diagnosis of breast cancer with largest lesion diameter of 5 cm or smaller, and one or more metastatic sentinel nodes, all of which were 2 mm or smaller and with no extracapsular extension. Patients were randomly assigned (1:1) before surgery (mastectomy or breast-conserving surgery) to no axillary dissection or axillary dissection using permuted blocks generated by a web-based congruence algorithm, with stratification by centre and menopausal status. The protocol-specified primary endpoint was disease-free survival, analysed in the intention-to-treat population (as randomly assigned). Safety was assessed in all randomly assigned patients who received their allocated treatment (as treated). We did a one-sided test for non-inferiority of no axillary dissection by comparing the observed hazard ratios (HRs) for disease-free survival with a margin of 1·25. This 10-year follow-up analysis was not prespecified in the trial's protocol and thus was not adjusted for multiple, sequential testing. This trial is registered with ClinicalTrials.gov, number NCT00072293.

Findings: Between April 1, 2001, and Feb 8, 2010, 6681 patients were screened and 934 randomly assigned to no axillary dissection (n=469) or axillary dissection (n=465). Three patients were ineligible and were excluded from the trial after randomisation. Disease-free survival at 10 years was 76·8% (95% CI 72·5-81·0) in the no axillary dissection group, compared with 74·9% (70·5-79·3) in the axillary dissection group (HR 0·85, 95% CI 0·65-1·11; log-rank p=0·24; p=0·0024 for non-inferiority). Long-term surgical complications included lymphoedema of any grade in 16 (4%) of 453 patients in the no axillary dissection group and 60 (13%) of 447 in the axillary dissection group, sensory neuropathy of any grade in 57 (13%) in the no axillary dissection group versus 85 (19%) in the axillary dissection group, and motor neuropathy of any grade (14 [3%] in the no axillary dissection group vs 40 [9%] in the axillary dissection group). One serious adverse event (postoperative infection and inflamed axilla requiring hospital admission) was attributed to axillary dissection; the event resolved without sequelae.

Interpretation: The findings of the IBCSG 23-01 trial after a median follow-up of 9·7 years (IQR 7·8-12·7) corroborate those obtained at 5 years and are consistent with those of the 10-year follow-up analysis of the Z0011 trial. Together, these findings support the current practice of not doing an axillary dissection when the tumour burden in the sentinel nodes is minimal or moderate in patients with early breast cancer.

Funding: International Breast Cancer Study Group.
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http://dx.doi.org/10.1016/S1470-2045(18)30380-2DOI Listing
October 2018

Meta-STEPP with random effects.

Res Synth Methods 2018 Jun 22;9(2):312-317. Epub 2018 Jan 22.

Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

We recently developed a method called Meta-STEPP based on the fixed-effects meta-analytic approach to explore treatment effect heterogeneity across a continuous covariate for individual time-to-event data arising from multiple clinical trials. Meta-STEPP forms overlapping subpopulation windows (meta-windows) along a continuous covariate of interest, estimates the overall treatment effect in each meta-window using standard fixed-effects method, plots them against the continuous covariate, and tests for treatment-effect heterogeneity across the range of covariate values. Here, we extend this method using random-effects methods and find it to be more conservative than the fixed-effects method. Both the random- and fixed-effects Meta-STEPP are implemented in R.
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http://dx.doi.org/10.1002/jrsm.1288DOI Listing
June 2018

A semiparametric joint model for terminal trend of quality of life and survival in palliative care research.

Stat Med 2017 Dec 17;36(29):4692-4704. Epub 2017 Aug 17.

School of Nursing, The University of Alabama at Birmingham, Birmingham, AL, 35233, USA.

Palliative medicine is an interdisciplinary specialty focusing on improving quality of life (QOL) for patients with serious illness and their families. Palliative care programs are available or under development at over 80% of large US hospitals (300+ beds). Palliative care clinical trials present unique analytic challenges relative to evaluating the palliative care treatment efficacy which is to improve patients' diminishing QOL as disease progresses towards end of life (EOL). A unique feature of palliative care clinical trials is that patients will experience decreasing QOL during the trial despite potentially beneficial treatment. Often longitudinal QOL and survival data are highly correlated which, in the face of censoring, makes it challenging to properly analyze and interpret terminal QOL trend. To address these issues, we propose a novel semiparametric statistical approach to jointly model the terminal trend of QOL and survival data. There are two sub-models in our approach: a semiparametric mixed effects model for longitudinal QOL and a Cox model for survival. We use regression splines method to estimate the nonparametric curves and AIC to select knots. We assess the model performance through simulation to establish a novel modeling approach that could be used in future palliative care research trials. Application of our approach in a recently completed palliative care clinical trial is also presented.
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http://dx.doi.org/10.1002/sim.7445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698117PMC
December 2017

Factors Associated With Shorter Colonoscopy Surveillance Intervals for Patients With Low-Risk Colorectal Adenomas and Effects on Outcome.

Gastroenterology 2017 06 20;152(8):1933-1943.e5. Epub 2017 Feb 20.

Department of Medicine, Department of Veterans Affairs Medical Center, White River Junction, Vermont; Department of Epidemiology for ELB, JAB, and LM and Department of Medicine in the Division of Gastroenterology and Hepatology for JCA and DJR, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.

Background & Aims: Endoscopists do not routinely follow guidelines to survey individuals with low-risk adenomas (LRAs; 1-2 small tubular adenomas, < 1 cm) every 5-10 years for colorectal cancer; many recommend shorter surveillance intervals for these individuals. We aimed to identify the reasons that endoscopists recommend shorter surveillance intervals for some individuals with LRAs and determine whether timing affects outcomes at follow-up examinations.

Methods: We collected data from 1560 individuals (45-75 years old) who participated in a prospective chemoprevention trial (of vitamin D and calcium) from 2004 through 2008. Participants in the trial had at least 1 adenoma, detected at their index colonoscopy, and were recommended to receive follow-up colonoscopy examinations at 3 or 5 years after adenoma identification, as recommended by the endoscopist. For this analysis we collected data from only participants with LRAs. These data included characteristics of participants and endoscopists and findings from index and follow-up colonoscopies. Primary endpoints were frequency of recommending shorter (3-year) vs longer (5-year) surveillance intervals, factors associated with these recommendations, and effect on outcome, determined at the follow-up colonoscopy.

Results: A 3-year surveillance interval was recommended for 594 of the subjects (38.1%). Factors most significantly associated with recommendation of 3-year vs a 5-year surveillance interval included African American race (relative risk [RR] to white, 1.41; 95% confidence interval [CI], 1.14-1.75), Asian/Pacific Islander ethnicity (RR to white, 1.7; 95% CI, 1.22-2.43), detection of 2 adenomas at the index examination (RR vs 1 adenoma, 1.47; 95% CI, 1.27-1.71), more than 3 serrated polyps at the index examination (RR=2.16, 95% CI, 1.59-2.93), or index examination with fair or poor quality bowel preparation (RR vs excellent quality, 2.16; 95% CI, 1.66-2.83). Other factors that had a significant association with recommendation for a 3-year surveillance interval included family history of colorectal cancer and detection of 1-2 serrated polyps at the index examination. In comparisons of outcomes, we found no significant differences between the 3-year vs 5-year recommendation groups in proportions of subjects found to have 1 or more adenomas (38.8% vs 41.7% respectively; P = .27), advanced adenomas (7.7% vs 8.2%; P = .73) or clinically significant serrated polyps (10.0% vs 10.3%; P = .82) at the follow-up colonoscopy.

Conclusions: Possibly influenced by patients' family history, race, quality of bowel preparation, or number or size of polyps, endoscopists frequently recommend 3-year surveillance intervals instead of guideline-recommended intervals of 5 years or longer for individuals with LRAs. However, at the follow-up colonoscopy, similar proportions of participants have 1 or more adenomas, advanced adenomas, or serrated polyps. These findings support the current guideline recommendations of performing follow-up examinations of individuals with LRAs at least 5 years after the index colonoscopy.
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http://dx.doi.org/10.1053/j.gastro.2017.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251057PMC
June 2017

Timing of Radiation Therapy and Chemotherapy After Breast-Conserving Surgery for Node-Positive Breast Cancer: Long-Term Results From International Breast Cancer Study Group Trials VI and VII.

Int J Radiat Oncol Biol Phys 2016 10;96(2):273-279

Institute of Radiotherapy, Klinik Hirslanden, Zürich, Switzerland.

Purpose: To update the previous report from 2 randomized clinical trials, now with a median follow-up of 16 years, to analyze the effect of radiation therapy timing on local failure and disease-free survival.

Patients And Methods: From July 1986 to April 1993, International Breast Cancer Study Group trial VI randomly assigned 1475 pre-/perimenopausal women with node-positive breast cancer to receive 3 or 6 cycles of initial chemotherapy (CT). International Breast Cancer Study Group trial VII randomly assigned 1212 postmenopausal women with node-positive breast cancer to receive tamoxifen for 5 years, or tamoxifen for 5 years with 3 early cycles of initial CT. For patients who received breast-conserving surgery (BCS), radiation therapy (RT) was delayed until initial CT was completed; 4 or 7 months after BCS for trial VI and 2 or 4 months for trial VII. We compared RT timing groups among 433 patients on trial VI and 285 patients on trial VII who received BCS plus RT. Endpoints were local failure, regional/distant failure, and disease-free survival (DFS).

Results: Among pre-/perimenopausal patients there were no significant differences in disease-related outcomes. The 15-year DFS was 48.2% in the group allocated 3 months initial CT and 44.9% in the group allocated 6 months initial CT (hazard ratio [HR] 1.12; 95% confidence interval [CI] 0.87-1.45). Among postmenopausal patients, the 15-year DFS was 46.1% in the no-initial-CT group and 43.3% in the group allocated 3 months initial CT (HR 1.11; 95% CI 0.82-1.51). Corresponding HRs for local failures were 0.94 (95% CI 0.61-1.46) in trial VI and 1.51 (95% CI 0.77-2.97) in trial VII. For regional/distant failures, the respective HRs were 1.15 (95% CI 0.80-1.63) and 1.08 (95% CI 0.69-1.68).

Conclusions: This study confirms that, after more than 15 years of follow-up, it is reasonable to delay radiation therapy until after the completion of standard CT.
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http://dx.doi.org/10.1016/j.ijrobp.2016.06.2448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014393PMC
October 2016

Lower Pectoralis Muscle Area Is Associated with a Worse Overall Survival in Non-Small Cell Lung Cancer.

Cancer Epidemiol Biomarkers Prev 2017 01 19;26(1):38-43. Epub 2016 May 19.

Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Background: Muscle wasting is a component of the diagnosis of cancer cachexia and has been associated with poor prognosis. However, recommended tools to measure sarcopenia are limited by poor sensitivity or the need to perform additional scans. We hypothesized that pectoralis muscle area (PMA) measured objectively on chest CT scan may be associated with overall survival (OS) in non-small cell lung cancer (NSCLC).

Methods: We evaluated 252 cases from a prospectively enrolling lung cancer cohort. Eligible cases had CT scans performed prior to the initiation of surgery, radiation, or chemotherapy. PMA was measured in a semi-automated fashion while blinded to characteristics of the tumor, lung, and patient outcomes.

Results: Men had a significantly greater PMA than women (37.59 vs. 26.19 cm, P < 0.0001). In univariate analysis, PMA was associated with age and body mass index (BMI). A Cox proportional hazards model was constructed to account for confounders associated with survival. Lower pectoralis area (per cm) at diagnosis was associated with an increased hazard of death of 2% (HR, 0.98; confidence interval, 0.96-0.99; P = 0.044) while adjusting for age, sex, smoking, chronic bronchitis, emphysema, histology, stage, chemotherapy, radiation, surgery, BMI, and ECOG performance status.

Conclusions: Lower PMA measured from chest CT scans obtained at the time of diagnosis of NSCLC is associated with a worse OS.

Impact: PMA may be a valuable CT biomarker for sarcopenia-associated lung cancer survival. Cancer Epidemiol Biomarkers Prev; 26(1); 38-43. ©2016 AACR SEE ALL THE ARTICLES IN THIS CEBP FOCUS SECTION, "THE OBESITY PARADOX IN CANCER EVIDENCE AND NEW DIRECTIONS".
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http://dx.doi.org/10.1158/1055-9965.EPI-15-1067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116279PMC
January 2017

Subpopulation Treatment Effect Pattern Plot (STEPP) analysis for continuous, binary, and count outcomes.

Clin Trials 2016 08 19;13(4):382-90. Epub 2016 Apr 19.

Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: For the past few decades, randomized clinical trials have provided evidence for effective treatments by comparing several competing therapies. Their successes have led to numerous new therapies to combat many diseases. However, since their conclusions are based on the entire cohort in the trial, the treatment recommendation is for everyone, and may not be the best option for an individual. Medical research is now focusing more on providing personalized care for patients, which requires investigating how patient characteristics, including novel biomarkers, modify the effect of current treatment modalities. This is known as heterogeneity of treatment effects. A better understanding of the interaction between treatment and patient-specific prognostic factors will enable practitioners to expand the availability of tailored therapies, with the ultimate goal of improving patient outcomes. The Subpopulation Treatment Effect Pattern Plot (STEPP) approach was developed to allow researchers to investigate the heterogeneity of treatment effects on survival outcomes across values of a (continuously measured) covariate, such as a biomarker measurement.

Methods: Here, we extend the Subpopulation Treatment Effect Pattern Plot approach to continuous, binary, and count outcomes, which can be easily modeled using generalized linear models. With this extension of Subpopulation Treatment Effect Pattern Plot, these additional types of treatment effects within subpopulations defined with respect to a covariate of interest can be estimated, and the statistical significance of any observed heterogeneity of treatment effect can be assessed using permutation tests. The desirable feature that commonly used models are applied to well-defined patient subgroups to estimate treatment effects is retained in this extension.

Results: We describe a simulation study to confirm that the proper Type I error rate is maintained when there is no treatment heterogeneity, and a power study to show that the statistics have power to detect treatment heterogeneity under alternative scenarios. As an illustration, we apply the methods to data from the Aspirin/Folate Polyp Prevention Study, a clinical trial evaluating the effect of oral aspirin, folic acid, or both as a chemoprevention agent against colorectal adenomas. The pre-existing R software package stepp has been extended to handle continuous, binary, and count data using Gaussian, Bernoulli, and Poisson models, and it is available on the Comprehensive R Archive Network.

Conclusion: The extension of the method and the availability of new software now permit STEPP to be applied to the full range of clinical trial end points.
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http://dx.doi.org/10.1177/1740774516643297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942365PMC
August 2016

Meta-STEPP: subpopulation treatment effect pattern plot for individual patient data meta-analysis.

Stat Med 2016 09 12;35(21):3704-16. Epub 2016 Apr 12.

Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, U.S.A.

We have developed a method, called Meta-STEPP (subpopulation treatment effect pattern plot for meta-analysis), to explore treatment effect heterogeneity across covariate values in the meta-analysis setting for time-to-event data when the covariate of interest is continuous. Meta-STEPP forms overlapping subpopulations from individual patient data containing similar numbers of events with increasing covariate values, estimates subpopulation treatment effects using standard fixed-effects meta-analysis methodology, displays the estimated subpopulation treatment effect as a function of the covariate values, and provides a statistical test to detect possibly complex treatment-covariate interactions. Simulation studies show that this test has adequate type-I error rate recovery as well as power when reasonable window sizes are chosen. When applied to eight breast cancer trials, Meta-STEPP suggests that chemotherapy is less effective for tumors with high estrogen receptor expression compared with those with low expression. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/sim.6958DOI Listing
September 2016

Identifying treatment effect heterogeneity in clinical trials using subpopulations of events: STEPP.

Clin Trials 2016 Apr 22;13(2):169-79. Epub 2015 Oct 22.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.

Background: Investigators conducting randomized clinical trials often explore treatment effect heterogeneity to assess whether treatment efficacy varies according to patient characteristics. Identifying heterogeneity is central to making informed personalized healthcare decisions. Treatment effect heterogeneity can be investigated using subpopulation treatment effect pattern plot (STEPP), a non-parametric graphical approach that constructs overlapping patient subpopulations with varying values of a characteristic. Procedures for statistical testing using subpopulation treatment effect pattern plot when the endpoint of interest is survival remain an area of active investigation.

Methods: A STEPP analysis was used to explore patterns of absolute and relative treatment effects for varying levels of a breast cancer biomarker, Ki-67, in the phase III Breast International Group 1-98 randomized clinical trial, comparing letrozole to tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. Absolute treatment effects were measured by differences in 4-year cumulative incidence of breast cancer recurrence, while relative effects were measured by the subdistribution hazard ratio in the presence of competing risks using O-E (observed-minus-expected) methodology, an intuitive non-parametric method. While estimation of hazard ratio values based on O-E methodology has been shown, a similar development for the subdistribution hazard ratio has not. Furthermore, we observed that the subpopulation treatment effect pattern plot analysis may not produce results, even with 100 patients within each subpopulation. After further investigation through simulation studies, we observed inflation of the type I error rate of the traditional test statistic and sometimes singular variance-covariance matrix estimates that may lead to results not being produced. This is due to the lack of sufficient number of events within the subpopulations, which we refer to as instability of the subpopulation treatment effect pattern plot analysis. We introduce methodology designed to improve stability of the subpopulation treatment effect pattern plot analysis and generalize O-E methodology to the competing risks setting. Simulation studies were designed to assess the type I error rate of the tests for a variety of treatment effect measures, including subdistribution hazard ratio based on O-E estimation. This subpopulation treatment effect pattern plot methodology and standard regression modeling were used to evaluate heterogeneity of Ki-67 in the Breast International Group 1-98 randomized clinical trial.

Results: We introduce methodology that generalizes O-E methodology to the competing risks setting and that improves stability of the STEPP analysis by pre-specifying the number of events across subpopulations while controlling the type I error rate. The subpopulation treatment effect pattern plot analysis of the Breast International Group 1-98 randomized clinical trial showed that patients with high Ki-67 percentages may benefit most from letrozole, while heterogeneity was not detected using standard regression modeling.

Conclusion: The STEPP methodology can be used to study complex patterns of treatment effect heterogeneity, as illustrated in the Breast International Group 1-98 randomized clinical trial. For the subpopulation treatment effect pattern plot analysis, we recommend a minimum of 20 events within each subpopulation.
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http://dx.doi.org/10.1177/1740774515609106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563513PMC
April 2016

A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas.

N Engl J Med 2015 Oct;373(16):1519-30

From the Departments of Medicine (J.A.B., D.J.R., R.R.) and Epidemiology (J.A.B., E.L.B., L.A.M., J.R.R.), Geisel School of Medicine at Dartmouth, Hanover, and Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon (D.J.R., R.R.) - both in New Hampshire; the Departments of Medicine (J.A.B., R.S.S.) and Biostatistics (A.I.), University of North Carolina at Chapel Hill, Chapel Hill; the Department of Pathology, Fairview Southdale Hospital, Edina (D.C.S.), and the Division of Environmental Health Sciences, University of Minnesota School of Public Health (T.R.C.), Minnesota Gastroenterology (A.S.K.), Department of Medicine, University of Minnesota (A.S.), and Minneapolis Veterans Affairs (VA) Medical Center (A.S.), Minneapolis - all in Minnesota; the Department of Epidemiology, Rollins School of Public Health, Emory University and Winship Cancer Institute, Emory University, Atlanta (R.M.B., M.G.); the Department of Mathematics and Statistics, University of Vermont, Burlington (B.F.C.), and VA Outcomes Group, White River Junction (D.J.R.) - both in Vermont; the Department of Medicine, University of Colorado School of Medicine, Denver (D.J.A.); the Departments of Quantitative Health Sciences (G.J.B.) and Gastroenterology and Hepatology (C.A.B.), Cleveland Clinic, Cleveland; the Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston (R.S.B.); Puerto Rico Cancer Center, Medical Sciences Campus, University of Puerto Rico, San Juan (M.C.-C.); the Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (J.C.F.); Consultants in Gastroenterology, West Columbia, SC (M.E.S.); and the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (R.W.S.).

Background: Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas.

Methods: We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2×2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopist's recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy.

Results: Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval [CI], 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events.

Conclusions: Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.).
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http://dx.doi.org/10.1056/NEJMoa1500409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643064PMC
October 2015

Growth Impairment of Small-Cell Cancer by Targeting Pro-Vasopressin with MAG-1 Antibody.

Front Oncol 2014 11;4:16. Epub 2014 Feb 11.

Woomera Therapeutics Inc. , Lebanon, NH , USA.

Previously we demonstrated that human small-cell lung cancer (SCLC) seems to universally express the vasopressin gene, and this leads to the presence of a cell surface marker representing the entire pro-hormone precursor. In this study, we show this marker can be targeted with MAG-1, a mouse monoclonal antibody against a C-terminal moiety on pro-vasopressin. In vitro targeting of cell lines derived from primary and recurrent disease demonstrates attachment of antibody to the cell surface followed by internalization. In vivo targeting with (99)Tc-labeled Fab fragments of MAG-1 shows selective attachment to xenografts. In vivo treatment of tumors from classical cell line, NCI H345, with either ~1.65 mCi (~1.65 mg)/kg body weight (BW) of (90)Yttrium-labeled MAG-1, or ~1.65 mg/kg BW native MAG-1, delivered every second day for 6 days produced similar reductions in the growth rate to ~50% (p < 0.03). When dosing with native MAG-1 was escalated to daily amounts of ~3.3 mg/kg BW over 16 days, tumor growth rates fell to ~33% of saline controls (p < 0.005). Examination of tumors treated with this higher dosing demonstrated the presence in several of extensive apoptosis. Normal tissues seemed to be unaffected. A larger dosage of MAG-1 (~6.6 mg/kg BW) given daily for 14 days was used to treat xenografts of the variant cell line NCI H82 representing recurrent disease. This treatment decreased the rate of increase in tumor size by half, and doubling time ~3-fold. Increases in cleaved PARP supported increased apoptosis with antibody treatment. We believe these data provide evidence that the growth rate of SCLC tumors can be extensively reduced by treatment with MAG-1 antibody, and that a humanized form of this antibody could, in future, be potentially used for targeting therapy onto recurrent SCLC in patients.
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http://dx.doi.org/10.3389/fonc.2014.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920095PMC
February 2014

Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial.

Lancet Oncol 2013 Apr 11;14(4):297-305. Epub 2013 Mar 11.

Molecular Senology Unit, Senology Division, European Institute of Oncology, Milan, Italy.

Background: For patients with breast cancer and metastases in the sentinel nodes, axillary dissection has been standard treatment. However, for patients with limited sentinel-node involvement, axillary dissection might be overtreatment. We designed IBCSG trial 23-01 to determine whether no axillary dissection was non-inferior to axillary dissection in patients with one or more micrometastatic (≤2 mm) sentinel nodes and tumour of maximum 5 cm.

Methods: In this multicentre, randomised, non-inferiority, phase 3 trial, patients were eligible if they had clinically non-palpable axillary lymph node(s) and a primary tumour of 5 cm or less and who, after sentinel-node biopsy, had one or more micrometastatic (≤2 mm) sentinel lymph nodes with no extracapsular extension. Patients were randomly assigned (in a 1:1 ratio) to either undergo axillary dissection or not to undergo axillary dissection. Randomisation was stratified by centre and menopausal status. Treatment assignment was not masked. The primary endpoint was disease-free survival. Non-inferiority was defined as a hazard ratio (HR) of less than 1·25 for no axillary dissection versus axillary dissection. The analysis was by intention to treat. Per protocol, disease and survival information continues to be collected yearly. This trial is registered with ClinicalTrials.gov, NCT00072293.

Findings: Between April 1, 2001, and Feb 28, 2010, 465 patients were randomly assigned to axillary dissection and 469 to no axillary dissection. After the exclusion of three patients, 464 patients were in the axillary dissection group and 467 patients were in the no axillary dissection group. After a median follow-up of 5·0 (IQR 3·6-7·3) years, we recorded 69 disease-free survival events in the axillary dissection group and 55 events in the no axillary dissection group. Breast-cancer-related events were recorded in 48 patients in the axillary dissection group and 47 in the no axillary dissection group (ten local recurrences in the axillary dissection group and eight in the no axillary dissection group; three and nine contralateral breast cancers; one and five [corrected] regional recurrences; and 34 and 25 distant relapses). Other non-breast cancer events were recorded in 21 patients in the axillary dissection group and eight in the no axillary dissection group (20 and six second non-breast malignancies; and one and two deaths not due to a cancer event). 5-year disease-free survival was 87·8% (95% CI 84·4-91·2) in the group without axillary dissection and 84·4% (80·7-88·1) in the group with axillary dissection (log-rank p=0·16; HR for no axillary dissection vs axillary dissection was 0·78, 95% CI 0·55-1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3-4) included one sensory neuropathy (grade 3), three lymphoedema (two grade 3 and one grade 4), and three motor neuropathy (grade 3), all in the group that underwent axillary dissection, and one grade 3 motor neuropathy in the group without axillary dissection. One serious adverse event was reported, a postoperative infection in the axilla in the group with axillary dissection.

Interpretation: Axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement, thus eliminating complications of axillary surgery with no adverse effect on survival.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(13)70035-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935346PMC
April 2013

Preoperative systemic therapy in locoregional management of early breast cancer: highlights from the Kyoto Breast Cancer Consensus Conference.

Breast Cancer Res Treat 2012 Dec 11;136(3):919-26. Epub 2012 Nov 11.

Breast Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.

Data reviewed at the Kyoto Breast Cancer Consensus Conference (KBCCC) showed that preoperative systemic therapy (PST) could optimize surgery through the utilization of information relating to pre- and post-PST tumor stage, therapeutic sensitivity, and treatment-induced changes in the biological characteristics of the tumor. As such, it was noted that the biological characteristics of the tumor, such as hormone receptors, human epidermal growth factor receptor-2, histological grade, cell proliferative activity, mainly defined by the Ki67 labeling index, and the tumor's multi-gene signature, should be considered in the planning of both systemic and local therapy. Furthermore, the timing of axillary sentinel lymph node diagnosis (i.e., before or after the PST) was also noted to be critical in that it may influence the likelihood of axillary preservation, even in node positive cases. In addition, axillary diagnosis with ultrasound and concomitant fine needle aspiration cytology or core needle biopsy (CNB) was reported to contribute to the construction of a treatment algorithm for patient-specific or individualized axillary surgery. Following PST, planning for breast surgery should therefore be based on tumor subtype, tumor volume and extent, therapeutic response to PST, and patient preference. Nomograms for predicting nodal status and drug sensitivity were also recognized as a tool to support decision-making in the selection of surgical treatment. Overall, review of data at the KBCCC showed that PST increases the likelihood of patients receiving localized surgery and individualized treatment regimens.
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http://dx.doi.org/10.1007/s10549-012-2333-9DOI Listing
December 2012

Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials.

Int J Cancer 2011 Jul 1;129(1):192-203. Epub 2011 Apr 1.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Observational data suggest that lower folate status is associated with an increased risk of colorectal neoplasia, implying that folate may be useful as a chemopreventive agent. We conducted a combined analysis of three large randomized trials of folic acid supplementation for the prevention of metachronous adenomas in patients with an adenoma history. Participants included 2,632 men and women who had a history of adenomas randomized to either 0.5 or 1.0 mg/day of folic acid or placebo and who had a follow-up endoscopy 6 to 42 months after randomization [mean = 30.6 (standard deviation = 8.1) months]. We used random-effects meta-analysis to estimate risk ratios (RRs) and 95% confidence intervals (CIs). The RR comparing folic acid versus placebo was 0.98 (95% CI = 0.82-1.17) for all adenomas and 1.06 (95% CI = 0.81-1.39) for advanced lesions. Folic acid was associated with a nonsignificant decreased risk of any adenoma among subjects in the lowest quartile of baseline plasma folate (≤ 11 nmol/L) and no effect among individuals in the highest quartile (> 29 nmol/L, p for trend = 0.17). There was a nonsignificant trend of decreasing risk of any adenoma associated with folic acid supplements with increasing alcohol intake. During the early follow-up reported here, more deaths occurred in the placebo group than in the folic acid group (1.7% vs. 0.5%, p = 0.002). In conclusion, after up to 3.5 years of folic acid use, there is no clear decrease or increase in the occurrence of new adenomas in patients with a history of adenoma.
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http://dx.doi.org/10.1002/ijc.25872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753215PMC
July 2011

Evaluation of treatment-effect heterogeneity using biomarkers measured on a continuous scale: subpopulation treatment effect pattern plot.

J Clin Oncol 2010 Oct 13;28(29):4539-44. Epub 2010 Sep 13.

Harvard School of Public Health, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

The discovery of biomarkers that predict treatment effectiveness has great potential for improving medical care, particularly in oncology. These biomarkers are increasingly reported on a continuous scale, allowing investigators to explore how treatment efficacy varies as the biomarker values continuously increase, as opposed to using arbitrary categories of expression levels resulting in a loss of information. In the age of biomarkers as continuous predictors (eg, expression level percentage rather than positive v negative), alternatives to such dichotomized analyses are needed. The purpose of this article is to provide an overview of an intuitive statistical approach-the subpopulation treatment effect pattern plot (STEPP)-for evaluating treatment-effect heterogeneity when a biomarker is measured on a continuous scale. STEPP graphically explores the patterns of treatment effect across overlapping intervals of the biomarker values. As an example, STEPP methodology is used to explore patterns of treatment effect for varying levels of the biomarker Ki-67 in the BIG (Breast International Group) 1-98 randomized clinical trial comparing letrozole with tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. STEPP analyses showed patients with higher Ki-67 values who were assigned to receive tamoxifen had the poorest prognosis and may benefit most from letrozole.
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http://dx.doi.org/10.1200/JCO.2009.27.9182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988642PMC
October 2010

Timing of radiotherapy and outcome in patients receiving adjuvant endocrine therapy.

Int J Radiat Oncol Biol Phys 2011 Jun 21;80(2):398-402. Epub 2010 Aug 21.

Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Purpose: To evaluate the association between the interval from breast-conserving surgery (BCS) to radiotherapy (RT) and the clinical outcome among patients treated with adjuvant endocrine therapy.

Patients And Methods: Patient information was obtained from three International Breast Cancer Study Group trials. The analysis was restricted to 964 patients treated with BCS and adjuvant endocrine therapy. The patients were divided into two groups according to the median number of days between BCS and RT and into four groups according to the quartile of time between BCS and RT. The endpoints were the interval to local recurrence, disease-free survival, and overall survival. Proportional hazards regression analysis was used to perform comparisons after adjustment for baseline factors.

Results: The median interval between BCS and RT was 77 days. RT timing was significantly associated with age, menopausal status, and estrogen receptor status. After adjustment for these factors, no significant effect of a RT delay ≤20 weeks was found. The adjusted hazard ratio for RT within 77 days vs. after 77 days was 0.94 (95% confidence interval [CI], 0.47-1.87) for the interval to local recurrence, 1.05 (95% CI, 0.82-1.34) for disease-free survival, and 1.07 (95% CI, 0.77-1.49) for overall survival. For the interval to local recurrence the adjusted hazard ratio for ≤48, 49-77, and 78-112 days was 0.90 (95% CI, 0.34-2.37), 0.86 (95% CI, 0.33-2.25), and 0.89 (95% CI, 0.33-2.41), respectively, relative to ≥113 days.

Conclusion: A RT delay of ≤20 weeks was significantly associated with baseline factors such as age, menopausal status, and estrogen-receptor status. After adjustment for these factors, the timing of RT was not significantly associated with the interval to local recurrence, disease-free survival, or overall survival.
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http://dx.doi.org/10.1016/j.ijrobp.2010.02.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992081PMC
June 2011

Native MAG-1 antibody almost destroys human breast cancer xenografts.

Breast Cancer Res Treat 2011 Jun 13;127(3):631-7. Epub 2010 Jul 13.

Departments of Physiology and Pathology, Dartmouth Medical School, Lebanon, NH 03756, USA.

A native form of mouse monoclonal IgG1 antibody called MAG-1, which recognizes an epitope on provasopressin, has been found to shrink and produce extensive necrosis of human breast tumor xenografts in nu/nu mice. We examined the ability of (90)Yttrium-labeled and native MAG-1 to affect the growth in nu/nu mice of cancer xenografts that were estrogen-responsive (from MCF-7 cells) and triple-negative (from MDA-MB231 cells). The growth rates of treated cells were compared to those receiving saline vehicle and those receiving (90)Yttrium-labeled and native forms of the ubiquitous antibody, MOPC21. Short-term treatments (4 doses over 6 days) not only with (90)Yttrium-MAG-1 but also native MAG-1 produced large reductions in size of rapidly growing tumors of both types, while both (90)Yttrium- MOPC21 and native MOPC21 had no effect. Native and (90)Yttrium-MAG-1 effects were similar, and arrested tumors recommenced growing soon after treatments stopped. Increasing native MAG-1 treatment to single dosing for 16 consecutive days shrank tumors of both types with no regrowth apparent over a 20-day post-treatment period of observation. Pathological examination of such tumors revealed they had undergone very extensive (>66%) necrosis.
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http://dx.doi.org/10.1007/s10549-010-1009-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521588PMC
June 2011

Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, node-negative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer.

J Clin Oncol 2010 Jun 10;28(18):2966-73. Epub 2010 May 10.

Research Unit in Medical Senology, Department of Medicine, European Institute of Oncology, Università degli Studi di Milano, Milan, Italy.

Purpose: Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents.

Patients And Methods: Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present.

Results: Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor-absent, and endocrine receptor-present subtypes. No clear chemotherapy benefit was observed in endocrine receptor-present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor-present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor-absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor-present disease).

Conclusion: The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.
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http://dx.doi.org/10.1200/JCO.2009.25.9549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982784PMC
June 2010

Adjuvant! Online estimation of chemotherapy effectiveness when added to ovarian function suppression plus tamoxifen for premenopausal women with estrogen-receptor-positive breast cancer.

Breast Cancer Res Treat 2010 Aug 27;123(1):303-10. Epub 2010 Feb 27.

Department of Medical Oncology, University Hospital Gasthuisberg, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium.

Adjuvant! Online (Adjuvant!) is a user-friendly, web-based tool that provides estimates of adjuvant therapy outcomes for individual patients. While reliable evidence underpins estimates for most patient cohorts, there is a paucity of data on the effect of adding chemotherapy to complete estrogen blockade for premenopausal women with estrogen-receptor positive breast cancer. International Breast Cancer Study Group (IBCSG) Trial 11-93 enrolled 174 premenopausal women with estrogen-receptor positive, node-positive breast cancer. Among these patients, 55% had one positive axillary lymph node and 97% had three or fewer positive nodes. Patients were randomized to receive ovarian function suppression plus 5 years of tamoxifen with or without anthracycline-based chemotherapy. Estimated hazard rates and corresponding 10-year relapse-free survival percentages obtained from Trial 11-93 data were compared with those predicted using Adjuvant!. The 10-year relapse-free survival percentages predicted from Adjuvant! were 64.4% (95% CI, 61.9-67.2%) for endocrine therapy alone and 74.9% (95% CI, 73.1-76.8%) for chemoendocrine therapy. By contrast, these estimates in Trial 11-93 were 76.4% (95% CI, 65.8-84.0%) for endocrine therapy alone and 74.9% (95% CI, 64.5-82.7%) for chemoendocrine therapy. The Adjuvant! estimate for the endocrine-alone control group is lower than that observed in Trial 11-93 (P = 0.03), while the estimates for the two chemoendocrine therapy groups are similar. Adjuvant! appears to underestimate the effectiveness of adjuvant endocrine therapy alone for premenopausal women with endocrine responsive breast cancer, thus overestimating the added benefit, if any, from chemotherapy for this patient population.
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http://dx.doi.org/10.1007/s10549-010-0794-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3588884PMC
August 2010

Prevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine.

AIDS 2010 Mar;24(5):675-85

Infectious Disease and International Health, Dartmouth Medical School, Hanover, New Hampshire, USA.

Objective: To determine whether a multiple-dose series of an inactivated whole cell mycobacterial vaccine, Mycobacterium vaccae, can prevent HIV-associated tuberculosis.

Design And Methods: The DarDar trial was a randomized, placebo-controlled, double-blind trial. The study was carried in an outpatient facility in Dar es Salaam, Tanzania. HIV-infected patients with CD4 cell counts of at least 200 cells/microl and a Bacille Calmette-Guérin scar were chosen for the study. The intervention was carried out by random 1:1 assignment to five intradermal doses of M. vaccae or placebo. Tuberculin skin tests were performed, and patients with reactions of at least 5 mm were administered isoniazid for 6 months. The main outcome measures were disseminated (primary endpoint), definite, and probable tuberculosis (secondary endpoints).

Results: Two thousand thirteen individuals were randomized (1006 to M. vaccae, 1007 to placebo) and followed every 3 months for a median of 3.3 years. The trial was terminated early because of slow accrual of cases of disseminated tuberculosis and significant protection against definite tuberculosis. Hazard ratios were disseminated tuberculosis 0.52 (95% confidence interval 0.21-1.34; seven cases in M. vaccae, 13 cases in placebo; log-rank P = 0.16), definite tuberculosis 0.61 (95% confidence interval 0.39-0.96; 33 cases in M. vaccae, 52 cases in placebo; P = 0.03), and probable tuberculosis 1.17 (95% confidence interval 0.76-1.80; 48 cases in M. vaccae, 40 cases in placebo; P = 0.46). Immunization was well tolerated, with no adverse effect on CD4 cell count or HIV viral load, and no increase in the rate of serious adverse events.

Conclusion: Administration of a multiple-dose series of M. vaccae to HIV-infected adults with childhood Bacille Calmette-Guérin immunization is safe and is associated with significant protection against definite tuberculosis. These results provide evidence that immunization with a whole cell mycobacterial vaccine is a viable strategy for the prevention of HIV-associated tuberculosis.
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http://dx.doi.org/10.1097/QAD.0b013e3283350f1bDOI Listing
March 2010

Brain metastases from colorectal cancer: risk factors, incidence, and the possible role of chemokines.

Clin Colorectal Cancer 2009 Apr;8(2):100-5

Department of Internal Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.

Background: Brain metastases from colorectal cancer (CRC) are uncommon. There has been relatively little published on the host and tumor factors that might lead to this clinical scenario. We reviewed all cases of brain metastases from CRC at Dartmouth-Hitchcock Medical Center over a more than 20-year period to establish incidence and to identify patient and cancer characteristics which were associated with their development.

Patients And Methods: We present a retrospective review of 39 confirmed cases of brain metastases from CRC diagnosed between 1984 and 2006. Immunohistochemical staining for CXCR4 was performed on all available brain metastasis biopsy specimens.

Results: The incidence of brain metastases from CRC was 2.3%. Left-sided primary colon tumors predominated. The majority of patients had pulmonary metastases at the time brain metastases were identified, and those with preexisting pulmonary metastases had progression of that disease. All patients were symptomatic from brain metastases, and the cerebellum was the most common area of brain involvement. Immunohistochemical analysis confirmed strong expression of CXCR4 in all brain metastases sampled.

Conclusion: The incidence of brain metastases from CRC is low. Primary tumor in the left colon, long-standing pulmonary metastases, especially those with recent progression, and CXCR4 expression by tumor cells are all associated with increased risk of brain metastases. Increased survival among patients with metastatic CRC will likely result in an increased incidence of brain metastases. Further characterization of the role of tumor and host factors might yield better insight into the development, and potentially the prevention, of this devastating situation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909497PMC
April 2009