Initial Safety and Feasibility Results From a Phase 1, Diagnose-and-Treat Trial of Neoadjuvant Intratumoral Cisplatin for Stage IV NSCLC.

Neoadjuvant intratumoral cisplatin has the potential to generate substantial cytotoxicity and immune priming within the tumor environment, while minimizing systemic, off-target, adverse events. We initiated a phase 1A, 3+3 dose-ranging study of neoadjuvant, intratumoral cisplatin, delivered through endobronchial ultrasound bronchoscopy, in the same procedure as the initial diagnosis. There were no dose-limiting toxicity identified at the 20mg level.

Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial.

AIM: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations. METHODS: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention. RESULTS: The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking. CONCLUSIONS: STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01358877.

Weekly vs Every-3-Week Carboplatin with Weekly Paclitaxel in Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Retrospective Analysis.

Background: Adding carboplatin to weekly paclitaxel as part of neoadjuvant chemotherapy (NACT) for stage II-III triple negative breast cancer (TNBC) has been shown to significantly increase the pathologic complete response (pCR) rate. Hematologic toxicities associated with every 3-week dosing of carboplatin have led some oncologists to explore weekly dosing as an alternative, but there are little published data comparing the two dosing schedules. Methods: We performed a retrospective analysis of patients who received paclitaxel and carboplatin, usually followed by AC, as initial NACT for TNBC at two academic cancer centers between 2008 and 2018 for whom pathologic results and post-operative follow-up were available. We recorded pCR, defined as ypT0/isN0, treatment delivery and disease-free survival, censored as of the patient's last follow-up visit. Results: A total of 76 patients were identified (median age 49 years). A total of 47 received weekly carboplatin, of whom 83% received at least 11 of 12 planned doses, and 29 received every 3-week carboplatin, of whom 90% received all 4 planned doses. pCR rates were similar, 53% with weekly and 55% with every 3-week carboplatin dosing. At median follow-up of 18 months (range <1-118), 93% of patients who achieved pCR were alive and free from recurrence, compared to 74% of those who did not. Conclusion: pCR rates were similar between patients receiving weekly or every 3-week carboplatin and were similar to those reported in prior trials with carboplatin. These data suggest that providers can choose either weekly or every 3-week carboplatin dosing without compromising the likelihood of achieving pCR.

A simple assessment of lung nodule location for reduction in unnecessary invasive procedures.

BACKGROUND: CT screening for lung cancer results in a significant mortality reduction but is complicated by invasive procedures performed for evaluation of the many detected benign nodules. The purpose of this study was to evaluate measures of nodule location within the lung as predictors of malignancy. METHODS: We analyzed images and data from 3,483 participants in the National Lung Screening Trial (NLST). All nodules (4-20 mm) were characterized by 3D geospatial location using a Cartesian coordinate system and evaluated in logistic regression analysis. Model development and probability cutpoint selection was performed in the NLST testing set. The Geospatial test was then validated in the NLST testing set, and subsequently replicated in a new cohort of 147 participants from The Detection of Early Lung Cancer Among Military Personnel (DECAMP) Consortium. RESULTS: The Geospatial Test, consisting of the superior-inferior distance (Z distance), nodule diameter, and radial distance (carina to nodule) performed well in both the NLST validation set (AUC 0.85) and the DECAMP replication cohort (AUC 0.75). A negative Geospatial Test resulted in a less than 2% risk of cancer across all nodule diameters. The Geospatial Test correctly reclassified 19.7% of indeterminate nodules with a diameter over 6mm as benign, while only incorrectly classifying 1% of cancerous nodules as benign. In contrast, the parsimonious Brock Model applied to the same group of nodules correctly reclassified 64.5% of indeterminate nodules as benign but resulted in misclassification of a cancer as benign in 18.2% of the cases. Applying the Geospatial test would result in reducing invasive procedures performed for benign lesions by 11.3% with a low rate of misclassification (1.3%). In contrast, the Brock model applied to the same group of patients results in decreasing invasive procedures for benign lesion by 39.0% but misclassifying 21.1% of cancers as benign. CONCLUSIONS: Utilizing information about geospatial location within the lung improves risk assessment for indeterminate lung nodules and may reduce unnecessary procedures. TRIAL REGISTRATION: NCT00047385, NCT01785342.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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.

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.

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

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.

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

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 cm2, 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 cm2) at diagnosis was associated with an increased hazard of death of 2% (HRadj, 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".

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.

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.

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

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.

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

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.

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

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.).

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

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.