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.

Implementation strategies to improve posttraumatic stress disorder care in rural veterans.

PURPOSE: Prior research has noted treatment inequalities in the care of rural veterans with posttraumatic stress disorder (PTSD). This project sought to increase the delivery, or reach, of recommended PTSD treatments in 2 rural health care systems of the Department of Veterans Affairs (VA) using implementation facilitation. METHODS: The quality improvement project involved 6 months of facilitation to 2 low-reach PTSD clinics within 2 VA health care systems. The clinics were matched to a control clinic at another regional system similar in reach, rurality, and patient volume. We compared the delivery of evidence-based psychotherapies (EBPs) for PTSD at 3 timepoints: baseline, 6 months, and 1 year using difference-in-difference effect estimation. Facilitators and barriers of EBP reach were identified through interviews with clinic staff and informed specific implementation plans. We also measured reductions in benzodiazepine prescriptions and polypharmacy to determine the impact of an academic detailing intervention aimed at improving PTSD prescribing practices at the 2 sites. FINDINGS: EBP reach at 6 months more than doubled in the 2 PTSD clinics that received facilitation, while our control clinic experienced a decrease in EBP reach (DID = 24.6; SE = 6.71%). Both intervention clinics identified similar administrative barriers to the delivery of EBPs, offering useful information for improvement at other rural clinics. The use of academic detailing as part of our facilitation intervention further appears to have positively impacted care. CONCLUSIONS: In this preliminary work, facilitation is a promising strategy for increasing the delivery of PTSD EBPs to veterans seen in under-resourced rural VA clinics.

"Will it work for me?" Developing patient-friendly graphical displays of posttraumatic stress disorder treatment effectiveness.

The goal of this study was to create simple visual displays to help patients understand the benefits of evidence-based treatment for posttraumatic stress disorder (PTSD). We reviewed randomized trials of the most effective individual, trauma-focused psychotherapies and first-line antidepressants for adults with PTSD. The analytic sample included 65 treatment arms from 41 trials. We used binomial logistic regression to estimate the proportion of participants who lost their PTSD diagnosis at posttreatment and created a sample icon array to display these estimates. We provide a range of estimates (0-100) based on varying the percentage of the sample with a military affiliation. The percentage of participants who no longer met the diagnostic criteria for PTSD among civilian populations was 64.3% for trauma-focused treatment, 56.9% for SSRI/SNRI, and 16.7% for waitlist/minimal attention. For military populations, the proportions of participants who no longer met the diagnostic criteria were 44.2%, 36.7%, and 8.1%, respectively. We present icon arrays for 0%, 7%, 50%, and 100% military affiliation displaying 100 icons, a portion of which were shaded to indicate the number of participants that no longer met the PTSD criteria following treatment. After evidence-based treatment, between one third and two thirds of participants no longer met the PTSD criteria. Providers can use the icon array developed in this study with patients to facilitate communication regarding PTSD treatment effectiveness.

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.

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

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.

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.

Meta-STEPP with random effects.

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.

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

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.

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.