Exact unconditional inference for analyzing contingency tables in finite populations.

With recent developments in computer power the application of exact inferential methods has become more feasible which has resulted in increasing popularity of these approaches. However, there is a lack of such methodology for populations with more complex structure, such as finite populations. When a small sample is drawn from a finite population, the number of individuals with a specific characteristic of interest follows hypergeometric distribution. In order to test for the comparison of two proportions in finite populations we develop an exact unconditional test. We utilize the information gained from the sample to restrict our search for the maximum p-value. Our proposed test has power equal to its competitors while maintains the pre-specified nominal significance level.

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy.

BACKGROUND: In SPARTAN, apalutamide improved metastasis-free and overall survival for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) with a prostate-specific antigen doubling time of ≤10 mo. OBJECTIVE: We evaluated health-related quality of life (HRQoL) at the final analysis of the SPARTAN study. INTERVENTION: Patients received apalutamide (240 mg/d) or placebo in 28-d cycles. All patients continued androgen deprivation therapy (ADT). DESIGN, SETTING, AND PARTICIPANTS: A total of 1207 patients with nmCRPC were randomized 2:1 to apalutamide or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires at day 1 of cycle 1 (predose/baseline), cycles 2-6, every two cycles during cycles 7-13, every four cycles thereafter, at the end of treatment, and every 4 mo after progression to 1 yr. Results are presented using descriptive statistics. A mixed model for repeated measures was fitted to estimate the mean scores at each scheduled visit during treatment. RESULTS: At final analysis, with 52 mo follow-up for survival, the median treatment duration was 32.9 mo for apalutamide and 11.5 mo for placebo. Patients had good baseline HRQoL. At each scheduled collection during treatment, >90% per group completed the questionnaires. The change in FACT-P total score from baseline to cycles 21 and 25 significantly favored apalutamide over placebo (p = 0.0138 and 0.0009, respectively). The apalutamide group generally maintained favorable FACT-P (total and subscales) and EQ-5D-3L scores, while placebo scores tended to decline over time (starting in cycles 11-13 and pronounced by cycles 21-25). Notably, patient-reported fatigue did not worsen with apalutamide. Most patients reported being "not at all bothered" by side effects, and bother did not increase over time with apalutamide or placebo. Patients receiving apalutamide had minimal change in side-effect bother following symptomatic adverse events. CONCLUSIONS: Final analysis of SPARTAN confirms that HRQoL is preserved in patients with nmCRPC receiving apalutamide plus ADT, but declines in patients receiving placebo plus ADT after approximately 1 yr. PATIENT SUMMARY: Responses from patients with prostate cancer who were included in the SPARTAN study indicated that treatment with apalutamide, even after the most extensive follow-up time possible, did not reduce their quality of life. These results, along with improved survival and longer time to the development of metastases (reported separately), confirm the benefits of apalutamide for patients with nonmetastatic castration-resistant prostate cancer.

Chronic Non-Malignant Pain in Patients with Cancer Seen at a Timely Outpatient Palliative Care Clinic.

Palliative care is seeing cancer patients earlier in the disease trajectory with a multitude of chronic issues. Chronic non-malignant pain (CNMP) in cancer patients is under-studied. In this prospective study, we examined the prevalence and management of CNMP in cancer patients seen at our supportive care clinic for consultation. We systematically characterized each pain type with the Brief Pain Inventory (BPI) and documented current treatments. The attending physician made the pain diagnoses according to the International Association for the Study of Pain (IASP) task force classification. Among 200 patients (mean age 60 years, 69% metastatic disease, 1-year survival of 77%), the median number of pain diagnosis was 2 (IQR 1-2); 67 (34%, 95% CI 28-41%) had a diagnosis of CNMP; 133 (67%) had cancer-related pain; and 52 (26%) had treatment-related pain. In total, 12/31 (39%) patients with only CNMP and 21/36 (58%) patients with CNMP and other pain diagnoses were on opioids. There was a total of 94 CNMP diagnoses among 67 patients, including 37 (39%) osteoarthritis and 20 (21%) lower back pain; 30 (32%) were treated with opioids. In summary, CNMP was common in the timely palliative care setting and many patients were on opioids. Our findings highlight the need to develop clinical guidelines for CNMP in cancer patients to standardize its management.

Prospective Comparison of Toxicity and Cosmetic Outcome After Accelerated Partial Breast Irradiation With Conformal External Beam Radiotherapy or Single-Entry Multilumen Intracavitary Brachytherapy.

PURPOSE: This study aimed to prospectively characterize toxicity and cosmesis after accelerated partial breast irradiation (APBI) with 3-dimensional conformal radiation therapy (CRT) or single-entry, multilumen, intracavitary brachytherapy. METHODS AND MATERIALS: A total of 281 patients with pTis, pT1N0, or pT2N0 (≤3.0 cm) breast cancer treated with segmental mastectomy were prospectively enrolled from December 2008 through August 2014. APBI was delivered using 3-dimensional CRT (n = 29) or with SAVI (n = 176), Contura (n = 56), or MammoSite (n = 20) brachytherapy catheters. Patients were evaluated at protocol-specified intervals, at which time the radiation oncologist scored cosmetic outcome, toxicities, and recurrence status using a standardized template. RESULTS: The median follow-up time is 41 months. Grade 1 seroma and fibrosis were more common with brachytherapy than with 3-dimensional CRT (50.4% vs 3.4% for seroma; P < .0001 and 66.3% vs 44.8% for fibrosis; P = .02), but grade 1 edema was more common with 3-dimensional CRT than with brachytherapy (17.2% vs 5.6%; P = .04). Grade 2 to 3 pain was more common with 3-dimensional CRT (17.2% vs 5.2%; P = .03). Actuarial 5-year rates of fair or poor radiation oncologist-reported cosmetic outcome were 9% for 3-dimensional CRT and 24% for brachytherapy (P = .13). Brachytherapy was significantly associated with inferior cosmesis on mixed model analysis (P = .003). Significant predictors of reduced risk of adverse cosmetic outcome after brachytherapy were D0.1cc (skin) ≤102%, minimum skin distance >5.1 mm, dose homogeneity index >0.54, and volume of nonconformance ≤0.89 cc. The 5-year ipsilateral breast recurrence was 4.3% for brachytherapy and 4.2% for 3-dimensional CRT APBI patients (P = .95). CONCLUSIONS: Brachytherapy APBI is associated with higher rates of grade 1 fibrosis and seroma than 3-dimensional CRT but lower rates of grade 1 edema and grade 2 to 3 pain than 3-dimensional CRT. Rates of radiation oncologist-reported fair or poor cosmetic outcomes are higher with brachytherapy. We identified dosimetric parameters that predict reduced risk of adverse cosmetic outcome after brachytherapy-based APBI. Ipsilateral breast recurrence was equivalent for brachytherapy and 3-dimensional CRT.

Combined surgery and radiation improves survival of tonsil squamous cell cancers.

OBJECTIVE: The study evaluated the addition of surgery (S) to radiation (RT) on survival of squamous cell carcinomas (SCC) of tonsillar-fossa (TF) in a modern cohort with similar epidemiology and treatment as current patients. STUDY DESIGN: Retrospective analysis utilizing Surveillance, Epidemiology, and End Results (SEER) Program data. RESULTS: For all stages combined TF patients who received S+RT had superior OS (p < 0.01) and DSS (p < 0.01). For each stage OS and DSS was superior for S+RT (p < 0.05). In multivariate analysis, HRs for OS were statistically significantly higher for TF patients (stage 2, 3, and 4) receiving RT alone (p < 0.001). MATERIALS AND METHODS: TF SCC patients treated with either S+RT or RT alone between 2004 and 2011 were examined (n = 6,476). Primary outcome measures included overall survival (OS) and disease specific survival (DSS). Cox proportional hazard ratios (HR) were estimated for patients treated with S+RT compared to RT alone. CONCLUSIONS: OS and DSS were superior for all stages combined and for stages 2, 3, and 4 in TF patients who received S+RT compared to RT alone.

Subsite variation in survival of oropharyngeal squamous cell carcinomas 2004 to 2011.

OBJECTIVES/HYPOTHESIS: To evaluate subsite-specific differences in survival between squamous cell carcinomas of the base of tongue and tonsillar fossa in a modern cohort likely to have been treated with intensity-modulated radiation therapy, chemotherapy for stage III and IV, and have had a high incidence of human papillomavirus-associated tumors. STUDY DESIGN: Retrospective cohort analysis utilizing data from the Surveillance, Epidemiology, and End Results program of patients with base of tongue and tonsillar fossa squamous cell carcinoma from 2004 to 2011. METHODS: The cohort included 15,299 primary base of tongue and tonsillar fossa squamous cell carcinoma patients without distant metastases treated between 2004 and 2011. Subsite differences in overall survival and disease-specific survival were examined with Kaplan-Meier curves. Multivariate cox proportional hazard ratios were estimated for overall and disease-specific survival. RESULTS: The cohort included 7,220 (47.2%) base of tongue and 8,079 (52.8%) tonsillar fossa squamous cell carcinoma patients. Overall survival with all stages combined favored tonsillar fossa (P < .001) and remained superior when stratified by stage. In multivariate analyses adjusted for age, gender, race, and treatment, the hazard ratio for overall survival was superior for tonsillar fossa tumors compared to base of tongue tumors for all stages (stage 1, P = .041; stage 2, P = .006; stages 3 and 4, P < .001). Disease-specific survival also favored improved outcomes for tonsillar fossa. CONCLUSIONS: In this large modern cohort, overall and disease-specific survival favored outcomes in tonsillar fossa compared with base of tongue. Further study is required to evaluate factors that influence survival differences between tonsillar fossa and base of tongue despite modern therapy. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:1087-1092, 2017.

Development, validation and clinical application of Pelvic Lymphadenectomy Assessment and Completion Evaluation: intraoperative assessment of lymph node dissection after robot-assisted radical cystectomy for bladder cancer.

OBJECTIVES: To develop a scoring tool, Pelvic Lymphadenectomy Appropriateness and Completion Evaluation (PLACE), to assess the intraoperative completeness and appropriateness of pelvic lymph node dissection (PLND) following robot-assisted radical cystectomy (RARC). PATIENTS, SUBJECTS AND METHODS: A panel of 11 open and robotic surgeons developed the content and structure of PLACE. The PLND template was divided into three zones. In all, 21 de-identified videos of bilateral robot-assisted PLNDs were assessed by the 11 experts using PLACE to determine inter-rater reliability. Lymph node (LN) clearance was defined as the proportion of cleared LNs from all PLACE zones. We investigated the correlation between LN clearance and LN count. Then, we compared the LN count of 18 prospective PLNDs using PLACE with our retrospective series performed using the extended template (No PLACE). RESULTS: A significant reliability was achieved for all PLACE zones among the 11 raters for the 21 bilateral PLND videos. The median (interquartile range) for LN clearance was 468 (431-545). There was a significant positive correlation between LN clearance and LN count (R2 = 0.70, P < 0.01). The PLACE group yielded similar LN counts when compared to the No PLACE group. CONCLUSIONS: Pelvic Lymphadenectomy Appropriateness and Completion Evaluation is a structured intraoperative scoring system that can be used intraoperatively to measure and quantify PLND for quality control and to facilitate training during RARC.

Development and Validation of a Quality Assurance Score for Robot-assisted Radical Cystectomy: A 10-year Analysis.

OBJECTIVE: To develop quality assessment tool to evaluate surgical performance for robot-assisted radical cystectomy program. METHODS: A prospectively maintained quality assurance database of 425 consecutive robot-assisted radical cystectomies performed by a single surgeon between 2005 and 2015 was retrospectively reviewed. Potentially modifiable factors, related to the management and perioperative care of patients, were used to evaluate patient care. Criteria included the following: preoperative (administration of neoadjuvant chemotherapy); operative (operative time <6.5 hours and estimated blood loss <500 cc); pathologic (negative soft tissue surgical margins and lymph node yield ≥20); and postoperative (no high-grade complications, readmission, or noncancer-related mortality within 30 days).The Quality Cystectomy Score (QCS) was developed (1 star: achieving ≤2 criteria or mortality within 30 days; 2 stars: 3 or 4 criteria met; 3 stars: 5 or 6 criteria met; and 4 stars: 7 or all criteria met). Univariate and multivariate Cox proportional hazard regression models were fitted to test for the association between QCS and survival outcomes. RESULTS: Most patients (85%) achieved at least 3 stars, and more patients achieved 4 stars with time. High QCS was associated with better recurrence-free, cancer-specific, and overall survival (P values <.05). None of the patients with 1-star were alive at 1 year. Patients with 4 stars achieved the best survival rates (recurrence-free survival [62%], cancer-specific survival [70%], and overall survival [53%] at 5 years) (log rank P < .0001). CONCLUSION: Continuous assessment for quality improvement facilitated implementation and maintenance of robot-assisted program for bladder cancer.

Smoking cessation is associated with improved survival in oropharynx cancer treated by chemoradiation.

OBJECTIVES/HYPOTHESIS: The effect of smoking and human papillomavirus (HPV) on overall survival (OS) of oropharyngeal squamous cell carcinoma (OPSCC) patients undergoing concurrent chemotherapy (CCRT) remains unclear. STUDY DESIGN: Retrospective review. METHODS: Clinical characteristics of OPSCC patients treated between 2008 and 2015 with CCRT were abstracted from medical records. OS curves and multivariate cox proportional hazard ratios (HRs) were examined. RESULTS: Of 120 evaluable patients, 71% had HPV+ tumors. Median follow-up duration for the entire cohort was 41.5 months (range = 6-88 months). HPV+ current smokers experienced significantly worse 5-year OS (73% alive vs. 36% alive, P = .01) and there was a similar trend in HPV- current smokers (66% alive vs. 31% alive, P = .28) compared to former/never smokers undergoing CCRT. In a multivariate cox proportional hazard model adjusted for age, gender, and overall tumor stage, HPV+ current smokers experienced nearly a fourfold increase in overall mortality in comparison to HPV+ never/former smokers (HR = 3.68, 95% CI = 1.35-10.0). Similarly, current smokers with HPV- tumors (HR = 6.80, 95% CI = 1.11-41.67) had increased mortality compared to never/former smokers. CONCLUSIONS: Current smoking is associated with poor prognosis, independent of HPV status, in CCRT-treated OPSCC patients. Current smoking produced an approximately four- to sevenfold increase in risk of mortality for HPV+ and HPV- patients, respectively. Regardless of pack years and HPV status, efforts should be made to achieve smoking cessation before CCRT. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2733-2738, 2016.

Reappraisal of Serosal Invasion in Patients With T3 Colorectal Cancer by Elastic Stain: Clinicopathologic Study of 139 Surgical Cases With Special Reference to Peritoneal Elastic Lamina Invasion.

CONTEXT: Peritoneal elastic lamina invasion (PELI) has been reported to be an important adverse prognostic factor in pT3 colorectal cancer (CRC). However, the data supporting this contention are limited. OBJECTIVE: To clarify the associations between PELI of pT3 CRC and prognostic significance, 139 consecutive surgical cases of pT3 CRC were examined. DESIGN: One hundred thirty-nine consecutive in-house surgical cases of pT3 CRC between 1993 and 2011 were examined. Thirty consecutive surgical cases of pT4a CRC resected during the same period were examined for comparison. Case selections were restricted to pT3 CRCs with the sections containing the deepest adenocarcinoma invasion partially or entirely covered with the peritoneum. Elastic staining was performed on one section containing the deepest tumor invasion partially or entirely covered with the peritoneum. The associations between the presence of PELI and clinicopathologic factors including prognosis of the patients were examined. RESULTS: Peritoneal elastic lamina invasion was identified in 23.0% (32 of 139) of the pT3 CRCs. PELI was associated with primary site (P = .006), lymph node metastasis (P < .001), lymphovascular invasion (P < .001), recurrence (P = .007), and patient's age (P = .002). The proportions of patients with a 4-year recurrence-free period in those with negative PELI, positive PELI, and pT4a tumor were 90.3%, 66.7%, and 28.9%, respectively (P < .001). CONCLUSIONS: Elastic staining is useful to evaluate the serosal invasion of CRC. Positive PELI is a significant predictive factor for lymph node metastasis and recurrence-free survival in patients with pT3 CRC. This indicates that pT3 tumors with PELI should be treated like pT4a tumors.

Effects of selenomethionine on acute toxicities from concurrent chemoradiation for inoperable stage III non-small cell lung cancer.

AIM: To prospectively determine the safety and tolerability of oral L-selenomethionine (SLM) with concurrent chemoradiation (CCRT) for Stage III non-small cell lung cancer (NSCLC) and estimate if the incidence and/or severity of adverse events could be reduced by its use. METHODS: Sixteen patients with stage III NSCLC were accrued to this single arm, phase II study. CCRT consisted of radiation given at 2 Gy per fraction for 30-33 fractions, 5 d per week with concurrent weekly IV paclitaxel 50 mg/m(2) followed by carboplatin dosed at an area under the time-concentration curve of 2. SLM was dosed in a loading phase at 4800 µg twice daily for one week prior to CCRT followed by once daily dosing during treatment. RESULTS: No selenium-related toxicity was observed. Analysis revealed grade 3 or higher esophagitis in 3 of 16 patients (19%), pneumonitis in 0, leukopenia in 2 (12.5%), and anemia in 1 (6%); the latter two were significantly reduced when compared to the protocol-stated expected rate of 35% (P = 0.045 for leukopenia, and P < 0.01 for anemia). Median overall survival was 14.9 mo and median failure-free survival was 9 mo (95%CI: 3.3-21.5). CONCLUSION: There may be some protective benefit of selenium in the setting of CCRT for inoperable NSCLC. The data suggests decreased rates of myelosuppression when compared to similarly-treated historical and contemporary controls. Further evaluation of selenium in this setting may be warranted.

Randomized phase II trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in squamous cell carcinoma of the head and neck.

AIM: To investigate whether selenomethionine (SLM) reduces mucositis incidence in patients with head and neck squamous cell cancer (HNSCC) undergoing concurrent chemoradiation (CRT). METHODS: In this multi-institutional, randomized, double-blind phase II trial, patients with Stage III or IV HNSCC received SLM 3600 µg/m(2) or placebo twice daily for 7 d prior to CRT, once daily during CRT, and daily for 3 wk following CRT. CRT consisted of 70 Gy at 2 Gy per fraction with cisplatin 100 mg/m(2) IV on days 1, 22, and 43. RESULTS: Eighteen patients were randomized, 10 received SLM, and there were no differences in baseline factors. There was no difference in mucositis or patient-reported side effects between groups. There was no difference in overall or relapse-free survival at 12 mo. CONCLUSION: Addition of SLM to CRT for HNSCC was well-tolerated but did not lower the incidence of severe mucositis or improve quality of life or survival outcomes.

Identifying Targeted Strategies to Improve Smoking Cessation Support for Cancer Patients.

INTRODUCTION: Although smoking causes adverse outcomes in cancer patients, most oncology providers do not regularly provide smoking cessation support. The purpose of this study was to identify key areas that can be targeted to improve delivery of evidence-based cessation support for cancer patients. METHODS: In 2012, the International Association for the Study of Lung Cancer surveyed members asking about tobacco assessment and cessation practices for cancer patients. Responses from 1153 physician level oncology providers were analyzed to evaluate the effects of respondent demographics, tobacco use perceptions, and perceived barriers to providing cessation support on practice patterns. RESULTS: Respondents from the United States generally reported higher rates of asking about tobacco use, advising patients to quit, and assisting patients in quitting smoking. Work setting, time since completing a terminal degree, percent of time devoted to clinical care, and history of tobacco use were generally associated with asking about tobacco use and advising patients to quit, but not associated with discussing medications or actively treating patients. The dominant multivariate barriers to providing cessation support were a lack of clinician education or experience and lack of available resources to refer patients for smoking cessation support. Patient resistance to treatment, inability for patients to quit smoking, or feeling that smoking was not an important part of cancer outcome or cancer care had less meaningful associations with providing support. CONCLUSIONS: Improving clinician education and developing dedicated resources to provide cessation support were identified as ideal targets to address for improving cessation support for cancer patients.

Long-term oncologic outcomes following robot-assisted radical cystectomy: results from the International Robotic Cystectomy Consortium.

BACKGROUND: Long-term oncologic data on patients undergoing robot-assisted radical cystectomy (RARC) are limited and based largely on single-institution series. OBJECTIVE: Report survival outcomes of patients who underwent RARC ≥5 yr ago. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of the prospectively populated International Robotic Cystectomy Consortium multi-institutional database identified 743 patients with RARC performed ≥5 yr ago. Clinical, pathologic, and survival data at the latest follow-up were collected. Patients with palliative RARC were excluded. Final analysis was performed on 702 patients from 11 institutions in 6 countries. INTERVENTION: RARC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes of interest, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were plotted using Kaplan-Meier survival curves. A Cox proportional hazards model was used to identify factors that predicted outcomes. RESULTS AND LIMITATIONS: Pathologic organ-confined (OC) disease was found in 62% of patients. Soft tissue surgical margins (SMs) were positive in 8%. Median lymph node (LN) yield was 16, and 21% of patients had positive LNs. Median follow-up was 67 mo (interquartile range: 18-84 mo). Five-year RFS, CSS, and OS were 67%, 75%, and 50%, respectively. Non-OC disease and SMs were associated with poorer RFS, CSS, and OS on multivariable analysis. Age predicted poorer CSS and OS. Adjuvant chemotherapy and positive SMs were predictors of RFS (hazard ratio: 3.20 and 2.16; p<0.001 and p<0.005, respectively). Stratified survival curves demonstrated poorer outcomes for positive SM, LN, and non-OC disease. Retrospective interrogation and lack of contemporaneous comparison groups that underwent open radical cystectomy were major limitations. CONCLUSIONS: The largest multi-institutional series to date reported long-term survival outcomes after RARC. PATIENT SUMMARY: Patients who underwent robot-assisted radical cystectomy for bladder cancer have acceptable long-term survival.

Cut-off value of 1-h, 50-g glucose challenge test for screening of gestational diabetes mellitus in an Iranian population.

AIM: This study aimed to investigate the cut-off value of the glucose challenge test in an Iranian population. MATERIALS AND METHODS: A total of 1804 consecutive native Iranian women who underwent a glucose challenge test were prospectively investigated. The test was performed between 24 and 28 weeks of gestation; each subject received a 50-g oral glucose load regardless of her fasting or fed state; the 1-h venous plasma glucose level was then determined. Women exceeding 130 mg/dl received the diagnostic 100-g, 3-h oral glucose tolerance test to determine whether or not they had gestational diabetes mellitus. RESULTS: The prevalence of the glucose challenge test for the whole cohort was 7.2%. The receiver-operator characteristic curve identified a glucose challenge test finding above 135 mg/dl as the cut-off value for detecting gestational diabetes mellitus, which showed a sensitivity and specificity of 95% and 80%, respectively. CONCLUSION: Our results suggest that the cut-off value of a 50-g glucose challenge test is 135 mg/dl to identify pregnancies with gestational diabetes mellitus in an Iranian population.