A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

BACKGROUND: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). RESULTS: A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. CONCLUSIONS: The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

Phase I study of capecitabine combined with radioembolization using yttrium-90 resin microspheres (SIR-Spheres) in patients with advanced cancer.

BACKGROUND: This was a prospective single-centre, phase I study to document the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended phase II dose for future study of capecitabine in combination with radioembolization. METHODS: Patients with advanced unresectable liver-dominant cancer were enrolled in a 3+3 design with escalating doses of capecitabine (375-1000 mg/m(2) b.i.d.) for 14 days every 21 days. Radioembolization with (90)Y-resin microspheres was administered using a sequential lobar approach with two cycles of capecitabine. RESULTS: Twenty-four patients (17 colorectal) were enrolled. The MTD was not reached. Haematologic events were generally mild. Common grade 1/2 non-haematologic toxicities included transient transaminitis/alkaline phosphatase elevation (9 (37.5%) patients), nausea (9 (37.5%)), abdominal pain (7 (29.0%)), fatigue (7 (29.0%)), and hand-foot syndrome or rash/desquamation (7 (29.0%)). One patient experienced a partial gastric antral perforation with a capecitabine dose of 750 mg/m(2). The best response was partial response in four (16.7%) patients, stable disease in 17 (70.8%) and progression in three (12.5%). Median time to progression and overall survival of the metastatic colorectal cancer cohort was 6.4 and 8.1 months, respectively. CONCLUSIONS: This combined modality treatment was generally well tolerated with encouraging clinical activity. Capecitabine 1000 mg/m(2) b.i.d. is recommended for phase II study with sequential lobar radioembolization.

Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer.

BACKGROUND: We previously reported results of a prospective trial evaluating the significance of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). This secondary analysis assessed the relationship of the CTC number with carcinoembryonic antigen (CEA) and overall survival. PATIENTS AND METHODS: Patients with mCRC had CTCs measured at baseline and specific time points after the initiation of new therapy. Patients with a baseline CEA value ≥ 10 ng/ml and CEA measurements within ± 30 days of the CTC collection were included. RESULTS: We included 217 patients with mCRC who had a CEA value of ≥ 10 ng/ml. Increased baseline CEA was associated with shorter survival (15.8 versus 20.7 months, P = 0.012). Among all patients with a baseline CEA value of ≥ 25 ng/ml, patients with low baseline CTCs (<3, n = 99) had longer survival than those with high CTCs (≥ 3, n = 58; 20.8 versus 11.7 months, P = 0.001). CTCs added prognostic information at the 3-5- and 6-12-week time points regardless of CEA. In a multivariate analysis, CTCs at baseline but not CEA independently predicted survival and both CTCs and CEA independently predicted survival at 6-12 weeks. CONCLUSIONS: This study demonstrates that both CEA and CTCs contribute prognostic information for patients with mCRC.

Relationship of increased aurora kinase A gene copy number, prognosis and response to chemotherapy in patients with metastatic colorectal cancer.

BACKGROUND: Increased Aurora kinase A gene copy number (AURKA-CN) has been reported in metastatic colorectal cancer (mCRC), with unknown relationship to clinical outcome. We correlated increased AURKA-CN in mCRC tumours with KRAS mutation status, overall and progression-free survival (OS, PFS). METHODS: Sixty-one mCRC tumours were analysed for AURKA-CN using q-PCR, and KRAS mutation status by direct sequencing. Expression of AURKA protein was analysed by immunohistochemistry. Cox-proportional hazard method, Kaplan-Meier curves and log-rank statistics were used to estimate and compare the hazard ratios and median survival between the groups. RESULTS: In all, 68% of tumour exhibited high AURKA-CN, and 29% had a KRAS mutation, without correlation between the two. Patients with high AURKA-CN tumours had longer median OS (48.6 vs 18.8 months, P=0.01), with stronger trend among KRAS wild-type tumours (median OS not reached vs 18.8 months, P=0.003). Progression-free survival was longer on first-line or second-line chemotherapy among patients with KRAS wild-type and high vs low AURKA-CN (first: 17.6 vs 5.13 months, P=0.04; second: 10.4 vs 5.1 months, P=0.01). AURKA-CN level did not affect outcomes among patients with KRAS mutant tumours. CONCLUSION: Increased AURKA-CN is common in mCRC tumours and is associated with longer OS and longer PFS during chemotherapy, particularly in KRAS wild-type tumours.

Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer.

BACKGROUND: We demonstrated that circulating tumor cell (CTC) number at baseline and follow-up is an independent prognostic factor in metastatic colorectal cancer (mCRC). This analysis was undertaken to explore whether patient and treatment characteristics impact the prognostic value of CTCs. PATIENTS AND METHODS: CTCs were enumerated with immunomagnetic separation from the blood of 430 patients with mCRC at baseline and on therapy. Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of > or = 3 or <3 CTCs/7.5 ml, respectively. Subgroups were analyzed by line of treatment, liver involvement, receipt of oxaliplatin, irinotecan, or bevacizumab, age, and Eastern Cooperative Oncology Group performance status (ECOG PS). RESULTS: Seventy-one percent of deaths have occurred. Median follow-up for living patients is 25.8 months. For all patients, progression-free survival (PFS) and overall survival (OS) for unfavorable compared with favorable baseline CTCs is shorter (4.4 versus 7.8 m, P = 0.004 for PFS; 9.4 versus 20.6 m, P < 0.0001 for OS). In all patient subgroups, unfavorable baseline CTC was associated with inferior OS (P < 0.001). In patients receiving first- or second-line therapy (P = 0.003), irinotecan (P = 0.0001), having liver involvement (P = 0.002), >/=65 years (P = 0.0007), and ECOG PS of zero (P = 0.04), unfavorable baseline CTC was associated with inferior PFS. CONCLUSION: Baseline CTC count is an important prognostic factor within specific subgroups defined by treatment or patient characteristics.

Why older community-dwelling adults do not discuss urinary incontinence with their primary care physicians.

OBJECTIVES: This study explored reasons why older adults with urinary incontinence (UI) do not initiate discussions with or seek treatment for UI from their primary care provider. DESIGN: A randomized, prospective controlled trial involving 41 primary care sites. SETTING: Primary care practice sites. PARTICIPANTS: 49 older adults age 60 and older not previously screened for UI by their primary care doctor. MEASUREMENTS: Demographic data, self-reported bladder-control information using questionnaires, and health status. RESULTS: Adults who did not discuss UI were older, had less-frequent leaking accidents and fewer nighttime voids and were less bothered by UI than those who did. The two main reasons why patients did not seek help were the perceptions that UI was not a big problem (45%) and was a normal part of aging (19%). CONCLUSIONS: Embarrassment or lack of awareness of treatment options were not significant barriers to discussing UI. Adults with a fairly high frequency of UI (average of 1.7 episodes per day) did not view UI as abnormal or a serious medical condition.

Factors influencing use of the prostate-specific antigen screening test in primary care.

OBJECTIVE: To evaluate the use of the prostate-specific antigen (PSA) test and digital rectal examination (DRE) in prostate cancer screening by primary care physicians. STUDY DESIGN: Physician survey and retrospective medical record review. METHODS: We randomly selected and reviewed the medical records of 3 cross-sectional samples of male patients and surveyed their primary care physicians at 1-year intervals. All the physicians practiced in Colorado. The study spanned 3 years, including late 1992, when the American Cancer Society recommended the use of PSA in a prostate cancer screening guideline. RESULTS: We reviewed the medical records of 4772 male patients and surveyed 109 primary care physicians. We found that PSA testing for men aged 50 or older increased significantly from 1992 to 1994, from 24% in 1992 to 35% in 1993 and 40% in 1994 (overall odds ratio, 2.94; P < .05). Over the same time period, the DRE rate remained relatively unchanged (39% in 1992, 41% in 1993, and 36% in 1994). Overall PSA use was positively associated with patient age greater than 59 years, patient non-smoking status, physician "readiness to change cancer screening behavior," private insurance status, and nonsolo practice. Before the release of a prostate cancer screening guideline, participating physicians cited the American Cancer Society as the organization that most influenced their practice with respect to cancer screening. The magnitude of the reported influence of the American Cancer Society was correlated with the subsequent use of PSA in 1994 by primary care physicians after adjustment for change in DRE and baseline PSA rates, although the association did not reach statistical significance in multivariable regression models. CONCLUSIONS: Primary care physicians in Colorado significantly increased their use of the PSA test from 1992 to 1994, during which time the American Cancer Society issued a guideline recommending the use of PSA for prostate cancer screening. The reported influence of the American Cancer Society on cancer screening practices correlated with the subsequent increase in PSA testing.

Community impact of anticoagulation services: rationale and design of the Managing Anticoagulation Services Trial (MAST).

We describe the design of the Managing Anti-coagulation Services Trial (MAST), a practice-improvement trial testing whether anticoagulation services are a preferred method of managing anticoagulation for stroke prevention among patients with atrial fibrillation. Most randomized trials within the health care environment are designed as efficacy studies to determine what works under ideal conditions or ideal clinical practice. In contrast, effectiveness trials seek to generalize the results of efficacy studies by determining what works under more typical practice conditions. Practice-improvement trials are effectiveness trials that examine the management of a clinical problem in the context in which care is usually given. Noteworthy features of the MAST include defining the intervention in functional terms and collaboration with managed care organizations.

The association of depressive symptoms and urinary incontinence among older adults.

OBJECTIVES: To examine the relationship of urinary incontinence (UI) and depressive symptoms (DS) in older adults. DESIGN: A randomized, controlled trial to determine the effects of clinical practice guideline implementation on provider attitudes and behavior, and patients' UI, health status, quality of life, and satisfaction with care. Baseline and endpoint data were collected from patients via computer-assisted telephone interviewing. SETTING: Forty-one nonacademic primary care practices (PCP) in North Carolina. PARTICIPANTS: A total of 668 community-dwelling adults (age > 60) who had visited the one of the selected PCPs. INTERVENTION: PCPs in the intervention group were given instruction in the detection and management of UI, educational materials for providers and patients, office system supports, and academic detailing. MEASUREMENTS: The dependent measure was assessed using an eight-item screener for DS. UI (status, frequency, amount), health (physical, mental), and demographic (age, gender, marital status) and self-report information about bladder control served as predictors. RESULTS: Wilcoxon rank sum tests showed that UI status was associated with moderate to severe DS (43% vs 30%, P = .05). Multivariate analyses showed that UI status, physical and mental health, and gender were significant predictors of DS. Among UI adults (n = 230), physical and mental health, life satisfaction, and the perception that UI interfered with daily life were significant predictors of DS. CONCLUSIONS: This study provides clear evidence that UI is related to DS in older adults.

Pancreatic cancer.

Optimal therapy for pancreatic adenocarcinoma requires surgical removal with tumor-free margins. Superior outcomes have been reported for high-volume centers incorporating a multidisciplinary approach. Postoperative ("adjuvant") chemotherapy and radiation should be considered in patients with successfully resected primary tumors. Combined modality treatment with chemotherapy and radiation should be considered for locally advanced, unresectable tumors. Gemcitabine can provide symptom relief and a modest improvement in survival for patients with metastatic disease. Strict attention to relief of symptoms such as pain, depression, anorexia/cachexia, and jaundice is essential in all patients with pancreatic cancer. All patients with pancreatic cancer should be encouraged to enter clinical trials of new therapies, given that long-term survival for all stages remains poor.

Measurement of continuous ambulatory peritoneal dialysis prescription adherence using a novel approach.

OBJECTIVE: The purpose of the study was to test a novel approach to monitoring the adherence of continuous ambulatory peritoneal dialysis (CAPD) patients to their dialysis prescription. DESIGN: A descriptive observational study was done in which exchange behaviors were monitored over a 2-week period of time. SETTING: Patients were recruited from an outpatient dialysis center. PARTICIPANTS: A convenience sample of patients undergoing CAPD at Piedmont Dialysis Center in Winston-Salem, North Carolina was recruited for the study. Of 31 CAPD patients, 20 (64.5%) agreed to participate. MEASURES: Adherence of CAPD patients to their dialysis prescription was monitored using daily logs and an electronic monitoring device (the Medication Event Monitoring System, or MEMS; APREX, Menlo Park, California, U.S.A.). Patients recorded in their logs their exchange activities during the 2-week observation period. Concurrently, patients were instructed to deposit the pull tab from their dialysate bag into a MEMS bottle immediately after performing each exchange. The MEMS bottle was closed with a cap containing a computer chip that recorded the date and time each time the bottle was opened. RESULTS: One individual's MEMS device malfunctioned and thus the data presented in this report are based upon the remaining 19 patients. A significant discrepancy was found between log data and MEMS data, with MEMS data indicating a greater number and percentage of missed exchanges. MEMS data indicated that some patients concentrated their exchange activities during the day, with shortened dwell times between exchanges. Three indices were developed for this study: a measure of the average time spent in noncompliance, and indices of consistency in the timing of exchanges within and between days. Patients who were defined as consistent had lower scores on the noncompliance index compared to patients defined as inconsistent (p = 0.015). CONCLUSIONS: This study describes a methodology that may be useful in assessing adherence to the peritoneal dialysis regimen. Of particular significance is the ability to assess the timing of exchanges over the course of a day. Clinical implications are limited due to issues of data reliability and validity, the short-term nature of the study, the small sample, and the fact that clinical outcomes were not considered in this methodology study. Additional research is needed to further develop this data-collection approach.

Communication between older adults and their physicians about urinary incontinence.

BACKGROUND: Urinary incontinence (UI) is a common but undertreated condition in older adults. The study objective was to determine older patients' characteristics related to communication patterns with their physicians about UI. METHODS: Telephone surveys of a sample of patients age 60 and older who visited a primary care provider (PCP) for any reason within the past 2 months were conducted. Participating physicians included general internists and family physicians from 41 primary care practices located in the 17 counties of northwest North Carolina whose 435 incontinent and 711 continent patients completed the surveys. The main outcome measures were patients' frequency and amount of urinary leakage, being asked about incontinence, and initiating a discussion of incontinence if not asked by their PCP. RESULTS: Age and gender were significant independent predictors of incontinence. PCPs were significantly more likely to assess incontinent women than incontinent men (21% vs 10%, p = .053). The older cohorts of older adults were significantly more likely to be symptomatic for UI than their younger counterparts. However, the younger cohorts were more likely to be screened for incontinence by their physicians. CONCLUSIONS: Despite the publication of guidelines on improving the screening and management of UI, the problem remains common and underdetected in older adults. Physicians don't ask and patients don't tell. Interventions are needed to remind physicians to screen high risk patients and to encourage patients with UI to communicate with their physicians.

Physician and patient predictors of health maintenance visits.

BACKGROUND: Because of a strong association between health maintenance visits (HMVs) and cancer screening, knowledge of the predictors of an HMV have implications for screening. OBJECTIVE: To examine the association of an HMV with patient, physician, and practice characteristics in the primary care setting. DESIGN: A statewide study of cancer screening was conducted in Colorado to determine concordance with the National Cancer Institute's guidelines for screening for breast, cervical, prostate, and skin cancer. Medical records form patients were randomly chosen from primary care practices. Predictors of an HMV were determined by fitting a logistic model to baseline data, adjusting for the cluster sampling of patients within practices. SETTING: Nonacademic primary care practices in Colorado. PARTICIPANTS: A total of 5746 patients aged 42 to 74 years from 132 primary care practices. MAIN OUTCOME MEASURE: Whether a patient had an HMV in the previous year. RESULTS: Of all patients, 31% had an HMV in the previous year. Patient characteristics associated with having HMVs included nonsmoking status, odds ratio (OR) (95% confidence interval [CI]) of 1.27 (1.11-1.46), age, and sex. Women aged 50 to 69 years were significantly more likely to have an HMV than men aged 50 to 69 years (OR, 1.30; 95% CI, 1.10-1.54). Among adults aged 70 years and older, there were no significant sex differences in receiving HMVs. Physician and practice characteristics associated with providing HMVs included practice size (> or = 3 full-time physicians) (OR, 1.34; 95% CI, 1.01-1.77), physician contemplation of changing approaches to cancer screening (OR, 1.33; 95% CI, 1.04-1.70), and physician female sex (OR, 1.33; 95% CI, 1.04-1.70). Physician age and specialty (general internist or family physician) were not associated with the level of health maintenance delivery. CONCLUSION: Certain subgroups, such as smokers, patients in smaller practices, and physicians not yet considering changing their approach to cancer screening, could be targeted in future intervention studies designed to provide preventive services in primary care settings.

The quality of life of older adults with urinary incontinence: determining generic and condition-specific predictors.

Urinary incontinence (UI) is an unpleasant problem for many adults. This study determined the importance of demographic, health and incontinence variables for the generic and incontinence-specific quality of life (QoL) of older adults (age > or = 60 years). Telephone surveys of adults reporting at least weekly episodes of UI (n = 435) were conducted as part of a randomized, controlled trial. Logistic regression analyses showed that the predictors of generic and incontinence-specific QoL differed. Life satisfaction, a generic outcome, was predicted by education, the number of days in bed due to health problems, the number of days not feeling well and the amount of urine lost. Generic health was related to education, the number of days sick in the previous 30 days and the number of days health issues restricted activities. The incontinence-specific QoL outcomes were predicted by age, mobility difficulties, the amount of urine lost, the frequency of UI, and the number of daytime and night-time voids. The specific QoL measures provide a different profile of those most affected in this sample than that obtained by the generic measures. The most affected are younger persons with severe urine loss. Older persons may have other conditions impinging on QoL and may have adapted behaviourally and psychologically to urine loss.

Relationship between patient reports of urinary incontinence symptoms and quality of life measures.

OBJECTIVE: To determine if patient reports of urinary incontinence symptoms can predict quality of life as measured by the short forms of the Incontinence Impact Questionnaire and the Urogenital Distress Inventory, two standardized, disease-specific instruments. METHODS: Telephone surveys were conducted of 384 community dwelling incontinent women, aged 60 years and older, who admitted to at least one episode of incontinence per week during the previous 3 months. Subjects were asked if they considered the incontinence a problem, as well as questions regarding volume and frequency of voids and urine loss. Each subject completed both standardized quality of life questionnaires. Responses to incontinence symptom questions were correlated with the standardized measures. RESULTS: The question, "Do you consider this accidental loss of urine a problem that interferes with your day-to-day activities or bothers you in other ways?" was the best predictor of the subject's responses to both quality-of-life measures, with a correlation coefficient of 0.69 for the Incontinence Impact Questionnaire and 0.67 for the Urogenital Distress Inventory. The patients' symptoms that best correlated with both quality of life measures and the report of bothersome incontinence were frequent episodes of incontinence (0.40-0.58), greater amounts of urine loss (0.26-0.54), and more frequent voids (0.24-0.41). CONCLUSION: Primary care practitioners may screen for problematic incontinence by asking if patients' incontinence is bothersome to them and by obtaining simple historic information on voiding and leaking patterns. These questions may provide an efficient tool to detect bothersome incontinence in older women.