A Randomized Controlled Trial of an Additional Funding Intervention to Improve Clinical Trial Enrollment.

Background: A low proportion of adults with cancer are recruited to clinical trials. Cancer Council Victoria provides funding to clinical trial sites through its statewide Cancer Trials Management Scheme (CTMS). Historically, there appeared to be a relationship between budget-allocated funding and the number of patients recruited. A randomized controlled trial was conducted to test whether additional funding in 2013 would increase trial recruitment. Methods: A total of 18 trial centers ("sites") received usual CTMS funds, whereas 16 intervention sites received usual funds plus additional funds, proportional to recruitment in 2011; additional payments to sites in the intervention group ranged from $6,750 to $234,000 AUD (≈$6,750-$234,000 USD at the time). This represented an average 11.8% (interquartile range [IQR], 8.0%, 12.3%) increase in sites' budgets. Sites were required to use the funds with the aim of increasing recruitment. The study end point was the number of new participants recruited to trials in 2013. An online survey assessed strategies used to increase recruitment. Results: The median number of new trial recruits per site in 2013 was 21 (IQR, 5-39) in the control arm and 12.5 (IQR, 3.5-44.5) in the intervention arm. The ratio of new trial recruitment numbers at the intervention sites compared with control sites in 2013, adjusting for respective 2012 numbers and institution type, was 0.99 (95% CI, 0.69, 1.43; P=.96). The survey revealed most intervention sites used funding to increase staffing. Conclusions: Additional funding at a site level did not lead to a contemporaneous increase in trial recruitment.

Patterns of Recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from international breast cancer study group trials VIII and IX.

PURPOSE: To retrospectively evaluate the pattern of recurrence and outcome of node-negative breast cancer (BC) according to major subtypes. PATIENTS AND METHODS: In all, 1,951 patients with node-negative, early-stage BC randomly assigned in International Breast Cancer Study Group Trials VIII and IX with centrally reviewed pathology data were included. BC subtypes were defined as triple negative (TN; n = 310), human epidermal growth factor receptor 2 (HER2) positive (n = 369), and hormone receptor positive with high (luminal B-like [LB-like]; n = 763) or low (luminal A-like [LA-like]; n = 509) proliferative activity by Ki-67 labeling index. BC-free interval (BCFI) events were invasive BC recurrence in local, contralateral breast, nodal, bone, or visceral sites. Time to first site-specific recurrence was evaluated by using cumulative incidence and competing risks regression analysis. RESULTS: Median follow-up was 12.5 years. The 10-year BCFI was higher for patients with LA-like (86%) BC compared with LB-like (76%), HER2 (73%), and TN (71%; P < .001) BC. TN and HER2 cohorts had higher hazard of BCFI event in the first 4 years after diagnosis (pre-trastuzumab). LB-like cohorts had a continuously higher hazard of BCFI event over time compared with LA-like cohorts. Ten-year overall survival was higher for LA-like (89%) compared with LB-like (83%), HER2 (77%), and TN (75%; P < .001) BC. LB-like subtypes had higher rates of bone as first recurrence site than other subtypes (P = .005). Visceral recurrence as first site was lower for the LA-like subgroup, with similar incidence among the other subgroups when treated with chemotherapy (P = .003). CONCLUSION: BC subtypes have different distant recurrence patterns over time. Defining different patterns of BC recurrence can improve BC care through surveillance guidelines and can guide the design of clinical studies.

Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study.

Hormone receptor-positive breast cancer is treated with estrogen inhibitors. Fulvestrant (FASLODEX™), an estrogen receptor (ER) antagonist with no known agonist effects, competitively binds, blocks and degrades the ER. Vascular endothelial growth factor (VEGF) may mediate resistance to ER antagonists. Cediranib is a highly potent VEGF signaling inhibitor with activity against all three VEGF receptors. This randomized Phase II study evaluated cediranib plus fulvestrant. Postmenopausal women with hormone-sensitive metastatic breast cancer were eligible. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate (CBR), safety/tolerability and pharmacokinetics (PK). Patients received cediranib 45 mg/day (n=31) or placebo (n=31) both plus fulvestrant. Demographic/baseline characteristics were well balanced. Patients treated with cediranib had a numerical advantage in PFS (hazard ratio=0.867, P=0.669; median 223 vs. 112 days, respectively) and ORR (22 vs. 8 %, respectively) vs. placebo, although not statistically significant. CBR was 42 % in both arms. The most common adverse events (AEs) in the cediranib arm were diarrhea (68 %), fatigue (61 %) and hypertension (55 %). The incidence of grade ≥ 3 AEs (68 % vs. 32 %), serious AEs (48 % vs. 13 %), discontinuation AEs (39 % vs. 10 %), and cediranib dose reductions/interruptions (74 % vs. 32 %) were higher in the cediranib arm. There was no evidence of a clinically relevant effect of cediranib on fulvestrant PK. Cediranib plus fulvestrant may demonstrate clinical activity in this population, but cediranib 45 mg was not sufficiently well tolerated. Investigation of lower doses of cediranib plus hormonal/chemotherapy could be considered.

A retrospective cohort study of metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy, with an exploratory analysis of changing serum carcinoembryonic antigen levels.

AIM: To examine the relationship between changes in serum carcinoembryonic antigen (CEA) levels and survival during oxaliplatin-based chemotherapy for metastatic colorectal cancer (mCRC). METHODS: A retrospective review of 142 patients with mCRC who were treated with oxaliplatin-based chemotherapies (mostly FOLFOX 6 or XELOX) by St Vincent's Hospital, from October 1999 until 30 November 2007. Survival analysis was used to determine median overall survival (OS) from commencement of chemotherapy. A CEA response was defined by ≥50% decline compared with baseline, maintained on two consecutive occasions at least 4 weeks apart. The Cox proportional hazard model and a landmark analysis at 3 months were used to evaluate survival differences between CEA responders (rCEA) and non-responders (non-rCEA). RESULTS: The median OS was 14.7 months. Using an intention-to-treat analysis, 76 (53.5%) patients achieved a CEA response, while 66 (46.5%) did not. Using the landmark analysis at 3 months, rCEA had a longer survival than non-rCEA (median 16.0 vs 7.8 months, P < 0.0001). The hazard ratio for patients dying of mCRC in non-rCEA was 2.2 (P < 0.0001). In multivariate analysis, CEA response and better baseline Eastern Cooperative Oncology Group (ECOG) predicted for survival (P < 0.0001 for both), while age, gender and histology grade did not. CONCLUSION: The median OS of our patients is similar to published randomized trials. A CEA response of ≥50% at 3 months and good ECOG were independent predictors of OS of patients with mCRC treated with oxaliplatin-based chemotherapies.

Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study.

BACKGROUND: Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. METHODS: Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m(2) on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681. FINDINGS: ORRs for the motesanib group and the placebo group did not differ significantly (49%vs 41%; absolute difference 8% [95% CI -6 to 22]; p=0.31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature. INTERPRETATION: Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population. FUNDING: Amgen.

Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials.

PURPOSE: To determine how patients with infiltrating lobular carcinoma (ILC) differ from patients with the more common infiltrating ductal carcinoma (IDC) with regard to patient and tumor factors, local treatment, and patterns of recurrence. PATIENTS AND METHODS: Twelve thousand two hundred six breast cancer patients entered onto 15 International Breast Cancer Study Group trials between 1978 and 2002 were categorized as having ILC, IDC, or other/mixed types. RESULTS: Seven hundred sixty-seven tumors (6.2%) were classified as ILC, 8,607 (70.5%) were classified as IDC, and 2,832 (23.2%) were classified as other. The analysis is limited to the 9,374 patients categorized as either pure IDC or ILC. The median follow-up time was 13 years. Compared with IDC, ILC was associated with older age; larger, better differentiated, and estrogen receptor (ER)-positive tumors; and less vessel invasion. Mastectomy was used more frequently for ILC (P < .01). There was a significant (P < .01) early advantage in disease-free survival and overall survival for the ILC cohort followed by a significant (P < .01) late advantage for the IDC cohort after 6 and 10 years, respectively. Similar patterns were observed in cohorts defined by ER status. ILC was associated with an increased incidence of bone events but a decrease in regional and lung events (all P < .01). CONCLUSION: ILC is more than a histologic variant of breast cancer. The diagnosis of ILC carries distinct prognostic and biologic implications.

Anemia during adjuvant non-taxane chemotherapy for early breast cancer: Incidence and risk factors from two trials of the International Breast Cancer Study Group.

UNLABELLED: GOAL OF THE WORK: Anemia is a common side effect of chemotherapy. Limited information exists about its incidence and risk factors. The objective of this study was to evaluate the incidence of anemia and risk factors for anemia occurrence in patients with early breast cancer who received adjuvant chemotherapy. MATERIALS AND METHODS: We evaluated risk factors for anemia in pre- and post/perimenopausal patients with lymph node-positive early breast cancer treated with adjuvant chemotherapy in two randomized trials. All patients received four cycles of doxorubicin and cyclophosphamide (AC) followed by three cycles of cyclophosphamide, methotrexate, fluorouracil (CMF). Anemia incidence was related to baseline risk factors. Multivariable analysis used logistic and Cox regression. MAIN RESULTS: Among the 2,215 available patients, anemia was recorded in 11% during adjuvant chemotherapy. Grade 2 and 3 anemia occurred in 4 and 1% of patients, respectively. Pretreatment hemoglobin and white blood cells (WBC) were significant predictors of anemia. Adjusted odds ratios (logistic regression) comparing highest versus lowest quartiles were 0.18 (P < 0.0001) for hemoglobin and 0.52 (P = 0.0045) for WBC. Age, surgery type, platelets, body mass index, and length of time from surgery to chemotherapy were not significant predictors. Cox regression results looking at time to anemia were similar. CONCLUSIONS: Moderate or severe anemia is rare among patients treated with AC followed by CMF. Low baseline hemoglobin and WBC are associated with a higher risk of anemia.

Supportive-expressive group therapy for women with metastatic breast cancer: survival and psychosocial outcome from a randomized controlled trial.

BACKGROUND: Mixed reports exist about the impact of supportive-expressive group therapy (SEGT) on survival. METHODS: From 485 women with advanced breast cancer recruited between 1996-2002, 227 (47%) consented and were randomized within an average 10 months of cancer recurrence in a 2:1 ratio to intervention with 1 year or more of weekly SEGT plus three classes of relaxation therapy (147 women) or to control receiving three classes of relaxation therapy (80 women). The primary outcome was survival; psychosocial well-being was appraised secondarily. Analysis was by intention-to-treat. RESULTS: SEGT did not prolong survival (median survival 24.0 months in SEGT and 18.3 in controls; univariate hazard ratio for death 0.92 [95% CI, 0.69-1.26]; multivariate hazard ratio, 1.06 [95% CI, 0.74-1.51]). Significant predictors of survival were treatment with chemotherapy and hormone therapy (p<0.001), visceral metastases (p<0.001) and advanced disease at first diagnosis (p<0.05). SEGT ameliorated and prevented new DSM-IV depressive disorders (p = 0.002), reduced hopeless-helplessness (p = 0.004), trauma symptoms (p = 0.04) and improved social functioning (p = 0.03). CONCLUSIONS: SEGT did not prolong survival. It improved quality of life, including treatment of and protection against depression.

Psychological morbidity and quality of life in women with advanced breast cancer: a cross-sectional survey.

OBJECTIVE: Our purpose was to determine the frequency of psychiatric morbidity and to assess the quality of life of women with advanced breast cancer. METHODS: The 227 women in the sample were recruited in Melbourne, Australia, and were interviewed (prior to intervention) for a randomized controlled trial of supportive-expressive group therapy. The main outcome measures were DSM-IV psychiatric diagnoses plus quality of life data based on the EORTC QLQ-C30 (core) and QLQ-BR23 (breast module) instruments. RESULTS: Forty-two percent of the women (97/227) had a psychiatric disorder; 35.7% (81) of these had depression or anxiety or both. Specific diagnoses were minor depression in 58 women (25.6%), major depression in 16 (7%), anxiety disorder in 14 (6.2%), and phobic disorder in 9 (4%). Seventeen (7.5%) women had more than one disorder. In terms of quality of life, one-third felt less attractive, one-quarter were dissatisfied with their body image, and, in most, sexual interest had waned. Menopausal symptoms such as hot flashes affected less than one-third, whereas symptoms of lymphedema were experienced by 26 (11.5%). SIGNIFICANCE: Women with advanced breast cancer have high rates of psychiatric and psychological disturbance. Quality of life is substantially affected. Clinicians need to be vigilant in monitoring psychological adjustment as part of a comprehensive biopsychosocial approach.

Reducing the global breast cancer burden: the importance of patterns of care research.

Breast cancer treatment guidelines are not uniformly followed in clinical practice, with evidence for substantial variations in treatment patterns, quality of care, and patient outcomes among and within countries. The factors that drive treatment decisions are unclear. Furthermore, the impact of different treatment strategies on survival is poorly understood outside the clinical trial setting. Sources of patterns of care information often have limitations in completeness, quality, timeliness of reporting, and relevance to the larger population. Patterns of care studies frequently lack details on cancer stage at diagnosis, tumor biology, and treatment received. It is difficult to compare data between studies and/or track changes over time because of variations in data sources and collection techniques. Thus, the design and implementation of a global registry is sorely needed in order to prospectively evaluate worldwide patterns of care and outcomes in patients with breast cancer. Components of this registry should include random selection of centers of variable practice settings in multiple countries and accurate and rapid data reporting at prestudy and follow-up timepoints. Data collected would include tumor and demographic factors, staging information, treatment rendered, and survival. Variables that influenced the treatment selected would be assessed. This unique international effort would allow the development of strategies to improve diagnostic and treatment-related standards of care and survival outcomes, thus reducing the breast cancer burden worldwide.

Attitudes of oncology health professionals to information from the Internet and other media.

OBJECTIVE: To investigate attitudes of Australian health professionals working in oncology to health-related information in the media and on the Internet and to patients who search for this information. DESIGN: Questionnaire-based survey. SETTING AND PARTICIPANTS: Questionnaires were mailed in January 2003 to all 333 health professionals belonging to the Victorian Cooperative Oncology Group. MAIN OUTCOME MEASURES: 27 items about attitudes to information in the media and the Internet, patient information-seeking and its effects on the doctor-patient relationship. RESULTS: 226 surveys (68%) were returned and assessable. Most respondents took notice of medical information reported on television/radio, in newspapers (80% each) and on the Internet (56%), mainly to be informed when patients ask questions (82%) and to check its accuracy (60%). Most were concerned about this accuracy (64% believed it accurate only sometimes, and 23% rarely), and 91% believed information from the Internet had the potential to cause harm to patients. Nevertheless, they generally supported patients' information-searching, believing it allowed them to be better informed (58%), and did not affect their ability to cope with their illness (49%), or their trust in, and relationship with, their doctor (69% and 67%, respectively). CONCLUSIONS: Oncology health professionals are aware of patients' use of the Internet and other media to obtain medical information. To ensure oncology patients find reliable and relevant information and to minimise the risk of harm, the health professionals treating them should provide guidance in finding information sources, and assistance in interpreting the information obtained.

Arsenic transport and transformation associated with MSMA application on a golf course green.

The impact of extensively used arsenic-containing herbicides on groundwater beneath golf courses has become a topic of interest. Although currently used organoarsenicals are less toxic, their application into the environment may produce the more toxic inorganic arsenicals. The objective of this work was to understand the behavior of arsenic species in percolate water from monosodium methanearsonate (MSMA) applied golf course greens, as well as to determine the influences of root-zone media for United State Golf Association (USGA) putting green construction on arsenic retention and species conversion. The field test was established at the Fort Lauderdale Research and Education Center (FLREC), University of Florida. Percolate water was collected after MSMA application for speciation and total arsenic analyses. The results showed that the substrate composition significantly influenced arsenic mobility and arsenic species transformation in the percolate water. In comparison to uncoated sands (S) and uncoated sands and peat (S + P), naturally coated sands and peat (NS + P) showed a higher capacity of preventing arsenic from leaching into percolate water, implying that the coatings of sands with clay reduce arsenic leaching. Arsenic species transformation occurred in soil, resulting in co-occurrence of four arsenic species, arsenite (As(III)), arsenate (As(V)), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) in percolate water. The results indicated that substrate composition can significantly affect both arsenic retention in soil and arsenic speciation in percolate water. The clay coatings on the soil particles and the addition of peat in the soil changed the arsenic bioavailability, which in turn controlled the microorganism-mediated arsenic transformation. To better explain and understand arsenic transformation and transport after applying MSMA in golf green, a conceptual model was proposed.

Site of primary tumor has a prognostic role in operable breast cancer: the international breast cancer study group experience.

PURPOSE: Cancer presenting at the medial site of the breast may have a worse prognosis compared with tumors located in external quadrants. For medial tumors, axillary lymph node staging may not accurately reflect the metastatic potential of the disease. PATIENTS AND METHODS: Eight-thousand four-hundred twenty-two patients randomly assigned to International Breast Cancer Study Group clinical trials between 1978 and 1999 were classified as medial site (1,622; 19%) or lateral, central, and other sites (6,800; 81%). Median follow-up was 11 years. RESULTS: A statistically significant difference was observed for patients with medial tumors versus those with nonmedial tumors in disease-free survival (DFS; 10-year DFS, 46% v 48%; HR, 1.10; 95% CI, 1.02 to 1.18; P = .01) and overall survival (10-year OS 59% v 61%; HR, 1.09; 1.01 to 1.19; P = .04). This difference increased after adjustment for other prognostic factors (HR, 1.22; 95% CI, 1.13 to 1.32 for DFS; and HR, 1.24; 95% CI, 1.14 to 1.35 for OS; both P = .0001). The risk of relapse for patients with medial presentation was largest for the node-negative cohort and for patients with tumors larger than 2 cm. In the subgroup of 2,931 patients with negative axillary lymph nodes, 10-year DFS was 61% v 67%, and OS was 73% v 80% for medial versus nonmedial sites, respectively (HR 1.33; 95% CI, 1.15 to 1.54; P = .0001 for DFS; and HR 1.40; 95% CI, 1.17 to 1.67; P = .0003 for OS). CONCLUSION: Tumor site has a significant prognostic utility, especially for axillary lymph node-negative disease, that should be considered in therapeutic algorithms. New staging procedures such as biopsy of the sentinel internal mammary nodes or novel imaging methods should be further studied in patients with medial tumors.

High-transfer-rate high-capacity holographic disk data-storage system.

We describe the design and implementation of a high-data-rate high-capacity digital holographic storage disk system. Various system design trade-offs that affect density and data-rate performance are described and analyzed. In the demonstration system that we describe, high-density holographic recording is achieved by use of high-resolution short-focal-length optics and correlation shift multiplexing in photopolymer disk media. Holographic channel decoding at a 1-Gbit/s data rate is performed by custom-built electronic hardware. A benchmark sustained optical data-transfer rate of 10 Gbits/s has been successfully demonstrated.

Effect of cognitive-existential group therapy on survival in early-stage breast cancer.

PURPOSE: Cognitive-existential group therapy (CEGT) was developed to improve mood and mental attitude toward cancer in women with early-stage breast cancer receiving adjuvant chemotherapy. Given the debate about group therapy's association with increased survival in women with metastatic breast cancer, we were curious to check its effect at a much earlier stage in the cancer journey. PATIENTS AND METHODS: We randomly assigned 303 women with early-stage breast cancer who were receiving adjuvant chemotherapy to either 20 sessions of weekly group therapy plus three relaxation classes (n = 154) or to a control condition of three relaxation classes alone (n = 149). The primary outcome was survival. RESULTS: CEGT did not extend survival; the median survival time was 81.9 months (95% CI, 64.8 to 99.0 months) in the group-therapy women and 85.5 months (95% CI, 67.5 to 103.6 months) in the control arm. The hazard ratio for death was 1.35 (95% CI, 0.76 to 2.39; P = .31). In contrast, histology and axillary lymph node status were significant predictors of survival. Low-grade histology yielded a hazard ratio of 0.342 (95% CI, 0.17 to 0.69), and axillary lymph node-negative status yielded a hazard ratio of 0.397 (95% CI, 0.20 to 0.78). CONCLUSION: CEGT does not prolong survival in women with early-stage breast cancer.