Page 1. Chapter 4 Biomarker Targets and Novel Therapeutics Mary Clouser, Lisa M. Hess, and Setsuko K. Chambers Introduction Epithelial ovarian cancer is the leading cause of gynecologic cancer death among developed ...
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Adherence is a common and essential measurement in clinical trials. This study evaluates the association between participant self-reported study diary records and the weight of the medication vessel at each study visit, in the setting of... more
Adherence is a common and essential measurement in clinical trials. This study evaluates the association between participant self-reported study diary records and the weight of the medication vessel at each study visit, in the setting of a phase IIb topical chemoprevention trial. One hundred and twenty-four eligible participants were randomized to one of four arms [34 to difluoromethylornithine (DFMO) plus triamcinolone, 31 to DFMO plus placebo, 31 to placebo plus triamcinolone, and 28 to double placebo] for 6 months of treatment for actinic keratosis. Adherence was assessed at each clinic visit by weighing each tube of dispensed and returned medication and the participant's study diary. Self-reported adherence was consistently higher than adherence measured by returned medication weight (96.5% versus 71.3%, 94.6% versus 82.4%, 95.3% versus 69.5%, and 95.8% versus 66.8% for DFMO, DFMO placebo, triamcinolone, and triamcinolone placebo, respectively; P < 0.001). Most participan...
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Factors that affect the concentration of secondary bile acids in the aqueous phase of stool may have a greater impact on colon carcinogenesis than those that only modify the total fecal bile acid concentration. This hypothesis was tested... more
Factors that affect the concentration of secondary bile acids in the aqueous phase of stool may have a greater impact on colon carcinogenesis than those that only modify the total fecal bile acid concentration. This hypothesis was tested using stool samples of a subset of participants enrolled in a Phase III colorectal adenomatous polyp prevention trial, which documented the inability of a 13.5 g/day wheat bran fiber (WBF) supplement to reduce polyp recurrence. Stool was collected from 68 consecutively consented participants who were enrolled in a Phase III clinical trial of WBF for the prevention of adenomatous polyp recurrence. Nineteen (27.9%) of these fecal bile acid substudy participants were on the low fiber (2.0 g/day) intervention group, whereas 49 (72.7%) were on the high fiber (13.5 g/day) intervention group for approximately 3 years. Sixty-four participants had both the aqueous and solid phases of stool samples analyzed for bile acid content. Bile acid concentrations, mea...
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The study summarizes results of karyometric measurements in epithelial cells of the colorectal mucosa to document evidence of a field effect of preneoplastic development among patients with colorectal adenocarcinoma or adenoma.... more
The study summarizes results of karyometric measurements in epithelial cells of the colorectal mucosa to document evidence of a field effect of preneoplastic development among patients with colorectal adenocarcinoma or adenoma. Karyometric analyses were done on high-resolution images of histologic sections from 48 patients with colorectal adenocarcinomas and 44 patients with adenomas and on images from matching normal-appearing mucosa directly adjacent to such lesions, at a 1-cm and 10-cm distance from the lesions or from the rectal mucosa of adenoma patients, as well as from 24 healthy normal controls with no family history of colonic disease. The nuclei recorded in the histologically normal-appearing mucosa of patients with either colorectal adenoma or adenocarcinoma exhibited differences in karyometric features in comparison with nuclei recorded in rectal mucosa from patients who were free of a colonic lesion. These differences were expressed to the same extent in tissue adjacent...
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The Wheat Bran Fiber (WBF) trial was a double-blind Phase III clinical trial in which participants were randomized to a cereal fiber supplement of either 13.5 or 2.0 g/day. No protective effect for adenoma recurrence was observed for... more
The Wheat Bran Fiber (WBF) trial was a double-blind Phase III clinical trial in which participants were randomized to a cereal fiber supplement of either 13.5 or 2.0 g/day. No protective effect for adenoma recurrence was observed for those randomized to the high-fiber group as compared with those in the low-fiber group. However, the high-fiber group had significantly lower adherence to the supplement as assessed by cereal box counts. The aim of this study was to determine whether reported supplemental and total fiber intake affected colorectal adenoma recurrence in the WBF trial population, regardless of treatment group assignment. A total of 1208 participants who completed the WBF trial had a colonoscopy before the date of the last cereal box count and/or at least one colonoscopy within 90 days after it and, thus, were eligible for the current analyses. Statistical analyses were done using multivariate logistic regression models that included potentially confounding variables. Comp...
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Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal... more
Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCI Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on intraperitoneal therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop.
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Platinum/Paclitaxel-based chemotherapy is a current treatment for advanced epithelial ovarian cancer. We sought to explore the association between weight change during treatment and survival, as well as the association between... more
Platinum/Paclitaxel-based chemotherapy is a current treatment for advanced epithelial ovarian cancer. We sought to explore the association between weight change during treatment and survival, as well as the association between pre-chemotherapy body mass index (BMI) and survival. A retrospective data review was conducted of 792 advanced ovarian cancer patients who participated in a phase III randomized trial of cisplatin/paclitaxel versus carboplatin/paclitaxel. Pre-chemotherapy BMI was calculated following surgery. Weight change was defined as the ratio of body weight at completion of protocol therapy to pre-chemotherapy body weight. Progression-free survival (PFS) and overall survival (OS), classified by BMI or relative weight change, were estimated by Kaplan-Meier, and associations were assessed using a Cox model controlled for known prognostic variables (age, race, performance status, histology, tumor grade, tumor residual and treatment group). There was no association between pr...
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This study was designed to establish estimates of the smallest effects due to chemopreventive intervention detectable by karyometry in skin biopsies. Estimates of the smallest change of statistical significance and estimates of the power... more
This study was designed to establish estimates of the smallest effects due to chemopreventive intervention detectable by karyometry in skin biopsies. Estimates of the smallest change of statistical significance and estimates of the power of the test were derived for several key features descriptive of the distribution of nuclear chromatin. Results from triplicate biopsies from the same case were used to provide estimates of the within-case, biopsy-to-biopsy variance. Generally, a change in feature value due to chemopreventive intervention can be statistically secured when it amounts to 5% to 10%. In clinical trials where matched baseline and end of study biopsies from the same cases are available, paired comparison ANOVA can detect a 2% change on samples of 25 cases. Establishing efficacy in individual cases requires a change in feature values on the order of 10% to 15%. Karyometry provides a sensitive, quantitative method for the assessment of efficacy of chemoprevention. The effec...
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A variety of measures have been developed to calculate refill adherence from administrative data such as pharmacy claims databases. These measures have focused on improving the accuracy of adherence measures or clarifying the evaluation... more
A variety of measures have been developed to calculate refill adherence from administrative data such as pharmacy claims databases. These measures have focused on improving the accuracy of adherence measures or clarifying the evaluation time frame. As a result, there are many measures used to assess adherence that may or may not be comparable or accurate. To compare available refill adherence measures. A systematic literature review was conducted to identify current or recently used measures of calculating adherence from administrative data. A MEDLINE search (January 1990-March 2006) was undertaken using the search terms adherence or compliance in the title combined with administrative, pharmacy, or records in any field, including subheadings medical, nursing, and hospital records. Non-English articles were excluded. Seven hundred fifteen articles were available for review. Review articles and letters were excluded from measure selection, but were included in the search terms and us...
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BackgroundThere is a high unmet need for effective treatments for patients with squamous non-small cell lung cancer (NSCLC). Eli Lilly and Company is conducting a phase III, randomized, multicenter, open-label study of gemcitabine plus... more
BackgroundThere is a high unmet need for effective treatments for patients with squamous non-small cell lung cancer (NSCLC). Eli Lilly and Company is conducting a phase III, randomized, multicenter, open-label study of gemcitabine plus cisplatin plus necitumumab (GC + N) versus gemcitabine plus cisplatin (GC) for the first-line treatment of patients with stage IV squamous NSCLC. Given GC is not the only treatment commonly used for the treatment of squamous NSCLC, this study was designed to compare the survival, toxicity, and quality of life outcomes of current treatment strategies for squamous NSCLC in the first-line setting.Methods/DesignA systematic review and meta-analysis (including indirect comparisons) of treatments used in squamous NSCLC will be conducted to assess the clinical efficacy (overall and progression-free survival), health-related quality of life (HRQoL), and safety (grade 3–4 toxicity) of GC + N compared to other treatments used in squamous NSCLC. PRISMA (Preferre...
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BACKGROUND: Cost-effectiveness/cost-utility analyses are increasingly needed to inform decisions about care. Algorithms have been developed using the Functional Assessment of Cancer Therapy (FACT) quality of life instrument to estimate... more
BACKGROUND: Cost-effectiveness/cost-utility analyses are increasingly needed to inform decisions about care. Algorithms have been developed using the Functional Assessment of Cancer Therapy (FACT) quality of life instrument to estimate utility weights for cost analyses. This study was designed to compare these algorithms in the setting of ovarian cancer. METHODS: GOG-0152 was a 550-patient randomized phase III trial of interval cytoreduction, and GOG-0172 was a 415-patient randomized phase III trial comparing intravenous versus intraperitoneal therapy among women with advanced ovarian cancer. QOL data were collected via the FACT at four time points in each study. Two published mapping algorithms (Cheung and Dobrez) and a linear transformation method were applied to these data. The agreement between measures was assessed by the concordance correlation coefficient (r(CCC)), and paired t-tests were used to compare means. RESULTS: While agreement between the estimation algorithms was go...
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Ovarian cancer is the leading cause of gynecologic cancer death worldwide (Harries and Gore 2002). It accounts for about 22,430 cancer diagnoses and 15,280 deaths annually in the US (Jemal et al. 2007). However, the incidence rate of... more
Ovarian cancer is the leading cause of gynecologic cancer death worldwide (Harries and Gore 2002). It accounts for about 22,430 cancer diagnoses and 15,280 deaths annually in the US (Jemal et al. 2007). However, the incidence rate of ovarian cancer varies internationally (Fig. 1), with lower incidence in Egypt and Japan and higher rates among women in Iceland, northern Europe and North America. It is likely that these variations are due to a number of inherited and environmental factors which have yet to be understood. The potential contributing factors related to ovarian cancer risk are described in more detail below. While a number of prognostic factors influence ovarian cancer survival (e.g. appropriate surgical care, stage of disease at diagnosis, age at diagnosis), if diagnosed in its early stages, ovarian cancer is curable in a high percentage of patients (Table 17.1) (McGuire et al. 2002). Therefore, advances in the early detection, risk reduction and prevention of gynecologi...
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It is estimated that one-third of women will experience abnormal menstrual bleeding. The majority of these cases are not due to cancer or pregnancy complications and, as a result, women are faced with a variety of treatment alternatives,... more
It is estimated that one-third of women will experience abnormal menstrual bleeding. The majority of these cases are not due to cancer or pregnancy complications and, as a result, women are faced with a variety of treatment alternatives, the selection of which is largely dependent on personal preferences for care rather than clinical outcomes.
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Page 1. Chapter 4 Biomarker Targets and Novel Therapeutics Mary Clouser, Lisa M. Hess, and Setsuko K. Chambers Introduction Epithelial ovarian cancer is the leading cause of gynecologic cancer death among developed ...
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Chemoprevention must target early molecular events involved in malignant transformation. The sequence of events leading from a normally functioning interphase cell to an uncontrolled tumor cell is only partially understood, impeding... more
Chemoprevention must target early molecular events involved in malignant transformation. The sequence of events leading from a normally functioning interphase cell to an uncontrolled tumor cell is only partially understood, impeding systematic design of chemopreventive agents. The respective roles of mutagenic and epigenetic mechanisms have not been definitively established. Also, traditional models do not appear to incorporate cellular response to events leading to carcinogenesis. A perspective on system response offered by complexity science elucidates the roles of feedback and control in maintaining functional stability during carcinogenesis. Carcinogenesis is seen as a process of epigenetic redifferentiation resulting in a cell behaving like an archetypal karyocyte free of growth restraints (phylogenetic reversion). Genes that evolved during the development of multicellular organisms, restraining uncontrolled growth and regulating intercell communication may be systematically si...
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As advances in treatment have prolonged survival for many patients with ovarian cancer, there has been growing interest in assessing the adverse effects of disease and treatment. The aim of this study was to review the literature on... more
As advances in treatment have prolonged survival for many patients with ovarian cancer, there has been growing interest in assessing the adverse effects of disease and treatment. The aim of this study was to review the literature on cognitive function and quality of life (QOL) in this population. A review of published studies including formal assessment of neurocognitive functions and self-reported domains of quality of life, with an emphasis on cognitive function, was performed. The small number of studies including formal evaluations of neurocognitive function suggests that many ovarian cancer patients experience cognitive difficulties associated with their disease and treatment. Several studies described declines in self-reported cognitive function that may impact QOL, but the results were not consistent across studies. Adequately powered longitudinal studies including formal neurocognitive and QOL assessments are needed to advance our understanding of the incidence of cognitive ...
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Change in cognitive function is increasingly being recognized as an adverse outcome related to chemotherapy treatment. These changes need not be severe to impact patient functional ability and quality of life. The primary goal of this... more
Change in cognitive function is increasingly being recognized as an adverse outcome related to chemotherapy treatment. These changes need not be severe to impact patient functional ability and quality of life. The primary goal of this study was to determine if there is evidence of changes in the cognitive function domains of attention, processing speed, and response time among women with newly diagnosed advanced ovarian cancer who receive chemotherapy. Eligible patients were women diagnosed with stage III–IV epithelial ovarian or primary peritoneal cancer who had not yet received chemotherapy but who were prescribed a minimum of six cycles (courses) of chemotherapy treatment. Cognitive function was assessed by a computerized, Web-based assessment (attention, processing speed, and reaction time) and by patient self-report. Cognitive function was assessed at three time points: prior to the first course (baseline), course three, and course six. Medical records were reviewed to abstract...
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Background: For advanced epithelial ovarian cancer, oncologists are faced with multiple treatment options that differ in terms of possible clinical and patient-reported outcomes. Objective: To explore oncologists' preferences for... more
Background: For advanced epithelial ovarian cancer, oncologists are faced with multiple treatment options that differ in terms of possible clinical and patient-reported outcomes. Objective: To explore oncologists' preferences for hypothetical outcome scenarios (i.e. health states) resulting from various treatment options. Methods: Six hypothetical health states reflecting varying levels of toxicity, treatment efficacy and emotional well-being were developed representing advanced ovarian