A Noninvasive Blood-based Combinatorial Proteomic Biomarker Assay to Detect Breast Cancer in Women over age 50 with BI-RADS 3, 4, or 5 Assessment.

PURPOSE: With improvements in breast cancer imaging, there has been a corresponding increase in false-positives and avoidable biopsies. There is a need to better differentiate when a breast biopsy is warranted and determine appropriate follow-up. This study describes the design and clinical performance of a combinatorial proteomic biomarker assay (CPBA), Videssa Breast, in women over age 50 years. EXPERIMENTAL DESIGN: A BI-RADS 3, 4, or 5 assessment was required for clinical trial enrollment. Serum was collected prior to breast biopsy and subjects were followed for 6-12 months and clinically relevant outcomes were recorded. Samples were split into training (70%) and validation (30%) cohorts with an approximate 1:4 case:control ratio in both arms. RESULTS: A CPBA that combines biomarker data with patient clinical data was developed using a training cohort (469 women, cancer incidence: 18.5%), resulting in 94% sensitivity and 97% negative predictive value (NPV). Independent validation of the final algorithm in 194 subjects (breast cancer incidence: 19.6%) demonstrated a sensitivity of 95% and a NPV of 97%. When combined with previously published data for women under age 50, Videssa Breast achieves a comprehensive 93% sensitivity and 98% NPV in a population of women ages 25-75. Had Videssa Breast results been incorporated into the clinical workflow, approximately 45% of biopsies might have been avoided. CONCLUSIONS: Videssa Breast combines serum biomarkers with clinical patient characteristics to provide clinicians with additional information for patients with indeterminate breast imaging results, potentially reducing false-positive breast biopsies.

A Combinatorial Proteomic Biomarker Assay to Detect Ovarian Cancer in Women.

Ovarian cancer is often fatal and incidence in the general population is low, underscoring the necessity (and the challenges) for advancements in screening and early detection. The goal of this study was to design a serum-based biomarker panel and corresponding multivariate algorithm that can be used to accurately detect ovarian cancer. A combinatorial protein biomarker assay (CPBA) that uses CA125, HE4, and 3 tumor-associated autoantibodies resulted in an area under the curve of 0.98. The CPBA Ov algorithm was trained using subjects who were suspected to have gynecological cancer and were scheduled for surgery. As a surgical rule-out test, the clinical performance achieves 100% sensitivity and 83.7% specificity. Although sample size (n = 60) is a limiting factor, the CPBA Ov algorithm performed better than either CA-125 alone or the Risk of Ovarian Malignancy Algorithm.

Breast density does not impact the ability of Videssa® Breast to detect breast cancer in women under age 50.

Breast density is associated with reduced imaging resolution in the detection of breast cancer. A biochemical approach that is not affected by density would provide an important tool to healthcare professionals who are managing women with dense breasts and suspicious imaging findings. Videssa® Breast is a combinatorial proteomic biomarker assay (CPBA), comprised of Serum Protein Biomarkers (SPB) and Tumor Associated Autoantibodies (TAAb) integrated with patient-specific clinical data to produce a diagnostic score that reliably detects breast cancer (BC) as an adjunctive tool to imaging. The performance of Videssa® Breast was evaluated in the dense (a and b) and non-dense (c and d) groups in a population of n = 545 women under age 50. The sensitivity and specificity in the dense breast group were calculated to be 88.9% and 81.2%, respectively, and 92.3% and 86.6%, respectively, for the non-dense group. No significant differences were observed in the sensitivity (p = 1.0) or specificity (p = 0.18) between these groups. The NPV was 99.3% and 99.1% in non-dense and dense groups, respectively. Unlike imaging, Videssa® Breast does not appear to be impacted by breast density; it can effectively detect breast cancer in women with dense and non-dense breasts alike. Thus, Videssa® Breast provides a powerful tool for healthcare providers when women with dense breasts present with challenging imaging findings. In addition, Videssa® Breast provides assurance to women with dense breasts that they do not have breast cancer, reducing further anxiety in this higher risk patient population.

The clinical utility of an elevated-risk multivariate index assay score in ovarian cancer patients.

OBJECTIVE: Early involvement of specialists is associated with improved survival in ovarian cancer patients. However, only 33-60% of patients are currently being referred. A more effective strategy to get patients with an elevated risk of ovarian cancer to gynecologic oncologists is needed. The objective of this study was to evaluate the clinical utility of a multivariate index assay, OVA1 * , by assessing its ability to drive referral of ovarian cancer patients to gynecologic oncologists prior to their first surgical intervention. RESEARCH DESIGN AND METHODS: Information on patients who received a multivariate index assay was collected retrospectively from 22 obstetricians/gynecologists through a chart review. Physicians were recruited from a variety of practices and hospitals representing major geographic regions within the United States. Clinical utility of the multivariate index assay was assessed by examining the rate at which obstetricians/gynecologists involved a gynecologic oncologist for patients with elevated-risk results prior to first surgical intervention. RESULTS: A total of 136 patients with elevated-risk assay results were assessed, of whom 122 underwent surgery to remove an adnexal mass. Prior to surgery, 98 (80%) of the patients were referred to a gynecologic oncologist with an additional 11 (9%) having a gynecologic oncologist available if required by intra-operative findings. Primary ovarian cancer was found in 65 (53%) patients, and gynecologic oncologists performed 61 (94%) of the initial surgeries these patients. Similar results were found in premenopausal and postmenopausal patients. CONCLUSIONS: A high proportion of patients with elevated-risk assay results were referred to a gynecologic oncologist prior to their initial surgery. Nearly all of the patients who had primary ovarian malignancies were appropriately referred to gynecologic oncologists, highlighting the clinical utility of the multivariate index assay. Nearly all patients identified with ovarian cancer received their initial surgery by a gynecologic oncologist - demonstrating a higher rate of gynecologic oncologist involvement in comparison to past studies. The study may be limited by unintentional bias in physician response and recall.

Ovarian serous carcinoma associated with a distinct "corded and hyalinized" pattern.

The "corded and hyalinized" pattern, described in endometrioid carcinoma, has not been previously reported in association with serous carcinoma. We describe a unique case of serous neoplasm of low malignant potential with low-grade serous carcinoma combined with a distinct pattern of high-grade carcinoma characterized by cords of epithelioid and spindled cells enmeshed in a hyalinized, collagenous stroma. This pattern was the predominant architecture in the patient's recurrence and caused a diagnostic challenge, as the splenic recurrence was initially diagnosed as a second primary high-grade spindle cell neoplasm. Both ovarian and splenic tumors displayed positive immunohistochemical staining for cytokeratin 7, cytokeratin 8/18, estrogen receptor, and paired box gene 8 (PAX-8) in the conventional serous carcinoma and the corded and hyalinized component, confirming the diagnosis of recurrent carcinoma. The behavior in this unique case of serous carcinoma associated with a distinct corded and hyalinized pattern was more aggressive than low-grade serous carcinoma, but more favorable than malignant mixed mullerian tumor.

Evaluation of pegylated liposomal doxorubicin dose on the adverse drug event profile and outcomes in treatment of recurrent endometrial cancer.

OBJECTIVE: This study aims to determine factors that may increase the likelihood of adverse drug events (ADEs) in patients with recurrent endometrial cancer treated with pegylated liposomal doxorubicin (PLD) as well as this agent's impact on clinical outcomes. METHODS: The treatment records of patients with endometrial cancer who received PLD at The University of Texas, MD Anderson Cancer Center, from 1996 to 2006 were reviewed. Patient demographics, PLD dose, ADEs, use of supportive care interventions, disease progression, and survival were extracted. Logistical regression analysis was used to identify factors that were associated with higher incidence of ADEs and that influenced survival. RESULTS: A total of 60 patients with recurrent endometrial cancer were identified who experienced 122 ADEs. The most commonly reported ADEs were nausea (18.9%), palmar-plantar erythrodysesthesia (PPE; 16.4%), muscle weakness (12.3%), mucositis (10.7%), and peripheral neuropathy (9.8%). Seventeen patients (28%) required a dose reduction because of ADEs. However, only 5 (8.3%) patients discontinued therapy because of toxicity. Cooling mechanisms were used in 19 patients to prevent PPE, although 9 of these patients still experienced PPE. Treatment with 6 or more cycles of PLD was associated with increased incidence of neutropenia (P = 0.045), peripheral neuropathy (P = 0.004), and PPE (P < 0.001). No differences in progression-free survival or time to progression were found between the doses of PLD; however, there was an assessable trend toward increased survival with doses of 40 mg/m(2). CONCLUSIONS: Although there was no association with dose level and ADEs, more cycles received increased the incidence of toxicities, including PPE and neuropathy. There was no association between different doses of PLD and progression-free survival or time to progression.

Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer.

OBJECTIVES: On the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer. METHODS: Patients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n=10; taxane refractory, n=11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and (18)F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies. RESULTS: Patients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9 months and 4.5 months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5 months, and another patient with a PIK3CA mutation had stable disease (SD) for 4 months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with KRAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with (18)F-FDG-PET responses. CONCLUSIONS: Patients tolerated perifosine 150 mg PO daily plus docetaxel at 75 mg/m(2) every 4 weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted.

A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients.

PURPOSE: Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine. EXPERIMENTAL DESIGN: Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer overexpressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received SC wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells IV. Interleukin-2 (IL-2) was administered to both cohorts in alternative cycles. RESULTS: Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B developed an immunologic response as determined by ELISPOT and tetramer assays. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced the expansion of T regulatory cells. The median overall survival was 40.8 and 29.6 months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7 months, respectively. CONCLUSION: We found that using either vaccination approach generates comparable specific immune responses against the p53 peptide with minimal toxicity. Accordingly, our findings suggest that the use of less demanding SC approach may be as effective. Furthermore, the use of low-dose SC IL-2 as an adjuvant might have interfered with the immune response. Therefore, it may not be needed in future trials.

The anterior gradient homolog 3 (AGR3) gene is associated with differentiation and survival in ovarian cancer.

Low-grade (LG) serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors; yet the progression from serous borderline tumors to LG serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the 2 groups. Expression profiles were generated from 6 human ovarian surface epithelia, 8 serous borderline ovarian tumors (SBOTs), 13 LG serous ovarian carcinomas, and 24 high-grade (HG) serous ovarian carcinomas. The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors. This finding was validated by real-time quantitative reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues, and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P<0.005) among SBOT, LG, and HG tumors. SBOTs exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P=0.013) and HG (P=0.008) serous ovarian carcinoma groups. The progression of SBOT to LG serous ovarian carcinoma may involve the dedifferentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with LG and HG serous ovarian carcinomas.

Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.

BACKGROUND: Sequential treatment with azacitidine can induce re-expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. A phase 1b-2a clinical trial of this sequential combination of azacitidine and carboplatin was initiated in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. METHODS: Patients with pathologically confirmed intermediate-grade or high-grade epithelial ovarian cancer who developed disease progression within 6 months (resistant disease, n = 18 patients) or during a platinum-based therapy (refractory disease, n = 12 patients) were eligible. All patients had measurable disease. RESULTS: Thirty patients received a total of 163 cycles of treatment. This regimen produced 1 complete response, 3 partial responses (overall response rate [ORR], 13.8%), and 10 cases of stable disease among 29 evaluable patients. For those patients who achieved clinical benefits, the median duration of the treatment was 7.5 months. The median progression-free survival (PFS) and overall survival (OS) for all patients were 3.7 months and 14 months, respectively. Patients with platinum-resistant disease achieved an ORR of 22%, with a median PFS of 5.6 months and a median OS of 23 months. The predominant toxicities were fatigue and myelosuppression. Correlative studies indicated that DR4 methylation in peripheral blood leukocytes was decreased during treatment in 3 of 4 objective responders (75%), but in only 5 of 13 nonresponders (38%). CONCLUSIONS: To the authors' knowledge, the results of the current study provide the first clinical evidence that a hypomethylating agent may partially reverse platinum resistance in patients with ovarian cancer. Further clinical evaluation of hypomethylating agents in combination with carboplatin is warranted.

BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas.

Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed.

Combination of gemcitabine and cisplatin is highly active in women with endometrial carcinoma: results of a prospective phase 2 trial.

BACKGROUND: The treatment of patients with advanced or recurrent endometrial cancer remains problematic, because chemotherapy and hormonal therapy have yielded low response rates and limited progression-free survival. Because the combination of gemcitabine and cisplatin demonstrated synergism in preclinical studies, the authors attempted to determine the efficacy and toxicity of this combination in women with advanced or recurrent endometrial cancer. METHODS: A prospective, single-institution, phase 2 study was performed in women with histologically documented International Federation of Gynecology and Obstetrics (FIGO) stage III or IV or recurrent endometrioid endometrial carcinoma. Gemcitabine at a dose of 1000 mg/m2 and cisplatin at a dose of 35 mg/m2 were administered intravenously on Days 1 and 8 of each 21-day cycle; because of myelosuppression, the protocol was revised to gemcitabine at a dose of 900 mg/m2 and cisplatin at a dose of 30 mg/m2. Patients were treated until disease progression, unacceptable toxicity, or complete response. RESULTS: A total of 21 patients were enrolled and received a median of 5 courses of therapy (range, 1-9 courses). The median age at the time of study enrollment was 62 years (range, 41-75 years). Of 20 evaluable patients, 2 (10%) had a confirmed complete response, 8 (40%) had a partial response, 6 (30%) had stable disease, and 4 (20%) developed progressive disease. The median progression-free survival was 7.5 months (range, 2.3-33.6 months), and the median overall survival was 18.2 months (range, 2.5-49.4 months). The development of toxicity mandated dose reductions in 16 of 20 patients (80%). Eighteen patients experienced grade 3 or 4 toxic effects (graded according to the Common Terminology Criteria for Adverse Events [version 3.0]). CONCLUSIONS: The objective response rate of 50% noted with gemcitabine and cisplatin combination chemotherapy merits the further development of this regimen in women with advanced or recurrent endometrial cancer.

A novel hTERT promoter-driven E1A therapeutic for ovarian cancer.

Currently, an effective gene therapy strategy, which not only retains cancer-specific expression but also limits toxicity, has yet to be developed for ovarian cancer. Mounting reports over the years have shown that human telomerase activity is significantly elevated in cancer cells compared with normal cells. In this study, we evaluated the human telomerase reverse transcriptase (hTERT; T) promoter and showed that it can direct target gene expression preferentially in ovarian cancer cells. However, its promoter (T) activity is much lower than that of cytomegalovirus (CMV), a commonly used nonspecific promoter. To overcome this problem, we have integrated the T promoter into our recently developed VP16-Gal4-WPRE integrated systemic amplifier (VISA) system and dramatically enhanced transgene expression. In addition, to further develop this cancer-specific promoter gene expression system into an applicable therapeutic vector, we expressed E1A (an adenoviral type 5 transcription factor that possesses anticancer properties) through this novel VISA platform. We showed that the T-VISA system specifically targeted the expression of E1A to ovarian cancer cells at a level greater than or comparable with the commonly used CMV promoter, yet remained nearly silent in normal cells, thus making this a suitable gene therapy construct. By using this cancer-specific promoter that limits target gene expression in normal cells/tissues, potential toxicity induced by the CMV promoter would be prevented. More importantly, we showed significant antitumor activity with much less toxicity in animal models through i.v. delivery of T-VISA-E1A:liposomal nanoparticles, suggesting a promising role of T-VISA-E1A for ovarian cancer treatment under a gene therapy setting.

PAX2 expression in low malignant potential ovarian tumors and low-grade ovarian serous carcinomas.

Ovarian tumors of low malignant potential and low-grade ovarian serous carcinomas are thought to represent different stages on a tumorigenic continuum and to develop along pathways distinct from high-grade ovarian serous carcinoma. We performed gene expression profiling on three normal human ovarian surface epithelia samples, and 10 low-grade and 10 high-grade ovarian serous carcinomas. Analysis of gene expression profiles of these samples has identified 80 genes upregulated and 232 genes downregulated in low-grade ovarian serous carcinomas. PAX2 was found to be one of the most upregulated genes in low-grade ovarian serous carcinoma. The upregulation of PAX2 was validated by real-time quantitative RT-PCR, western blot and immunohistochemical analyses. Real-time RT-PCR showed a statistically significant difference in PAX2 mRNA expression (expressed as fold change in comparison to normal human ovarian surface epithelia) among ovarian tumors of low malignant potential (1837.38, N=8), low-grade (183.12, N=17), and high-grade (3.72, N=23) carcinoma samples (P=0.015). Western blot analysis revealed strong PAX2 expression in ovarian tumors of low malignant potential (67%, N=3) and low-grade carcinoma samples (50%, N=10) but no PAX2 protein expression in high-grade carcinomas (0%, N=10). Using immunohistochemistry, tumors of low malignant potential (59%, N=17) and low-grade carcinoma (63%, N=16) samples expressed significantly stronger nuclear staining than high-grade ovarian carcinoma samples (9.1%, N=263). Furthermore, consistent with earlier immunohistochemical findings, PAX2 expression was expressed in the epithelial cells of fallopian tubes but not in normal ovarian surface epithelial cells. Our findings further support the two-tiered hypothesis that tumors of low malignant potential and low-grade ovarian serous carcinoma are on a continuum and are distinct from high-grade ovarian carcinomas. In addition, the absence of PAX2 expression in normal ovarian epithelia but expression in fallopian tube fimbria and ciliated epithelial inclusions would suggest the potential development of tumors of low malignant potential and of low-grade ovarian serous carcinomas from secondary Müllerian structures.

Therapeutic Targeting of ATP7B in Ovarian Carcinoma.

PURPOSE: Resistance to platinum chemotherapy remains a significant problem in ovarian carcinoma. Here, we examined the biological mechanisms and therapeutic potential of targeting a critical platinum resistance gene, ATP7B, using both in vitro and in vivo models. EXPERIMENTAL DESIGN: Expression of ATP7A and ATP7B was examined in ovarian cancer cell lines by real-time reverse transcription-PCR and Western blot analysis. ATP7A and ATP7B gene silencing was achieved with targeted small interfering RNA (siRNA) and its effects on cell viability and DNA adduct formation were examined. For in vivo therapy experiments, siRNA was incorporated into the neutral nanoliposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). RESULTS: ATP7A and ATP7B genes were expressed at higher levels in platinum-resistant cells compared with sensitive cells; however, only differences in ATP7B reached statistical significance. ATP7A gene silencing had no significant effect on the sensitivity of resistant cells to cisplatin, but ATP7B silencing resulted in 2.5-fold reduction of cisplatin IC(50) levels and increased DNA adduct formation in cisplatin-resistant cells (A2780-CP20 and RMG2). Cisplatin was found to bind to the NH(2)-terminal copper-binding domain of ATP7B, which might be a contributing factor to cisplatin resistance. For in vivo therapy experiments, ATP7B siRNA was incorporated into DOPC and was highly effective in reducing tumor growth in combination with cisplatin (70-88% reduction in both models compared with controls). This reduction in tumor growth was accompanied by reduced proliferation, increased tumor cell apoptosis, and reduced angiogenesis. CONCLUSION: These data provide a new understanding of cisplatin resistance in cancer cells and may have implications for therapeutic reversal of drug resistance.

Predisposing risk factors for palmar-plantar erythrodysesthesia when using liposomal doxorubicin to treat recurrent ovarian cancer.

OBJECTIVE: Pegylated liposomal doxorubicin (PLD) was introduced to reduce the adverse effect of doxorubicin in treating recurrent ovarian cancer. We sought to characterize the efficacy and adverse-effect profile of PLD in different doses and to evaluate predictive factors of palmar-plantar erythrodysesthesia (PPE). METHODS: Patients with recurrent ovarian, primary peritoneal, and fallopian tube carcinoma treated with single-agent PLD between 1996 and 2006 at The University of Texas M. D. Anderson Cancer Center were retrospectively identified, and charts were reviewed for patient demographics, PLD data, adverse effects, use of cooling mechanisms, and survival. RESULTS: Three hundred-thirty patients were included and PPE of any grade occurred in 30.9%. Patients received a median of 3 (mean 4.32) cycles of PLD treatment. The different PLD doses (<30, 35, 40, and >50 mg/m(2)) were not associated with differences in overall survival (OS), progression-free survival (PFS), or time to progression (TTP). The incidences of mucositis, neutropenia, peripheral neuropathy, and vomiting were significantly higher at doses >50 mg/m(2) than at doses <40 mg/m(2). More patients who used cooling mechanisms (39%) had PPE than those who did not (26%). There was an association between mucositis, neutropenia, and peripheral neuropathy and PPE. More cycles of PLD (>6) also increased the incidence of PPE. In our study, only 7% of women discontinued PLD for toxicity while 74% discontinued for progression. CONCLUSION: There was no association between different doses of PLD and OS, PFS, or TTP. A higher dose and more cycles increased the incidence of several toxicities, including PPE. The use of cooling mechanisms, higher number of PLD cycles, and occurrence of mucositis, neutropenia, and peripheral neuropathy are possible predictors of PPE.

A phase II study of GM-CSF and rIFN-gamma1b plus carboplatin for the treatment of recurrent, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer.

OBJECTIVE: To evaluate the efficacy and toxicity of carboplatin, granulocyte-macrophage colony-stimulating factor (GM-CSF) and recombinant interferon gamma 1b (rIFN-gamma1b) in women with recurrent, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer. METHODS: In this phase II study, patients with recurrent, platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer were treated with subcutaneous GM-CSF and rIFN-gamma1b before and after intravenous carboplatin until disease progression or unacceptable toxicity. All patients had measurable disease and a chemotherapy-free interval >6 months. Response was determined using RECIST criteria and CA 125 levels. RESULTS: Between 2003 and 2007, 59 patients received a median of 6 cycles of therapy (range, 1 to 13 cycles). Median age at enrollment was 61 years (range, 35 to 79 years). Median time to progression prior to enrollment was 11 months (range, 6 to 58 months). Of 54 patients evaluable for response, 9 (17%) had a complete response, 21 (39%) had a partial response, and 24 (44%) had progressive disease. The overall response rate was 56% (95% CI: 41% to 69%). With a median follow-up of 6.4 months, median time to progression was 6 months. Myeloid derived cells and platelets increased on day 9 of each chemotherapy cycle. The most common adverse effects were bone marrow suppression, carboplatin hypersensitivity, and fatigue. Responders reported improved quality of life. CONCLUSION: This pre and post-carboplatin cytokine regimen resulted in a reasonable response and a hematologic profile that could invite further evaluation of its components in the treatment of patients with ovarian cancer.

Dosing chemotherapy in obese patients: actual versus assigned body surface area (BSA).

Obesity is a chronic disease that has increased dramatically in the past few decades worldwide. More concerning, obesity is linked to many other disease states including cancer and has been shown to increase mortality. Unfortunately, oncology drug development and most clinical trials fail to address the problem of appropriate chemotherapy dosing in obese patients. This can potentially lead to either increased toxicity or decreased efficacy. Although dosing schemas may vary among practices and institutions, many oncologists tend to remain conservative and empirically dose-reduce obese patients despite data suggesting otherwise. The goals of this review were to consider the various aspects of pharmacokinetics in obese patients, to examine the existing literature regarding chemotherapy dosing in obese patients, and to determine the most appropriate weight estimation for body surface area (BSA) dose calculations. Based upon the current clinical data of obesity and chemotherapy dosing it can be concluded there is very limited if any data to support the perception that capping the doses of obese patients is beneficial and more likely this practice may have negative implications on survival outcomes. Under dosing patients with treatable or even curable disease to prevent toxicities could be costing the obese oncology patient population months to years of overall survival.

In vitro evaluation of the effects of gefitinib on the cytotoxic activity of selected anticancer agents in a panel of human endometrial cancer cell lines.

PURPOSE: This study was conducted to determine the in vitro optimal combination of selected anticancer agents with gefitinib and evaluate its effect on the expression of correlative biological targets in the cell-signaling pathway. In addition, the effect of gefitinib on the expression of ATP-binding cassette (ABC) transport proteins was evaluated. METHODS: Growth inhibition assays were conducted in six human endometrial cancer cell lines to evaluate the activity of selected anticancer agents with gefitinib compared to each alone. Enzyme linked immunosorbant assay (ELISA) assessed the presence of pEGFR in treated and untreated cells. Evaluation of the suppression of correlative biological targets in the cell-signaling pathway was completed by immunoblotting. RT-PCR was used to characterize the expression of MRP and ABC transport proteins. RESULTS: This in vitro study gefitinib did not observe cytotoxic activity as a single agent. However, the activity of gefitinib as EGFR inhibitor was confirmed. The combination of gefitinib with paclitaxel and docetaxel exhibited improved in vitro cytotoxic activity compared to each antineoplastic agent alone. Suppression of pAKT and p27 in the human endometrial cancer cells treated with selected combinations of chemotherapeutic drugs and gefitinib was observed. CONCLUSION: These data suggest that EGFRinhibitors, such as gefitinib, have the potential to modulate common mechanisms of drug resistance and may have a role in optimizing antineoplastic regimens for the treatment of recurrent endometrial cancer. This may represent a promising option for this class of agents in the treatment of endometrial cancer.