National Cancer Institute®
Last Modified: April 1, 2002
UI - 11735647
AU - Waterhouse D N; Tardi P G; Mayer L D; Bally M B
TI - A comparison of liposomal formulations of doxorubicin with drug administered in free form: changing toxicity profiles.
SO - Drug Saf 2001;24(12):903-20
AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. email@example.com
The anthracycline antibiotic doxorubicin has wide activity against a number of human neoplasms and is used extensively both as a single agent and in combination regimens. In addition to the use of free, unencapsulated doxorubicin, there are two US Food and Drug Administration approved liposomal formulations of doxorubicin currently available, with several additional liposomal formulations being researched either in the laboratory or in clinical trials. The two approved liposomal formulations of doxorubicin have significantly different lipid compositions and loading techniques, which lead to both unique pharmacokinetic and toxicity profiles, distinct from those of the unencapsulated form. This article discusses the toxicities associated with the free form of doxorubicin, as well as those associated with the two most common liposomal formulations, namely Doxil and Myocet. One of the key toxicity issues linked to the use of free doxorubicin is that of both an acute and a chronic form of cardiomyopathy. This is circumvented by the use of liposomal formulations, as these systems tend to sequester the drug away from organs such as the heart, with greater accumulation in liver, spleen and tumours. However, as will be discussed, the liposomal formulations of doxorubicin are not without their own related toxicities, and, in the case of Doxil, may be associated with the unique toxicity of palmar-plantar erythrodysaesthesia. Overall, the use of liposomal doxorubicin allows for a greater lifetime cumulative dose of doxorubicin to be administered, however acute maximal tolerated doses differ significantly, with that of Myocet being essentially equivalent to free doxorubicin, while higher doses of Doxil may be safely administered. This review highlights the differences in both toxicity and pharmacokinetic properties between free doxorubicin and the different liposomal formulations, as have been determined in pre-clinical and clinical testing against a number of different human neoplasms. The need for further testing of the liposomal formulations prior to the replacement of free doxorubicin with liposomal doxorubicin in any established combination therapy regimens, as well as in combination with the newer therapeutics such as monoclonal antibodies is also discussed.
UI - 11772158
AU - Young M; Plosker GL
TI - Paclitaxel: a pharmacoeconomic review of its use in the treatment of ovarian cancer.
SO - Pharmacoeconomics 2001;19(12):1227-59
AD - Adis International Limited, Auckland, New Zealand.
Paclitaxel belongs to the group of antitumour agents called the taxanes. Its efficacy in advanced ovarian cancer has been established in large, randomised phase III clinical trials. When used in combination with cisplatin for first-line treatment of advanced ovarian cancer, it is superior to cyclophosphamide/cisplatin, with gains in median survival of around 1 year. Paclitaxel plus carboplatin has similar efficacy to paclitaxel plus cisplatin. There is now consensus that paclitaxel plus either carboplatin or cisplatin is the recommended first-line therapy for patients with advanced ovarian cancer. The particular combination employed may vary between institutions and geographical regions, although paclitaxel plus carboplatin is generally better tolerated (i.e. lower incidence of non-haematological adverse events) than paclitaxel plus cisplatin and is widely used in many countries. Paclitaxel is also used as monotherapy in second-line (salvage) treatment of ovarian cancer. Pharmacoeconomic analyses performed to date have primarily focused on first-line therapy comparing the combination of paclitaxel/cisplatin with cyclophosphamide/cisplatin. All studies incorporated clinical outcomes data, most commonly from the Gynecologic Oncology Group (GOG) 111 trial, showing a survival advantage for paclitaxel/cisplatin. These studies report incremental cost-effectiveness ratios (ICERs) ranging from $US 6395 per additional life-year gained (LYG) in Spain (1995/96 values) to $US 44,690 per additional progression-free LYG in France (year of costs not reported). Five studies were based in the US and Canada and these reported very similar ICERs of $US 13,135 (year of costs not reported) to $US 25,131 (1993 costs) per additional LYG. In all of these studies the incremental costs of paclitaxel/cisplatin therapy fall well within the commonly cited threshold limit of $US 50,000 for new therapies and compare well with incremental costs reported for other oncological and life-saving therapies. Patient preferences and quality of life are important issues due to the short survival of patients with advanced ovarian cancer. Two cost-utility studies reported similar incremental cost-utility ratios (ICURs). In the study based on US costs, the ICUR of paclitaxel/cisplatin treatment was US $18,200 per additional quality-adjusted life-year (QALY) [1995 drug costs]. In a Canadian study the ICUR ranged from 11,600 Canadian dollars ($Can) to $Can 24,200 (1996 costs) per additional progression-free QALY depending on the choice of second-line treatment. CONCLUSIONS: Paclitaxel used in combination with cisplatin offers survival and utility gains versus cyclophosphamide plus cisplatin, when used as first-line treatment in patients with stage III or IV ovarian cancer. The incremental cost for these gains is within the accepted range for healthcare interventions. However, pharmacoeconomic analyses of paclitaxel plus carboplatin--a combination widely accepted for use in women with advanced ovarian cancer and with clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile--are currently lacking. Nevertheless, results of available pharmacoeconomic data support the clinical use of paclitaxel/platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced ovarian cancer.
UI - 11788818
AU - Baum RP; Przetak C
TI - Evaluation of therapy response in breast and ovarian cancer patients by positron emission tomography (PET).
SO - Q J Nucl Med 2001 Sep;45(3):257-68
AD - Zentralklinik Bad Berka Clinic of Nuclear Medicine, Center for PET, Bad Berka, Germany. firstname.lastname@example.org
Positron emission tomography (PET) has the potential to contribute significantly to treatment planning and to the evaluation of response to therapy in patients with cancer. For disease recurrence PET imaging provides information non-invasively. The final goal is to biologically characterize an individual patient's tumor and to predict the response to treatment at the earliest possible time. Since the development of neoadjuvant chemotherapy, PET has been proved to be the most sensitive and accurate imaging technique for early therapy response evaluation of breast tumors. Quantitative and/or semi-quantitative PET studies yield valuable information in breast cancer regarding prognosis and response to chemohormontherapy in a timely fashion. In ovarian cancer, up to now only few studies have been performed applying PET techniques for the evaluation of treatment response. These preliminary studies indicate that serial assessment of tumor metabolism by FDG-PET early during effective chemotherapy may predict subsequent response to such therapy. PET studies can be repeated without any side-effects and with low radiation exposure and results can be directly correlated with clinical laboratory data and histology. The role of PET in the context of patient management and the cost-effectiveness of this approach needs further evaluation. Therapy monitoring by PET could help to optimize neoadjuvant therapy protocols and to avoid ineffective preoperative therapy in non-responders, but this has to be proven in a larger number of patients and in different neoadjuvant settings such as chemotherapy, radiation therapy, hormone therapy or a combination of these.
UI - 11781646
AU - Morgan RJ; Doroshow JH; Leong L; Schriber J; Shibata S; Forman S;
TI - Hamasaki V; Margolin K; Somlo G; Alvarnas J; McNamara M; Longmate J; Raschko J; Chow W; Vasilev S; McGonigle K; Yen Y Phase II trial of high-dose intravenous doxorubicin, etoposide, and cyclophosphamide with autologous stem cell support in patients with residual or responding recurrent ovarian cancer.
SO - Bone Marrow Transplant 2001 Nov;28(9):859-63
AD - Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
This study was performed in order to evaluate the toxicities, progression-free and overall survival of patients with responsive residual or recurrent ovarian cancer treated with high-dose chemotherapy. Twenty-seven patients were treated. Doxorubicin, 165 mg/m(2) over 96 h (days -12 to -8), etoposide 700 mg/m(2) every day x3 (days -6 to -4), and cyclophosphamide 4.2 g/m(2) on d -3 was followed by stem cells and granulocyte colony-stimulating factor. The median days of granulocyte count <500/microl was 14 (range 10-42) and platelets <20,000/microl was 13 (range 2-80). Median numbers of red cell and platelet transfusions were 15 (5-16) and 14 (4-103). Toxicity included mucositis requiring narcotic analgesia in all patients. Asymptomatic decreases in ejection fraction to values <50% were observed in four patients. No clinical congestive heart failure was observed. One death due to sepsis was observed. Median progression-free survival is 7.5 months (1.0-56 months); five patients remain alive, two of whom remain progression-free at 19.5 and 24.5 months post transplant. Median overall survival is 14.0 months (1-68 months). We conclude that high-dose anthracyclines may be safely administered to ovarian cancer patients. The short overall and progression-free survivals observed in our population suggest that this combination is not optimal.
UI - 11900231
AU - Dimopoulou I; Galani H; Dafni U; Samakovii A; Roussos C; Dimopoulos MA
TI - A prospective study of pulmonary function in patients treated with paclitaxel and carboplatin.
SO - Cancer 2002 Jan 15;94(2):452-8
AD - Department of Pulmonary and Critical Care, Evangelismos Hospital, Medical School, Athens, Greece. email@example.com
BACKGROUND: Adverse effects of paclitaxel and carboplatin have been well described; however, pulmonary toxicity after patients receive this regimen has not been investigated extensively. METHODS: To clarify this issue, 33 consecutive patients who were treated with paclitaxel and carboplatin underwent prospective evaluation of respiratory function, which included pulmonary symptoms, pulmonary function tests (PFTs), arterial blood gas levels, and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patients. Patients with substantial declines in PFTs, defined as a decline > or = 20 percent in forced expiratory volume in 1 second (FEV1), total lung capacity (TLC), or diffusion capacity for carbon monoxide (DLCO), were reassessed 5 months later. RESULTS: After chemotherapy, there were no significant changes in forced vital capacity (FVC; 111%+/-21% of the predicted value before chemotherapy vs. 111+/-20% of the predicted value after chemotherapy), FEV1 (108%+/-24% of the predicted value before chemotherapy vs. 107%+/-22% of the predicted value after chemotherapy), FEV1/FVC ratio (79%+/-8% before chemotherapy vs. 78%+/-6% after chemotherapy), alveolar volume (VA; 95%+/-14% of the predicted value before chemotherapy vs. 96%+/-14% of the predicted value after chemotherapy), or TLC (96%+/-14% of the predicted value before chemotherapy vs. 97%+/-13% of the predicted value after chemotherapy). In contrast, there was a significant decline in DLCO (101%+/-20% of the predicted value before chemotherapy vs. 96+/-21% of the predicted value after chemotherapy; P < 0.05). Arterial blood gas levels did not change after treatment. No patient had decreased FEV1 or TLC levels by > or = 20%, whereas 4 of 33 patients (12%) exhibited a substantial decline (> or = 20%) in DLCO that persisted 5 months after treatment (DLCO at baseline, immediately after chemotherapy, and 5 months after the completion of chemotherapy, respectively: 99%+/-36% of the predicted value vs. 75%+/-28% of the predicted value vs. 74%+/-31% of the predicted value; P < 0.05). None of the 33 patients developed respiratory symptoms or had radiologic signs suggestive of lung toxicity. Among the various risk factors examined, baseline DLCO and FEV1 levels were associated with changes in DLCO post-treatment. CONCLUSIONS: This prospective analysis showed that the combination of paclitaxel with carboplatin induced an isolated decrease in DLCO level in the absence of clinical or radiologic evidence of toxicity. Further studies are needed to clarify whether this reduction in DLCO is predictive of subsequent pulmonary impairment.
UI - 11870154
AU - Cannistra SA
TI - Is there a "best" choice of second-line agent in the treatment of recurrent, potentially platinum-sensitive ovarian cancer?
SO - J Clin Oncol 2002 Mar 1;20(5):1158-60
UI - 11870165
AU - Cantu MG; Buda A; Parma G; Rossi R; Floriani I; Bonazzi C; Dell'Anna T;
TI - Torri V; Colombo N Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens.
SO - J Clin Oncol 2002 Mar 1;20(5):1232-7
AD - Department of Gynaecology Oncology, Universita degli Studi di Milano-Bicocca, Ospedale San Gerardo dei Tintori, Monza, Italy.
PURPOSE: To assess the activity, efficacy, and tolerability of single-agent paclitaxel and a platinum-containing regimen in previously treated patients with recurrent ovarian cancer. PATIENTS AND METHODS: Patients who achieved complete remission with platinum-based regimens and whose disease recurred after a progression-free interval of more than 12 months were included in the study. Every 21 days, patients received paclitaxel 175 mg/m(2) intravenously (IV) over 3 hours or cyclophosphamide 500 mg/m(2), doxorubicin 50 mg/m(2), and cisplatin 50 consecutive patients with assessable or measurable disease were randomized to paclitaxel (n = 50) or CAP (n = 47). The median number of cycles on each arm was six. Toxicities included grade 3/4 leukopenia (4% for paclitaxel v 34% for CAP), grade 3/4 neutropenia (13% v 36%), grade 1/2 myalgia (19% v 4%), allergic reactions (15% v 2%), and grade 2/3 nausea and vomiting (17% v 51%). Complete responses were achieved in 17% and 30% of patients receiving paclitaxel and CAP, respectively, and partial responses were achieved in 28% and 25%, respectively (P =.062). At a median follow-up time of 49 months, median progression-free intervals were 9 months for paclitaxel and 15.7 months for CAP (Cox analysis: hazards ratio [HR], 0.60; 95% confidence interval [CI], 0.37 to 0.97; P =.038); median overall survival times were 25.8 months for paclitaxel and 34.7 months for CAP (Cox analysis: HR, 0.58; 95% CI, 0.34 to 0.98; P =.043). CONCLUSION: Rechallenge with either single-agent paclitaxel or platinum-based chemotherapy is effective in this patient population. Preliminary results suggest that single-agent paclitaxel may not be as active as platinum-based chemotherapy in recurrent ovarian cancer. Larger randomized trials are needed.
UI - 11870166
AU - Dizon DS; Hensley ML; Poynor EA; Sabbatini P; Aghajanian C; Hummer A;
TI - Venkatraman E; Spriggs DR Retrospective analysis of carboplatin and paclitaxel as initial second-line therapy for recurrent epithelial ovarian carcinoma: application toward a dynamic disease state model of ovarian cancer.
SO - J Clin Oncol 2002 Mar 1;20(5):1238-47
AD - Department of Medicine, Division of Developmental Chemotherapy, and Department of Gynecologic Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY.
PURPOSE: The majority of patients with epithelial ovarian cancer (EOC) who achieve a complete remission with front-line chemotherapy develop recurrent disease. Carboplatin and paclitaxel are used for patients with platinum-sensitive recurrent disease, although there is little information regarding the response and survival in unselected patients treated with this strategy. We sought to determine the outcomes for patients with EOC treated with carboplatin and paclitaxel at the time of first recurrence. In addition, we sought to define a new paradigm for disease transition in patients with EOC. PATIENTS AND METHODS: Eighty-nine patients were identified who had a complete response to front-line platinum-based chemotherapy for EOC, relapsed 6 months after completion of front-line chemotherapy, and were treated with carboplatin and paclitaxel as second-line therapy. RESULTS: Eighty-four cases were available for analysis of survival end points, and 66 were assessable for response. The median follow-up was 27 months. The overall response rate was 70%. The median progression-free interval for the cohort was 13 months (95% confidence interval [CI], 10.7 to 13.8 months). The 3-year survival rate was 72% (95% CI, 59.4 to 86.1%). Toxicity was limited, and no deaths from treatment were observed. Using this data, it is possible to construct a disease states model of EOC, which provides risk estimates for transitions between clinically distinct categories. CONCLUSION: Re-treatment with carboplatin and paclitaxel is effective as initial therapy in recurrent EOC. This should form the basis of a randomized trial to determine the best agents for initial treatment of relapse from EOC in potentially platinum-sensitive patients.
UI - 11870167
AU - Bristow RE; Tomacruz RS; Armstrong DK; Trimble EL; Montz FJ
TI - Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis.
SO - J Clin Oncol 2002 Mar 1;20(5):1248-59
AD - Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21287-1248, USA. firstname.lastname@example.org
PURPOSE: To evaluate the relative effect of percent maximal cytoreductive surgery and other prognostic variables on survival among cohorts of patients with advanced-stage ovarian carcinoma treated with platinum-based chemotherapy. MATERIALS AND METHODS: Eighty-one cohorts of patients with stage III or IV ovarian carcinoma (6,885 patients) were identified from articles in MEDLINE (1989 through 1998). Linear regression models, with weighted correlation calculations, were used to assess the effects on log median survival time of the proportion of each cohort undergoing maximal cytoreduction, dose-intensity of the platinum compound administered, proportion of patients with stage IV disease, median age, and year of publication. RESULTS: There was a statistically significant positive correlation between percent maximal cytoreduction and log median survival time, and this correlation remained significant after controlling for all other variables (P <.001). Each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time. When actuarial survival was estimated, cohorts with < or = 25% maximal cytoreduction had a mean weighted median survival time of 22.7 months, whereas cohorts with more than 75% maximal cytoreduction had a mean weighted median survival time of 33.9 months--an increase of 50%. The relationship between platinum dose-intensity and log median survival time was not statistically significant. CONCLUSION: During the platinum era, maximal cytoreduction was one of the most powerful determinants of cohort survival among patients with stage III or IV ovarian carcinoma. Consistent referral of patients with apparent advanced ovarian cancer to expert centers for primary surgery may be the best means currently available for improving overall survival.
UI - 11870168
AU - Scheuer L; Kauff N; Robson M; Kelly B; Barakat R; Satagopan J; Ellis N;
TI - Hensley M; Boyd J; Borgen P; Norton L; Offit K Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers.
SO - J Clin Oncol 2002 Mar 1;20(5):1260-8
AD - Clinical Genetics, Breast Cancer Medicine, and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New york, NY 10021, USA.
PURPOSE: To prospectively determine the impact of genetic counseling and testing on risk-reduction strategies and cancer incidence in a cohort of individuals at hereditary risk for breast and ovarian cancer. PATIENTS AND METHODS: Two hundred fifty-one individuals with BRCA mutations were identified at a single comprehensive cancer center from May 1, 1995, through October 31, 2000. Uniform recommendations regarding screening and preventive surgery were provided in the context of genetic counseling. Patients were followed for a mean of 24.8 months (range, 1.6 to 66.0 months) using standardized questionnaires, chart reviews, and contact with primary physicians. RESULTS: Frequency of cancer surveillance by physical examinations and imaging studies increased after genetic counseling and testing. Twenty-one breast, ovarian, primary peritoneal, or fallopian tube cancers were detected after receipt of genetic test results. Among 29 individuals choosing risk-reducing mastectomy after testing, two were found to have occult intraductal breast cancers. Among 90 individuals who underwent risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm and one early-stage fallopian tube neoplasm were found. Radiographic or tumor marker-based screening detected six breast cancers, five of which were stage 0/I, one early-stage primary peritoneal cancer, and three stage I or II ovarian cancers. Six additional breast cancers were detected by physical examination between radiographic screening intervals; four of these six tumors were stage I. No stage III or stage IV malignancies were detected after genetic testing. CONCLUSION: This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.
UI - 11408492
AU - Fracasso PM; Brady MF; Moore DH; Walker JL; Rose PG; Letvak L; Grogan
TI - TM; McGuire WP Phase II study of paclitaxel and valspodar (PSC 833) in refractory ovarian carcinoma: a gynecologic oncology group study.
SO - J Clin Oncol 2001 Jun 15;19(12):2975-82
AD - Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. email@example.com
PURPOSE: A phase II study was conducted to determine the efficacy of paclitaxel and valspodar (PSC 833) in patients with advanced epithelial ovarian cancer. Valspodar, a nonimmunosuppressive cyclosporine D analogue that reverses P-glycoprotein-mediated multidrug resistance, in combination with paclitaxel might be active in paclitaxel-resistant and refractory ovarian cancer. PATIENTS AND METHODS: Patients received valspodar 5 mg/kg orally qid x 12 doses. Paclitaxel (70 mg/m(2) intravenously for 3 hours) was administered on day 2, 2 hours after the fifth or sixth dose of valspodar. This treatment was repeated every 21 days. One blood sample was collected before the sixth dose of valspodar for the first three cycles to evaluate valspodar trough concentration. Tumor tissue was obtained from patients for immunohistochemical staining of P-glycoprotein. RESULTS: Of 60 patients entered, 58 were assessable for response. There were five partial responses (8.6%; 90% confidence interval [CI], 3.8 to 20.0; median duration of response, 5.0 months [range, 1.9 to 10.5 months]). Median progression-free survival was 1.5 months (90% CI, 1.4 to 2.4). Grade 3 or 4 toxicities observed were neutropenia, anemia, nausea and vomiting, peripheral neuropathy, and cerebellar ataxia. The trough concentrations of valspodar were > or = 1,000 ng/mL in all but two of 40 patients in the first cycle. Immunohistochemical staining for P-glycoprotein was positive for one of two responding patients. CONCLUSION: Valspodar in combination with paclitaxel has limited activity in patients with paclitaxel-resistant ovarian carcinoma. An international randomized clinical trial of paclitaxel and carboplatin with or without valspodar as first-line therapy in advanced ovarian cancer is underway.
UI - 11762813
AU - Misset JL; Vennin P; Chollet PH; Pouillart P; Laplaige PH; Frobert JL;
TI - Castera D; Fabro M; Langlois D; Cortesi E; Lucas V; Gamelin E; Laadem A; Otero J Multicenter phase II-III study of oxaliplatin plus cyclophosphamide vs. cisplatin plus cyclophosphamide in chemonaive advanced ovarian cancer patients.
SO - Ann Oncol 2001 Oct;12(10):1411-5
AD - Federation des Services des Maladies Sanguines Immunitaires et Tumorales, Hjpital Paul Brousse, Villejuif, France. firstname.lastname@example.org
PURPOSE: A phase II-III randomised study to compare safety and efficacy of an oxaliplatin/cyclophosphamide (OXAC) combination, vs. the reference combination of cisplatin/cyclophosphamide (CPC), in untreated advanced ovarian cancer patients. PATIENTS AND METHODS: 182 patients were enrolled, of whom 177 were treated: 86 with OXAC (130 mg/m2 oxaliplatin two-hour intravenous (i.v.) infusion, 1,000 mg/m2 cyclophosphamide two-hour i.v. infusion), and 91 with CPC (100 mg/m2 cisplatin one-hour i.v. infusion. 1,000 mg/m2 cyclophosphamide two-hour i.v. infusion). Treatment cycles were repeated every three weeks (maximum of six cycles). RESULTS: The main toxicities, which were significantly less severe in the OXAC arm, were myelosuppression and vomiting, including (OXAC vs CPC, % patients): grade 3-4 leukopenia (37% vs. 56%), and anaemia (7% vs. 32%), with blood transfusions in 8% vs. 21%. In the OXAC arm, 64% of surgically assessable patients and 33% of clinically assessable patients achieved an objective response. In the CPC arm, 67% patients achieved a surgical response and 42% achieved an objective clinical response. In the OXAC and CPC arms, median progression free-survival was 13.0 and 13.3 months, and overall survival was 36.0 and 25.1 months respectively, without statistically significant difference. CONCLUSION: The activity and time-related parameters of the OXAC and CPC combinations in advanced ovarian cancer patients, are comparable. Combined with the better safety profile of the oxaliplatin-containing regimen, this confirms the interest of oxaliplatin combined with active new agents in this indication.
UI - 11823045
AU - Bagnis C; Chabannon C; Gravis G; Imbert AM; Maroc C; Bardin F; Ladaique
TI - P; Viret F; Genre D; Faucher C; Stoppa AM; Vey N; Blaise D; Maraninchi D; Viens P; Mannoni P Transient detection of beta-galactosidase activity in hematopoietic cells, following reinjection of retrovirally marked autologous blood progenitors in patients with breast or ovarian cancer receiving high-dose chemotherapy.
SO - Exp Hematol 2002 Feb;30(2):108-15
AD - Institut Paoli-Calmettes, Centre Regional de Lutte Contre le Cancer Provence-Alpes-Cote d'Azur, Marseille, France.
OBJECTIVE: The aim of this report is to demonstrate the feasibility and safety of genetically modifying autologous human blood CD34(+) cells in vitro, with a retroviral vector that encodes a marker gene. The fate of genetically modified cells and their progeny was followed in vivo, after reinfusion in patients treated with high-dose chemotherapy for poor-prognosis breast or ovarian carcinomas. PATIENTS AND METHODS: Six patients received genetically modified autologous peripheral blood progenitors, together with unmanipulated aphereses, following high-dose chemotherapy. CD34(+) cells were immunoselected from aphereses, and retrovirally transduced by coculture with the retroviral vector producing cell line, to express a nuclear localized version of E. coli beta-galactosidase, encoded by a defective Moloney-murine leukemia virus-derived retroviral vector. Cells were reinfused to the patients after myeloablation, without prior ex vivo selection. RESULTS: Five out of six patients showed the transient presence of low numbers of beta-galactosidase(+) cells, as detected with an immunocytochemical assay, in the peripheral blood, during the first month following infusion. One patient had beta-galactosidase(+) clonogenic progenitors in her marrow at two months after transplantation, including HPP-CFC; intriguingly, this patient had the lowest percentage of X-gal(+) cells in her graft. Patients experienced side effects that are often observed after high-dose chemotherapy. CONCLUSIONS: Feasibility and safety of genetic modification of human hematopoietic stem and progenitor cells are demonstrated by this study. Ex vivo or in vivo selection is not mandatory, even in clinical situations where transduced cells have no survival advantage over wild-type cells; however, significant improvements in gene transfer technology are needed to achieve potentially useful levels of expression in such clinical situations.
UI - 11801569
AU - Kanerva A; Mikheeva GV; Krasnykh V; Coolidge CJ; Lam JT; Mahasreshti PJ;
TI - Barker SD; Straughn M; Barnes MN; Alvarez RD; Hemminki A; Curiel DT Targeting adenovirus to the serotype 3 receptor increases gene transfer efficiency to ovarian cancer cells.
SO - Clin Cancer Res 2002 Jan;8(1):275-80
AD - Division of Human Gene Therapy, Departments of Medicine, Pathology, and Surgery and the Gene Therapy Center, University of Alabama at Birmingham, 35294-3300, USA.
Gene delivery efficiency in clinical cancer gene therapy trials with recombinant adenoviruses (Ads) based on serotype 5 (Ad5) has been limited partly because of variable expression of the primary Ad5 receptor, the coxsackie and adenovirus receptor (CAR), on human primary cancer cells. As a means of circumventing CAR deficiency, Ad vectors have been retargeted by creating chimeric fibers possessing knob domains of alternate Ad serotypes. In this study, we have constructed an Ad5-based vector, Ad5/3luc1, with a chimeric fiber protein featuring a knob domain derived from Ad3. This virus is retargeted to the Ad3 receptor and, therefore, has different tissue tropism. A novel knob binding assay was used to measure expression of CAR and the Ad3 receptor. Further, to evaluate the correlation of receptor expression and infectivity by Ad, a panel of ovarian cancer cell lines and purified primary cancer cells were infected with Ad5luc1 and Ad5/3luc1 at 50, 200, and 1000 viral particles/cell. Our results confirm that Ad5/3luc1 is retargeted to the Ad3 receptor. Furthermore, the Ad3 receptor is present at higher levels than CAR on ovarian adenocarcinoma cells. Also, the amount of binding to primary receptor appears to be the major factor determining the efficiency of transgene expression. The Ad5/3 chimera displays enhanced infectivity for ovarian cancer cell lines and purified primary tumor cells, which could translate into increased efficacy in clinical trials.
UI - 11697814
AU - Distefano M; Ferlini C; De Vincenzo R; Gaggini C; Mancuso S; Scambia G
TI - Antagonistic effect of the combination gemcitabine/topotecan in ovarian cancer cells.
SO - Oncol Res 2001;12(9-10):355-9
AD - Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy.
The in vitro interaction between the new antimetabolite gemcitabine (GEM) and topotecan (TPT) was analyzed in A2780 ovarian cancer cells. The growth inhibitory effect was assessed after 3 days of drug exposure. GEM and TPT obtained in vitro IC50 values of 2.1 +/- 0.9 and 33.7 +/- 10.2 nM, respectively. The interaction between GEM and TPT was evaluated by exposing cancer cells at increasing doses of GEM (0.1, 1, and 10 nM) and TPT (1, 10, 100, and 1000 nM). Analysis of data about the interaction between GEM and TPT was performed by applying the isobole method. An antagonistic effect was noticed when GEM was combined with TPT in the tested concentration range. DNA analysis was also performed and showed an augmentation of cells blocked in the G2/M phase during TPT exposure, while an increase of blocked cells in the G0/1, phase was observed after GEM treatment. This latter effect was predominant when the two drugs were used in combination. We also investigated the effect of sequential exposure to drugs, pretreating A2780 cells for 24 h with TPT and then for 48 h with GEM, and, conversely, pretreating A2780 cells with GEM for 24 h and thereafter with TPT for 48 h. Both these combined sequential treatments showed an antagonist effect of the drugs' combination. Long-term growth inhibition effect was established by clonogenic assay performed after 10 days of culture after drug treatment. Also these data confirmed the antagonistic effect between GEM and TPT in A2780 ovarian cancer cells.
UI - 11898145
AU - Mahon SM; Williams MT; Spies MA
TI - Screening for second cancers and osteoporosis in long-term survivors.
SO - Cancer Pract 2000 Nov-Dec;8(6):282-90
AD - Saint Louis University, Division of Hematology/Oncology, P.O. Box 15250, St. Louis, MO 63110-0250, USA.
PURPOSE: The purpose of this preliminary study was to describe the extent to which healthcare providers recommend the screening strategies for early detection described by the American Cancer Society (ACS), for breast, gynecologic, and colorectal cancer, and by the National Osteoporosis Foundation (NOF), for osteoporosis, to women who are long-term survivors of breast, ovarian, or endometrial cancer. DESCRIPTION OF THE STUDY: A four-part survey was developed for this study, with the first three parts based on the ACS guidelines for breast, gynecologic, and colorectal cancer screening and the NOF guidelines for osteoporosis screening. The fourth part related to personal characteristics, setting, knowledge, and perceptions of the nurses surveyed. A random sample of outpatient nurses was obtained from the Oncology Nursing Society. Of 668 nurses, 321 (48%) responded (Oncology Certified Nurse (OCN) 68.1%; Advanced Oncology Certified Nurse (AOCN) 16.6%). RESULTS: The most consistently performed screenings that were reported were mammogram (range 74.2-87.7%), professional breast examination (range 73.9-83.7%), and Pap test and pelvic examination (range 61.8-85.2%). The least frequently performed screenings are flexible sigmoidoscopy/colonoscopy (range 20.2-27.7%), bone mineral density testing (range 16.9-19.0%), and height measurement (range 22.5-28.3%). Less than one third of survivors are offered counseling on strategies to promote bone health. CLINICAL IMPLICATIONS: Knowledge of factors associated with osteoporosis and the use of screening strategies for second malignancies in survivors of breast, ovarian, and endometrial cancers can be used to implement activities such as patient education and clinical practice protocols that will increase the use of current screening recommendations.
UI - 11896105
AU - Vasey PA; Shulman LN; Campos S; Davis J; Gore M; Johnston S; Kirn DH;
TI - O'Neill V; Siddiqui N; Seiden MV; Kaye SB Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer.
SO - J Clin Oncol 2002 Mar 15;20(6):1562-9
AD - Beatson Oncology Centre and Stobhill Hospital, Glasgow, United Kingdom. email@example.com
PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS: We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10) pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS: The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10) pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 10(11) pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION: This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.
UI - 11822989
AU - Paley PJ
TI - Angiogenesis in ovarian cancer: molecular pathology and therapeutic strategies.
SO - Curr Oncol Rep 2002 Mar;4(2):165-74
AD - Department of Obstetrics and Gynecology, University of Washington School of Medicine, Box 356460, Seattle, WA 98195, USA. firstname.lastname@example.org
Ovarian cancer claims the lives of more women in North America each year than all other gynecologic malignancies combined. Despite the high initial response rates of patients with advanced ovarian cancer to aggressive primary surgical debulking followed by combination chemotherapy, the majority of patients will ultimately develop disease recurrence. The high risk of relapse and nearly guaranteed incurability after relapse is due to genetic instability and a high mutation rate of neoplastic cells that together allow for a high risk of selection for drug resistance. Given the seemingly insurmountable obstacle that acquired drug resistance presents in a setting of minimal, often undetectable, residual tumor burden in women with ovarian cancer, antiangiogenic-targeted therapies offer an attractive strategy for enhanced long-term disease-free survival. The past decade has witnessed a substantial proliferation in our knowledge regarding tumor angiogenesis, which has spurred interest in antiangiogenesis drug development. Current clinical trials are evaluating these agents in a variety of solid tumors, including ovarian cancer. Preliminary work has provided hope that the addition of antiangiogenic therapies may be incorporated into the treatment of women afflicted with ovarian cancer and may translate into enhanced survival.
UI - 1960550
AU - Pai LH; Bookman MA; Ozols RF; Young RC; Smith JW 2nd; Longo DL; Gould B;
TI - Frankel A; McClay EF; Howell S; et al Clinical evaluation of intraperitoneal Pseudomonas exotoxin immunoconjugate OVB3-PE in patients with ovarian cancer.
SO - J Clin Oncol 1991 Dec;9(12):2095-103
AD - Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
OVB3-PE is an immunotoxin composed of a murine monoclonal antibody reactive with human ovarian cancer and conjugated to Pseudomonas exotoxin (PE). Twenty-three patients with refractory ovarian cancer were treated intraperitoneally (IP) with escalating doses of OVB3-PE to study toxicity, pharmacokinetics, antiimmunotoxin antibody formation, and antitumor response. Dose-limiting CNS toxicity occurred after repeated doses at 5 and 10 micrograms/kg. Other non-dose-limiting toxicities included transient elevation of liver enzymes, fever, and gastrointestinal toxicity. Pharmacokinetics of IP and serum OVB3-PE were determined in 16 patients. Peak peritoneal fluid levels exceeded the in vitro median effective dose at all doses tested. At doses of 1 to 2 micrograms/kg, the immunotoxin concentration in the peritoneal fluid remained constant for up to 8 hours and dropped to negligible levels after 12 hours. At the 5 and 10 micrograms/kg doses, levels remained high for up to 24 hours (greater than 100 ng/mL) and then gradually decreased and became undetectable (less than 4 ng/mL) after 72 hours. Serum levels of OVB3-PE were also analyzed in 16 patients. At doses of 1 micrograms/kg and 2 micrograms/kg, serum levels were not detectable (less than 5 ng/mL). However, after doses of 5 or 10 micrograms/kg, peak serum level occurred at 24 hours after each dose and dropped to negligible levels by 72 hours. Sera from 12 patients were analyzed for anti-PE antibodies and antibodies to mouse immunoglobulin (HAMA). All patients developed antibodies against PE within 14 days of therapy. Domain II of PE appeared to be the most immunogenic portion of the PE molecule. HAMA was detected on day 14 of therapy in nine patients, on day 21 in two, and on day 28 in one patient. No clinical antitumor responses were observed. We conclude that IP OVB3-PE at dose levels of 5 micrograms/kg (x 3) and 10 micrograms/kg (x 2) is accompanied by dose-limiting toxic encephalopathy. Neurologic toxicity is likely to be due to crossreactivity of OVB3 to normal human brain tissue, which was not appreciated during preclinical screening.
UI - 2981613
AU - Pirker R; FitzGerald DJ; Hamilton TC; Ozols RF; Willingham MC; Pastan I
TI - Anti-transferrin receptor antibody linked to Pseudomonas exotoxin as a model immunotoxin in human ovarian carcinoma cell lines.
SO - Cancer Res 1985 Feb;45(2):751-7
The present in vitro study was performed to evaluate the potential usefulness of immunotoxins in treating human ovarian carcinomas. A monoclonal antibody against the human transferrin receptor was covalently linked to Pseudomonas exotoxin. The activity of this immunotoxin (anti-TFR-PE) was studied in five ovarian carcinoma cell lines, a breast carcinoma cell line (MCF-7), and in KB cells. The ovarian carcinoma cell lines included one previously established cell line (A1847) and four recent isolates obtained from the malignant ascites of patients with metastatic ovarian carcinoma (OVCAR cell lines). While all cell lines showed inhibition of protein synthesis by anti-TFR-PE, there were quantitative differences when the level of protein synthesis was assayed after a 12-hr incubation with the immunotoxin. These differences resulted from different kinetics of anti-TFR-PE activity in the various cell lines. Higher levels of cellular binding and internalization of anti-TFR were shown to contribute to increased toxicity of anti-TFR-PE. Verapamil increased the rate of protein synthesis inhibition and thus enhanced the toxicity of anti-TFR-PE in the OVCAR cell lines.
UI - 3930572
AU - Pirker R; FitzGerald DJ; Hamilton TC; Ozols RF; Laird W; Frankel AE;
TI - Willingham MC; Pastan I Characterization of immunotoxins active against ovarian cancer cell lines.
SO - J Clin Invest 1985 Sep;76(3):1261-7
The purpose of the present study was to develop immunotoxins directed against human ovarian carcinoma cells. Four monoclonal antibodies (260F9, 454C11, 280D11, and 245E7) were chosen because they were found to bind to various ovarian carcinoma cell lines. These antibodies were covalently linked to either Pseudomonas exotoxin (PE) or ricin A chain (RTA), and the conjugates were tested against five ovarian cancer cell lines (OVCAR-2, -3, -4, -5; A1847). The ability of the immunotoxins to inhibit both protein synthesis and colony formation was evaluated. Qualitatively similar results were obtained for both types of assays. Usually, PE conjugates were more toxic than their corresponding RTA conjugates. 454C11-PE was very toxic for all ovarian carcinoma lines, whereas 454C11-RTA had low activity. Both 260F9-PE and 260F9-RTA were active in all OVCAR cell lines but not in A1847 cells. 280D11-PE was toxic for OVCAR-4; otherwise, 280D11-PE and RTA conjugates of both 280D11 and 245E7 had little activity. Specificity of immunotoxin action was shown by competition by excess antibody, nontoxicity in nontarget cells, and inactivity of an irrelevant immunotoxin. To investigate the basis of antibody-dependent differences in activity of the various immunotoxins, antibody uptake was studied in OVCAR-2 cells, and the results indicate that antibody internalization is one important factor in the activity of immunotoxins.
UI - 9170525
AU - Kimura E; Niimi S; Watanabe A; Tanaka T
TI - [Clinical effect of two azasetron treatment methods against nausea and vomiting induced by anticancer drugs including CDDP]
SO - Gan To Kagaku Ryoho 1997 May;24(7):855-9
AD - Dept. of Obstetrics and Gynecology, Jikei University School of Medicine.
Azasetron, a selective 5-HT3 receptor antagonist, has been previously shown to be highly effective in the prophylaxis of nausea and vomiting induced by anticancer drugs, and is widely used in the clinical setting in Japan. In order to improve the antiemetic effect of azasetron, we designed two treatment methods using this drug and compared the antiemetic effect of this method with that of standard bolus intravenous injection on nausea and vomiting associated with anticancer drug including 75 mg/m cisplatin (CDDP). The two-treatment group received an intravenous bolus injection of 5 mg azasetron before and 8 hours after the start of chemotherapy, and a standard group was given an intravenous bolus injection of 10 mg azasetron only once a day. The inhibitory effect on vomiting in the two-treatment group was significantly greater than those of the standard group on day 1 and 2 (p = 0.0458, p = 0.0273), and the inhibitory effect on nausea of the two-treatment group tended to be superior those of the bolus group on day 2 (p = 0.0533). No adverse effects were observed in either group of this study. From these data, the two-treatment approach was considered to be highly effective in prophylaxis of nausea and vomiting induced by anticancer drug.
UI - 9233776
AU - Brown R; Hirst GL; Gallagher WM; McIlwrath AJ; Margison GP; van der Zee
TI - AG; Anthoney DA hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents.
SO - Oncogene 1997 Jul 3;15(1):45-52
AD - Department Medical Oncology, CRC Beatson Laboratories, Glasgow University, UK.
Loss of expression of the hMLH1 and hPMS2 subunits of the MutL alpha-mismatch repair complex is a frequent event (9/10) in independent cisplatin resistant derivatives of a human ovarian carcinoma cell line. However, only hMLH1 mRNA is decreased in these MutL alpha-deficient lines. No alterations in the levels of the hMSH2 and hMSH6 (GTBP) subunits of the MutS alpha-complex are observed. An increase in the proportion of ovarian tumours negative for the hMLH1 subunit is observed in samples taken at second look laparotomy after chemotherapy (36%: 4/11), compared to untreated tumours (10%: 4/39). No significant difference is observed for hMSH2, hMS