• [Surgical treatment of ovarian cancer should be centralized]

• Primary chemotherapy in stage IV ovarian cancer. A prospective phase II study.

• Macrophage colony-stimulating factor prevents febrile neutropenia induced by chemotherapy.

• Phase II evaluation of 3-day topotecan with cyclophosphamide in the treatment of recurrent ovarian cancer.

• Cellular glutathione content, in vitro chemoresponse, and the effect of BSO modulation in samples derived from patients with advanced ovarian

• First-line chemotherapy with weekly paclitaxel and carboplatin for advanced ovarian cancer: a phase I study.

• The benefits of comprehensive surgical staging in the management of early-stage epithelial ovarian carcinoma.

• A phase I dose-finding study of a combination of pegylated liposomal doxorubicin (Doxil), carboplatin and paclitaxel in ovarian cancer.

• A dose-finding study of carboplatin-epirubicin-docetaxel in advanced epithelial ovarian cancer.

• [Phase II study of combination therapy with paclitaxel and carboplatin against postoperative small residual disease in patients with stage I

• Nuclear and mitochondrial distribution of organoamidoplatinum(II) lesions in cisplatin-sensitive and -resistant adenocarcinoma cells.

• A comparison of liposomal formulations of doxorubicin with drug administered in free form: changing toxicity profiles.

• Acetaminophen modulations of chemotherapy efficacy in MDAH 2774 human endometrioid ovarian cancer cells in vitro.

• Adjuvant whole abdominal radiotherapy in epithelial cancer of the ovary.

• Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial.

• Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines.

• [Clinical characteristics of clear cell carcinoma of the ovary]

• Secondary cytoreductive surgery for recurrent epithelial ovarian cancer.

• Activity of ALRT 1550, a new retinoid, with interferon-gamma on ovarian cancer cell lines.

• Use of herbs in women diagnosed with ovarian cancer.

• Capecitabine in treatment of platinum-resistant recurrent ovarian cancer.

• Assessment of the classical MDR phenotype in epithelial ovarian carcinoma using primary cultures: a feasibility study.

• A phase I/II study of carboplatin and paclitaxel in patients with epithelial ovarian cancer.

• Timing of G-CSF administration based on the circadian rhythm in patients with ovarian cancer.

• Advanced ovarian cancer.

• Epithelial ovarian cancer.

• [Early results of topotecan therapy in patients with recurrent ovarian cancer]

1
UI - 11989013
AU - Lehtovirta P
TI - [Surgical treatment of ovarian cancer should be centralized]
SO - Duodecim 2000;116(10):1033-5

2
UI - 11695811
AU - Recchia F; De Filippis S; Rosselli M; Saggio G; Carta G; Rea S
TI - Primary chemotherapy in stage IV ovarian cancer. A prospective phase II study.
SO - Eur J Gynaecol Oncol 2001;22(4):287-91
AD - Oncologic Unit, Avezzano, Italy.
BACKGROUND AND RATIONALE: Non-curative surgical cytoreduction of advanced tumors is associated with increased proliferation of the remaining tumor cells. Thus, appropriate preoperative chemotherapy should prevent both cell proliferation and the increase of resistant cells. The aim of the present study was to evaluate the efficacy and toxicity of primary chemotherapy (P-CT) in previously untreated patients with stage IV ovarian cancer (OC). PATIENTS AND METHODS: Thirty-four with P-CT. Eligibility criteria included: histologically or cytologically confirmed, unresectable stage IV OC and performance status < or = 3. P-CT consisted of four courses of carboplatin, carboplatin thereafter. Surgery followed P-CT. After the operation patients received two further courses of chemotherapy that were tailored according to their individual response. Median (M) age was 61 years, range 32-73; median performance status was 2. A total number of 197 courses of CT were administered, median 5.7 per patient. RESULTS: Complete or partial response (CR, PR) was observed in 28 patients (response rate 82%, 95% CI: 65.4% to 93.2%), disease stability and progression (SD, PD) was observed in three and three patients, respectively. Median time to progression was 16.45 months (range 4.8-90.4+), median survival time was 28 months (range 4.5 - 90.4+): 1-year survival rate was 94%. Toxicity according to WHO: nausea and vomiting grade (G) 2, 30% of patients; gastrointestinal G 2-3, 20% of patients; alopecia G 3, 88% of patients; hematological G 3-4, 73% of patients; neurologic G 2, 12% of patients. Nine pathological CRs were observed. CONCLUSION: Neoadjuvant treatment with CBDCA with either CTX and EPI or Taxol is feasible and shows activity in OC.

3
UI - 11714451
AU - Hidaka T; Fujimura M; Sakai M; Saito S
TI - Macrophage colony-stimulating factor prevents febrile neutropenia induced by chemotherapy.
SO - Jpn J Cancer Res 2001 Nov;92(11):1251-8
AD - Department of Obstetrics and Gynecology, Toyama Medical and Pharmaceutical University, Toyama-shi, Toyama 930-0194.
There are very few studies describing the preventive effect of macrophage colony-stimulating factor (M-CSF/CSF-1) on chemotherapy-induced infection. In this study, we evaluated the changes in superoxide anion production by granulocytes before and after chemotherapy in ovarian cancer patients and investigated the preventive effect of M-CSF on chemotherapy-induced febrile neutropenia. Three courses of chemotherapy [paclitaxel 180 mg/m(2) and carboplatin (area under the curve; AUC 5)] were administered to 32 ovarian cancer patients, and seven patients presented febrile neutropenia. In the 25 afebrile patients, the percentage of superoxide anion production by granulocytes was significantly decreased from 86.5 +/- 7.7 (%) to 75.1 +/- 8.8 (%) at day 7 and 71.0 +/- 6.3 (%) at day 14 without administration of CSF. However, in the patients who presented febrile neutropenia, it was more severely decreased from 86.8 +/- 6.8 (%) to 60.0 +/- 9.9 (%) at day 7 and 56.8 +/- 5.0 (%) at day 14 without administration of CSF. When M-CSF was administered to all patients in the next course with the same dose of chemotherapy, the incidence of febrile neutropenia was significantly decreased (P = 0.0195), and the duration of fever (>or= 38.0 degrees C) and high serum C-reactive protein (CRP) (>or= 2.0 mg/dl) were also significantly shortened (P = 0.0023, P = 0.0051). Moreover, in these M-CSF-treated patients, the percentage of superoxide anion production by granulocytes was maintained at the level before chemotherapy. These findings indicate that severe impairment of granulocyte function leads to febrile neutropenia, and that M-CSF reduces the incidence of febrile neutropenia by maintaining or improving granulocyte function.

4
UI - 11972388
AU - Hanjani P; Nolte S; Shahin MS
TI - Phase II evaluation of 3-day topotecan with cyclophosphamide in the treatment of recurrent ovarian cancer.
SO - Gynecol Oncol 2002 May;85(2):278-84
AD - Division of Gynecologic Oncology, Abington Memorial Hospital, 1 Widener Building, 1200 Old York Road, Abington, PA 19001, USA. phanjani@amh.org
OBJECTIVE: The aim of this trial was to investigate the toxicity and efficacy of a 3-day topotecan administration schedule in combination with cyclophosphamide in the management of recurrent ovarian cancer. METHODS: Patients with recurrent measurable ovarian cancer who had up to two prior chemotherapy regimens for the management of their disease participating in this phase II trial were to receive topotecan at a dose of 1.25 mg/m(2)/day x 3 days in combination with cyclophosphamide at 600 mg/m(2) on Day 1 every 21 days. Dose escalation and reductions were permitted. RESULTS: A total of 36 patients (median age = 65; range 37-84) were treated with this combination regimen. Seventeen were platinum-sensitive and 19 were platinum-resistant. A total of 169 cycles of chemotherapy was administered (median = 4; range 1-10). Major toxicity included grade 4 neutropenia (68.6%), neutropenic fever (7.1%), grade 3 thrombocytopenia (18.3%), and requirement for blood transfusion (19.5%). Dose escalation was possible in 3 (8.3%), and dose reduction was required in 14 (38.9%) patients. Overall response rate was 25 and 44.5% stable disease. Median progression-free interval and overall survival was 5.4 and 23.5 months, respectively, independent of platinum sensitivity. CONCLUSION: The 3-day topotecan schedule in combination with cyclophosphamide appears to have good activity in recurrent ovarian cancer regardless of platinum sensitivity. Neutropenia was the only severe toxicity and was less prevalent than other reported trials of topotecan. This tolerable regimen offers patients more convenience and appears to have moderate activity. (c) 2002 Elsevier Science (USA).

5
UI - 11972391
AU - Lewandowicz GM; Britt P; Elgie AW; Williamson CJ; Coley HM; Hall AG;
TI - Sargent JM Cellular glutathione content, in vitro chemoresponse, and the effect of BSO modulation in samples derived from patients with advanced ovarian cancer.
SO - Gynecol Oncol 2002 May;85(2):298-304
AD - Haematology Research, Pembury Hospital, Pembury, Tunbridge Wells, Kent TN2 4QJ, United Kingdom.
OBJECTIVES: The objective was to assess the relationship between glutathione content and drug sensitivity with glutathione modulation in ovarian cancer in a pilot study using 31 samples of freshly obtained ovarian tumor material from 26 patients with advanced disease. METHODS: Processed tumor samples were screened to determine the glutathione content using an enzyme recycling assay modified for use in a 96-well plate format. Chemosensitivity testing (MTT assay) was used to assess sensitivity to cisplatin and doxorubicin and modulation using buthionine sulfoximine. Multidrug-resistance-associated protein MRP1 (putative drug-glutathione conjugate transporter) expression was also assessed. RESULTS: There was a significant increase in the tumor cell GSH levels in samples from patients who had received previous chemotherapy (9) versus those from chemotherapy-naive patients (20), P = 0.005. In vitro chemosensitivity testing with doxorubicin and cisplatin (using LC(50) values, i.e., drug dose causing 50% reduction in cell survival relative to untreated control) failed to show a relationship with glutathione levels. Coincubation of cisplatin and doxorubicin with buthionine sulfoximine resulted in a significant increase in sensitivity to both of these drugs overall (cisplatin, P = 0.05; doxorubicin, P = 0.025), with 20 samples showing sensitization to a drug to which they were previously resistant. MRP1 expression failed to show a correlation with drug sensitivity and glutathione levels. CONCLUSIONS: Our study supports the use of glutathione modulation using agents such as buthionine sulfoximine in patients with heavily pretreated, drug-resistant ovarian cancer. (c) 2002 Elsevier Science (USA).

6
UI - 11972395
AU - Sehouli J; Stengel D; Elling D; Ortmann O; Blohmer J; Riess H;
TI - Lichtenegger W; Ovarian Cancer Study Group of the Nordostdeutsche Gesellschaft fur Gynakologische Onkologie (NOGGO) First-line chemotherapy with weekly paclitaxel and carboplatin for advanced ovarian cancer: a phase I study.
SO - Gynecol Oncol 2002 May;85(2):321-6
AD - Department of Gynecology and Obstetrics, Charite Virchow University Hospital, Augustenberger Platz 1, 13353 Berlin, Germany. sehouli@aol.com
OBJECTIVES: Carboplatin and paclitaxel can be applied safely and effectively as single agents for the treatment of ovarian cancer on a weekly basis. A multicenter, phase-I study was conducted to investigate the maximum tolerated dose of a weekly combination regimen. METHODS: We enrolled 21 patients with primary, surgically resected, advanced ovarian cancer (FIGO III/ IV) and a median age of 59 (range, 35 to 79) years. For a fixed dose of paclitaxel at 100 mg/m(2), carboplatin was administered at levels equating an area under the curve of 2.0 (6 patients), 2.5 (7 patients), and 3.0 (8 patients), respectively. Treatment schedule consisted of six cycles with drug delivery once a week, followed by a 2-week break, and another six cycles. After a treatment-free interval of 28 days, three more cycles were administered. RESULTS: No dose-limiting toxicity was observed at the first level. Three patients developed dose-limiting toxicity (thrombocytopenia, neutropenic fever, and grade 3 neuropathy) receiving carboplatin at area under the curve 2.5. Another three patients developed dose-limiting toxicity at the highest carboplatin dose, of whom two encountered refractory thrombocytopenia, whereas another experienced neutropenic fever despite prophylactic granulocyte-colony-stimulating factor use. Alopecia was documented in 17 patients. Neurotoxicity was usually mild to moderate. CA-125 concentrations normalized (<35 U/ml) in 13 of 19 patients (68%) by the end of therapy. A 50% response was observed in 16 of 19 subjects. CONCLUSIONS: Weekly carboplatin and paclitaxel is a well-tolerated combination regimen in patients with primary, advanced ovarian cancer. The recommended dose for a phase II study is carboplatin at 100 mg/m(2) and carboplatin at area under the curve 2.0. (c) 2002 Elsevier Science (USA).

7
UI - 11972399
AU - Le T; Adolph A; Krepart GV; Lotocki R; Heywood MS
TI - The benefits of comprehensive surgical staging in the management of early-stage epithelial ovarian carcinoma.
SO - Gynecol Oncol 2002 May;85(2):351-5
AD - Division of Gynecologic Oncology, Dept. of Obstetrics, Gynecology, and Reproductive Sciences, University of Saskatchewan, Royal University Hospital, 103 Hospital Drive, Saskatoon, Saskatchewan, Canada S7N 0W8. letien@duke.usask.ca
OBJECTIVE: The management of understaged patients with apparent clinically early ovarian cancer is difficult. Options include offering chemotherapy based on histopathologic factors or reoperation to obtain the necessary information needed to assign an accurate surgical stage. This study aims to compare these two approaches and to define the role of staging surgery in this common patient population. METHODS: Retrospective chart reviews were carried out at the Universities of Manitoba and Saskatchewan over the period 1975 to 1999. Demographic data and surgical findings were abstracted and entered into a computerized database for analysis. Patients not having surgical staging procedures were offered platinum-based chemotherapy based on high tumor grades, dense adhesions, and presence of surface excrescences or large necrotic areas. Patients with surgically proven stage I disease were treated with no further therapy regardless of histopathologic factors. Descriptive statistics are used to summarize the data. Logistic and Cox regression models are used to identify significant predicting factors for recurrences and progression-free intervals. RESULTS: One hundred and thirty-eight patients presented with tumor macroscopically confined to the ovary at the time of laparotomy. The median age at presentation is 56.5 (18-90). The histology distribution was serous tumor in 28.3%, mucinous in 26.1%, endometrioid in 23.2%, clear cell in 14.5%, anaplastic in 2.2%, and mixed types in 5.8%. The grade distribution was 47.1% grade 1, 27.5% Grade 2, and 25.4% Grade 3. Sixty-eight percent of the patients had a comprehensive surgical staging procedure initially. Thirty-six percent of these patients were found to have extraovarian metastases and were subsequently treated with adjuvant chemotherapy. Forty-three percent of those not having staging laparotomy were offered chemotherapy based on high risk factors only. At a median follow-up of 58 months. 77% of patients remained disease-free and 23% had recurrent disease. Of 60 patients with surgically proven stage I treated expectantly, 6 (10%) recurred, whereas of 25 unstaged patients treated expectantly due to lack of risk factors 7 (28%) recurred (P = 0.036). In patients treated expectantly, a significant survival advantage was noted in the staged group. Logistic regression showed age (OR 1.032, P = 0.043), high grade (OR 4.16, P = 0.003), and lack of a proper staging surgery (OR 2.62, P = 0.032) to be important factors predicting recurrence. In terms of progression-free interval, only age (OR 1.027, P = 0.048) and tumor grade (OR 3.62, P = 0.05) are significant predictors. CONCLUSION: Absence of surgical pathologic high-risk factors is inferior to comprehensive staging laparotomy findings in guiding recommendations for subsequent adjuvant therapy. Patients who have not been properly staged stand a significant risk of recurrent disease despite more frequent use of chemotherapy. All clinically early-stage ovarian cancer patients should be considered for comprehensive staging surgery prior to further treatment recommendations. (c) 2002 Elsevier Science (USA).

8
UI - 11986767
AU - Gibbs DD; Pyle L; Allen M; Vaughan M; Webb A; Johnston SR; Gore ME
TI - A phase I dose-finding study of a combination of pegylated liposomal doxorubicin (Doxil), carboplatin and paclitaxel in ovarian cancer.
SO - Br J Cancer 2002 May 6;86(9):1379-84
AD - Department of Medicine, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
Standard chemotherapy for advanced epithelial ovarian cancer is a combination of platinum-paclitaxel. One strategy to improve the outcome for patients is to add other agents to standard therapy. Doxil is active in relapsed disease and has a response rate of 25% in platinum-resistant relapsed disease. A dose finding study of doxil-carboplatin-paclitaxel was therefore undertaken in women receiving first-line therapy. Thirty-one women with epithelial ovarian cancer or mixed Mullerian tumours of the ovary were enrolled. The doses of carboplatin, paclitaxel and doxil were as follows: carboplatin AUC 5 and 6; paclitaxel, 135 and 175 mg m(-2); doxil 20, 30, 40 and 50 mg m(-2). Schedules examined included treatment cycles of 21 and 28 days, and an alternating schedule of carboplatin-paclitaxel (q 21) with doxil being administered every other course (q 42). The dose-limiting toxicities were found to be neutropenia, stomatitis and palmar plantar syndrome and the maximum tolerated dose was defined as; carboplatin AUC 5, paclitaxel 175 mg m(-2) and doxil 30 mg m(-2) q 21. Reducing the paclitaxel dose to 135 mg m(-2) did not allow the doxil dose to be increased. Delivering doxil on alternate cycles at doses of 40 and 50 mg m(-2) also resulted in dose-limiting toxicities. The recommended doses for phase II/III trials are carboplatin AUC 6, paclitaxel 175 mg m(-2), doxil 30 mg m(-2) q 28 or carboplatin AUC 5, paclitaxel 175 mg m(-2), doxil 20 mg m(-2) q 21. Grade 3/4 haematologic toxicity was common at the recommended phase II doses but was short lived and not clinically important and non-haematologic toxicities were generally mild and consisted of nausea, paraesthesiae, stomatitis and palmar plantar syndrome. Copyright 2002 Cancer Research UK

9
UI - 11986768
AU - O'Neill VJ; Kaye SB; Reed NS; Paul J; Davis JA; Vasey PA
TI - A dose-finding study of carboplatin-epirubicin-docetaxel in advanced epithelial ovarian cancer.
SO - Br J Cancer 2002 May 6;86(9):1385-90
AD - Cancer Research UK Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow GL1 6NT, UK. vjon1q@udcf.gla.ac.uk
The docetaxel-carboplatin combination is active and well tolerated in patients with epithelial ovarian cancer. We added epirubicin to this combination to investigate additional benefits of anthracyclines in epithelial ovarian cancer. Twenty-one patients, FIGO Ic-IV, performance status 0-1, were treated in four dose cohorts. Docetaxel was fixed at 75 mg m(-2), carboplatin doses were AUC 4-5 and epirubicin doses were 50-60 mg m(-2). Drugs were given on day 1, every 3 weeks, except in cohort 3, where epirubicin was given on day 8. Dexamethasone was given prophylactically. One dose-limiting toxicity occurred in cohorts 1, 2 and 4, two occurred in cohort 3. Complicated neutropenia occurred in two patients in cohorts 1 and 2 and one patient in cohorts 3 and 4. Two patients experienced grade III diarrhoea or stomatitis in cohort 1 and two in cohort 3. There were no treatment-related deaths. Grade II sensory neuropathy occurred in one patient. No cardiac toxicity or significant oedema was observed. The overall response rate was 36%, and 62% were CA125 responders. The predefined maximum tolerated dose was exceeded in cohort 3. The cohort 4 dose level (epirubicin 50 mg m(-2), carboplatin AUC 4, docetaxel 75 mg m(-2)), warrants further study. Copyright 2002 Cancer Research UK

10
UI - 12040675
AU - Nakata Y; Yamada T; Itoh R; Koishi K; Hiraoka K; Yamagami K; Itani Y;
TI - Toyoda S; Itoh K; Kimura T; Hosokawa K; Honjo H; Fujita H; Koshiba H; Hara Y; Tsuchiya H; Adachi S [Phase II study of combination therapy with paclitaxel and carboplatin against postoperative small residual disease in patients with stage I c-IV ovarian cancer--KCOG 989 trial]
SO - Gan To Kagaku Ryoho 2002 May;29(5):717-22
AD - Obstetrics and Gynecology, Kyoto First Redcross Hospital.
The tolerability and feasibility of combination therapy with paclitaxel (TXL) and carboplatin (CBDCA) against small residual disease following first-line optimal debulking of stage I c-IV ovarian cancer were evaluated in a multicenter dose-finding study. Eligibility criteria included histologically diagnosed stage I c-IV epithelial ovarian cancer with a postoperative residual lesion < or = 10 mm in diameter, no prior chemotherapy, and written informed consent of the patient and his/her family members to the chemotherapy. Twenty-two patients were enrolled and 20 of them were eligible. The patients were to receive 5 courses of TXL (175 mg/m2) and CBDCA (AUC 5) every 3 weeks. Hematological toxicities occurred in the form of grade 3 leukopenia during 25.7% of all courses, grade 3 neutropenia during 32.0% of all courses, and grade 4 neutropenia during 56.0% of all courses. No courses were associated with grade 4 leukopenia. G-CSF support was needed during 48 of 109 courses (44%) and caused normalization of the leukocyte count from a nadir of 1,921 +/- 434/mm3 after a mean time of 6 +/- 3.1 days, compared with 6 +/- 3.6 days needed for recovery from a nadir of 2, 357 +/- 360/mm3 without G-CSF support. This indicates similarly rapid recovery from severe leukopenia with the use of G-CSF. All eligible patients completed at least 5 courses of the chemotherapy. Some courses were given at a reduced dose or delayed due to toxicity but these dosage modifications were thought to be acceptable for both TXL and CBDCA. Five courses of TXL combined with CBDCA were tolerated well in this patient population.

11
UI - 11962511
AU - Talarico T; Cullinane CM; Gray PJ; Webster LK; Deacon GB; Phillips DR
TI - Nuclear and mitochondrial distribution of organoamidoplatinum(II) lesions in cisplatin-sensitive and -resistant adenocarcinoma cells.
SO - Anticancer Drug Des 2001 Apr-Jun;16(2-3):135-41
AD - Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Fitzroy, Australia.
The DNA binding pattern of the organoamidoplatinum(II) compound 1a is of considerable interest because of its known activity against cisplatin-resistant cells. The activity of 1a appears to be due at least in part to a greater cellular uptake than cisplatin into cisplatin-resistant cells, but little is known of the DNA reactions of the organoamidoplatinum(II) compounds. In this study the level of DNA cross-linking and total DNA lesions formed by 1 a were measured by gene-specific Southern hybridization cross-linking assays and by quantitative PCR in cisplatin-sensitive (2008) and in cisplatin-resistant 2008/R human adenocarcinoma cell lines. The surprising result was that the major difference between cisplatin and 1a was that the number of interstrand cross-links induced by 1a were approximately 5-fold greater than that induced by cisplatin in the nuclear (but not mitochondrial) DNA of resistant cells, even though the total number of lesions were essentially the same in both sensitive and resistant cells. This result suggests that the extent of interstrand cross-linking is a critical determinant of the cellular response to 1a and that the enhanced uptake of 1a into resistant cells results in this elevated level of cross-linking, leading to good activity of 1a against cisplatin-resistant cells. It remains unclear as to why 1a exhibits such selective damage to nuclear DNA, and insight into the molecular aspects of this selectivity will provide new opportunities for the further development of new platinum-based agents with activity against cisplatin-resistant cells.

12
UI - 11735647
AU - Waterhouse DN; Tardi PG; Mayer LD; Bally MB
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. dsaxon@bccancer.bc.ca
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.

13
UI - 12044058
AU - Bilir A; Altinoz MA; Attar E; Erkan M; Aydiner A
TI - Acetaminophen modulations of chemotherapy efficacy in MDAH 2774 human endometrioid ovarian cancer cells in vitro.
SO - Neoplasma 2002;49(1):38-42
AD - Department of Histology and Embryology, Istanbul Medical School, Faculty of Science, Turkey. bilira@istanbul.edu.tr
Epidemiological data have correlated consumption of nonsteroidal antinflammatory drugs with lowered risk for many types of cancer, and some recent studies indicate a reverse correlation with acetaminophen consumption and ovarian malignancy. In this study we examined effects of acetaminophen on plating, S-phase and colony growth of MDAH 2774 human endometrioid ovarian carcinoma, as well as sensitivity of this cell line to carboplatin in all three tests, and paclitaxel to clonogenic assay. Acetaminophen significantly enhanced S-phase in first 72 hours and enhanced cell population in 96 hours of plating monitorization, but decreased one week colony growth by approximately 80%, which was in the range of cytotoxic drugs. Interestingly with low dose carboplatin in first 72 hours acetaminophen enhanced cell proliferation more profoundly, but only thereafter decreased cell growth synergistically with carboplatin. It did not effect paclitaxel colony growth inhibiting acitivity. MDAH-2774 cell line lack p-53 and MSH-2, which are both 'gatekeeper' apoptosis inducing genes against genome damaging insult. Thus, presence of lower doses of oxidizing drugs may help the induction of proliferative signals, but only their sustained presence may overcome such signals and ultimately bring to cell demise.

14
UI - 12023140
AU - Hepp R; Baeza MR; Olfos P; Suarez E
TI - Adjuvant whole abdominal radiotherapy in epithelial cancer of the ovary.
SO - Int J Radiat Oncol Biol Phys 2002 Jun 1;53(2):360-5
AD - Radiation Oncology, Instituto de Radiomedicina, Santiago, Chile.
PURPOSE: To reexamine the use of adjuvant radiotherapy in optimally 1998, 60 patients were treated with adjuvant whole abdominal radiotherapy (A-WART). The stage distribution was Stage IC in 17 patients, Stage II in 9, and Stage III in 34. The grade distribution was Grade 1 in 9 patients, Grade 2 in 27, and Grade 3 in 24; thus, 60% of the patients had Stage III disease and 40% had Grade 3 tumors. After surgery, no residuum was left in 42 (70%), 2 cm in 5 (8%) of 60 patients. Of the 60 patients, 19 also received platinum-based chemotherapy; in 12 of the 19, the chemotherapy was before A-WART. Thirty-seven of the patients had undergone previous abdominal procedures and a second-look operation was performed in 25% of them. A-WART consisted of 22 Gy in 22 fractions, at 5 fractions weekly in 90% of the patients. The remaining 10% received 25 Gy in 25 fractions within 5 weeks. The A-WART was delivered using a 4-MV linear accelerator. After abdominal irradiation, a boost to the pelvis was given to reach 45 Gy at 1.8 cGy/fraction, using a 4-15-MV linear accelerator. RESULTS: Treatment was delivered in a median of 50 days (range 48-70). In 12 (20%) of the 60 patients, a transient treatment interruption occurred because of acute toxicity, mainly vomiting and diarrhea. The overall survival rate was 55% at 5 years (median follow-up 96.5 months). Patients with low-histologic grade tumors (Grade 1-2) had a better 5-year survival rate (66%) than those with Grade 3 tumors (35%; p <0.03). A tendency for better survival was found for those with Stage I-II than for those with Stage III (69% vs. 43%). Nonetheless, this difference did not reach statistical significance (p = 0.17). For patients receiving chemotherapy, the 5-year survival rate was 51%, not statistically different from the 58% 5-year survival rate observed among those patients without adjuvant chemotherapy (p = 0.9). The abdominal control rate was 83%. Thirty-five percent of the patients sustained acute Grade 2-3 complications. Late complications were observed in 6 of 60 patients, 4 had Grade 3 (7%) and 2 had Grade 4 (3%). Two patients died of intestinal occlusion, both had undergone previous abdominal procedures and in 1, no tumor was found in the abdomen at the postmortem examination. CONCLUSION: A-WART achieves a quite favorable 5-year survival rate with a low complication rate in properly selected patients. A-WART should be included in the elective postoperative treatment of ovarian cancer patients who are at risk of abdominal failure, and this should be explored in a randomized trial.

15
UI - 11454891
AU - Hortobagyi GN; Ueno NT; Xia W; Zhang S; Wolf JK; Putnam JB; Weiden PL;
TI - Willey JS; Carey M; Branham DL; Payne JY; Tucker SD; Bartholomeusz C; Kilbourn RG; De Jager RL; Sneige N; Katz RL; Anklesaria P; Ibrahim NK; Murray JL; Theriault RL; Valero V; Gershenson DM; Bevers MW; Huang L; Lopez-Berestein G; Hung MC Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial.
SO - J Clin Oncol 2001 Jul 15;19(14):3422-33
AD - Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. ghorto@notes.mdacc.tmc.edu
PURPOSE: Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu-overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu-overexpressing and low HER-2/neu-expressing breast and ovarian cancers in a phase I clinical trial. PATIENTS AND METHODS: An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12). RESULTS: E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites. CONCLUSION: These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.

16
UI - 12039923
AU - Disis ML; Gooley TA; Rinn K; Davis D; Piepkorn M; Cheever MA; Knutson
TI - KL; Schiffman K Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines.
SO - J Clin Oncol 2002 Jun 1;20(11):2624-32
AD - Division of Oncology and Department of Dermatology, University of Washington, Seattle 98195-6527, USA. ndisis@u.washington.edu
PURPOSE: The HER-2/neu protein is a nonmutated tumor antigen that is overexpressed in a variety of human malignancies, including breast and ovarian cancer. Many tumor antigens, such as MAGE and gp100, are self-proteins; therefore, effective vaccine strategies must circumvent tolerance. We hypothesized that immunizing patients with subdominant peptide epitopes derived from HER-2/neu, using an adjuvant known to recruit professional antigen-presenting cells, granulocyte-macrophage colony-stimulating factor, would result in the generation of T-cell immunity specific for the HER-2/neu protein. PATIENTS AND METHODS: Sixty-four patients with HER-2/neu-overexpressing breast, ovarian, or non-small-cell lung cancers were enrolled. Vaccines were composed of peptides derived from potential T-helper epitopes of the HER-2/neu protein admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally. Peripheral-blood mononuclear cells were evaluated at baseline, before vaccination, and after vaccination for antigen-specific T-cell immunity. Immunologic response data are presented on the 38 subjects who completed six vaccinations. Toxicity data are presented on all 64 patients enrolled. RESULTS: Ninety-two percent of patients developed T-cell immunity to HER-2/neu peptides (stimulation index, 2.1 to 59) and 68% to a HER-2/neu protein domain (stimulation index range, 2 to 31). Epitope spreading was observed in 84% of patients and significantly correlated with the generation of a HER-2/neu protein-specific T-cell immunity (P =.03). At 1-year follow-up, immunity to the HER-2/neu protein persisted in 38% of patients. CONCLUSION: The majority of patients with HER-2/neu-overexpressing cancers can develop immunity to both HER-2/neu peptides and protein. In addition, the generation of protein-specific immunity, after peptide immunization, was associated with epitope spreading, reflecting the initiation of an endogenous immune response. Finally, immunity can persist after active immunizations have ended.

17
UI - 11953086
AU - Shi M; Zhang Y; Shen K; Lang J; Huang H; Wu M
TI - [Clinical characteristics of clear cell carcinoma of the ovary]
SO - Zhonghua Fu Chan Ke Za Zhi 2002 Mar;37(3):161-3
AD - Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
OBJECTIVE: To study the clinical characteristics of clear cell carcinoma of the ovary. METHODS: Forty three patients with clear cell carcinoma of the ovary and 51 patients with serous adenocarcinoma of the ovary who were admitted in Peking Union Medical College Hospital between 1984 to 2000 were analyzed retrospectively, and their chemosensitivities and the survival rates were compared. RESULTS: The percentage of early stage patients in the clear cell carcinoma of the ovary and the serous adenocarcinoma of the ovary was 14.4% and 3.8% respectively, the difference was significant (P < 0.005). In the late stage patients who underwent satisfactory cytoreductive surgery, the chemo-resistant rate (88.9%) in the clear cell carcinoma of the ovary was significantly higher than that (57.1%) of the serous adenocarcinoma of the ovary (P < 0.02), the 1-year survival rate (79.0%) in the clear cell carcinoma of the ovary was significantly lower than that (96.2%) of the serous adenocarcinoma of the ovary (P < 0.01). In the late stage patients who underwent unsatisfactory cytoreductive surgery, the chemo-resistant rate and the survival rate had no significant difference between the clear cell carcinoma of the ovary and the serous adenocarcinoma of the ovary (P > 0.05). CONCLUSIONS: There are more early stage patients with clear cell carcinoma of the ovary. We should conduct auxiliary therapy and close follow up to them after surgery. Clear cell carcinoma of the ovary is chemo-resistant to platinum-based chemotherapy and has poor prognosis.

18
UI - 12052591
AU - Tay EH; Grant PT; Gebski V; Hacker NF
TI - Secondary cytoreductive surgery for recurrent epithelial ovarian cancer.
SO - Obstet Gynecol 2002 Jun;99(6):1008-13
AD - Gynaecological Cancer Centre, Royal Hospital for Women, Department of Obstetrics and Gynaecology, University of New South Wales, Sydney, Australia.
OBJECTIVE: To review our experience with secondary cytoreductive surgery for recurrent epithelial ovarian cancer with regard to its feasibility, morbidity, mortality, patient selection, and survival. METHODS: Forty-six patients who underwent secondary cytoreductive surgery at the were retrospectively reviewed. The mean age at surgery was 50.3 years, and the median disease-free interval was 26 months. Eighty-nine percent of patients had a disease-free interval of at least 12 months. Twenty-five patients (54%) had localized disease at the time of surgery. Univariate survival outcomes were analyzed using the log rank test, and survival curves were calculated using the method of Kaplan-Meier. RESULTS: Two patients (4%) were inoperable and 19 patients (41%) were cytoreduced to no macroscopic disease. There was one postoperative death (2%), and four patients (8.7%) had significant postoperative morbidity. With a median follow-up of 88 months, the overall median survival was 22.5 months. Patients with a disease-free interval of less than 12 months after their initial treatment had a median survival of 6 months, compared with 11 months if the disease-free interval was 12-24 months and 39 months for those with a disease-free interval of 24 months or more (P =.001, log rank). Patients who had any residual disease had a median survival of 11 months, whereas those with no residual disease had a median survival of 38 months (P =.002, log rank). CONCLUSION: For carefully selected patients with recurrent epithelial ovarian cancer: 1) complete surgical resection is feasible more commonly than with primary cytoreduction, 2) serious morbidity and mortality are acceptable, and 3) significant survival benefit accrues when a) all macroscopic disease can be resected, or b) the disease-free interval is 24 months or more.

19
UI - 11975681
AU - Hu W; Verschraegen CF; Wu WG; Nash M; Freedman RS; Kudelka A; Kavanagh
TI - JJ Activity of ALRT 1550, a new retinoid, with interferon-gamma on ovarian cancer cell lines.
SO - Int J Gynecol Cancer 2002 Mar-Apr;12(2):202-7
AD - Department of Gynecologic Medical Oncology, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. weihu@mdanderson.org
Retinoids have been shown to be effective regulators of cell proliferation and differentiation in many human cancers. The major biologic activity of the retinoids is mediated by two families of nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). ALRT 1550 is one of the most potent RAR selective retinoids discovered to date, with 10-100 times more activity than ATRA in competitive binding and cotransfection assays and 300 times more inhibiting activity against proliferation of cervical carcinoma cell. To evaluate the role of ALRT 1550 in ovarian cancer, the growth inhibitory activity of ALRT 1550 was determined in the ATRA-resistant ovarian cancer cell line SKOV-3 and ovarian cancer cell line 2774 after exposure to concentrations of 0.1, 1, 2.5, 5, and 10 microM for 7 days. SKOV-3 showed 51%, 53%, and 68% cell growth inhibition after treatment with ALRT 1550 at concentrations of 2.5, 5, and 10 microM, respectively, and the 2774 cell line showed 46% inhibition after treatment at 10 microM. Because interferon (IFN)-gamma was found to synergistically amplify the growth inhibition of retinoids in cultured breast cancer cells, we investigated the combination of ALRT 1550 with IFN-gamma in two ovarian cancer cell lines. ALRT 1550 (5 microM) in combination with IFN-gamma at a concentration of 500 U/ml inhibited cell growth of SKOV-3 by as much as 81% (CI = 1.88). This is a 28% greater effect than with ALRT alone. Cell line 2774 showed a 69% cell growth inhibitory effect with ALRT 1550 (5 microM) in combination with IFN-gamma at a concentration of 1000 U/ml (CI = 1.03). ALRT 1550 and IFN-gamma may act synergistically in the SKOV-3 ovarian cancer cell line and additively in the 2774 cell line. In conclusion, ALRT 1550 may be a promising drug with a high biologic modulating activity against ovarian cancer. In combination with IFN-gamma, additive and perhaps synergistic effects may be seen in some ovarian cancer cell lines. Combining these two biologic modifiers for the treatment of ovarian cancer may lower the effective dose of the retinoids, thus decreasing their side effects.

20
UI - 11975683
AU - Powell CB; Dibble SL; Dall'Era JE; Cohen I
TI - Use of herbs in women diagnosed with ovarian cancer.
SO - Int J Gynecol Cancer 2002 Mar-Apr;12(2):214-7
AD - Department of Obstetrics, Gynecology, and Reproductive Services, Comprehensive Cancer Center, University of California-San Francisco, Box 1702, San Francisco, CA 94143-1702, USA. Bethan.Powell@ucsfmedctr.org
Of 113 consecutive ovarian cancer patients identified in a gynecologic clinic in a major academic medical center in San Francisco, 41 patients were successfully contacted, were eligible, and participated in a telephone survey. We contacted women identified consecutively in the clinic database as having ovarian cancer and sent a letter introducing our research team and asking for help. Members of the research team then contacted the women to conduct the telephone interviews. Fifty-one percent (95% CI 35-67) of the women had taken herbs sometime since they were diagnosed with ovarian cancer. Most herb uses occurred concurrently with chemotherapy. Only 12% (95% CI 4-26) used an herbalist or other health practitioner for guidance in herb use. Only one woman took herbs instead of chemotherapy. A large number of women attending our practice in the San Francisco Bay area use herbs as complementary medicine during their cancer treatment.

21
UI - 12017329
AU - Boehmer Ch; Jaeger W
TI - Capecitabine in treatment of platinum-resistant recurrent ovarian cancer.
SO - Anticancer Res 2002 Jan-Feb;22(1A):439-43
AD - Department of Obstetrics and Gynecology, University of Erlangen-Nuremberg, Erlangen, Germany. chboehmer@yahoo.de
The aim of this study was to analyze the toxicity and response rate of capecitabine in patients with recurrent ovarian cancer resistant to platinum and paclitaxel. Fourteen patients were enrolled in this phase I/II protocoL Capecitabine was administered orally in a dose of 2500 mg/m2/24 hours. A single therapy cycle consisted of a 2-week treatment, followed by a 2-week treatment-free interval. Patients were eligible for response evaluation if they completed more than one cycle of capecitabine. Cessation of chemotherapy due to toxicity was necessary in two patients. Diarrhea and hand-foot syndrome were the most common side-effects. In twelve patients eligible for response, there was one complete responder (8.3%), two partial responders (16.7%) and no change in three patients (25.0%). Progression of disease occurred in six patients (50.0%). Capecitabine exhibits antitumoral activity in ovarian cancer resistant to platinum and paclitaxel and should be evaluated in further studies.

22
UI - 12017336
AU - Coley HM; Sargent JM; Williamson CJ; Titley J; Scheper RJ; Gregson SE;
TI - Elgie AW; Lewandowicz GM; Taylor CG Assessment of the classical MDR phenotype in epithelial ovarian carcinoma using primary cultures: a feasibility study.
SO - Anticancer Res 2002 Jan-Feb;22(1A):69-74
AD - Haematology Research, Pembury Hospital, Kent, UK.
This in vitro feasibility study has assessed a number of techniques and their applicability when looking at the role of multidrug resistance (MDR) in solid tumours. Fresh tumour material was obtained from 34 patients, (11 previously treated, 23 untreated) with ovarian adenocarcinoma. Doxorubicin sensitivity was measured using the MTT assay +/- the cyclosporins, Pgp expression was assessed by immunocytochemistry with the MRK-16 MoAb and flow cytometry was used to assess intracellular drug accumulation +/- PSC 833. 85% of samples showed some evidence of modest chemosensitisation by the cyclosporins (median 1.74-fold). We saw a marked variation in the number of Pgp positive cells between patients (1-87%, median 31%). 63% of samples tested showed an enhancement of DNR accumulation in the presence of PSC 833, with a median increase of 7% (sample range 0-29%). The present study highlights some of the technical difficulties encountered when working with fresh tumour material ex vivo. We conclude that screening of patients for their suitability to enter clinical trials incorporating MDR modulating agents is technically demanding, but feasible.

23
UI - 12072422
AU - Yamamoto R; Minobe S; Kaneuchi M; Sakuragi N; Fujimoto S; Ishizaki Y;
TI - Domon H; Hareyama H; Sato C; Fujino T; Kawaguchi I; Yamaguchi T; Fujimoto T; Yoshiaki K A phase I/II study of carboplatin and paclitaxel in patients with epithelial ovarian cancer.
SO - Jpn J Clin Oncol 2002 Apr;32(4):128-34
AD - Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Sapporo, Japan. rityam@med.hokudai.ac.jp
BACKGROUND: This study was conducted to investigate the recommended dose of paclitaxel for use in combination with a fixed dose of carboplatin and to evaluate the toxicity and efficacy of carboplatin-paclitaxel combination chemotherapy in patients with epithelial ovarian cancer. METHODS: One hundred and ten patients were enrolled in the Phase I/II study and 97 patients were evaluated for further analysis, excluding 13 ineligible patients or patients with infringement of protocol: 15 patients for the Phase I and 82 for the Phase II study. In the Phase I trial, we studied dose escalation using a carboplatin dose of AUC 5 and paclitaxel levels of 150, 175 and 200 mg/m(2). The grades of toxicity of the regimen of all patients enrolled in the Phase II study (n = 82), the progression-free survival time (PFS) of optimal-debulked patients and complete responders (n = 62) and the response rate of suboptimal-debulked patients (n = 39) were investigated. RESULTS: After observing grade 4 neutropenia in four of six patients in the paclitaxel 200 mg/m(2) administration group, we chose 175 mg/m(2) as the recommended dose of paclitaxel in this regimen. At this dose, the median of PFS and response rate were 432 days (range, 19-907 days) and 66.7%, respectively. CONCLUSION: Combination chemotherapy using paclitaxel 175 mg/m(2) and carboplatin AUC 5 is very well tolerated and highly effective for the treatment of ovarian cancer.

24
UI - 12040291
AU - Sato S; Kigawa J; Irie T; Itamochi H; Kanamori Y; Kamazawa S; Akeshima
TI - R; Terakawa N Timing of G-CSF administration based on the circadian rhythm in patients with ovarian cancer.
SO - Am J Clin Oncol 2002 Jun;25(3):289-90
AD - Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan.
The aim of this study was to determine the relationship between the timing of granulocyte colony-stimulating factor (G-CSF) administration and its efficacy in patients with chemotherapy-induced granulocytopenia. Twenty patients in whom chemotherapy-induced leukopenia developed after the first course were enrolled in this prospective study. Subjects were randomly divided in two groups according to G-CSF injection time as follows: at 7:00 am and 7:00 pm. Before the G-CSF injection, the plasma G-CSF level for all patients was significantly lower at 7:00 am than that at 7:00 pm. After the injection, plasma G-CSF level did not differ between the two groups. The nadir of the leukocyte was 2,554 +/- 379/mm3 (granulocyte 1,530 +/- 689) for the group injected at 7:00 am, and 2,300 +/- 426/mm3 (granulocyte 1,203 +/- 848) for the group injected at 7:00 pm. The duration of leukocytes less than 2,000/mm3 and granulocytes less than 1,000/mm3 were 2.8 +/- 1.8 days and 3.2 +/- 1.8 days, respectively. Those differences were not significant. The present study showed the circadian rhythm of G-CSF levels in patients with ovarian cancer with chemotherapy-induced granulocytopenia, but there was no remarkable difference depending on administration time.

25
UI - 12057129
AU - van der Burg ME
TI - Advanced ovarian cancer.
SO - Curr Treat Options Oncol 2001 Apr;2(2):109-18
AD - Department of Medical Oncology, University Hospital Rotterdam Dijkzigt, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
Ovarian cancer spreads early in the disease into the abdomen. An en bloc resection of the tumor, according to surgical principle, is not possible in patients with high-stage ovarian cancer. At surgery, large pelvic tumor lesions are found together with multiple tumor lesions involving the omentum, bowel, and mesentery together with a diffuse peritoneal carcinomatosis and diaphragmatic involvement. A multimodality approach with cytoreductive surgery and taxol platinum-based chemotherapy is therefore the mainstay of treatment of advanced ovarian cancer. The size of residual disease after surgery is one of the most important prognostic factors for survival. Patients with an opt

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