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NCI CANCERLIT® Search: Therapy of Ovarian Cancer - September 2001
Last Modified: November 1, 2001

Table of Contents

CancerMail from the National Cancer Institute

1
UI - 21221407
AU - Erickson JR; Hasegawa Y; Fang X; Eder A; Mao M; Furui T; Aoki J; Morris A; Mills GB
TI - Lysophosphatidic acid and ovarian cancer: a paradigm for tumorogenesis and patient management.
SO - Prostaglandins Other Lipid Mediat 2001 Apr;64(1-4):63-81
AD - Atairgin Technologies, Irvine, CA 92612 USA.

2
UI - 21356201
AU - Perez-Calvo J; Martinez-Aguillo M; Garcia-Rayo S; Ramon y Cajal T; Santisteban M; Ordonez JM; Inoges S; Subira ML; Martin-Algarra S; Brugarolas A
TI - Factors determining the actual received dose intensity in a program of multicyclic dose-intensive alternating chemotherapy with sequential stem cell support.
SO - Acta Haematol 2001;105(3):137-42
AD - Department of Oncology and Cell Therapy Area, Clinica Universitaria de Navarra, Pamplona, Spain. jpcalvo@unav.es
Dose intensity has been related to clinical outcome in several solid tumors. We studied the influence of clinical and cellular parameters on dose intensity received in a series of 53 patients with metastatic breast cancer or advanced ovarian cancer. They received courses of cisplatin 120 mg/m(2) plus etoposide 600 mg/m(2) alternating every 14 days with ifosfamide 8 g/m(2) plus paclitaxel 200--350 mg/m(2). Blood stem cell support was administered after every course except for the first one. Patients with excellent mobilization underwent immunomagnetic selection of CD34+ cells. We found a significant inverse correlation between the CD34+ cell dose infused and the delay for the administration of the next cycle. A CD34+ cell dose between 1.5 and 5 x 10(6)/kg per cycle was found to be feasible and was followed by a median delay of 1 day (not different from doses above 5 x 10(6)/kg). Three factors independently predicted the actually received dose intensity in a multiple regression model (R(2) = 0.4): previous autologous transplantation, eligibility for immunomagnetic selection (excellent response to mobilization) and median CD34+ cell dose received along the treatment. Copyright 2001 S. Karger AG, Basel

3
UI - 21388246
AU - Fraifeld V; Seidman R; Sagi O; Muradian K; Wolfson M
TI - Aurintricarboxylic acid decreases proliferative potential of SKOV3 and MCF7 human carcinoma cells.
SO - Anticancer Res 2001 May-Jun;21(3B):1975-8
AD - Department of Clinical Pharmacology, Center for the Multidisciplinary Research in Aging, Ben-Gurion University of the Negev, Beer-Sheva, Israel. vadimfra@zahav.net.il
The effect of aurintricarboxylic acid (ATA) on cell growth and proliferative capacity was studied in human ovarian SKOV3 and breast MCF7 carcinoma cells. ATA moderately inhibited cell growth measured by a Neutral red assay after a 24-hour incubation of the cells in the presence of ATA. The ATA-treated cells displayed a markedly decreased capacity to proliferate, as was evident from a colony formation assay. The initial and delayed anti-proliferative effects of ATA were dose-dependent. Together, the results indicated that ATA offers the potential of being recognized as an anti-tumor drug, at least in certain types of cancers.

4
UI - 21388250
AU - Kraemer S; Jaeger WH; Lang N
TI - Growth regulation effects of gonadotropin induced steroidogenic response in human ovarian cancer.
SO - Anticancer Res 2001 May-Jun;21(3B):2005-10
AD - Department of Obstetrics and Gynecology, University of Erlangen-Nuremberg, Erlangen, Germany. stefan.kraemer@gyn.med.uni-erlangen.de
BACKGROUND: Despite a substantial body of epidemiological evidence, there is only a limited indication that gonadotropins and steroids have growth regulating functions in ovarian cancer. To elucidate the role of gonadotropins in regulating steroid metabolism in human ovarian cancer, we analyzed the modulation of estradiol secretion by FSH and hCG and the gonadotropic regulation of hCG secretion in vitro. Furthermore, we analyzed estradiol and hCG levels in serum and cyst fluids of patients with ovarian cancer. MATERIALS AND METHODS: OVCAR3 cells were incubated with estradiol (1, 5, 10 nM), FSH (100 microg/L) and hCG (10, 25 microg/L). Growth stimulation was evaluated by MTT assay. Estradiol was measured in the supernatant after incubation with hCG and FSH, while hCG was measured after FSH incubation. FSH, estradiol and hCG levels were measured in serum and cyst fluids of patients with ovarian cancer. RESULTS: OVCAR3 cells responded to hCG and FSH by increased estradiol secretion (p<0.001), while estradiol led to a dose-dependent stimulation of cell growth (p<0.05). 100 microg/L FSH led to a 75% decrease of hCG secretion (p<0.001). CONCLUSION: Gonadotropins stimulate estradiol secretion in ovarian cancer cells and modulate steroid dependent growth stimulation. FSH modulates hCG related growth stimulation in ovarian cancer. These results were supported by in vivo measurements in ovarian cancer patients.

5
UI - 21395112
AU - Deraco M; Rossi CR; Pennacchioli E; Guadagni S; Somers DC; Santoro N; Raspagliesi F; Kusamura S; Vaglini M
TI - Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion in the treatment of recurrent epithelial ovarian cancer: a phase II clinical study.
SO - Tumori 2001 May-Jun;87(3):120-6
AD - Department of Surgery, National Cancer Institute, Milan, Italy. marcelloderaco@hotmail.com
AIMS AND BACKGROUND: The optimal salvage therapy for recurrent ovarian carcinoma has not been clearly established. Response to second-line chemotherapy is low, with a short median survival (8.8-15 months). We investigated the effect of an aggressive approach consisting of surgery followed by intraperitoneal drug delivery and local hyperthermia. PATIENTS AND METHODS: In a phase II clinical study, 27 patients with advanced/recurrent ovarian carcinoma were treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Median patient age was 53 years (range, 30-67) and mean follow-up was 17.4 months (range, 0.3-36.0). Patients had been surgically staged and heavily pretreated with cisplatin-based, taxol-based or taxol/platinum-containing regimens. Nineteen (70%) patients were cytoreduced to minimal residual disease <2.5 mm. The intraperitoneal hyperthermic perfusion was performed with the closed abdomen technique, using a preheated polysaline perfusate containing cisplatin (25 mg/m2/L) + mitomycin C (3.3 mg/m2/L) through a heart-lung pump (mean flow of 700 mL/min) for 60 min in the hyperthermic phase (42.5 degrees C). RESULTS: Two-year overall survival was 55%. Median times to overall progression and local progression were 16 months and 21.8 months, respectively. Variables that affected the overall survival or time to progression were as follows: residual disease (P = 0.00025), patient age (P = 0.04), and lag time between diagnosis and cytoreductive surgery + intraperitoneal hyperthermic perfusion (P = 0.04). Treatment-related morbidity, mortality and acute toxicity (grade II-III) rates were 11%, 4% and 11%, respectively. Eight (89%) of 9 patients had ascites resolution. CONCLUSION: Our results suggest that cytoreductive surgery + intraperitoneal hyperthermic perfusion is a well-tolerated, feasible and promising alternative in the management of selected patients with recurrent ovarian cancer, but further randomized controlled studies are needed in order to confirm our findings.

6
UI - 21401143
AU - Orlando M; Mandachain M
TI - Gemcitabine in ovarian cancer.
SO - Semin Oncol 2001 Jun;28(3 Suppl 10):62-9
AD - Gynecologic and Genitourinary Tumors Department, Medical Oncology Division, Alexander Fleming Institute, Av Cramer 1180, Buenos Aires, Argentina.
Newer agents and combinations are needed in order to improve current results in the treatment of ovarian cancer. Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) is a novel agent with a unique mechanism of action that has shown consistent activity as a single-agent in platinum-resistant ovarian cancer, with remission rates of nearly 20% and a favorable toxicity profile. Because of these benefits and its shown clinical and preclinical synergism with platinum analogues, gemcitabine has been combined with carboplatin as a rational approach for the treatment of ovarian cancer patients. The combination has been studied in phase I and II trials aimed at determining the optimal schedule and potential activity. Triplets including paclitaxel are also feasible. Further combinations of gemcitabine and other agents are being actively studied in both treated and untreated patients with ovarian cancer in order to establish its role in the management of this disease. Semin Oncol 28 (suppl 10):62-69. Copyright 2001 by W.B. Saunders Company.

7
UI - 21416734
AU - Nakayama S; Torii Y; Noda T
TI - [Evaluation of efficacy of ramosetron orally disintegrating tablets and patient preference as to the dosage form in gynecological cancer chemotherapy]
SO - Gan To Kagaku Ryoho 2001 Aug;28(8):1121-7
AD - Dept. of Gynecology, Seirei Hamamatsu General Hospital.
The efficacy of an oral 5-HT3 antagonist, ramosetron orally disintegrating tablet (ODT), in the treatment of chemotherapy-induced emesis was investigated in 21 female patients with cancer. Patient preference for the dosage form was also investigated. Eighteen (85.7%) of 21 patients answered that ODT is easy to take. Eleven (68.8%) of 16 patients who had previously taken granisetron tablets preferred ramosetron ODT to conventional tablets. The complete suppression rate of nausea or vomiting was more than 90% for 6 days. No adverse drug reactions associated with ramosetron were observed. As ambulatory or home chemotherapy becomes frequent, the use of oral 5-HT3 antagonists rather than intravenous agents will be increased. Chemotherapy for elderly cancer patients is becoming frequently used. Considering these circumstances, it is suggested that ramosetron ODT is a palatable and useful treatment of chemotherapy-induced emesis.

8
UI - 21329004
AU - Roovers JP; Sijmons EA; van Leeuwen JH; Mol BW; Witteveen PO; Slee PH; Heintz AP
TI - Is platinum-based chemotherapy with paclitaxel effective in optimally debulked patients with advanced ovarian cancer?
SO - Eur J Obstet Gynecol Reprod Biol 2001 Jul;97(1):80-4
AD - Department of Obstetrics and Gynecology, University Medical Center, Utrecht, The Netherlands. j.p.roovers@azu.nl
OBJECTIVE: Suboptimally debulked patients with advanced ovarian cancer who are treated with a combination of cisplatin plus paclitaxel (TP therapy) have a better survival as compared to patients treated with a combination of cisplatin plus cyclophosphamide (CP therapy), but this advantage has not been demonstrated in optimally debulked patients. We performed a retrospective study to compare the effectiveness of TP therapy and CP therapy in optimally debulked patients. STUDY DESIGN: From 1991 to 1996, 87 consecutive patients with advanced ovarian cancer treated in the University Hospital Utrecht and the St. Antonius Hospital were included in the study. Overall survival (OS) of patients treated with TP or CP were compared. Multivariable Cox-regression analysis was used to calculate a hazard rate ratio (HRR) for OS. RESULTS: In the study period, 51 patients were treated with CP, and 36 patients were treated with TP. In the 18 patients with a tumorrest >2cm, there was a clear, but not statistically significant benefit from TP. In 69 patients with a tumorrest

9
UI - 21423703
AU - Rothenberg ML; Liu PY; Wilczynski S; Hannigan EV; Weiner SA; Weiss GR; Hunter VJ; Chapman JA; Tiersten A; Kohler PC; Alberts DS
TI - Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG-9326).
SO - Gynecol Oncol 2001 Aug;82(2):317-22
AD - Vanderbilt University Medical Center, Nashville, Tennessee 37232-5536, USA.
OBJECTIVE: The aim of this study was to evaluate the 2-year survival rate in a group of women in complete clinical remission (cCR) from Stage III ovarian cancer following front-line therapy who were then treated with a 6-month course of altretamine. METHODS: Patients were documented to be in cCR by physical examination, computed tomography or magnetic resonance imaging scan, and serum CA-125. Treatment consisted of altretamine (Hexalen) 260 mg/m(2)/day po divided into four doses taken after meals and at bedtime for 14 of 28 days for six cycles. Based on previous experience in the Southwest Oncology Group, the treatment would be considered promising if the 2-year survival rate was > or = 65% as measured from study registration. RESULTS: From 9/1/93 and 7/1/97, 112 patients were registered and 97 were fully evaluable. The majority of patients had optimally debulked (< or = 1 cm: 63%), high-grade (Grade 3: 82%) tumors. The 2-year survival rate in this study was 75% (95% CI: 66-84%). For those patients with optimal disease, the 2-year survival rate was 82% (95% CI: 72-92%) and for those with suboptimal disease it was 64% (95% CI: 48-79%). Four patients (4%) experienced Grade 4 and 21 patients (22%) experienced Grade 3 toxicities consisting primarily of nausea/vomiting, neutropenia, fatigue, anxiety, and paresthesias. CONCLUSIONS: The 2-year survival rate in this study warrants further evaluation of consolidation therapy for women in clinical complete remission following front-line chemotherapy for Stage III ovarian cancer. Caution is advised in the interpretation of these data, however, because of the nonrandomized nature of the trial and the unknown contribution of front-line use of paclitaxel to the durability of clinical complete response. Copyright 2001 Academic Press.

10
UI - 21423704
AU - Rose PG; Maxson JH; Fusco N; Mossbruger K; Rodriguez M
TI - Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages.
SO - Gynecol Oncol 2001 Aug;82(2):323-8
AD - Division of Gynecologic Oncology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
PURPOSE: The aim of this study was to evaluate the relative activity and tolerance of liposomal doxorubicin in recurrent ovarian, peritoneal, and tubal carcinoma at an initial dose of 40 or 50 mg/m(2) every 4 weeks. METHODS: A retrospective single-institution study was performed on patients who received liposomal doxorubicin from 1/97 to 12/00. Demographic data, liposomal doxorubicin dose, dose reductions, response, and progression-free and overall survival were recorded. RESULTS: Seventy-eight patients, 38 treated at 40 mg/m(2) and 40 treated at 50 mg/m(2), were identified. There was no difference with respect to patient age, performance status, percentage of patients who were platinum resistant or paclitaxel resistant, or tumor bulk. The response rate in this highly resistant population was 13.5 and 7.7% for liposomal doxorubicin at 40 and 50 mg/m(2) every 4 weeks, respectively. Stable disease was observed in 49 and 51% of patients treated with liposomal doxorubicin at a dose of 40 and 50 mg/m(2) every 4 weeks, respectively. The progression-free survival for patients with responding and stable disease was similar. Dose reductions were required in 27.5% of patients treated at 50 mg/m(2) versus no patients treated at 40 mg/m(2) (P < 0.001). Treatment delays due to toxicity were required in 32.5% of patients treated at 50 mg/m(2) versus 16% of patients treated at 40 mg/m(2) (P = 0.14). CONCLUSION: Liposomal doxorubicin at a dose of 40 mg/m(2) appears to be as active as liposomal doxorubicin at a dose of 50 mg/m(2) in ovarian, peritoneal, and tubal carcinoma and is better tolerated based on the frequency of dose reductions and treatment delays. Copyright 2001 Academic Press.

11
UI - 20203955
AU - Yamamoto K; Kikuchi Y; Kudoh K; Nagata I
TI - Modulation of cisplatin sensitivity by taxol in cisplatin-sensitive and -resistant human ovarian carcinoma cell lines.
SO - J Cancer Res Clin Oncol 2000 Mar;126(3):168-72
AD - Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama, Japan. QWL04765@niftyserve.ne.jp
PURPOSE: The aim of this study was to determine whether taxol can circumvent cisplatin resistance, using a KF28 cell line derived from human ovarian carcinoma and a cisplatin-resistant line, KFr13, derived from the parental cell line, KF28, and taxol-resistant cell lines, KF28TX and KFr13TX, derived from the respective parental counterpart. METHODS: KF28 is a single-cell clone of the human ovarian carcinoma cell line KF. The cisplatin-resistant KFr13 subline was established by repeated exposure of the parent KF28 cell line to escalating doses of cisplatin. Similarly, KF28TX and KFr13TX were established by repeated exposure of the KF28 and KFr13 cell lines to escalating doses of taxol. A cytotoxicity assay was performed using a crystal violet staining method. Platinum and taxol accumulation were assayed by atomic absorption and reverse-phase high-performance liquid chromatography. The quantitative assay of MDR1 mRNA used polymerase chain reaction. RESULTS: KFr13 cells were about 4.8-fold more resistant to cisplatin and about 1.8-fold more sensitive to taxol than were KF28 cells. When taxol resistance was induced in KF28 and KFr13 cells, sensitivity to cisplatin rose about 1.3- and 1.6-fold respectively. Elevation of sensitivity was correlated with platinum uptake by both KF28TX and KFr13TX cells. Expression of multidrug resistance (MDR1) mRNA, which was not observed in KF28 and KFr13 cells, was observed after induction of taxol resistance. CONCLUSIONS: These results may suggest rational therapeutic strategies for patients with cisplatin-resistant or refractory ovarian carcinoma.

12
UI - 88229817
AU - Piver MS; Lele SB; Marchetti DL; Baker TR; Tsukada Y; Emrich LJ
TI - The impact of aggressive debulking surgery and cisplatin-based chemotherapy on progression-free survival in stage III and IV ovarian carcinoma.
SO - J Clin Oncol 1988 Jun;6(6):983-9
AD - Department of Gynecologic Oncology, Roswell Park Memorial Institute, Buffalo, NY 14263.
Forty consecutive patients with stage III and IV invasive ovarian carcinoma were treated on a phase II protocol consisting of optimal debulking surgery, induction cisplatin, cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy, 6-month interval laparoscopy, reinduction cisplatin, PAC chemotherapy, and second-look procedure. All 40 patients have either disease progression or have completed the 12-month protocol. Eighty-seven percent of the patients (35) underwent optimal (less than or equal to 2 cm residual) debulking surgery before chemotherapy, in spite of the fact that 50% (20) were referred to Roswell Park Memorial Institute (RPMI) as inoperable after initial surgery elsewhere. There were no postoperative deaths and chemotherapy was started in less than or equal to 14 days in 97% of the patients. Of the 40 patients, 30% (12) achieved a pathologic complete remission (11) or a clinical complete remission (one patient refused second-look surgery). The estimated 3-year survival rate was 62%, but the 3-year progression-free survival rate was only 29%. The median survival time was 48 months. The estimated 3-year progression-free survival rate was 31% for residual disease less than or equal to 2 cm. For the five patients with residual disease greater than 2 cm, four died within 3 years. The median survival time of patients with less than or equal to 2 cm residual disease was 48 months, as compared with 21 months for those with greater than 2 cm residual disease. Although the estimated 3-year survival rate of 62% is noteworthy, the 3-year progression-free survival rate of only 29% is probably indicative that in spite of extensive debulking surgery and cisplatin-based chemotherapy as used in this protocol, the long range proportion of patients "cured" will remain small.

13
UI - 20475788
AU - Burger MP; Mol BW
TI - Treatment for patients with stage-1 endometrial carcinoma.
SO - Lancet 2000 Sep 2;356(9232):853-4

14
UI - 20569282
AU - Hoskins P; Eisenhauer E; Vergote I; Dubuc-Lissoir J; Fisher B; Grimshaw R; Oza A; Plante M; Stuart G; Vermorken J
TI - Phase II feasibility study of sequential couplets of Cisplatin/Topotecan followed by paclitaxel/cisplatin as primary treatment for advanced epithelial ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group Study.
SO - J Clin Oncol 2000 Dec 15;18(24):4038-44
AD - British Columbia Cancer Agency, Vancouver Clinic, Vancouver, British Columbia, Canada.
PURPOSE: Despite the improved results in advanced ovarian cancer achieved with the addition of paclitaxel to frontline therapy, there remains room for improvement. One approach is to add new agents such as topotecan. Because myelosuppression limits the delivery of topotecan with paclitaxel/cisplatin in a three-drug combination, we explored giving sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin. PATIENTS AND METHODS: Forty-four patients with residual epithelial ovarian carcinoma after primary surgery were studied. Cisplatin 50 mg/m(2) on day 1 and topotecan 0.75 mg/m(2) on days 1 through 5 were administered at 21-day intervals for four cycles, followed by interval debulking surgery (if optimal debulking was not achieved with primary surgery), and then paclitaxel 135 mg/m(2) over 24 hours on day 1 and cisplatin 75 mg/m(2) on day 2 at 21-day intervals for four cycles. RESULTS: Such sequential couplets are feasible. Myelotoxicity was the major toxic effect, but it was of short duration. The granulocyte nadir with topotecan/cisplatin occurred late (median, day 18), so retreatment on day 21 was not always possible. There was no unexpected nonhematologic toxicity. The regimen was active in this group of patients who had undergone largely suboptimal debulking surgery. In 34 patients with clinically measurable disease, the overall response rate was 78%, and 30 (77%) of the 39 patients with elevated CA 125 levels at baseline had normalization of CA 125 levels by the end of therapy. CONCLUSION: Sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin are feasible. The efficacy data in this suboptimal group of patients has encouraged us to proceed with a randomized study based on this approach.

15
UI - 21201298
AU - Piver MS
TI - Surgery in advanced epithelial ovarian cancer.
SO - J Clin Oncol 2001 Apr 15;19(8):2364

16
UI - 21303164
AU - Murphy ME
TI - The battle between tumor suppressors: is gene therapy using p16(INK4a) more efficacious than p53 for treatment of ovarian carcinoma?
SO - Clin Cancer Res 2001 Jun;7(6):1487-9
AD - Department of Pharmacology, Fox Chase Cancer Center, Philadelphia Pennsylvania 19111, USA.

17
UI - 21303188
AU - Birner P; Schindl M; Obermair A; Breitenecker G; Oberhuber G
TI - Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy.
SO - Clin Cancer Res 2001 Jun;7(6):1661-8
AD - Institute of Clinical Pathology, University of Vienna, A-1090 Vienna, Austria. peter.birner@akh-wien.ac.at
PURPOSE: To investigate the impact of expression of hypoxia-inducible factor (HIF)-1alpha on prognosis and on response to chemotherapy in epithelial ovarian tumors. EXPERIMENTAL DESIGN: Expression of HIF-1alpha protein was studied by immunohistochemistry in 102 specimens of epithelial ovarian cancers, in 50 borderline tumors, and in 20 cystadenomas. Results were correlated with p53, p21, and bcl-2 expression, microvessel density (MVD), apoptotic rate of tumor cells, and survival. RESULTS: In 68.6% of ovarian cancers and 88% of borderline tumors, expression of HIF-1alpha was observed. There was a significant correlation of HIF-1alpha protein expression and MVD (P < 0.001). HIF-1alpha overexpression alone and MVD showed no impact on survival of cancer patients. Furthermore, the response to platinum-based chemotherapy was independent from HIF-1alpha expression. Expression of HIF-1alpha correlated with apoptotic rate in the majority of cases, especially in low malignant potential tumors. In contrast, in cancer patients with strong expression of HIF-1alpha and p53 protein overexpression, not only a significantly increased MVD (P = 0.032, Mann-Whitney test) but also a significantly shorter overall survival was observed (P < 0.0001, Cox regression). The apoptotic rate was very low in these tumors. CONCLUSIONS: HIF-1alpha protein overexpression alone has no impact on the prognosis of ovarian cancer. The combination of HIF-1alpha protein overexpression with nonfunctional p53, however, indicates a dismal prognosis.

18
UI - 21382086
AU - Favalli G; Odicino F; Torri V; Pecorelli S
TI - Early stage ovarian cancer: the Italian contribution to clinical research. An update.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():12-9
AD - Department of Gynecologic Oncology, Spedali Civili, University of Brescia, Brescia, Italy. giuseppe.favalli@inwind.it
Early ovarian cancer (stages IA-IIA) accounts for 30% of all epithelial ovarian cancer. Even if relatively uncommon, when "high risk" patients are considered, it is lethal in 25-30% of the cases. Mainstay of treatment is surgery followed by either adjuvant chemotherapy or radiotherapy when indicated on the basis of still debatable prognostic factors. Literature data show a great variability in survival rate due to the great heterogeneity of patients considered in different reports and few randomized trials affected by a consequent low power. Italian groups have contributed both in investigating the role of surgery and of chemo or radiotherapy in the treatment of this disease. An important contribution in surgery has been made by Italian institutions in reducing the extent of surgery in young patients wishing to retain their reproductive capability showing that a "conservative surgery" (unilateral oophorectomy) can be safely performed in initial stages without affecting the probability of cure. Another important surgical topic investigated by Italian institutions concerns the role of lymphadenectomy. In early ovarian cancer the node involvement ranges between 14-24% in stage I and 37-50% in stage II. Although the node positivity rate detectable by sampling (SA) is lower than the one shown by a systematic procedure (LY), no data at the moment show that patients undergoing a sampling evaluation have a poorer prognosis. From 1992 through 1994, 202 patients (SA: 99; LY: 103) were enrolled by six Italian institutions in a randomized trial aimed to assess the diagnostic and therapeutic role of SA vs. LY in early stage ovarian cancer. Positive nodes were detected in 9.9% vs. 19.3% respectively as well as a different proportion of intra/perioperative complications occurred. No difference in time to relapse nor in overall survival were detected in the two groups showing no evidence of efficacy in favor of extensive staging of the retroperitoneum. From 1983 to 1990, 271 stage I ovarian cancer patients entered two prospective multicentric randomized trials conducted by Italian institutions. Trial I compared cisplatin (50 mg/m2, six cycles repeated every 28 days) vs. no further treatment in stage IA-B grade 2-3 patients; Trial II compared the same dose and schedule of cisplatin vs. intraperitoneal P32 in stage IC patients. Cisplatin significantly reduced the relapse rate by 65% in Trial I and by 61% in Trial II, but survival was not affected (Trial I: HR = 1.15, 95% CI = 0.44-2.98; Trial II: HR = 0.72, 95% CI = 0.37-1.43). The final conclusion drawn by these two important Italian studies was that adjuvant cisplatin treatment in early ovarian cancer prevents relapse although the impact of chemotherapy remains unclear. For this reason two international trials have been performed (ICON1 and ACTION) aimed at assessing the role of platinum-based chemotherapy on survival. Italian collaboration in both trials has been important, including about half of the total number of the 900 randomized patients. Results will probably be available during this year and are expected with a great interest by the whole scientific international community.

19
UI - 21382088
AU - Vermorken JB
TI - The integration of paclitaxel and new platinum compounds in the treatment of advanced ovarian cancer.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():21-30
AD - Department of Medical Oncology, University Hospital Antwerp, Edegem, Belgium. Jan.B.Vermorken@uza.uia.ac.be
There has been a steady improvement in the survival of patients with advanced ovarian cancer. This has been the result of a more skilled surgical approach to these patients and the development of more effective chemotherapy with a better integration of both modalities in first-line treatment. The current optimal chemotherapeutic approach consists of a platinum compound together with paclitaxel. This recommendation is based upon level I evidence of two large randomized trials which established that the combination of paclitaxel-cisplatin was superior to cyclophosphamide-cisplatin. The long-term follow-up of one of these studies continues to show a significant difference in survival at 5 years. Neurotoxicity has been problematic with these regimens, in particular when paclitaxel was given with the higher dosed shorter infusion schedule, as was done in the European-Canadian Intergroup study. Several approaches to reduce this toxicity have been studied. Among these are the use of different paclitaxel infusion schedules, and the application of less neurotoxic platinum compounds. Weekly paclitaxel has a different toxicity profile than the higher dosed three-weekly schedules, with less neutropenia, alopecia, arthralgia and neurotoxicity. Four platinum compounds are currently marketed: cisplatin, carboplatin, oxaliplatin, and nedaplatin. Of these only cisplatin, carboplatin, and nedaplatin have been approved for the treatment of patients with ovarian cancer (nedaplatin only in Japan). The equivalence of carboplatin and cisplatin has been suggested from trials without a taxoid. Three randomized studies of paclitaxel-carboplatin vs. paclitaxel-cisplatin concluded that paclitaxel-carboplatin is the preferred regimen in terms of (less) toxicity and, where studied, in terms of quality of life. So far, no difference in response rates or progression-free survival has been shown. More mature data on overall survival are awaited. Oxaliplatin (a diaminocyclohexane platinum compound) is of interest because it is only partially cross-resistant with cis- or carboplatin and devoid of severe bone marrow suppression, nephrotoxicity, or ototoxicity. Its dose-limiting toxicity is an unusual form of sensory neuropathy, which is cumulative and, contrary to cisplatin's neurotoxicity, generally reversible. Combinations with other active standard agents, as well as platinum compounds and/or taxoids, are feasible and have shown interesting activity. Similar to carboplatin and oxaliplatin, nedaplatin (cis-diammineglycolatoplatinum) can be given without hydration; its dose-limiting toxicity is myelosuppression, in particular thrombocytopenia. Although activity has been shown, no data from randomized comparative trials are available to allow a judgement on its potential advantages.

20
UI - 21382089
AU - Kaye SB; Scottish Gynaecological Cancer Trials Group
TI - The integration of docetaxel into first-line chemotherapy for ovarian cancer.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():31-3
AD - Dept of Medical Oncology, Royal Marsden Hospital, London, UK.
Docetaxel is being explored as an alternative to paclitaxel in the treatment of ovarian cancer for several reasons: a) evidence of superiority in preclinical models; b) at least comparable activity in platinum-refractory patients (28% response rate in four pooled Phase II trials), together with activity (23% response rate) in paclitaxel-refractory patients; c) indirect evidence of superiority in breast cancer; d) easier administration, i.e., 1 h q3 week schedule vs. 3 or 24 h infusions; and e) potentially superior toxicity profile, particularly regarding neurotoxicity. The Scottish Gynaecological Cancer Trials Group (SGCTG) has performed successive first-line feasibility trials of docetaxel in combination with cisplatin (100 patients) and carboplatin (141 patients). For docetaxel/carboplatin, a regimen of 75 mg/m2 and AUC 5 proved optimal. Over 90% of patients completed six cycles, q3 weekly, and toxicity was very acceptable; a low level of neurotoxicity (5%) was particularly noteworthy, since levels of over 30% are regularly reported for paclitaxel-carboplatin. Activity comparable to paclitaxel-carboplatin (median progression free survival of 16 months) therefore justified a randomized comparison between the two regimens (with paclitaxel 175 mg/m2 in 3 h and carboplatin AUC 5). This has now been completed, with 1077 patients (FIGO stage IC-IV disease) randomized, from 83 centers in 10 countries. Accrual was accomplished in 17 months (October 1998 to May 2000). A toxicity analysis has been completed, since the last patient finished treatment in October 2000. Treatment was delivered as prescribed (6 cycles) in a similar number of patients (79-84%). Significant differences in toxicity were seen, and this analysis together with response data is scheduled for presentation at the May 2001 ASCO meeting.

21
UI - 21382090
AU - Luck HJ; Du Bois A; Weber B; Pfisterer J; Goupil A; Kuhn W; Barats JC; Blohmer J; Mousseau M; Schroder W; Meier W; Mobus V; Richter B; AGO-GINECO Intergroup
TI - The integration of anthracyclines in the treatment of advanced ovarian cancer.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():34-8
AD - Med. Hochschule Hannover, Department of Gynecologic Oncology, Hannover, Germany. fkmhhonk@aol.com
Since the publication of the Gynecologic Oncology Group (GOG) protocol 111 in 1996, and the results of the Arbeitgemeinschaft Gyna kologische Onkologie (AGO) trial Ovar-3 and the GOG protocol 158, the combination of platinum and paclitaxel has been adopted as the standard therapy in advanced ovarian cancer. One option for achieving further progress in the first-line treatment of advanced ovarian cancer might be the addition of noncross-resistant drugs to the two-drug regimen. Meta-analysis showed a survival benefit for platinum-anthracycline based combinations as compared to platinum-based combinations without anthracyclines. An AGO phase I/II trial compared epirubicin in combination with carboplatin and paclitaxel in untreated patients with gynecological malignancies. Based on the results of this study a randomized phase III trial together with the French GINECO group was conducted. The trial started 11/97 and was closed 11/99. All 1281 patients were randomized. Currently, 1132 end-of-therapy reports have been issued. Nine hundred eighty nine (87%) patients completed six cycles of treatment. Treatment and toxicity data are available for these patients. Three hundred thirty five patients had a measurable residual tumor after initial debulking surgery. Response data of 228 patients (111 ET-Carbo, 117 Carbo-T) are available.

22
UI - 21382091
AU - Hansen SW
TI - Gemcitabine in the treatment of ovarian cancer.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():39-41
AD - National Board of Health, Copenhagen, Denmark.
Gemcitabine is a nucleoside antimetabolite with established activity against several solid tumors. The activity of the drug in patients with ovarian cancer has been reviewed both in patients who have received single drug treatment and in patients who have received combination chemotherapy. The response rates, with single agent gemcitabine, range from 13 to 24% both in previously treated and untreated patients. Doublets consisting of gemcitabine-cisplatin or gemcitabine-paclitaxel, in previously treated patients, induced response in 53% and 40% of the patients, respectively. In three studies, first-line treatment with the combination of cisplatin and gemcitabine induced remission in 53% to 71% of the patients. The triplet, including gemcitabine, paclitaxel, and cisplatin or carboplatin, has been examined in previously treated patients and a response rate of 100% was observed. In previously untreated patients the combination of gemcitabine, paclitaxel, and carboplatin has been preferred due to a more favorable toxicity profile. The activity of this combination, observed in 25 evaluable patients, was very high as all patients responded. Complete remission was observed in 60% of the patients and partial remission in 40%. Based on these promising data the triplet consisting of gemcitabine, paclitaxel, and carboplatin has been included in randomized trials both in the US and in Europe.

23
UI - 21382092
AU - Bookman MA
TI - Developmental chemotherapy in advanced ovarian cancer: incorporation of topoisomerase-I inhibitors and perspective of the Gynecologic Oncology Group.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():42-51
AD - Division of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. ma_bookman@fccc.edu
Despite improvements in median and overall survival using a combination of platinum and paclitaxel, long-term survival rates for patients with advanced epithelial ovarian carcinoma (EOC) remain disappointing, and the development of more effective primary therapy remains a priority. In particular, several interesting chemotherapy agents have demonstrated activity individually in patients with recurrent EOC. Among these are gemcitabine, topotecan, liposomal doxorubicin, and prolonged oral etoposide. Preclinical models have suggested an advantage for combinations of these agents with platinum, which has been attributed to inhibition of DNA synthetic pathways involved in the repair of platinum-DNA adducts. However, efforts to develop multidrug combinations with platinum and paclitaxel have encountered substantial bone marrow toxicity, prompting exploration of alternative schedules and sequences of drug administration. In this regard, the Gynecologic Oncology Group (GOG) has conducted a series of phase I pilot studies in previously untreated patients to define combinations that are suitable for group-wide phase III trials. With international collaboration, GOG has launched a five-arm trial (GOG-0182) that will compare these combinations against carboplatin-paclitaxel. The selection of candidate regimens for this trial illustrate the challenges of drug development in EOC.

24
UI - 21382093
AU - Conte PF; Gadducci A; Cianci C
TI - Second-line treatment and consolidation therapies in advanced ovarian cancer.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():52-6
AD - Department of Oncology, Division of Medical Oncology, University of Pisa, Italy.

25
UI - 21382094
AU - Hager ED; Dziambor H; Hohmann D; Muhe N; Strama H
TI - Intraperitoneal hyperthermic perfusion chemotherapy of patients with chemotherapy-resistant peritoneal disseminated ovarian cancer.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():57-63
AD - BioMed-Hospital, Department of Hyperthermia, Bad Bergzabern, Germany. biomed_bbz@compuserve.com
The purpose of this article is to evaluate in a prospective, open-label clinical trial the feasibility and efficacy of intraperitoneal hyperthermic perfusion chemotherapy (IPHC) on the survival and quality of life of patients with advanced, peritoneal disseminated ovarian cancer. Thirty-six patients with ovarian cancer were accrued for the study, their selection being based on their progression following different systemic therapies with anti-neoplastic (multiple chemotherapy-resistant or -refractory) agents. The average number of chemotherapy cycles given before the first IPHC was 12.5. The patients' average Karnofsky-performance status was 60% and 17 out of 36 patients had ascites before IPHC. The input temperature of the solution for abdominal lavage was 48-49 degrees C: the intraperitoneal temperature was 42-43 degrees C. The flow-rate of the solution for heat exchange was 190-220 ml/min with treatment lasting 1 h at temperatures greater than or equal to 42 degrees C. Median overall survival time (MOS) from first diagnosis of disease (1stDx) was 49 +/- 8 months and from the first IPHC-treatment 19 +/- 4 months. The observed 1-year overall survival rate (OSR) of all patients from the start of the first IPHC was 65 +/- 8% and the 5-year OSR was 16 +/- 7%. Malignant ascites vanished within less than 3-5 IPHCs. Quality of life could be improved. The adverse effects were mild especially compared to systemic chemotherapy. In 3 out of 162 treatments, peritoneal disturbances with symptoms of subileus were observed. We conclude that IPHC is technically feasible, safe, and associated with a marked prolongation of survival and improvement in quality of life. Even heavily pretreated patients could be treated safely. Some patients did respond to IPHC even after 25 IPHC treatments. From these results, it can be concluded that IPHC may also improve the treatment outcome of patients with ovarian cancer as salvage therapy, in second-line treatment or even as consolidation or maintenance therapy following induction chemotherapy to patients with suboptimal stage III and IV disease. This should be demonstrated in randomized controlled studies.

26
UI - 21382095
AU - Pujade-Lauraine E; Cure H; Battista C; Guastalla JP; Chiurazzi B; Fabbro M; Tubiana-Mathieu N; Bourgeois H; Lioure B; Paraiso D; Lotz JP
TI - High dose chemotherapy in ovarian cancer.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():64-7
AD - GINECO trials, Departement of Hematology and Medical Oncology, Hotel-Dieu, Paris, France.

27
UI - 21382096
AU - Eisenhauer E; Dancey J
TI - Impact of new non-cytotoxics in the treatment of ovarian cancer.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():68-72
AD - NCIC Clinical Trials Group, Queen's University, Kingston, Canada. eeisenhauer@ctg.queensu.ca
Over the last decade, a number of new cytotoxic chemotherapy agents have shown evidence of antitumor activity in patients with ovarian carcinoma. These agents are currently being evaluated in large multinational randomized trials to determine whether their addition either concurrently or sequentially to standard paclitaxel and carboplatin regimens will result in improved survival. Whether these new combinations will provide additional benefit may be uncertain; however, it is certain that additional toxicity will limit the continued evaluation of the strategy of adding cytotoxics together. New approaches to improve the systemic therapy of ovarian cancer need to be explored. The next decade will see many trials of non-cytotoxics having a wide range of subcellular and extracellular targets. Many of these targets are abnormally expressed in a variety of solid tumors; thus, it is expected that many of these agents will be appropriate to evaluate in patients with ovarian carcinoma. Based on promising data from preclinical and early clinical studies as well as the presumed applicability of these targets to ovarian carcinoma, the inhibitors of growth factor receptors such as epidermal growth factor receptor and inhibitors of angiogenesis are of particular interest. Despite the interest of the investigators, the rapid evaluation of these target-specific non-cytotoxics is limited by the lack of accurate information on the expression of target in ovarian tumors and the relevance of target expression and its modulation to this tumor type. Early clinical trials are being designed to address these concerns; however, the clinical impact of non-cytotoxic agents in epithelial ovarian carcinoma patients must await the completion of randomized evaluations in combination with standard chemotherapeutic regimens.

28
UI - 21382097
AU - Vermorken JB
TI - Intergroup collaboration in ovarian cancer: the Gynecologic Cancer Intergroup (GCIG).
SO - Int J Gynecol Cancer 2001;11 Suppl 1():73-6
AD - Department of Medical Oncology, University Hospital Antwerp, Edegem, Belgium. Jan.B.Vermorken@uza.uia.ac.be
Randomized clinical trials are considered the definitive source of evidence for guiding decisions in clinical practise. In patients with ovarian cancer many of the randomized trials from the 1970s and 1980s did not have the statistical power to detect realistic and clinically important differences. Therefore, evolution of so-called "optimal therapy" has been rather slow and some important questions have gone unanswered. In order to overcome this challenge, representatives of different Cooperative Groups started an Ovarian Cancer Trials Intergroup Network in the mid 1990s, as a vehicle to develop future trial collaboration and as a mechanism for communication about strategic directions of phase I/II trials within individual Groups. In 1997 this network became more formalized, going beyond ovarian cancer as a single focus, and the Gynecologic Cancer Intergroup (GCIG) was created. At present GCIG includes representatives of 12 Cooperative Groups and the NCI-US, and functions as a forum for development of global trial collaborations, which hopefully will answer important questions in a more timely fashion and make them more rapidly available for the oncologic community.

29
UI - 21382098
AU - Poveda A
TI - Remarks and conclusions on ovarian cancer treatment.
SO - Int J Gynecol Cancer 2001;11 Suppl 1():77-81
AD - Fundacion Instituto Valenciano de Oncologia, Valencia, Spain. apoveda@fivo.org
Ovarian cancer is still the fourth cause of death by cancer among women and the most fatal among gynecological tumors. The purpose of this symposium has been to report and discuss the new developments in the treatment of patients with ovarian cancer, the majority of whom still present with advanced disease. It also tries to make clear to the participants what is evidence-based and what is not. Although the main topic of the symposium is advanced disease, this edition included some updated information on the treatment of early disease under the heading "is early disease really early"; the importance of screening and molecular approaches are highlighted. In addition studies reported in the literature on the role of chemotherapy versus no chemotherapy in high-risk patients with early ovarian cancer have been updated. The pace of new agent development has increased, and it would be helpful to have more efficient preclinical models and early phase-clinical trials to guide the selection of active agents for phase III evaluation. Reaching international consensus is a challenge, but offers the opportunity to test multiple regimens more efficiently against a single control population, rather than conducting multiple smaller studies with redundant internal controls. If indeed answers to the relevant questions are to be obtained more quickly, then a network of current national or international groups could potentially facilitate this.

30
UI - 21411772
AU - Donato ML; Gershenson DM; Wharton JT; Ippoliti CM; Aleman AS; Bodurka-Bevers D; Bevers MW; Burke TW; Levenback CF; Wolf JK; Freedman RS; Bast RC Jr; Gajewski JL; Champlin RE
TI - High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer.
SO - Gynecol Oncol 2001 Sep;82(3):420-6
AD - Department of Blood and Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. mdonato@mdanderson.org
OBJECTIVE: The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer. METHODS: Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m(2)/day on Days -6, -5, -4; melphalan 70 mg/m(2)/day on Days -3, -2; and topotecan at escalating doses from 1.25 to 4.0 mg/m(2)/day on Days -6 to -2. Peripheral blood stem cells were infused on Day 0. RESULTS: The optimal topotecan dose selected for future trials was 4.0 mg/m(2)/day x 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1-2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11-37) 77% of patients are alive. CONCLUSION: With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for futu

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