National Cancer Institute®
Last Modified: January 1, 2002
UI - 11148564
AU - Safra T; Groshen S; Jeffers S; Tsao-Wei DD; Zhou L; Muderspach L; Roman
TI - L; Morrow CP; Burnett A; Muggia FM Treatment of patients with ovarian carcinoma with pegylated liposomal doxorubicin: analysis of toxicities and predictors of outcome.
SO - Cancer 2001 Jan 1;91(1):90-100
AD - Department of Medical Oncology, Kenneth Norris Jr. Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
BACKGROUND: Pegylated liposomal doxorubicin is a new formulation with activity against epithelial ovarian carcinoma (EOC). The authors sought to determine patient characteristics that may predict for response to this treatment and favorable time to failure as well as survival. METHODS: Eight patients in a Phase I study and 44 patients in two consecutive Phase II studies who were treated with pegylated liposomal doxorubicin (40-60 mg/m2 every 3 weeks for the first two cycles and 40 mg/m2 every 4 weeks thereafter) after failing initial platinum-based chemotherapies for ovarian carcinoma were analyzed. Associations were sought for response, time to failure (TTF), and survival after the treatment and various pretreatment characteristics. RESULTS: Treatment with pegylated liposomal doxorubicin yielded 23% objective responses in measurable disease and 31% overall responses, including serum CA 125-defined responses. The median TTF was 5.2 months (95% confidence interval, 4.1-6.9 months) in all patients, and the median response duration in all responders was 13.2 months (95% confidence interval, 11.9-18.5 months). The overall median survival was 15 months (95% confidence interval, 11-40 months). The main predictive factors were tumor size and baseline hemoglobin level for TTF, and these plus Karnofsky performance status were the main predictive factors for survival. CONCLUSIONS: Pegylated liposomal doxorubicin is an effective drug when it is given as secondary therapy to patients with EOC. Lack of bulky disease is the major predictor for a favorable response, TTF, and survival. The role of this treatment in combination with other effective drugs should be explored in both previously treated and untreated patients with ovarian carcinoma. Copyright 2001 American Cancer Society.
UI - 11369252
AU - Markman M
TI - Intraperitoneal chemotherapy is appropriate first line therapy for patients with optimally debulked ovarian cancer.
SO - Crit Rev Oncol Hematol 2001 Jun;38(3):171-5
AD - Department of Hematology/Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. email@example.com
The intraperitoneal administration of antineoplastic agents in the front-line treatment of advanced ovarian cancer is a rational strategy, based on anatomic and pharmacokinetic considerations, as well as an understanding of the natural history of the malignancy. Phase 1 and 2 clinical trial data have supported the potential role for this unique method of drug delivery as a safe and effective management approach in this clinical setting. Two randomized phase 3 trials have demonstrated a favorable impact of cisplatin-based front-line intraperitoneal therapy on survival for patients with 'optimal residual' advanced ovarian cancer. However, for several reasons, additional investigative efforts are required to convince oncologists the time, effort and potential toxicity of intraperitoneal therapy justify its routine use as initial therapy of this malignancy.
UI - 11432630
AU - Ledermann JA; Herd R; Maraninchi D; Viens P; Buclon M; Philip T; Cure H;
TI - Lotz JP; Chauvin F; Ferrante P; Rosti G High-dose chemotherapy for ovarian carcinoma: long-term results from the Solid Tumour Registry of the European Group for Blood and Marrow Transplantation (EBMT).
SO - Ann Oncol 2001 May;12(5):693-9
AD - Department of Oncology, Royal Free & University College Medical School, UCL, London, UK. firstname.lastname@example.org
PURPOSE: to determine the outcome of epithelial ovarian cancer in patients registered with the European Group for Blood and Marrow Transplantation (EBMT). PATIENTS AND METHODS: A retrospective analysis was performed on 254 patients with advanced or recurrent disease, median age 46 years (14-63) from 39 centres treated between 1982 and 1996. Only 25% of patients were known to have no or microscopic disease after initial surgery; in approximately 20% the disease status was unknown, the remainder had macroscopic disease. RESULTS: One hundred five patients received high-dose chemotherapy in complete or very good partial remission, twenty-seven in second remission and the remainder in the presence of residual disease. Most received melphalan or carboplatin, or a combination (86%) supported by autologous bone marrow or peripheral blood stem cells. The survival of patients treated in remission was significantly better than in other groups (median 33 vs. 14 months; P = 0.0001). The durability of remission was longer after transplantation in first remission than in second remission (median disease-free survival 18 vs. 9 months; P = 0.005). With a median follow-up of 76 months from diagnosis the median disease-free and overall survival in stage III disease transplanted in remission is 42 and 59 months and for stage IV disease 26 and 40 months. CONCLUSIONS: High-dose chemotherapy has a potential benefit for patients in remission. The results support the conduct of randomised studies to determine whether there is a real value from this treatment.
UI - 11446487
AU - Boardman CH; Webb MJ
TI - Surgery in ovarian cancer.
SO - Eur J Gynaecol Oncol 2001;22(2):89-95
AD - Section of Gynecologic Surgery, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
The role of surgery in the management of primary and recurrent ovarian cancer is reviewed. The data to support primary and secondary cytoreduction are summarized. The role of second-look surgery and of surgery in the palliation of ovarian cancer is also discussed.
UI - 11465869
AU - Markman M
TI - Intraperitoneal drug delivery of antineoplastics.
SO - Drugs 2001;61(8):1057-65
AD - The Cleveland Clinic Taussig Cancer Center, Department of Hematology/Medical Oncology, The Cleveland Clinic Foundation, Ohio 44195, USA. email@example.com
The administration of antineoplastic agents directly into the peritoneal cavity as treatment of localised cancer is based on sound pharmacokinetic principles. This unique technique has to the potential to optimise outcome in settings where preclinical and clinical data suggest that cytotoxicity of a specific drug against a particular tumour type is enhanced by either increasing the drug concentration or duration of exposure. Phase I trials have confirmed the safety and pharmacokinetic advantage for a number of agents delivered by the intraperitoneal relative to the systemic route, including cisplatin (10- to 20-fold advantage for regional delivery), carboplatin (10- to 20-fold advantage), and paclitaxel (1,000-fold advantage). In phase II trials, performed mostly in patients with ovarian cancer, this approach has achieved objective responses in settings where intravenous drug delivery has not achieved the desired effect (e.g. surgically documented complete response using intraperitoneal cisplatin as second-line therapy of ovarian cancer). Phase III trials employing intraperitoneal cisplatin as initial treatment of small volume advanced ovarian cancer have demonstrated that regional therapy results in a modest, but statistically significant, improvement in both progression-free and overall survival compared to intravenous cisplatin. Further exploration of this novel method of treatment, including the conduct of definitive randomised phase III clinical trials, is indicated in ovarian cancer and in other tumour types where clinical manifestations are principally localised to the peritoneal cavity.
UI - 11465872
AU - Gibbs DD; Gore ME
TI - Pursuit of optimum outcomes in ovarian cancer: methodological approaches to therapy.
SO - Drugs 2001;61(8):1103-20
AD - Department of Medicine, The Royal Marsden Hospital, London, England.
The treatment of ovarian cancer is an evolving area and important clinical questions remain unanswered at all stages from early disease to relapse. This review outlines current practice at each disease stage, some of the current unanswered questions and issues surrounding the design of clinical trials to answer these questions. The gold standard test for new treatments must remain the randomised controlled trial with survival as the major endpoint because other outcome measures such as radiological response do not bear a strong relationship to survival. Patient factors greatly influence the likelihood of response to treatment and subsequent survival, hence failure to control for these in trial design may lead to spurious results. Quality of life is an important endpoint but quality-of-life measures in clinical trials should be interpreted carefully. The introduction of novel, target directed anticancer therapies will require new study designs as the phase I/II/III paradigm may not be relevant. It is current practice to offer adjuvant chemotherapy to women with early stage disease who are considered at high risk of relapse despite conflicting evidence from clinical trials. Current questions include the optimal choice of regimen and the duration of treatment. However, the relative rarity of early stage disease and the likely small difference between treatments makes evaluations difficult. Advanced disease is currently treated using a combination of surgical cytoreduction and platinum-paclitaxel chemotherapy. Women with poor risk disease are unlikely to be cured of their disease and the investigation of strategies to minimise treatment may be appropriate. Conversely, women with good risk disease may be better candidates for experimental treatment to increase cure rate. Strategies that have been tried include dose-intensification, high-dose therapy and intraperitoneal therapy. Whereas there is some evidence to support the latter, there is no current evidence for dose-intensification or high-dose therapy, and these must remain areas of investigation. Most current trials investigate the addition of agents to platinum-paclitaxel. Relapsed disease is an important area. Despite this, only 9 randomised controlled trials have been undertaken. Uncertainties exist in the role of surgery, both surgical cytoreduction and palliative surgery. The mainstay of treatment at disease relapse is chemotherapy and the choice of agent revolves around the concept of platinum sensitivity. Many agents are active in platinum-resistant disease, but uncertainties remain about the relative efficacies of each and the place of combination therapy.
UI - 11489506
AU - Tijerina M; Kopeckova P; Kopecek J
TI - The effects of subcellular localization of N-(2-hydroxypropyl)methacrylamide copolymer-Mce(6) conjugates in a human ovarian carcinoma.
SO - J Control Release 2001 Jul 6;74(1-3):269-73
AD - Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 South 2000 East, Room 301, Salt Lake City, UT 84112, USA.
Photosensitizers, light-sensitive compounds, become activated upon illumination with a specific wavelength of light generating cytotoxic oxygen species. Due to the short half-life of singlet oxygen, the subcellular site of localization and excitation affects the type of cellular damage produced as well as cellular responses to different types of photodamage created within the cell. Here, we investigated the effects of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-mesochlorin e(6) monoethylenediamine (Mce(6)) conjugates localized to different subcellular compartments. Temperature was utilized to achieve subcellular localization of conjugates and subcellular fractionation was performed to confirm localization patterns of HPMA copolymer-Mce(6) conjugates. Cytotoxicity studies suggest plasma membrane and late endosomes were more sensitive to photodamage than lysosomal compartments as observed by an approximate 2-fold decrease in the IC(50) compared to lysosomally accumulated conjugate. Releasing Mce(6) from the polymer backbone within lysosomal compartments significantly lowered the IC(50) when compared to HPMA copolymer conjugates with Mce6 bound via a nondegradable linkage. These differences will prove useful in the future design of HPMA copolymer-Mce(6) conjugates for the treatment of ovarian cancer.
UI - 11501778
AU - Trope C; Kristensen G; Kisic J; Kaern J
TI - Long-term results from a phase II study of paclitaxel combined with doxorubicin in recurrent platinum refractory ovarian cancer.
SO - Eur J Gynaecol Oncol 2001;22(3):223-7
AD - Department of Gynecologic Oncology, The Norwegian Radium Hospital, Montebello, Oslo.
BACKGROUND: There is still a need for newer non-cross-resistant agents and combinations to be tried in cases of failure after first line platinum-based therapy. Several agents have demonstrated activity after failure of platinum-containing regimens. Response rate in true platinum refractory disease up to 20% but with poor long-term survival, has been reported by single drug paclitaxel. In an effort to improve response rate and survival duration obtainable with single drug paclitaxel, we have combined paclitaxel with doxorubicin for the treatment of patients refractory to cisplatin-cyclophosphamide. PATIENTS AND METHODS: Between cisplatin-cyclophosphamide were enrolled for toxicity and survival analysis after receiving the combination doxorubicin 50 mg/m2 and paclitaxel 135 mg/m2 every third week for four courses. Responding patients continued on single drug paclitaxel 175 mg/m2 every third week until unacceptable toxicity or tumor progression occurred. RESULTS: The objective response rate (CR + PR) was 33%, 95% CI (14.6-57). The median duration of response was 8.5 months (range 4.0-62.5+) and the median overall survival was 15.5 months (range 4.0-63.5+). No serious toxicity was registered. CONCLUSION: Doxorubicin combined with paclitaxel could safely be administered using this schedule. This study shows that some patients obtaining CR can be rendered disease-free for a substantial period of time, sometimes five years or more. A median overall survival of 15.5 months with a 5-year survival probability of 15% is impressive. However, although responses can be induced in a significant number of patients, the survival figures remain poor.
UI - 11501784
AU - Elsheikh A; Milingos S; Kallipolitis G; Loutradis D; Vlachos G; Liapi A;
TI - Michalas S Ovarian tumors in young females. A laparoscopic approach.
SO - Eur J Gynaecol Oncol 2001;22(3):243-4
AD - 1st Department of Obstetrics & Gynecology, University of Athens, Alexandra Hospital, Greece.
Ovarian tumors are one of the major preoccupations in the everyday 2000, 54 cases of ovarian tumors in young females aged 14-20 years were diagnosed and managed laparoscopically in our institution. Twenty-two cases of mature cystic teratoma, 12 cases of endometriosis, eight cases of serous cystadenoma, five cases of mucinous cystadenoma, three cases of fibroma-thecoma, two cases of serous low-malignant tumors and one case of mucinous low-malignant tumor were found. The management of ovarian tumors during this age by laparoscopic techniques represents an efficient and safe procedure.
UI - 11499181
AU - Memarzadeh S; Berek JS
TI - Advances in the management of epithelial ovarian cancer.
SO - J Reprod Med 2001 Jul;46(7):621-9; discussion 629-30
AD - Division of Gynecologic Oncology, University of California-Los Angeles School of Medicine, 27-136 CNS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1740, USA.
More than 23,400 new cases of ovarian cancer and 13,900 deaths are expected in the United States this year. Epithelial ovarian cancer is the most common histologic type of ovarian malignancy. Although there have been advances in the chemotherapeutic treatment of ovarian cancer, the five year survival of women with advanced-stage disease is 25-30%. Because the disease is typically asymptomatic until the disease has metastasized and because effective screening strategies are not unavailable, 70-75% of women present with advanced-stage disease. Of ovarian cancer cases, 90-95% are sporadic and 5-10% associated with germ-line mutations, including BRCA1 and BRCA2. Known risk factors for ovarian cancer include nulliparity and a strong family history of ovarian cancer. The use of oral contraceptives is known to decrease the risk of ovarian cancer: five years of use will decrease the risk by 50%. The staging of ovarian cancer (according to the International Federation of Obstetrics and Gynecology) requires surgical exploration. Determining the extent of disease is essential to appropriate management. Survival in patients with metastatic disease is improved in those who undergo optimal primary cytoreductive surgery. Adjuvant chemotherapy is recommended in patients with high-risk, early-stage disease and all patients with advanced-stage disease. Standard chemotherapy is a combination of paclitaxel and carboplatin. Selected patients with recurrent disease can undergo secondary cytoreductive surgery. Second-line chemotherapy for patients who initially respond to paclitaxel and carboplatin and who have a prolonged disease progression-free intervals (longer than 12 months) can be re-treated with either drug or both. Those whose responses to initial therapy were less successful can be treated with other chemotherapeutic agents--e.g., liposomal doxorubicin, topotecan, etoposide, gemcitabine or taxotere.
UI - 11562749
AU - Yunmbam MK; Li QQ; Mimnaugh EG; Kayastha GL; Yu JJ; Jones LN; Neckers L;
TI - Reed E Effect of the proteasome inhibitor ALLnL on cisplatin sensitivity in human ovarian tumor cells.
SO - Int J Oncol 2001 Oct;19(4):741-8
AD - Medical Ovarian Cancer Section, Developmental Therapeutics Department, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Small molecules suppressing proteasome function inhibit the post-translational ubiquitination of selected proteins. Ubiquitin H2A is an example of an abundant chromatin-associated protein that is known to be ubiquitinated, which is important for several proteins involved in the repair of DNA damage. We therefore studied the effect of the proteasome inhibitor, N-acetyl leucyl-leucyl norlucinal (ALLnL), on cisplatin sensitivity in three human ovarian tumor cell lines. The proteasome inhibitor ALLnL was administered for 4 h before cells were subsequently exposed to cisplatin for 1 h. Our results showed that ALLnL, at its respective IC20 concentration, increased cellular sensitivity to cisplatin in an additive manner in human ovarian cancer A2780, A2780/CP70, and OVCAR3 cells. We also demonstrated that ALLnL caused a 50% increase in total cellular accumulation of cisplatin, and reduced the rate of cisplatin efflux by about 50%. In addition, DNA damage levels were increased after ALLnL treatment. By contrast, DNA repair was inhibited 2 to 3-fold in ALLnL-pretreated cells, as compared to the controls. Furthermore, our study showed that ALLnL deubiquitinated nucleosomal histone H2A in these cells in a concentration-dependent fashion, as assessed by Western blot analysis. These data suggest that sublethal levels of exposure to agents that inhibit proteasome function may alter the subcellular pharmacology of platinum in human ovarian carcinoma cells.
UI - 11585973
AU - Twelves C
TI - Vision of the future: capecitabine.
SO - Oncologist 2001;6 Suppl 4():35-9
AD - Cancer Research Campaign Department of Medical Oncology, University of Glasgow, and Beatson Oncology Centre, Glasgow, United Kingdom. firstname.lastname@example.org
Capecitabine is a thymidine phosphorylase (TP)-activated oral fluoropyrimidine, rationally designed to generate 5-fluorouracil (5-FU) preferentially within tumors. This tumor selectivity is achieved through exploitation of the significantly higher activity of TP in tumor compared with healthy tissue. The high single-agent activity of capecitabine in breast and colorectal cancer suggests that capecitabine may have a role in the treatment of other tumor types that are sensitive to 5-FU, such as pancreatic cancer. Tumor types known to have a high level of TP activity, such as renal cancer, are especially attractive targets for capecitabine therapy. Capecitabine has potential as monotherapy in these tumor types, or as a combination partner for other cytotoxic agents with different mechanisms of action and little overlap of key toxicities. In particular, some cytotoxic drugs, such as the taxanes and cyclophosphamide, are known to upregulate TP activity in tumor tissue, offering the potential for synergistic action. The combination of capecitabine and docetaxel has demonstrated significant activity in women with anthracycline-pretreated breast cancer, and is the only cytotoxic combination to significantly increase survival compared with standard therapy in this setting. In addition, capecitabine as monotherapy or in combination with other cytotoxic agents has shown encouraging activity in pancreatic, ovarian, and renal cell cancers. This article discusses recent data from clinical trials investigating capecitabine in a range of tumor types, highlighting the potential future role of capecitabine as an alternative to traditional i.v. chemotherapy.
UI - 11593052
AU - Wilailak S; Linasmita V; Srisupundit S
TI - Phase II study of high-dose megestrol acetate in platinum-refractory epithelial ovarian cancer.
SO - Anticancer Drugs 2001 Oct;12(9):719-24
AD - Department of Obstetrics & Gynaecology, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok 10400, Thailand. email@example.com
Our objective was to determine the efficacy of megestrol acetate in the treatment of platinum-refractory epithelial ovarian cancer (EOC), and to evaluate the toxicities and quality of life (QOL) associated with this therapy. Patients with platinum-resistant epithelial ovarian cancer were treated with megestrol acetate (800 mg/day) orally for 28 days and then 400 mg/day for a minimum of 28 days before being assessed ready for evaluation of response to therapy. Patients who demonstrated a complete response (CR), partial response (PR) or stable disease were continued in the study until there was objective evidence of disease progression. All patients who went off study were followed up at regular intervals, every 2 months, to assess overall survival. Thirty-six patients were enrolled. Response was observed in seven of 36 patients (three CR and four PR). The response rate was 19.4% (95% CI 9-36). Four of the responders had the endometrioid cell type, while two were clear cell carcinoma and one was serouscystadenocarcinoma. All three CR patients had the histology of endometrioid carcinoma with the tumors located in the pelvis. Median survival of the study population was 5.8 months. Median survival in the responders was 12 months, while median survival in the non-responders was 5.5 months. Median progression-free survival in the responders was 8.3 months, while median progression-free survival in the non-responders was only 2 months. The majority of patients gained weight and had a fair quality of life score during treatment. The only toxicity observed was alopecia (grade 1) in four patients. We conclude that megestrol acetate has modest but definite activity in patients with platinum-refractory EOC, particularly in a small subset of the endometrioid subtype with limited disease in the pelvis. Only minimal toxicity was observed and the patients had a fair QOL score during the treatment.
UI - 11604551
AU - Underhill CR; Parnis FX; Highley MS; Ahern J; Harper PG; Hansen H; Lund
TI - B; Dombernowsky P; Hirsch F; Hansen M; Carmichael J; Williams C Multicenter phase II study of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer.
SO - Anticancer Drugs 2001 Sep;12(8):647-52
AD - Guys Hospital, London, UK. firstname.lastname@example.org
Gemcitabine has activity in advanced ovarian cancer, with responses in platinum-resistant disease. This study assessed the activity of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer. All patients had histologically verified invasive epithelial ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease and no prior chemotherapy. Patients received gemcitabine 1250 mg/m(2) on days 1, 8 and 15 of a 28-day cycle. Radiological response was assessed after two cycles. evaluable patients, there was one complete response and five partial responses, for an overall response rate of 18% (95% confidence interval 7-36%). Forty-two percent of patients had a greater than 50% decrease in their CA-125 levels. Of the 25 patients who received platinum-based chemotherapy following treatment with gemcitabine, 12 achieved an overall response rate of 48%. Toxicity was mild, with two episodes of WHO grade 4 neutropenia (not associated with fever) and two episodes of grade 4 thrombocytopenia (not associated with bleeding). Gemcitabine has single-agent activity for poor-prognosis patients with advanced ovarian cancer. Similar results with subsequent platinum-based therapy indicate a lack of cross-resistance. This, combined with gemcitabine's favorable toxicity profile, warrants testing in comparative trials.
UI - 11606393
AU - Kumar A; Soprano DR; Parekh HK
TI - Cross-resistance to the synthetic retinoid CD437 in a paclitaxel-resistant human ovarian carcinoma cell line is independent of the overexpression of retinoic acid receptor-gamma.
SO - Cancer Res 2001 Oct 15;61(20):7552-5
AD - Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Treatment of ovarian carcinomas with the antimitotic antitumor drug paclitaxel is highly efficacious. However, development of drug resistance presents a major obstacle. The common cellular phenotypes associated with paclitaxel resistance are an increased expression of the drug transport protein P-glycoprotein (P-gp), an alteration in the levels of beta-tubulin isotypes, and/or changes in the drug binding affinity of the microtubules. We established two paclitaxel-resistant human ovarian carcinoma cell lines. The 2008/17/4 cells exhibited a "classic" multidrug-resistant phenotype (overexpression of P-gp associated with cross-resistance to natural product drugs), whereas the 2008/13/4 cells were an atypical multidrug-resistant subline (no overexpression of P-gp). In addition to being paclitaxel resistant (250-fold), the 2008/13/4 cells were also cross-resistant to etoposide (39-fold) and vincristine (460-fold). To identify the alterations in the gene expression profile associated with the development of atypical paclitaxel resistance, we used the Clontech Atlas Human Cancer cDNA Microarray (spotted with 588 genes). The expression of retinoic acid receptor (RAR)-gamma was significantly higher in the paclitaxel-resistant (2008/13/4 and 2008/17/4) cells than in the parental (2008) cells. Northern blotting analysis demonstrated that the expression of RAR-gamma was 7-fold higher in the 2008/13/4 and 2008/17/4 cells than in the 2008 cells, whereas the expression of RAR-alpha and RAR-beta was not observed in any cell line. Whereas the 2008, 2008/13/4, and 2008/17/4 cells were found to resist the antiproliferative effects of all-trans-retinoic acid, the paclitaxel-resistant cells were 6- to 7-fold cross-resistant to the antiproliferative effects of CD437 (a synthetic RAR-gamma-selective agonist; 6-[-(1-admantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid) compared with the sensitivity of the parental cells. To further understand the association of paclitaxel and CD437 resistance with the observed RAR-gamma overexpression, we transfected the 2008 cells with a full-length RAR-gamma cDNA construct. Two transfectants with increased expression of the RAR-gamma mRNA and protein were isolated and subjected to growth inhibition assays in the presence of various concentrations of paclitaxel, etoposide, vincristine, and CD437. The sensitivity of the 2008 transfected clones (displaying increased expression of RAR-gamma) to the cytotoxic effects of paclitaxel, etoposide, vincristine, and CD437 was similar to that observed in the parental 2008 cells. These results suggest that the overexpression of RAR-gamma (observed in the 2008/13/4 and 2008/17/4 cells) by itself is not capable of inducing paclitaxel and CD437 resistance (or resistance to etoposide and vincristine).
UI - 11606072
AU - Tournigand C; Louvet C; Molitor JL; Dehni N; Lejeune V; Sezeur A; Pigne
TI - A; Marpeau L; Cady J; de Gramont A Intravenous chemotherapy, early debulking surgery, and consolidation intraperitoneal chemotherapy in advanced ovarian carcinoma.
SO - Gynecol Oncol 2001 Nov;83(2):198-204
AD - Service d'Oncologie Medicale, Hopital Saint Antoine, Paris, France. email@example.com
OBJECTIVE: The efficacy of a cisplatin-anthracycline combination, early debulking surgery, and intraperitoneal chemotherapy has been demonstrated through separate studies. We evaluated a multimodal treatment strategy integrating these therapeutic options. METHODS: Women with stage III or IV ovarian carcinoma received six cycles of cisplatin/epirubicin alternating with leucovorin and 5-fluorouracil. Patients with a residual disease (RD) measuring more than 2 cm after the initial laparotomy underwent an early debulking surgery after the first three cycles of chemotherapy. A second-look laparotomy (SLL) was performed after six cycles of intravenous chemotherapy. Intraperitoneal chemotherapy with cisplatin, VP16, and mitoxantrone was then administered in patients with no or RD < 2 cm after SLL. RESULTS: A total of 87 patients were included. After initial laparotomy, 11 patients (12%) had no macroscopic residual disease, 38 (44%) had a RD < or =2 cm, and 38 (44%) had a RD > 2 cm. After early debulking surgery, an additional 18 patients (21%) had a RD < 2 cm. Seventy-five patients were evaluable for response to intravenous chemotherapy: the overall response rate was 80%, and 30 patients achieved a pathological complete response (40%). Eight percent of the patients had stable disease and 12% had a progression. Sixty-eight patients received intraperitoneal chemotherapy after second-look laparotomy. With a 72-month median follow-up, median overall survival and progression-free survival were, respectively, 37 and 19 months. Five-year survival was 41%. CONCLUSION: The prognosis of patients with advanced ovarian carcinoma may be improved by a sequential treatment strategy including intravenous chemotherapy, early debulking surgery, and intraperitoneal chemotherapy. Copyright 2001 Academic Press.
UI - 11606080
AU - Rodriguez M; Rose PG
TI - Improved therapeutic index of lower dose topotecan chemotherapy in recurrent ovarian cancer.
SO - Gynecol Oncol 2001 Nov;83(2):257-62
AD - Michiana Hematology and Oncology, Northern Indiana Cancer Research Consortium, South Bend, Indiana 46617, USA. firstname.lastname@example.org
OBJECTIVE: Topotecan (1.5 mg/m(2)) administered daily for 5 consecutive days of a 21-day cycle is an established chemotherapeutic regimen in recurrent ovarian cancer. However, noncumulative myelosuppression has limited its use by many clinicians. We sought to determine whether a lower dose of topotecan could provide comparable tumor activity and higher tolerability in pretreated ovarian cancer patients. METHODS: A retrospective chart review was conducted on recurrent ovarian, peritoneal, or fallopian tube cancer patients with measurable disease or elevated cancer antigen 125 levels (evaluable disease). Patients were treated with topotecan (1.0 mg/m(2)) given by 30-min intravenous infusion for 5 consecutive days every 21 days until disease progression or unacceptable toxicity. RESULTS: Treatment records from 37 women who had been treated with a median of 3 courses (range, 1 to 17) of lower dose topotecan were evaluated; all were evaluable for tolerability and 36 were evaluable for response. Patients had received a median of 3 (range, 1 to 6) previous treatments. The overall response rate was 22% (8/36); the response rates for patients with evaluable disease and measurable disease were 35.7 (5/14) and 13.6% (3/22), respectively. An additional 8 patients (22%) achieved stable disease. Grade 4 neutropenia, thrombocytopenia, and anemia occurred in 48.6, 5.4, and 5.4% of patients, respectively. Granulocyte colony-stimulating factor support was used in 37% of patients, including 5 who experienced febrile neutropenia. CONCLUSION: Topotecan at 1.0 mg/m(2) x 5 days every 21 days is active in platinum- and paclitaxel-resistant ovarian cancer, with significant improvements in hematologic toxicity. In heavily pretreated patients-topotecan can be safely given at reduced doses without apparent loss of efficacy. Copyright 2001 Academic Press.
UI - 11606086
AU - Jaeger W; Ackermann S; Kessler H; Katalinic A; Lang N
TI - The effect of bowel resection on survival in advanced epithelial ovarian cancer.
SO - Gynecol Oncol 2001 Nov;83(2):286-91
AD - Department of Obstetrics and Gynecology, University of Erlangen-Nuremberg, Erlangen, Germany. email@example.com
OBJECTIVE: FIGO stage III ovarian cancer is further categorized according to the size of tumor, but not according to the organs affected. In this study we evaluated the outcome of patients with and without macroscopic bowel involvement in stage III ovarian cancer. METHODS: This retrospective study analyzed the outcome of 194 ovarian cancer patients with FIGO III with and without bowel involvement who were operated on in our institution between 1985 and 1994. RESULTS: The study demonstrated that maximum tumor reduction without remaining macroscopic cancer offered the best overall survival times in FIGO III ovarian cancer patients. However, whenever the bowel was involved, even maximum bowel resections did not prolong survival compared to patients with remaining tumor after surgery. CONCLUSIONS: This retrospective study demonstrated that bowel involvement in ovarian cancer had a bad prognosis and that survival in these patients could not substantially be prolonged when the affected parts of bowel were resected. To further substantiate these findings, future studies on advanced ovarian cancer should differentiate between patients with and without bowel involvement. Copyright 2001 Academic Press.
UI - 11606094
AU - O'Meara AT; Sevin BU
TI - Predictive value of the ATP chemosensitivity assay in epithelial ovarian cancer.
SO - Gynecol Oncol 2001 Nov;83(2):334-42
AD - Division of Gynecologic Oncology, University of Southern California, Keck School of Medicine, 1240 N. Mission Road, Room 1L4, Los Angeles, California 90033, USA. firstname.lastname@example.org
OBJECTIVE: The aims of this study were to define the specific parameters of the ATP chemosensitivity assay which most accurately predict a patient's clinical response to chemotherapeutic agents in epithelial ovarian cancer and to assess the clinical utility of the ATP assay. METHODS: In our laboratory from 1992 to 1994, fresh tumor specimens from patients with epithelial ovarian carcinomas were assayed with the ATP chemosensitivity assay (ATP-CSA) for their in vitro responses to several chemotherapeutic agents including cisplatin, paclitaxel, and cyclophosphamide. Clinical data on 161 of those patients including all follow-up assessments were then collected, and an investigator blinded to the in vitro assay results determined the patients' responses to chemotherapy. In order to determine which parameter of the assay was the best predictor of clinical response for each drug, receiver-operator characteristic (ROC) curves were constructed for several parameters, including the amount of cell kill at particular dosage levels of drug, the slope of the dose-response curve, and the IC50, or the average concentration of drug at which 50% of the cells were nonviable. RESULTS: The specific parameter of the ATP-CSA which was most predictive of clinical response differed for each drug tested. The resulting positive predictive values for cisplatin, cyclophosphamide, and paclitaxel ranged from 70.0 to 78.3% and negative predictive values from 46.2 to 60.9%, with overall ATP-CSA positive and negative predictive values of 83.0 and 56.5%. Overall, patients whose tumors tested sensitive to an agent in vitro were almost twice as likely (83% versus 43%) to show a clinical response (RR 1.91, 95% CI 1.34-2.71). CONCLUSION: Analysis of the ROC curves in this study shows that different parameters of the ATP-CSA need to be utilized for each drug tested in order to give the best prediction of clinical chemosensitivity. Although the ATP-CSA shows predictive ability, routine use of the ATP-CSA for clinical selection of drug therapy in patients with epithelial ovarian cancer would not be warranted without a prospective study comparing chemotherapy treatment based on assay results versus clinician selection of drug. Copyright 2001 Academic Press.
UI - 11606100
AU - Ghosh K; Downs LS; Padilla LA; Murray KP; Twiggs LB; Letourneau CM;
TI - Carson LF The implementation of critical pathways in gynecologic oncology in a managed care setting: a cost analysis.
SO - Gynecol Oncol 2001 Nov;83(2):378-82
AD - Division of Gynecologic Oncology, University of Minnesota Medical Center, Minneapolis, Minnesota 55455, USA.
OBJECTIVES: The aim of the study is to determine whether critical pathways can be implemented at an academic institution to limit cost, without compromising patient satisfaction and quality of care. PATIENTS AND METHODS: Patients undergoing a hysterectomy with either cervical or endometrial cancer were placed on specific critical pathways consecutively for an 18-month study period. Preoperative teaching was intensified to educate the patient regarding expectations during the postoperative period. All patients were started on early feeding and patients were also placed on separate care pathways addressing pain and deep vein thrombosis prophylaxis. Total direct costs and patient satisfaction were obtained throughout the study period. During the year prior to care pathway implementation, patient data and direct costs were obtained for the preintervention group utilized for comparison. Postintervention groups were summarized every 6 months during the study cervical carcinoma undergoing a radical hysterectomy (DRG 353) and 21 patients with endometrial cancer who underwent a hysterectomy and lymph node sampling (DRG 355) were utilized as the preintervention group. (DRG 353) and 25 patients (DRG 355) were accrued. The average length of stay was reduced from 5.2 (DRG 353) and 4.7 days (DRG 355) prior to implementation of pathways to 3.4 days in both groups. In addition, total direct costs were reduced by 29 (DRG 353) and 32% (DRG 355) after implementation of care pathways. Patient satisfaction data recorded during the study did not demonstrate any change throughout the study period nor were there any higher rates of readmission after implementation of the care pathways. CONCLUSIONS: Critical pathways in gynecologic oncology can be implemented in a managed care environment in order to maintain high quality of care, maintain outcomes, and help reduce costs. Copyright 2001 Academic Press.
UI - 11606103
AU - Homesley HD; Hall DJ; Martin DA; Lewandowski GS; Vaccarello L; Nahhas
TI - WA; Suggs CL; Penley RG A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients.
SO - Gynecol Oncol 2001 Nov;83(2):394-9
AD - Brookview Research, Inc., Nashville, Tennessee 37203, USA. email@example.com
OBJECTIVE: Topotecan is an established topoisomerase I inhibitor for the treatment of relapsed ovarian cancer. Myelotoxicity and suboptimal patient convenience associated with daily topotecan, however, have prompted investigators to explore alternate regimens, including a weekly regimen of topotecan. The objective of this study was to determine the maximum tolerated dose (MTD) of topotecan given as a weekly bolus in previously treated ovarian cancer patients. METHODS: Second- and third-line ovarian cancer patients with measurable disease or elevated cancer antigen 125 received weekly bolus topotecan intravenously starting at 1.5 mg/m(2). Topotecan was escalated in dose increments of 0.5 mg/m(2) every 21 days as tolerability allowed. Dose-limiting toxicity was defined as grade 3/4 neutropenia or thrombocytopenia. RESULTS: Thirty-two of 35 patients were evaluable for safety and tolerability. No notable toxicity was observed with weekly topotecan doses < 4 mg/m(2). Additionally, there was an absence of dose-limiting myelotoxicity and thrombocytopenia with weekly topotecan. The MTD of weekly topotecan without the use of granulocyte colony-stimulating factor support was 4 mg/m(2), with grade 2 anemia, chronic fatigue, and grade 2 gastrointestinal toxicity limiting further dose escalation. Weekly topotecan also demonstrated antitumor activity at doses >2 mg/m(2). CONCLUSIONS: The establishment of a well-tolerated, weekly regimen of topotecan (4 mg/m(2), with a maximum recommended dose of 6 mg/m(2)) provides the basis for further investigation in phase II studies of single-agent and combination regimens in previously treated ovarian cancer patients. Copyright 2001 Academic Press.
UI - 11677705
AU - Watson E; Clements A; Yudkin P; Rose P; Bukach C; Mackay J; Lucassen A;
TI - Austoker J Evaluation of the impact of two educational interventions on GP management of familial breast/ovarian cancer cases: a cluster randomised controlled trial.