Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel

PURPOSE: Topotecan, a topoisomerase I inhibitor, was evaluated in a multicenter, phase II study of women with epithelial ovarian carcinoma who relapsed after one or two prior regimens that included platinum and paclitaxel. PATIENTS AND METHODS: Topotecan 1.5 mg/m2 daily was administered as a 30-minute infusion for 5 consecutive days on a 21-day cycle. Eligibility criteria included bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of 2 or less, and adequate bone marrow, liver, and renal function. Efficacy was assessed by independent radiologic review. RESULTS: One hundred thirty-nine patients were treated; 81% were platinum resistant. Sixty-two patients had received one prior regimen and 77 patients had received two prior regimens. Nine patients were not assessable for response; however, all patients were included in the response analysis. The overall response rate was 13.7%; 12.4% in platinum-resistant and 19.2% in platinum-sensitive patients. Stable disease lasted at least 8 weeks in 27.3% of the patients. The median duration of response and time to progression were 18.1 and 12.1 weeks, respectively. The median survival was 47.0 weeks. Grade 4 neutropenia occurred in 82% of the patients (34% of the courses) and thrombocytopenia in 30% of the patients (9% of the courses). Infectious complications occurred in 6% of the courses. Nonhematologic toxicities were mild. There were no drug-related toxic deaths. CONCLUSION: As a single agent, topotecan has modest activity in women with advanced epithelial ovarian carcinoma who have progressed or not responded after one or two prior regimens with platinum and paclitaxel. Further investigation of combination regimens is indicated in the primary therapy for ovarian cancer based on the mechanism of action and tolerability.     

A rational treatment of stage I epithelial ovarian cancer

OBJECTIVE: To evaluate the incidence of lymph node metastasis and the role of lymphadenectomy in stage I epithelial ovarian cancer. METHODS: Forty patients with stage I epithelial ovarian cancer treated from 1985 to 1990, were divided into two groups and retrospectively analyzed. First group of 20 patients were treated by routine surgery and cis-platinum based chemotherapy. Second group of 20 patients were treated by routine surgery and cis-platinum based chemotherapy plus retroperitoneal lymphadenectomy, and on the basis of with normal ovary and uterus preserved in the younger stage I a patients. A comparison was made between the five-year survival rates of the two groups. RESULTS: Four patients in the second group were found to have retroperitoneal lymph node metastasis and should be staged as II c postoperatively. In three of the four patients aortic lymph node metastasis were diagnosed. The chances of metastasis to the pelvic and to the aortic lymph nodes were nearly equal. There is a significant difference in the 5-year survival rates between the two groups (85% vs 100%, P < 0.05). Ten patients with their ovaries and uteri preserved are living and well. CONCLUSION: It is suggested that to obtain accurate FIGO staging and to improve survival and its quality, retroperitoneal lymphadenectomy should be performed in all patients with stage I eipthelial ovarian cancer, and younger patients with stage I a cancer may preserve their gestational functions if desired.     

Topotecan. A review of its potential in advanced ovarian cancer

The topoisomerase I inhibitor topotecan has shown antitumour activity against a variety of tumour types in vitro and in vivo. Topotecan in combination with drugs that induce DNA damage generally results in synergistic killing of tumour cells in vitro. As the activity of topotecan is related to exposure time, the drug is administered by intravenous infusion either continuously or once daily over a 30-minute period for several consecutive days. A 30-minute infusion of topotecan 1.5 mg/m2 on 5 consecutive days every 3 weeks produced response rates of up to approximately 20% in patients with advanced ovarian cancer who had failed to respond to platinum-based regimens or relapsed after initial response to such regimens. No significant differences in efficacy were apparent between topotecan and paclitaxel in a phase III study in patients with recurrent ovarian cancer, although a trend in favour of topotecan was evident for all major efficacy parameters. Non-cumulative myelosuppression, including neutropenia, thrombocytopenia and anaemia, is the dose-limiting toxicity associated with topotecan. Myelo-suppression was significantly more common with topotecan than with paclitaxel in a single comparative study. Non-haematological adverse events in topotecan recipients are generally mild and include alopecia, nausea, vomiting, and other gastrointestinal problems. Thus, topotecan has modest efficacy in the treatment of recurrent advanced ovarian cancer, with clinical activity similar to that of paclitaxel in a large randomised phase III study in this setting. Combinations of paclitaxel and a platinum compound are being used increasingly for first-line therapy, although relapse rates remain significant. Topotecan is therefore a suitable second-line option, providing antitumour response for some patients whose disease has relapsed after, or is refractory to, platinum-based therapy. Its wider potential when used either alone or in combination regimens should become clearer from ongoing studies.     

WART revisited: the treatment of epithelial ovarian cancer by whole abdominal radiotherapy

The present study investigated outcomes for 78 women with epithelial ovarian carcinoma treated by whole abdominal radiotherapy (WART) after cyto-reductive surgery at Westmead Hospital between 1980 and 1993. These patients had 5-year relapse-free and overall survival rates of 52 and 55%, respectively. The median follow-up was 7.5 years. Fifty-eight of the 78 women fulfilled the criteria as defined by the Princess Margaret Hospital's intermediate risk' category. These patients had both a relapse-free and overall survival rate of 62% at 5 years (P = 0.001 as compared with the remaining 20 women). Mild gastrointestinal upset was common during radiotherapy. Five women did not complete treatment. Late toxicity (grade 3 or more, using the Radiotherapy Oncology Group (RTOG) system) occurred in eight women, and five women required surgery for intestinal complications (6.4%). There were no deaths due to late side effects. In conclusion the results are consistent with those of other series in the treatment of epithelial ovarian cancer by adjuvant WART. When compared to a similar-stage disease treated with cisplatin-based chemotherapy, there is no evidence to support the exclusive use of chemotherapy.     

Management of early-stage epithelial ovarian cancer

"Early" epithelial ovarian carcinoma encompasses a spectrum of patients with diseases that have markedly different survivals, ranging from indolent lesions truly confined to the ovary to high-grade lesions that have a significant chance of occult metastasis at the time of diagnosis. The basic principles of management rest on an adequate primary surgical procedure that removes all gross disease and accurately assesses the sites at risk for metastasis with a comprehensive staging laparotomy. After a comprehensive staging laparotomy, patients can be stratified into low-risk and high-risk groups. Those with low-risk disease have such a low risk of recurrence that the toxicity of adjuvant therapy is not warranted. Although patients with high-risk disease have a high enough of a risk of recurrence to justify consideration of adjuvant therapy, their ultimate prognosis may be determined more by an accurate determination of the stage of disease rather than by currently available, marginally effective or ineffective therapy. Patients who are thought to have early stage disease on the basis of inadequate staging procedures either should undergo a restaging laparotomy or receive therapy for the possibility of occult advanced disease.     

First-line chemotherapy for advanced ovarian cancer: paclitaxel, cisplatin and the evidence

As of June 1998, four randomized trials have been completed comparing the combination of paclitaxel and cisplatin with a cisplatin-based control arm. The results of three of these trials are available; one has been published as a full paper, the other two in abstract form only. Two of the reported trials (GOG-111 and the Intergroup trial) provide clear evidence that cisplatin combined with paclitaxel is a more effective regimen than one using the same dose of cisplatin combined with cyclophosphamide. The results of the third reported trial (GOG-132) are rather different, suggesting that a higher dose of single-agent cisplatin may be as effective as the paclitaxel/cisplatin combination tested in the other two trials. A number of explanations for these unexpected results have been proposed: false-positive results in GOG-111 and the Intergroup trial; false-negative results in GOG-132; high crossover in GOG-132 (including crossover before progression); the cyclophosphamide in the control arm of GOG-111 and the Intergroup trial had a negative impact on outcome in the control group in these trials; the higher dose of cisplatin when used as a single agent in GOG-132 had a positive impact on outcome for the control group in this trial. These explanations are discussed in detail, and their implications explored.     

Single agent paclitaxel in resistant and relapsed epithelial ovarian cancer after first-line platinum-based chemotherapy--experience in an Asian population

In 1997, a new GCP has taken effect by the Ministry of Health and Welfare, Japan, and will be enforced as of April, 1998. The GCP regulates the method of clinical trials in the light of ethics and science. The New GCP requires written informed consent, enforcement of the responsibility of the client and so on.     

Treatment for infertility and risk of invasive epithelial ovarian cancer

The relationship between the use of fertility drugs and the risk of ovarian cancer was analysed using data from an Italian case-control study. The study comprised 971 women below the age of 75 years with histologically confirmed invasive epithelial ovarian cancer diagnosed within the year before the interview. The controls were 2758 women admitted to the same network of hospitals where the cases of ovarian cancer had been identified. Five cases (0.5%) and 11 controls (0.4%) reported use of fertility drugs. In comparison with women who had never used fertility drugs, the multivariate odds ratio (OR) for women who had taken fertility drugs was 1.1 [95% confidence interval (CI) 0.4-3.3]. The OR were 0.7 (95% CI 0.1-7.9) and 1.0 (95% CI 0.2-3.8) for women who had used fertility drugs for <6 and > or =6 cycles respectively. Considering the 14 cases and 45 controls reporting difficulty in conception, the risk of ovarian cancer was 0.5 (95% CI 0.1-3.6) for women who reported use of fertility drugs. Considering nulliparous women only, the estimated OR of ovarian cancer for any fertility drug use was 0.6 (95% CI 0.1-3.5). Although the present results have limitations in terms of statistical power and available information, they provide reassuring evidence of the absence of a strong association between fertility drugs and subsequent risk of developing epithelial ovarian cancer.     

Ninety-six-hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens

PURPOSE: To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer. PATIENTS AND METHODS: A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program. RESULTS: Although the regimen generally was well tolerated, no objective responses were observed. CONCLUSION: In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question.     

BAD partly reverses paclitaxel resistance in human ovarian cancer cells

Although paclitaxel is an important chemotherapy agent for the treatment of patients with epithelial ovarian cancer, its utility is significantly limited by the frequent development of drug resistance. Recent evidence suggests that resistance to chemotherapy may be partly related to defects in the apoptotic pathway. In this study we have investigated whether enhancement of apoptotic pathway function through stable expression of the BAD protein is capable of sensitizing human epithelial ovarian cancer cells to the effects of chemotherapy. Expression of HA-BAD in six separate clonal transfectants from two different ovarian cancer cell lines was found to significantly enhance the cytotoxic effects of paclitaxel, vincristine, and, to a lesser extent, etoposide. Enhancement of paclitaxel-induced apoptosis in HA-BAD-expressing clones was demonstrated by trypan blue exclusion, clonogenic cell assay, and flow cytometric evaluation. Importantly, this effect was associated with binding of HA-BAD to BCL-xL and concomitant disruption of BAX:BCL-xL interaction. Taken together, these data suggest that the development of small molecules which mimic the effects of BAD may represent a new class of drugs capable of preventing or reversing resistance to chemotherapy agents such as paclitaxel.     

GnRH analogs for treatment of ovarian cancer

To make use of antigonadotropin and antiproliferating action of the synthetic analogs of GnRH there was applied this decapeptide in 33 patients with ovarian cancer who were treated traditionally by chemotherapeutics PAC and radiotherapy. The monitoring of treatment was supported on the clinical opinion of the whole and locally state of health, the USG examinations of pelvic and diaphragm, the measure of level of CA-125 and second-look operations. There were got statistically characteristic rise of remissions and stabilizations of neoplastic process.     

Segregation analysis of epithelial ovarian cancer in Finland

Epithelial ovarian cancer is known to aggregate in families. The dominantly inherited ovarian cancer predisposing genes, BRCA1, BRCA2 and genes involved in the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, have recently been identified. However, in the majority of families with more than one case of ovarian cancer, dominant inheritance cannot be recognized. We investigated familial clustering of epithelial ovarian cancer in a population-based sample of 663 Finnish ovarian cancer patients. A segregation analysis with the POINTER software was conducted on the 937 nuclear families from these 663 pedigrees. The major gene model was favoured, and the sporadic and multifactorial models were strongly rejected. In the studied population, the best fitting model was a recessive mode of inheritance, and 8% of ovarian cancer patients were estimated to be homozygous for the deleterious genotype. This evidence for recessively inherited ovarian cancer predisposition should be interpreted cautiously, as the analysis is subject to certain errors, which are discussed in the article. Results of this analysis, however, strongly emphasize the role of genetic factors in all familial aggregation of epithelial ovarian cancer.     

Angiogenic protein expression in advanced epithelial ovarian cancer

We set out to determine whether advanced epithelial ovarian cancer (EOC) is associated with elevated serum and ascitic concentrations of the angiogenic factors angiogenin (ANG), basic fibroblastic growth factor (bFGF), and vascular endothelial growth factor (VEGF), and whether the expression of angiogenic factors was associated with tumor vascularity. Serum and ascitic samples were collected from previously untreated patients with FIGO stage III and IV EOC and stored at -70 degreesC. Levels of the three factors were determined by enzyme-linked immunoassay. Histological sections from paraffin blocks of ovarian cancers were stained immunochemically for factor VIII, CD34, and VEGF. Thirty-nine patients were studied, although not all had paired serum and ascitic samples. For each angiogenic factor, the following findings were noted: (a) there was a wide range in serum and ascitic fluid concentrations; (b) the mean serum concentration was higher (P < 0.05) than the mean concentration in normal serum; and (c) the mean serum concentration was lower (P < 0. 05) than the mean ascitic concentration. Overall, the most consistent pattern of elevated serum and ascitic concentrations was with bFGF. With serum samples, 38.9% of patients had a normal VEGF concentration, as did 15.3% for ANG and 7.7% for bFGF. In ascites, the VEGF concentration was in the range for normal serum in 24.5% of samples, compared to 39.4% for ANG and 2.8% for bFGF. In paired samples, both VEGF and bFGF showed higher ascitic concentrations in 100 and 88.3% of samples, compared to 53.3% for ANG. There was no correlation between the serum and/or ascitic concentration of one factor and that of another, suggesting that these factors are independently regulated. Staining with anti-CD34 was more sensitive and reliable than with anti-factor VIII. VEGF staining was most prominent in poorly differentiated tumors and was observed only on tumor cells. There was no correlation between the serum or ascitic concentrations of angiogenic factors and tumor vascularity. Advanced EOC is associated with raised serum and ascitic bFGF concentrations and with markedly elevated ascitic VEGF in most cases. Serum VEGF and serum and ascitic ANG are less often elevated. There was no correlation between the angiogenic profile in serum and ascites and tumor vascularity.     

Psychotropic medication use and risk of epithelial ovarian cancer

New cytotoxics with significant activity both in preclinical and clinical situations continued to be applied in the clinic by empiric means. The use of defined cell lines allows unanticipated antagonism between agents to be identified and to suggest synergistic combinations which need to be tested. By means of a semi-automated MTT assay and median effect analysis, we have identified antagonism in two couplets being evaluated in the clinic: etoposide with paclitaxel and vinorelbine with gemcitabine. Optimal use of these agents in man may require spacing these agents in time to prevent an adverse drug interaction between the agents which may diminish the potential response rate.     

Field cancerization: why late "recurrent" ovarian cancer is not recurrent

OBJECTIVE: Late "recurrence" of ovarian cancer may result from either regrowth of dormant tumor cells or from development of a new cancer caused by the phenomenon of field cancerization. Clinically, some recurrent ovarian cancers show the same therapeutic sensitivities to chemotherapy and surgery as did the primary disease, whereas others are refractory to all therapy. We hypothesize that recurrent ovarian cancers are distinguishable on the basis of a molecular genetic fingerprint and that some are actually new primary cancers of the peritoneum rather than recurrent ovarian cancer. STUDY DESIGN: We constructed molecular genetic fingerprints of 13 paired primary and late recurrent ovarian cancers to study their clonal relationships. The tumor pairs were analyzed for p53 mutations and allelotypes, patterns of X-chromosome inactivation, loss of heterozygosity, and microsatellite instability at 12 different loci on 6 different chromosomes. Techniques used included single-strand conformational polymorphism mutation screening and polymerase chain reaction-based sequence analysis of the p53 locus, restriction digestion of the androgen receptor locus to determine X-chromosome inactivation, and polyacrylamide gel electrophoresis of highly polymorphic dinucleotide, trinucleotide, and tetranucleotide repeats. RESULTS: The average age at initial diagnosis for this cohort was 54.7 years (range 45.3 to 65.5). Mean interval to recurrence was 42.7 months (range 28 to 62). Molecular fingerprints were characterized for 4 to 8 informative loci per tumor pair. The fingerprints of 10 (77%) differed significantly, strongly suggesting that a second primary cancer had developed. The remaining 3 tumor pairs demonstrated identical allelotypes consistent with regrowth of dormant tumor cells. CONCLUSION: Our results are consistent with the "field cancerization" hypothesis of ovarian carcinogenesis but could also be explained by a polyclonal tumor origin, which contrasts with the currently accepted monoclonal theory of ovarian carcinogenesis. Late development of a new primary cancer may herald the proband as a member of a familial cancer phenotype. These studies provide a molecular genetic rationale that both explains and prognosticates the clinical course of recurrent ovarian cancer.