Dose intensity analysis in advanced ovarian cancer patients

To determine if chemotherapy dose intensity influences treatment outcome in advanced ovarian cancer, all randomised studies of first line chemotherapy, published between 1975 and 1989, were analysed for relationships between planned dose intensity and (a) objective response and (b) median survival. Total dose intensity of each study regimen was calculated and a weighted regression model providing for systemic differences in response or survival among studies was utilised. Hence, treatment arms of different studies were never directly compared. In addition, relative dose intensities of individual drugs within combinations was similarly evaluated. The improvement in objective response rate when adding one unit of total dose intensity ranged between 12% and 16% depending on baseline response rate. The improvement in median survival when adding one unit of total dose intensity ranged between 2 and 4 months. One unit of total dose intensity corresponds to, for example, 20 mg m2 week of cisplatin, or 25 mg m2 week of doxorubicin, or 350 mg m2 week of cyclophosphamide. The analysis of individual drugs suggested that doxorubicin and the platinum compounds were about equally effective, with cyclophosphamide being less effective. The methodological benefits and limitations of the approach used and the implication of the results are discussed.     

Increased cell-surface urokinase in advanced ovarian cancer

Urokinase-type plasminogen activator (uPA), uPA receptors, and cathepsin B were quantitated by using an immunological method, enzyme-linked immunosorbent assay, and amidolytic activity assays in 15 malignant and 10 benign epithelial ovarian tumors. The levels of uPA and uPA receptors, as well as cathepsin B, were found to be higher in membrane preparations obtained from malignant tumors than in those obtained from benign tumors. Acid-treated membranes acquired the ability to bind uPA, indicating that uPA is bound to a specific surface receptor that is not completely saturated. Levels of single-chain uPA (pro-uPA) and high-molecular-weight uPA in membrane preparations were measured by immunoadsorbent-amidolytic assay. The finding of a significant increase in amidolytic activity following activation of uPAs by plasmin suggested that less than half (30-40%) of all membrane immunoreactive uPAs is present in the enzymatically inactive pro-uPA form. In the membranes of malignant tumors, levels of uPA receptor and cathepsin B did not vary with stage of disease. On the other hand, we found that the level of receptor-bound uPA antigen/activity was significantly increased in advanced malignant tumors. Receptor-bound uPA may play an important role in determining invasive potential of tumor cells. Since ovarian cancer cells produce both pro-uPA and cathepsin B, the possibility of activation of tumor cell-derived pro-uPA by cellular protease cathepsin B must be considered.     

Maximal cytoreductive surgery in advanced ovarian cancer

The standard form of surgical intervention in advanced ovarian cancer is to undertake a pelvic clearance, and remove all tumour. When the latter is not feasible, then a ‘debulking’ operation is performed. This is a procedure whereby the intra-abdominal tumour load is reduced to what is termed ‘optimum’ residual disease (which has varied definitions). Compared with other intra-abdominal solid tumours, this approach is unique to ovarian malignancies. Whilst many retrospective studies, and meta-analyses may indicate that patients with ‘optimum’ debulking survive longer than those with a greater amount of residual disease, the reality is that this surgical intervention has never been exposed to a randomised controlled trial. Therefore, rather than ‘optimum’ debulking enhancing survival, it could be that the ability to achieve the ‘optimum’ is only reflecting the inherent tumour biology of a more chemo-sensitive disease. This debate will continue until such studies are completed.     

The evidence for increasing cytotoxic dose intensity in the treatment of advanced ovarian cancer

Clinically, lipomas of the hypopharynx may be confused with other benign or even malignant lesions. Barium flow radiography allows depiction of lesions cranial to the epiglottis, but often fails to be accurate for subepiglottic lesions. CT however has allowed a certain diagnosis to be made in many cases in the past. MRI is still more accurate, and allows not only a more specific diagnosis of the lesion, but also a better depiction of the origin of the pedunculated lesion and its extension in the parapharyngeal space. This paper adds three cases to the 52 cases in the literature already described and presents the typical features of hypopharyngeal lipoma by MRI for the first time.     

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.     

Evaluation of efficacy and toxicity of tamoxifen in patients with advanced chemotherapy resistant ovarian cancer

47 patients with advanced ovarian cancer after routine treatment were treated with tamoxifen. Objective response rate (CR + PR) was 6.4%. 46.8% patients had stable disease with median time of stabilisation 6.9 m. Because of low toxicity and non satisfactory results of second line chemotherapy tamoxifen seems to be a useful treatment for this group of patients.     

A combination of ifosfamide and mitoxantrone as salvage therapy in patients with advanced ovarian cancer

Ifosfamide (IFX) and mitoxantrone (MXN) have been found to be effective against advanced epithelial ovarian cancer. The combination of these two agents has not yet been tested in this setting but seems to be rational, given the different action mechanisms of these drugs and their not completely overlapping side effects. Between June 1987 and November 1991, 37 patients with advanced ovarian carcinoma recurrent or refractory to primary cisplatin-based chemotherapy entered the study. Therapy consisted of MXN, given i.v. at 10 mg/m2 on day 1 and IFX given i.v. at 2,000 mg/m2 per day on days 1-3 with mesna. The cycles were repeated every 3 weeks. Four patients achieved a complete remission and three achieved a partial remission, for response rates of 18.9% [95% confidence interval (CI) 6.3-31.5%] in the whole sample and 38.8% (95% CI 16.3-61.3%) in the subset of 18 patients responding to first-line cisplatin. No response was obtained in the remaining patients, whose disease was refractory to primary platinum-based chemotherapy. Clinically significant toxicity (WHO grades 3-4) included leukopenia in 46% of the patients and anemia in 32.5%. The non-hematologic toxicity was mild, except for reversible alopecia (57%) and nausea and vomiting (48.5%). This regimen seems attractive for patients who have either failed or not received platinum retreatment, especially when limiting neurotoxicity occurs. Further studies are warranted to establish the relative impact of both of these agents.     

A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer

BACKGROUND: Most patients with advanced ovarian cancer will relapse following platinum-based combination chemotherapy and be considered for second-line treatment. Gemcitabine, a nucleoside analogue, is active against a range of solid tumors. This phase II study investigated the activity of single-agent gemcitabine in patients with recurrent ovarian cancer. PATIENTS AND METHODS: Thirty-eight patients with FIGO stage III (34%) or IV (64%) ovarian cancer who were previously treated with platinum-containing regimens were enrolled. Patients received 1200 mg/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle. RESULTS: Patients completed an average of 3.6 cycles. Two complete and three partial responses were seen in 36 evaluable patients, for an overall response rate of 13.9% (95% CI: 4.7%-29.5%). The median survival time was 6.7 months. Toxicities were generally mild. The most common were grade 3-4 neutropenia and grade 3 leukopenia reported in 23.7% and 10.5% of patients, respectively. One patient had grade 4 pulmonary toxicity. CONCLUSION: Single-agent gemcitabine is active and well tolerated in patients with recurrent ovarian cancer.     

The management of diabetes in patients with advanced cancer

Although a form of eating disorders had been described by Kampo (Chinese traditional medicine) physicians during the last quarter of the 18th century, the modern study on eating disorders in Japan dates from the end of the 1950s. With the rapid increase in the number of cases, research activities have become very active recently. Both the past and present status of eating disorders and of research activities relating to them in Japan are not well known in other countries. This study concentrates on a review of the literature, with a focus on prevalence, etiology, and symptoms.     

Mobilization of peripheral blood stem cells in advanced ovarian cancer

High-dose chemotherapy with hematopoietic support has been expected to improve the survival of advanced ovarian cancer patients in recent years. An essential component of such treatment has been the ability to collect and reinfuse a large number of peripheral blood stem cells (PBSCs) following high dose therapy. This study was designed to determine which clinical and hematological factors would be better indicators to collect the proper volume of PBSCs. Thirteen patients received a total of 24 courses of induction chemotherapy and 69 of apheresis. We usually mobilized stem cells using CEP chemotherapy (cisplatin 50-70 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 1.5 g/m2) with G-CSF and CEE regimen (cyclophosphamide 2.0 g/m2, epirubicin 50 mg/m2, and etoposide 50 mg/m2) as a salvage for mobilization. We obtained an average 5 x 10(6)/kg of CD34+ cells for 3 days as one course. The number of CD34+ cells collected significantly depended on the platelets and reticulocytes on the first day of apheresis, but not a nadir of WBCs. It is concluded that apheresis should be started on recovery of WBCs to 5,000-10,000/microliters, of immature granulocytes to > or = 10% and of reticulocytes to > or = 20%. This study confirmed the feasibility of collecting enough PBSCs to use standard chemotherapy of ovarian cancer patients.     

The use of antioxidants together with polysorb enterosorption in the combined treatment of patients with III-IV-stage ovarian cancer

Studied in the course of a multiple-modality treatment of patients with stage III to IV ovarian cancer were effects of retinol and tocopheroli acetas and enterosorption with a silicone sorbent polysorb on the processes of lipid peroxidation and indices for the antioxidant system, for which purpose 75 female subjects were examined. The results obtained showed that retinol and tocopheroli acetas and enterosorption combined in treatment of patients with stage III-IV ovarian cancer made for stabilization of the processes of lipid peroxidation as well as for normalization of blood plasma content of factors of the antioxidant defence.     

Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes

Thirteen patients with epithelial ovarian cancer, who did not show any detectable lesion after cisplatin-containing chemotherapy following primary operation, were treated with adoptive transfer of tumor-infiltrating lymphocytes (TIL group). Eleven patients with almost equivalent conditions of disease, who were treated with only chemotherapy following primary operation, served as a control group. The median time of follow-up was 36 (range, 23-44) months in the TIL group and 33 (range, 14-48) months in the control group. The estimated 3-year overall survival rate of disease-free patients in the TIL group and in the control group was 100% and 67.5%, respectively. A significant difference was noticed between the overall survival rate of the TIL group and the control group (P < 0.01). Furthermore, the estimated 3-year disease-free survival rate of the patients in the TIL group and in the control group was 82.1% and 54.5%, respectively. The disease-free survival rate of patients in the TIL group and in the control group was significantly different (P < 0.05). These results suggest that the adoptive transfer of TILs after all chemotherapy has been finished might be one promising method to achieve complete cure of advanced epithelial ovarian cancer.     

Cytoreductive surgery plus combined chemotherapy for the treatment of advanced ovarian cancer

OBJECTIVE: To evaluate the impact of cytoreductive surgery plus combined chemotherapy on advanced ovarian cancer. METHODS: From Jan. 1980 to Dec. 1992, 76 patients admitted to our hospital for primary treatment, were eligible for retrospective evaluation. 26 patients with stage II and 50 with stage II. All patients with ovarian cancer were given cytoreductive surgery followed by systemic and intraabdominal chemotherapy. Regimens were CAP (Cyclophosphamide, Adriamycin, Cisplatin), AP (Adriamycin, cisplatin) or CE (Carboplatin, Epi-adriamycin). RESULTS: In 52 patients no residual tumor was found in 24 patients there were residual lesions less than 2cm in diameter. Postoperative chemotherapy ranged from 1 to 12 courses. The overall 5-year-survival rate was 33.6%, with 34.9% for stage II and 29.5% for stage II (P > 0.1). The 5-year-survival rates of cases with and without residual tumor were 16.5% and 37.6% respectively, the rates of those cases receiving less or more than 8 courses of chemotherapy were 20.0% and 60.1% respectively. CONCLUSION: The prognosis of ovarian cancer following cytoreductive surgery is influenced by residual tumor, and the number of courses of chemotherapy.     

Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients

Ascites from ovarian cancer patients contain potent growth-promoting activity toward human ovarian cancer cells both in vitro and in vivo. This activity is associated with rapid increases in cytosolic free calcium ([Ca2+]i) as a consequence of phosphoinositide hydrolysis. In this study, we describe the purification, characterization, and identification of an ovarian cancer activating factor (OCAF) from ascites of ovarian cancer patients. We have isolated OCAF by a combination of solvent extraction, silica gel chromatography, and TLC. Mass spectral analysis, phospholipase sensitivity, and gas chromatographic behavior of purified OCAF indicate that OCAF is composed of various species of lysophosphatidic acid (LPA), including LPAs with polyunsaturated fatty acyl chains (linoleic, arachidonic, and docosahexaenoic acids). However, OCAF is more potent than sn-1 palmitoyl, oleoyl, or stearoyl LPA in increasing [Ca2+]i in ovarian cancer cells. The ability of OCAF to alter [Ca2+]i is sensitive to the effects of lipoxidase, whereas the activity of sn-1 oleoyl, stearoyl, or palmitoyl LPA is not, suggesting that polyunsaturated bonds in the fatty acyl chain of OCAF may account for its increased ability to activate ovarian cancer cells. Furthermore, a sn-2 linoleoyl LPA generated by phospholipase A1 treatment of synthetic phosphatidic acid is much more active than are sn-1 palmitoyl, stearoyl, or oleoyl LPA in increasing [Ca2+]i in ovarian cancer cells. Taken together, these data suggest that the ability of OCAF to increase cellular calcium may reside in the structure and/or location of the fatty acyl chain of LPA. Purified OCAF, at concentrations similar to those present in ascites from ovarian cancer patients, was sufficient to induce proliferation of ovarian cancer cells, as indicated by thymidine incorporation, reduction of 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, or colony formation. However, even at optimal concentrations of OCAF, proliferation was lower than that induced by FCS or ascites from ovarian cancer patients, indicating that, although OCAF may be a major regulator of ovarian cancer cells in vivo, it is not the sole mediator present in ascites, and it likely functions in concert with other growth factor activities.     

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.     

Weekly CAF chemotherapy for advanced breast cancer patients

BACKGROUND: Seromas and impaired shoulder function are well-known complications after modified radical mastectomy for breast cancer. Early postoperative physiotherapy is a common treatment to avoid shoulder dysfunction. The aim of this study was to evaluate if the frequency of postoperative seromas could be reduced, without increasing shoulder dysfunction, by delayed postoperative shoulder exercises. METHODS: In a prospective study 163 patients with breast cancer undergoing modified radical mastectomy were randomized to physiotherapy starting on postoperative day 1 or day 7. Patients were seen by the surgeons and the physiotherapists during hospital stay and in the outpatient department. Seromas and other complications were registered by the surgeons. The physiotherapists instructed the patients pre- and postoperatively and assessed shoulder function. RESULTS: There was a significantly higher incidence of postoperative seromas in the group of patients that started physiotherapy postoperative day 1 (38%) compared to the group that started physiotherapy postoperative day 7 (22%) (p < 0.05). There was no significant difference between the groups in the late outcome of shoulder function. CONCLUSION: The incidence of seromas after modified radical mastectomy for breast cancer is reduced by delaying shoulder exercises one week postoperatively. Earlier postoperative physiotherapy is not necessary to avoid impaired shoulder function.     

Carboplatin in combination with epirubicin and cyclophosphamide in patients with advanced ovarian cancer. A phase II study

Seventy-one patients with epithelial ovarian cancer stage III (n = 56) or IV (n = 15) were treated with carboplatin 300 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 400 mg/m2 every fourth week. Patients clinically free of tumour after six courses (n = 58) underwent a second-look laparotomy. Seventeen patients were microscopically tumour-free (24% of all) and an additional 10 (14%) had only microscopic cancer. Median time to progression was 19 months. The median survival was 33 months and the estimated 5-year survival 27%. The toxicity was mainly haematological, with leukopenia WHO grade 3-4 seen in 88% and thrombocytopenia grade 3-4 in 42% of the patients. The gastrointestinal toxicity was mild and no renal toxicity was seen. This chemotherapy regimen was effective with acceptable toxicity and could be given on an out-patient basis. The possibility of increasing the efficacy and decreasing the toxicity was discussed.