Phase II study of mitomycin-C and cisplatin in disseminated, squamous cell carcinoma of the uterine cervix. A European Organization for Research and Treatment of Cancer (EORTC) Gynecological Cancer Group study.

The aim of this study was to investigate the tumour response rate and toxicity of a combination chemotherapy consisting of mitomycin-C and cisplatin in patients with disseminated squamous-cell carcinoma of the uterine cervix. Chemotherapy consisted of mitomycin, 6 mg/m(2) intravenously (i.v.), and cisplatin, 50 mg/m(2) given i.v., both administered on day 1 of each cycle. The regimen was repeated at 4-weekly intervals. Mitomycin-C/cisplatin were used to treat 33 evaluable patients aged 29-67 years (median: 50 years). All patients except 1 had previously been treated with either surgery, radiation or both. At the initiation of chemotherapy, 8 patients had loco-regional and disseminated disease and 25 women had only distant metastases. The overall response rate was 42% (95% confidence interval (CI): 26-61%). Five complete and nine partial responses were observed with a median duration of response of 7.9 months (95% CI: 3.7-23.5 months). 9 patients had stable disease and 10 developed progressive disease during mitomycin-C/cisplatin-treatment. World Health Organization (WHO) grade III/IV side-effects were documented in 15 women, of whom 10 had gastro-intestinal toxicity, 3 had haematological toxicity, 1 had alopecia and 1 developed an allergic reaction to cisplatin. There were neither drug-related deaths nor severe or irreversible renal or hepatic dysfunction or peripheral neuropathy. The median progression-free survival was 5.0 months (95% CI: 3.6-6.2 months) for all patients and 10.5 months (95% CI: 6.2-15.2 months) for the responders. The median overall survival was 11.2 months (95% CI: 6.5-18.4 months).The mitomycin-C/cisplatin combination showed antitumour activity in the treatment of advanced or recurrent squamous-cell carcinoma of the uterine cervix. The regimen was well tolerated and could be administered on an outpatient basis.

Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer.

PURPOSE: To determine the side effects and feasibility of cisplatin and carboplatin each in combination with paclitaxel as front-line therapy in advanced epithelial ovarian cancer. PATIENTS AND METHODS: Patients were randomly allocated to receive paclitaxel 175 mg/m(2) intravenously as a 3-hour infusion followed by either cisplatin 75 mg/m(2) or carboplatin (area under the plasma concentration-time curve of 5), both on day 1. The schedule was repeated every 3 weeks for at least six cycles. Women allocated to paclitaxel-cisplatin were admitted to the hospital, whereas the carboplatin regimen was administered to outpatients. RESULTS: A total of 208 eligible patients were randomized. Both regimens could be delivered in an optimal dose and without significant delay. Paclitaxel-carboplatin produced significantly less nausea and vomiting (P: <.01) and less peripheral neurotoxicity (P: =.04) but more granulocytopenia and thrombocytopenia (P: <.01). The overall response rate in 132 patients with measurable disease was 64% (84 of 132 patients), and in patients with elevated CA 125 levels at start, it was 74% (132 of 178 patients). With a median follow-up time of 37 months, the median progression-free survival time of all patients was 16 months and the median overall survival time was 31 months. The small number of patients entered onto the study caused wide confidence intervals (CIs) around the hazards ratio for progression-free survival of paclitaxel-carboplatin compared with paclitaxel-cisplatin (hazards ratio, 1.07; 95% CI, 0.78 to 1.48) and did not allow conclusions about efficacy. CONCLUSION: Paclitaxel-carboplatin is a feasible regimen for outpatients with ovarian cancer and has a better toxicity profile than paclitaxel-cisplatin.

[Diverse expression of multiple endocrine neoplasia type 1]. / Pluriforme expressie van multipele endocriene neoplasie type 1.

MEN-1 is an autosomal dominantly inherited disorder, characterised by the occurrence of multiple tumours, particularly in the parathyroid glands, the pancreatic islets, the pituitary gland and the adrenal glands, as well as by neuroendocrine carcinoid tumours. Various clinical manifestations are presented by description of three patients harbouring a MEN1 gene germline mutation. A 44-year-old man had symptoms of hyperparathyroidism and in addition to parathyroid adenomas proved to have tumours in the thymus, adrenal and pituitary glands. A 48-year-old woman from a family with MEN-1 had suffered since her 40th year from headache and heartburn; she appeared to have adenomas in the parathyroid glands and gastrinomas in the pancreas, leading to a Zollinger-Ellison syndrome. One of her relatives, a man aged 29, had suffered from childhood from convulsions due to attacks of hypoglycaemia, and an insulinoma was assessed. In all patients, surgical and/or medical treatment alleviated symptoms. Clearly, the position or nature of the mutations in the MEN1 gene do not correlate with the clinical expression of the disease. Family investigation, DNA analysis and periodic examination improve quality of life and the life expectancy.

[Cytostatic treatment of ovarian carcinoma]. / De cytostatische behandeling van het ovariumcarcinoom.

Shortly after treatment with the cytostatic combination of cisplatin and paclitaxel was generally accepted as the standard therapy for patients with epithelial ovarian carcinoma, many have come to regard the combination of carboplatin and paclitaxel as a better choice. The latter combination causes fewer side effects and may be used in the outpatient clinic. Conceivably, the carboplatin-paclitaxel scheme will shortly have to be adjusted again owing to results of current research. The intensive basic research of recent years, namely, is beginning to yield benefits for the therapeutic arsenal against ovarian carcinoma. Possibilities are inhibitors of the breakdown of extracellular matrix (such as marimastat) and inhibitors of signal transduction (such as trastuzumab).

Phase II study of gemcitabine in ovarian cancer.

This phase II study evaluated the response rate and toxicity of single-agent gemcitabine in 40 women with epithelial ovarian cancer, previously treated with platinum-based chemotherapy. Patients had stage III or IV disease and progressive disease 1-12 months after the last treatment. Gemcitabine 1250 mg/m2 was administered on days 1, 8 and 15 of each 28-day cycle as a 30-minute infusion. The overall response rate to gemcitabine was 22% (95% confidence intervals: 10-39%). Responses to gemcitabine were observed in patients with platinum-refractory disease, which suggests no cross resistance to platinum. Gemcitabine was well tolerated and no grade 4 toxicity was seen. This study confirms that gemcitabine is active and well tolerated in pre-treated women with ovarian cancer.

Ovarian cancer: should we be managing patients with good and bad prognostic factors in the same manner?

There are only rare circumstances where knowledge of a patient's prognostic features appropriately guides therapy. The last few years a plethora of studies have been published which attempt to refine our understanding of determinants of prognosis in ovarian cancer patients by analysing molecular markers thought to be of relevance in malignant biology. Unfortunately, only a few studies have simultaneously evaluated, in a large patient sample, the relative prognostic importance of traditional clinical pathological variables together with molecular markers through application of multivariate analysis techniques. No firm conclusions can be drawn about which markers add meaningful prognostic information to standard variables of stage, residual disease, and grade. The work on BAX (a promoter of apoptosis) in a small series of patients suggests how knowledge of the molecular attributes of certain tumours may guide treatment towards or away from certain agents. If our understanding of molecular basis of aggressive disease improves, new treatments may evolve which will turn "prognostic" indicators into "predictive" indicators, allowing selection of treatment by molecular subset.

First line chemotherapy with carboplatin plus paclitaxel in advanced ovarian cancer--a new standard of care?

Cisplatin 75 mg/m2 plus paclitaxel 135 mg/m2 administered over 24 hours have been established as the standard treatment for advanced ovarian cancer. This schedule can not be administered in an outpatient setting. A European-Canadian trial confirmed the superiority of cisplatin-paclitaxel, but failed to improve the therapeutic index of this combination by reducing infusion length of paclitaxel from 24 to 3 hours. The reduction of infusion duration combined with a dose escalation of paclitaxel from 135 mg/m2 to 175 mg/m2 induced a high rate of neurotoxicity. A further attempt to improve the therapeutic index of platinum-taxane combinations was started with the substitution of cisplatin by carboplatin. At least 7 phase I/II trials evaluated this combination. The promising results of these studies led to the initiation of 5 randomised phase III trials with carboplatin plus paclitaxel administered in 3-hours. Two of these trials have completed accrual and preliminary data were available for this review. Although long-term survival data are not available, the current results warrant the conclusion that the combination of carboplatin AUC 5-6 plus paclitaxel 175 mg/m2 in a 3-hours infusion can be regarded as an alternative for the first-line treatment in patients with advanced ovarian cancer. Final analysis of the above mentioned phase III trials with longer follow-up is awaited and will define the ultimate role of this combination.

Advanced epithelial ovarian cancer: 1998 consensus statements.

BACKGROUND: During an international workshop held in September 1998, a group of specialists in the field of ovarian cancer reached consensus on a number of issues with implications for standard practice and for research of advanced epithelial ovarian cancer. METHODS: Five groups of experts considered several issues which included: biologic factors, prognostic factors, surgery, initial chemotherapy, second-line treatment, the use of CA 125, investigational drugs, intra-peritoneal treatment and high-dose chemotherapy. The group attempted to arrive at answers to questions such as: Are there prognostic factors, which help to identify patients who will not do well with current therapy? What is the current best therapy for advanced ovarian carcinoma? What directions should research take in advanced ovarian cancer? These issues were discussed in a plenary meeting. RESULTS: One of the major conclusions drawn by the consensus committee was that in previously untreated advanced ovarian cancer, cisplatin plus paclitaxel has been shown to be superior to previous standard therapy with cisplatin plus cyclophosphamide (level I evidence). However, for many patients, carboplatin plus paclitaxel is a reasonable alternative because of toxicity and convenience considerations. Most participants felt that the benefits in terms of toxicity for the paclitaxel-carboplatin are such that its widespread adoption at this stage is justified. Until mature survival data are available a minority of investigators would recommend continued use of cisplatin plus paclitaxel, specifically for those patients with advanced disease with the best prognostic characteristics. For future clinical research in this area, new end points for randomised clinical trials, together with a new Trials Network, are proposed.

Paclitaxel/carboplatin for the initial treatment of advanced ovarian cancer.

In 1996, the combination of cisplatin 75 mg/m2 plus 24-hour infusion of 135 mg/m2 paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) was proved to prolong survival in comparison with cyclophosphamide/cisplatin in women with advanced ovarian cancer. As a result, the paclitaxel/cisplatin combination was recommended to serve as the new standard of care. One year later, a European-Canadian group confirmed the efficacy of paclitaxel/cisplatin in a study in which the infusion period of paclitaxel was reduced from 24 to 3 hours and the dose of paclitaxel escalated to 175 mg/m2. These changes resulted in a lower incidence of myelosuppression but a higher rate of neurotoxicity. Replacing cisplatin with carboplatin, a platinum analogue without the neurotoxic effects, proved feasible, and several trials were initiated to compare the safety and efficacy of paclitaxel/carboplatin with paclitaxel/cisplatin. The results of two of these studies that have completed accrual and reported preliminary data have shown that paclitaxel/carboplatin can be administered safely to outpatients, is better tolerated than paclitaxel/cisplatin, and results in a better quality of life. So far, the larger study (accrual, 800 patients) has yielded equal durations of progression-free survival for both the carboplatin and cisplatin combinations. If future updates of these studies confirm the current results and show similar long-term survival, the combination of carboplatin area under the concentration-time curve 5 or 6 plus paclitaxel 175 mg/m2 given over 3 hours is an attractive regimen for the treatment of newly diagnosed epithelial ovarian cancer.

A development protocol for a diagnostic DSS.

A diagnostic decision support system (DSS) in medicine is an expert system that aids the physician in the determination of the diagnosis based on findings and test results. The DSS can be divided into 2 different types of components: the knowledge component and the information system component. Methods from software engineering, knowledge engineering and management are combined into a dynamic development cycle that allows stepwise update and refinement. The development of the knowledge component is based on knowledge engineering. In the starting phases, rapid prototyping is convenient to determine and evaluate the specification. The content of the knowledge base is frequently updated during its life time. For this purpose, a knowledge modelling protocol is supplied.

Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic testicular non-seminoma: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group. European Organization for Research and Treatment of Cancer.

We investigated the efficacy and toxicity of induction chemotherapy with cisplatin and etoposide with either bleomycin or ifosfamide in patients with intermediate-prognosis testicular non-seminoma. A total of 84 eligible patients were randomized to receive four cycles of etoposide, ifosfamide, cisplatin (VIP), or four cycles of bleomycin, etoposide, cisplatin (BEP). Intermediate prognosis was defined as any of the following: lymph node metastases 5-10 cm in diameter, lung metastases more than four in number or > 3 cm, HCG 5000-50,000 IU l(-1), AFP > 1000 IU l(-1). The complete response (CR) rates to VIP and BEP were similar, 74% and 79% respectively (P = 0.62). Including the cases in whom viable cancer was completely resected with post-chemotherapy debulking surgery, the percentages of patients who achieved a no-evidence-of-disease status were 80% on VIP and 82% on BEP (P = 0.99). In addition, there were no differences in relapse rate, disease-free and overall survival after a median follow-up of 7.7 years. The 5-year progression-free survival was 85% (95% CI 74-96%) in the VIP arm and 83% (95% CI 71-96%) in the BEP arm, hazard ratio (VIP/BEP) 0.83 (95% CI 0.30-2.28). The VIP regimen was more toxic with regard to bone marrow function; the frequency of leucocytes below 2000 microl(-1) throughout four cycles was 89% on VIP and 37% on BEP (P < 0.001). Our study does not indicate that ifosfamide is superior to bleomycin in combination with cisplatin and etoposide. The sample size in this study is small as the study was prematurely discontinued when data became available from a competing study that showed no improved effectiveness of VIP compared with BEP. Taken together with these data, bleomycin should not be replaced by conventional-dose ifosfamide.

Paclitaxel (175 mg/m2 over 3 hours) with cisplatin or carboplatin in previously untreated ovarian cancer: an interim analysis.

The side effects of cisplatin (75 mg/m2) in combination with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (175 mg/m2 over 3 hours) are expected to be more severe and frequent than those of carboplatin (area under the concentration-time curve of 5) in combination with the same dose of paclitaxel, but the combinations are expected to be equally effective. A disadvantage of the cisplatin-based regimen is that patients need to be admitted to the hospital. The carboplatin regimen can be administered to outpatients. We tested both combinations administered every 3 weeks in a randomized phase III study in patients with previously untreated epithelial ovarian cancer. An interim analysis for toxicity was performed in 145 patients shortly after study closure. We observed a difference in the incidence of nausea, vomiting, and neurotoxicity favoring the women treated with the carboplatin regimen, but this regimen caused more myelotoxicity. Maturation of the study is awaited before survival data can be analyzed and final conclusions can be drawn.

Paclitaxel with carboplatin for the treatment of ovarian cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (135 mg/m2 over 24 hours) plus cisplatin (75 mg/m2 at a rate of I mg/min) every 3 weeks is widely accepted as the new standard of treatment for women with advanced epithelial ovarian cancer. A higher dose of paclitaxel over a shorter infusion period is under investigation as an alternative because it looks at least as effective and is more convenient to administer. However, in combination with cisplatin this dose-time schedule causes neurotoxicity in an important number of patients that can preclude the delivery of an adequate total dose. One way to decrease the incidence of this side effect is to substitute cisplatin with the analogue carboplatin. From the present data the conclusion is warranted that it is feasible to combine both drugs in an adequate dose and with acceptable toxicity. The combination would allow administration to outpatients and may be more tolerable, allowing prolonged treatment. The combination also looks attractive for re-treatment of women who relapse after completing their first-line paclitaxel/cisplatin-based therapy and who have chemotherapy-sensitive disease and prognostic features indicating that there is a high likelihood of achieving a second durable remission.

Gemcitabine in cisplatin-resistant ovarian cancer.

Many new drugs have been tested in phase II studies in recent years. With a number of drugs the results vary because of differences in the patients recruited to these studies. A number of factors impact the response to second-line therapy, including the treatment-free interval between the end of previous therapy and the entry into phase II study, the bulk and stage of disease, the histology of the tumor, and hemoglobin level. The activity of the new drug tested is also important. It may be difficult to compare the results of different studies, as not all reports contain the same information. A report of a phase II study should contain information on all previous treatment, time since diagnosis, time since last treatment, tumor size at entry, hemoglobin values, performance status, histology, frequency of tests performed to evaluate toxicity, and clear definitions of response. Of the new drugs recently tested, the taxane paclitaxel has shown promising activity even in platinum-resistant patients. Gemcitabine, the novel nucleoside analog, also has shown activity in platinum-resistant patients in a phase II study. The response rate in this study was 19% (95% confidence limits, 9% to 34%). More importantly the responses were observed in a poor prognostic group of patients, characterized by primary platinum resistance, International Federation of Gynecology and Obstetrics stage IV, a treatment-free interval < or = 6 months, large bulky disease, and poorly differentiated/undifferentiated tumors. Both hematologic and nonhematologic toxicities were modest. The data suggest that gemcitabine, like paclitaxel, is non-cross-resistant to platinum.

Upregulation of B50/GAP-43 protein mRNA in rat dorsal root ganglia during cisplatin intoxication.

Expression of the growth-associated protein B50 (GAP-43) mRNA in dorsal root ganglia (DRG) of rats was studied by in situ hybridization. In response to treatment with the neurotoxic agent cisplatin, B50 mRNA expression was significantly enhanced following a cumulative cisplatin dose of 14 mg/kg. In the untreated age-matched control animals, only half of the ganglion cells exhibited expression of B50 mRNA (mean hybridization signal, 10 times background), whereas at a cumulative cisplatin dose of 14 mg cisplatin every neuron exhibited well above background expression (mean hybridization signal, 34 times background). Cotreatment with a neuroprotective ACTH4-9 analog known to prevent cisplatin neuropathy in rats did not affect the overall expression of B50 mRNA. However, in the subpopulation of large sensory neurons, B50 mRNA content was significantly higher in the group cotreated with the ACTH4-9 analog as compared with the saline-cotreated group after 14 mg/kg of cisplatin. We conclude that in analogy with the well-known upregulation of B50 mRNA following mechanical nerve lesions, treatment with the neurotoxic drug cisplatin also leads to an increase in B50 mRNA expression. This observation lends strength to the hypothesis that in neuropathies an imbalance between regenerative and degenerative mechanisms exists. The ability of the larger sensory neurons to retain an increased B50 mRNA expression better after cotreatment with the peptide than without may be related to stimulation of regenerative processes by this ACTH4-9 analog.

Value of quantitative pathological variables as prognostic factors in advanced ovarian carcinoma.

AIMS: To evaluate correlations among clinical, pathological, morphometric, stereological, and DNA flow cytometric variables and their prognostic value in advanced ovarian cancer. METHODS: Tissue was collected from 180 patients with advanced ovarian cancer. All 180 had undergone debulking surgery and were being treated with cisplatin. Long term follow up was available for all patients. The mitotic activity index (MAI), volume % of epithelium (VPE), mean nuclear area (MNA), standard deviation of the nuclear area (SDNA), estimates of volume weighted mean nuclear volume (nu v), and variables obtained from minimum spanning tree (MST) analysis were assessed in the least differentiated tumour section in each case. DNA flow cytometry was also performed. RESULTS: Quantitative pathological features differed significantly with respect to histological grade. The MAI, MNA, SDNA, and the number of points connected to three neighbours differed significantly among the different DNA ploidy groups. The VPE and number of points connected to two or three neighbours differed significantly between FIGO stages III and IV. Fifty two (29%) patients survived. FIGO stage, residual disease and SDNA had prognostic significance on both univariate and multivariate survival analysis. In patients with FIGO III stage disease and residual tumour nodes < or = 2 cm in diameter (67 patients, 29 (43%) survivors) a prognostic index was established based on SDNA and of the line length of the MST. The median survival time was not reached in a subgroup of patients with favourable prognosis (overall survival 57%). Median survival was 32 months for patients with an unfavourable index score (overall survival 28%). CONCLUSION: Morphometric variables have important additional value in predicting prognosis in patients with advanced ovarian cancer.