Jan P. Neijt

Exploratory Phase III Study of Paclitaxel and Cisplatin Versus Paclitaxel and Carboplatin in Advanced Ovarian Cancer

PURPOSEnTo determine the side effects and feasibility of cisplatin and carboplatin each in combination with paclitaxel as front-line therapy in advanced epithelial ovarian cancer.nnnPATIENTS AND METHODSnPatients 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.nnnRESULTSnA 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.nnnCONCLUSIONnPaclitaxel-carboplatin is a feasible regimen for outpatients with ovarian cancer and has a better toxicity profile than paclitaxel-cisplatin.

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.

The ACTH-(4–9) analog, ORG 2766, prevents taxol-induced neuropathy in rats

Taxol is a novel and promising oncolytic agent the use of which is hampered by its neurotoxicity. We now describe a taxol-induced neuropathy in rats and its prevention by the adrenocorticotropic hormone-(4-9) (ACTH-(4-9)) analog, ORG 2766. A decrease in sensory nerve conduction velocity was seen in taxol-treated rats, both with daily injections of small amounts (6 mg/kg per week) and with weekly injections of higher amounts (9 mg/kg per week) of taxol. Concomitant administration of ORG 2766 completely prevented the occurrence of a neuropathy.

Phase II study of gemcitabine in previously platinum-treated ovarian cancer patients.

Fifty-one patients with histologically confirmed epithelial stage III or IV ovarian cancer were entered into a study in which gemcitabine 800 mg/m2 was given as a 30 min intravenous infusion in a cycle once a week for 3 weeks followed by a week of rest. Patients were aged 58 years (range 23-70 years) with WHO performance status 0-2, and had received up to two different chemotherapy regimens. Thirty-eight patients had received only one prior platinum-containing chemotherapy regimen whereas 9 had received a first-line regimen on more than one occasion. A further 3 patients had received two different regimens. Of 42 patients evaluable for response, 8 (19%; 95% Cl: 9%34%) were partial responders. Seven of the 8 responders were resistant to first-line platinum-based therapy. Median duration of response was 8.1 months (range 4.4-12.5 months). Median progressionfree survival was 2.8 months (range 0.2-12.5 months). Haematological toxicity with gemcitabine was modest, with grade 3 leukopenia (11 patients) and grades 3 and 4 thrombocytopenia (6 patients). Grade 3 non-haematological toxicity included nausea/vomiting (6 patients) and elevated AST/ ALT (1 patient), while dose-limiting non-haematologic toxicity consisted of flu-like symptoms (2 patients), peripheral oedema (1 patient) and lethargy (1 patient). The activity and modest haematological and non-haematological toxicity seen with gemcitabine suggest that this agent should be further evaluated in the treatment of patients with ovarian cancer and in combination chemotherapy regimens, primarily in combination with platinum.

A new standard of care for treatment of ovarian cancer

Ovarian cancer is the second most frequent gynaecological cancer in Western Europe and causes approximately 82 000 deaths per year. The majority of patients present with advanced disease and require a combination of surgery and chemotherapy. Important features that determine the outcome of treatment include the stage of disease and the size of the residual tumour after initial surgery. Women with sub-optimally debulked tumours (residual tumour nodules >1 cm) have a poorer prognosis than women whose tumours have been optimally debulked. In recent years several large randomised studies, comparing a variety of platinum-based chemotherapy regimens, have been performed in women with advanced ovarian cancer. Data from these studies are now available and the broad consensus is that what constitutes standard practice needs to be re-evaluated.

Gemcitabine in Ovarian Cancer

In the last decade many therapeutic options have been investigated for ovarian cancer. Most of them have not led to results with implications for standard practice. It is obvious that new drugs are needed to improve the results in advanced disease. Recently the introduction of taxanes in the treatment of ovarian cancer has engendered hope that treatment may further improve. Gemcitabine is another promising candidate to be added to the list of drugs active in ovarian cancer. The drug showed activity in a group of patients not very likely to respond. In this review we will first discuss the factors that determine the outcome of phase II studies, such as the initial treatment and previous second-line treatment, and then we will take a closer look at the results obtained with gemcitabine.