Lynda R. Wiseman

Cisapride : an updated review of its pharmacology and therapeutic efficacy as a prokinetic agent in gastrointestinal motility disorders

Cisapride is an orally administered prokinetic agent which facilitates or restores motility throughout the length of the gastrointestinal tract. It is a substituted piperidinyl benzamide, chemically related to metoclopramide, but unlike metoclopramide, cisapride is largely devoid of central depressant or antidopaminergic effects. In placebo-controlled trials, cisapride improved healing rates and symptoms in both adults and children with reflux oesophagitis. Maintenance therapy with cisapride at half the healing dose is effective in reducing the incidence of relapse. Symptoms are also alleviated in patients with functional dyspepsia, and gastric emptying and symptoms are improved in most patients with gastroparesis, an effect which is sustained during long term administration. However, the efficacy of cisapride in end-stage gastroparesis remains less clear. Cisapride increases stool frequency in patients with chronic constipation, and limited data suggest that the drug may also be beneficial in treating chronic intestinal pseudo-obstruction and irritable bowel syndrome. Cisapride demonstrated efficacy comparable with or superior to that of metoclopramide, and was at least as effective as cimetidine and ranitidine in patients with reflux disease. In patients with functional dyspepsia, cisapride has shown at least equal efficacy to domperidone, metoclopramide and ranitidine, and superior efficacy to cimetidine in the small comparative trials conducted to date. Adverse effects in patients receiving cisapride are generally transient and mild, with abdominal cramping, borborygmi, diarrhoea or loose stools most frequently reported. Central nervous system adverse effects are rare. Thus, with its favourable tolerability profile and demonstrated efficacy in a variety of gastrointestinal motility disorders, the position of cisapride as a valuable agent in the management of patients with gastrointestinal motility disorders is strengthening. However, larger well-controlled comparative trials of the drug with other agents are necessary before the relative position of cisapride in therapy can be categorically defined.

Pantoprazole. A review of its pharmacological properties and therapeutic use in acid-related disorders.

G. Brunner, Medizinische Hochschule Hannover, Abt fUr Gastroenterologie und Hepatologie, Hannover, Germany; G. Dobrilla, Divisione di Gastroenterologia, Ospedale Generale Regionale, Bolzano, Italy; C. Howden, Division of Digestive Diseases and Nutrition, The University of South Carolina, Columbia, South Carolina, USA; G. ]udmaier, Clinic of Internal Medicine, Department of Gastroenterology, Innsbruck, Austria; U. Klotz, Dr. Margarete Fischer-Bosch-Institut fUr Klinische Pharmakologie, Stuttgart, Germany; H. Koop, 4th Department of Medicine, Klinikum Buch, Berlin, Germany; T. Miwa, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan; ]. Mossner, Zentrum fUr Innere Medizin, Medizinische Klinik und Poliklinik II, Universitat Leipzig, Leipzig, Germany; EO. Maller, FARMOVS Institute for Clinical Pharmacology and Drug Development, Department of Pharmacology, University of the Orange Free State, Bloemfontein, South Africa; G. Sachs, Department of Physiology and Medicine, Wadsworth VAMC and ACLA Medical Center, Los Angeles, California, USA; B. Simon, Facharzt fUr Innere Medizin-Gastroenterologie, Krankenhaus Schwetzingen, Schwetzingen, Germany; C.]. van Rensburg, Gastroenterology Unit, Department of Internal Medicine, Tygerberg Hospital, Tygerberg, South Africa.

Oxaliplatin : A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies

UNLABELLED Oxaliplatin is a platinum compound that inhibits DNA synthesis, primarily by causing intrastrand cross-links in DNA. Oxaliplatin has a broad spectrum of antineoplastic activity and has demonstrated a lack of cross-resistance with other platinum compounds. In patients with metastatic colorectal cancer, intravenous oxaliplatin has been trialled as a monotherapy and in combination with other agents. The highest response rates were achieved when oxaliplatin was used in combination with fluorouracil/folinic acid (leucovorin; calcium folinate), typically > or = 50% in the first-line setting and 13 to 45% as a second-line therapy. First-line triple therapy with oxaliplatin and fuorouracil/folinic acid achieved significantly higher response rates and longer median progression-free survival than fluorouracil/folinic acid therapy alone. However, no significant difference in the median duration of overall survival was found. This may be a consequence of the subsequent use of oxaliplatin and/or surgery after disease progression in patients who relapsed after fluorouracil/folinic acid therapy alone. Neoadjuvant therapy with oxaliplatin/fluorouracil/folinic acid has proven beneficial in enabling surgical removal of previously unresectable liver metastases. In 2 studies, surgery with curative intent was performed in 16 and 51% of patients with initially unresectable liver metastases following oxaliplatin/fluorouracil/folinic acid therapy; the 5-year survival rates were 40 and 50%, respectively. In patients with advanced ovarian cancer, first-line therapy with oxaliplatin/cyclophosphamide achieved an objective response rate which did not differ significantly from that of cisplatin/cyclophosphamide (33 vs 42%). In addition, oxaliplatin has shown efficacy in patients with platinum-pretreated ovarian cancer and achieved objective response rates similar to paclitaxel in this setting (16 vs 17%). Promising results have also been found with oxaliplatin in patients with non-Hodgkins lymphoma, breast cancer, mesothelioma and non-small cell lung cancer. Reversible, cumulative, peripheral sensory neuropathy is the principle dose-limiting factor of oxaliplatin therapy. Haematological and gastrointestinal toxicities occur frequently but are generally mild to moderate in intensity. CONCLUSION Oxaliplatin in combination with fluorouracil/folinic acid is an effective treatment option for patients with metastatic colorectal cancer, both as a first-line therapy and in patients refractory to previous chemotherapy. Although preliminary results failed to show any overall survival advantage of this regimen over fluorouracil/folinic acid alone, this may be a consequence of trial design and requires further examination. Additional clinical investigation of oxaliplatin in patients with other cancers is warranted given the promising results achieved in early trials, most notably in patients with platinum-pretreated ovarian cancer.

Meropenem. A review of its antibacterial activity, pharmacokinetic properties and clinical efficacy.

The parenteral carbapenem meropenem is relatively stable to inactivation by human renal dehydropeptidase (DHP-1) and does not require concomitant administration of a DHP-1 inhibitor such as cilastatin. It has a broad spectrum of antibacterial activity in vitro, the majority of Gram-negative, Gram-positive and anaerobic pathogens being highly susceptible to the drug. Meropenem has shown clinical and bacteriological efficacy in the treatment of a wide range of serious infections in adults and children which is at least comparable with that of currently available treatment options. Its clinical and bacteriological efficacy is similar to that of imipenem/cilastatin, clindamycin plus tobramycin and cefotaxime plus metronidazole in the treatment of intraabdominal infections; cefotaxime or ceftriaxone in the treatment of meningitis; imipenem/cilastatin, and ceftazidime with or without an aminoglycoside, in lower respiratory tract infections; and imipenem/cilastatin or ceftazidime in the treatment of urinary tract infections. Satisfactory clinical and bacteriological response rates have also been achieved in patients with skin and skin structure infections, obstetric and gynaecological infections or septicaemia, and in immunocompromised patients with febrile episodes. Preliminary findings also indicate efficacy in the treatment of respiratory tract infections in patients with cystic fibrosis. The tolerability profile of meropenem is generally similar to that of comparator agents, although it is associated with a lower incidence of adverse gastrointestinal effects (nausea and vomiting) than imipenem/cilastatin. Importantly, the incidence of seizures in patients with meningitis is not increased following administration of meropenem. Thus, meropenem is an effective broad spectrum antibacterial drug for the treatment of a wide range of infections including polymicrobial infections in both adults and children, with comparable efficacy to imipenem/cilastatin and various other treatment regimens. Meropenem is likely to be of greatest value as empiric monotherapy in the treatment of serious infections for those caused by multiply-resistant pathogens. Further clinical experience is necessary, however, to ultimately define its place in therapy.

Oral Pilocarpine: A Review of its Pharmacological Properties and Clinical Potential in Xerostomia

SynopsisPilocarpine is a cholinergic agonist which stimulates salivary secretion both in individuals with normal salivary gland function and in those with impaired salivary flow (xerostomia or oral dryness). A rapid increase in salivary flow rate is observed following oral pilocarpine administration and peak levels are maintained for at least 1 to 2 hours. Mean salivary flow rates after administration of pilocarpine are 2- to 10-fold higher than after placebo, and no evidence of tolerance to the pharmacological effects of the drug has been observed during prolonged administration for up to 5 months.The clinical efficacy of oral pilocarpine in relieving symptoms of xerostomia (resulting from radiation therapy to the head and neck region or salivary gland dysfunction), including oral dryness and difficulty in chewing, swallowing and speaking, has been demonstrated in double-blind placebo-controlled clinical trials. In these studies, pilocarpine 5 to 10mg 3 times daily increased salivary flow and improved symptoms of xerostomia in a significantly higher percentage of patients than did placebo (54 versus 25% in one study).Preliminary findings indicate that administration of pilocarpine during radiation therapy may reduce the severity of xerostomia; however, this requires further investigation.The majority of patients receiving oral pilocarpine therapy for xerostomia experience adverse events (most commonly sweating); however, these are generally mild and tolerable in nature.Thus, pilocarpine is an effective agent for the treatment of xerostomia, increasing salivary flow and reducing symptom severity to a significantly greater extent than placebo. Further clinical trials should evaluate the potential beneficial effects of pilocarpine on the incidence of dental caries and oral candidiasis during prolonged therapy, its prophylactic efficacy during radiation therapy and its efficacy relative to that of other salivary stimulants.XerostomiaXerostomia (oral dryness) is caused by changes in salivary gland function. This may result from radiation therapy to the head and neck region, the use of drugs with anticholinergic/antiadrenergic properties, or systemic disease such as the autoimmune disease Sjögren’s syndrome, which causes structural damage to the glands. The symptoms of xerostomia, which include increased dental caries, difficulty in chewing, swallowing and speaking, and an increased incidence of oral candidiasis, can have a significant effect on quality of life. Treatment options (including salivary stimulants and saliva substitutes) are largely palliative and generally offer only short term relief of symptoms.Pharmacological PropertiesPilocarpine is a muscarinic cholinergic agonist. Its ability to stimulate salivary secretion in both healthy volunteers and patients with xerostomia has been known to Western medicine for more than a century, with recent studies demonstrating its superior efficacy relative to that of placebo. Salivary flow can be stimulated within 15 minutes of oral pilocarpine administration and peak flow rates maintained for at least 1 to 2 hours in patients with xerostomia. In one study, the mean salivary flow rate was 2- to 10-fold higher after pilocarpine treatment than after placebo, and the drug appeared to increase salivary flow to a greater extent than citrate. No evidence of tolerance to the salivary stimulating properties of pilocarpine was observed during prolonged therapy for 5 months.While studies in partially desalivated animals have indicated that prolonged administration of pilocarpine may reduce the incidence of caries and oral infection, this remains to be shown in humans.The pharmacokinetic properties of oral pilocarpine in patients with xerostomia require further study. Peak plasma drug concentrations following 2 days’ oral administration of pilocarpine 5 or 10mg 3 times daily to 30 healthy male volunteers were 15 and 41 μg/L, respectively, and were reached in 1.25 and 0.85 hours, respectively. The rate of absorption was decreased when the drug was taken with food. Pilocarpine was eliminated predominantly in the urine with an elimination half-life of 0.76 and 1.35 hours following administration of a 5 or 10mg dose 3 times daily, respectively.Clinical PotentialThe clinical efficacy of pilocarpine as a salivary stimulant has been investigated in patients with salivary gland dysfunction (predominantly Sjögren’s syndrome) or radiation-induced xerostomia in double-blind placebo-controlled studies. Pilocarpine 5 to 10mg 3 times daily was effective in stimulating salivary secretion and improving symptoms of xerostomia, including dry mouth, difficulty in swallowing, chewing and speaking, in a significantly higher percentage of patients than placebo.In a large multicentre study (n = 191), the overall severity of xerostomia was reduced in a significantly higher percentage of patients following 12 weeks’ treatment with pilocarpine 5mg 3 times daily (54%) than in those receiving placebo (25%). Pilocarpine treatment was associated with an increased ability to speak without requiring liquids, and a reduced need for oral comfort agents. The percentage of patients with an increase in whole and unstimulated parotid salivary flow rates was also higher in pilocarpine recipients versus placebo.Unstimulated major salivary gland output was significantly increased in 26 of 39 patients after initial exposure to pilocarpine 5mg, and 27 of 31 patients showed symptom improvement after 1 months’ treatment with pilocarpine 5mg 3 times daily. A global assessment after 6 months of treatment showed 27 of 31 patients to have some symptom improvement (pronounced in 6 patients and moderate in 14) in this study.Preliminary results of a small double-blind placebo-controlled study indicate that pilocarpine administration during radiation therapy may reduce the severity of xerostomia. Patients treated with pilocarpine 5mg 3 times daily starting the day before radiation therapy had smaller losses in salivary gland function following irradiation than those receiving placebo and reported fewer symptoms of xerostomia.Tolerability ProfilePilocarpine has been generally well tolerated in clinical trials. While adverse events were reported by most patients and were usually mild in severity, their incidence and severity were dose-related. Sweating was the most common effect, and occurred in 37 to 65% of patients treated with pilocarpine 5mg 3 times daily and in 80% of patients treated with the 10mg 3 times daily dosage in a large multicentre study. 5.5 and 29% of patients, respectively, withdrew from therapy during the 3-month treatment period because of excessive sweating.Other events, which were probably related to the cholinergic activity of pilocarpine, included chills, nausea, dizziness, rhinitis, flushing, asthenia, urinary frequency, increased lacrimation, palpitations and gastrointestinal tract disturbance.No significant effects have been observed on heart rate, blood pressure, or cardiac conductivity during pilocarpine therapy in patients with xerostomia to date; however, this requires further examination, especially in patients with possible complicating medical conditions.Dosage and AdministrationOral pilocarpine 5mg 3 times daily is recommended for the initial treatment of xerostomia. This may be titrated up to 10mg 3 times daily in patients showing a poor response who tolerate the lower dosage. The lowest dosage that is effective and tolerable should be used for maintenance therapy.Pilocarpine is contraindicated in patients with uncontrolled asthma, and in patients with acute iritis or narrow-angle glaucoma (unless required before surgery). Caution is advised when administering the drug to patients with controlled asthma, chronic bronchitis, chronic obstructive pulmonary disease or cardiovascular disease, or when coadministering the drug with β-adrenergic antagonists or drugs with parasympathomimetic or anticholinergic effects.

Irinotecan. A review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer.

Irinotecan (CPT-II) is a semisynthetic derivative of camptothecin. It and other camptothecin analogues/derivatives appear to exert their antitumour activity by binding to topoisomerase I. The active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), has demonstrated potent growth inhibition of human colorectal cancer cells in vitro, with superior activity to fluorouracil. In phase II clinical studies in patients with advanced colorectal cancer, objective response rates after irinotecan therapy ranged between 20.5 and 32%. These studies used a range of irinotecan regimens including 350 mg/m2 once every 3 weeks (Europe), 125 to 150 mg/m2 once a week for 4 weeks followed by a 2-week drug-free interval (US) and 100 mg/m2/week or 150 mg/m2 every 2 weeks (Japan). The median duration of response ranged between 5.6 and 10.6 months. Disease stabilisation occurred in 30 to 71.2% of patients. Objective response rates to irinotecan therapy in patients who had received no prior chemotherapy were similar to those in patients pretreated with fluorouracil. Importantly, irinotecan also induced responses in some patients with tumours refractory to fluorouracil. Severe (grade 3 or 4) neutropenia and diarrhoea, which occurred in up to 40% of patients receiving irinotecan therapy in phase II studies, require careful monitoring and appropriate management. Thus, irinotecan is a valuable agent for the second-line treatment of patients with advanced colorectal cancer who fail to respond to or relapse after fluorouracil therapy.

Dexrazoxane. A review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy.

UNLABELLED Dexrazoxane has been used successfully to reduce cardiac toxicity in patients receiving anthracycline-based chemotherapy for cancer (predominantly women with advanced breast cancer). The drug is thought to reduce the cardiotoxic effects of anthracyclines by binding to free and bound iron, thereby reducing the formation of anthracycline-iron complexes and the subsequent generation of reactive oxygen species which are toxic to surrounding cardiac tissue. Clinical trials in women with advanced breast cancer have found that patients given dexrazoxane (about 30 minutes prior to anthracycline therapy; dexrazoxane to doxorubicin dosage ratio 20:1 or 10:1) have a significantly lower overall incidence of cardiac events than placebo recipients (14 or 15% vs 31%) when the drug is initiated at the same time as doxorubicin. Cardiac events included congestive heart failure (CHF), a significant reduction in left ventricular ejection fraction and/or a > or = 2-point increase in the Billingham biopsy score. These results are supported by the findings of studies which used control groups (patients who received only chemotherapy) for comparison. The drug appears to offer cardiac protection irrespective of pre-existing cardiac risk factors. In addition, cardiac protection has been shown in patients given the drug after receiving a cumulative doxorubicin dose > or = 300 mg/m2. It remains to be confirmed that dexrazoxane does not affect the antitumour activity of doxorubicin: although most studies found that clinical end-points (including tumour response rates, time to disease progression and survival duration) did not differ significantly between treatment groups, the largest study did show a significant reduction in response rates in dexrazoxane versus placebo recipients. Dexrazoxane permits the administration of doxorubicin beyond standard cumulative doses; however, it is unclear whether this will translate into prolonged survival. Preliminary results (from small nonblind studies) indicate that dexrazoxane reduces cardiac toxicity in children and adolescents receiving anthracycline-based therapy for a range of malignancies. The long term benefits with regard to prevention of late-onset cardiac toxicity remain unclear. With the exception of severe leucopenia [Eastern Cooperative Oncology Group (ECOG) grade 3/4 toxicity], the incidence of haematological and nonhaematological adverse events appears similar in patients given dexrazoxane to that in placebo recipients undergoing anthracycline-based chemotherapy. Although preliminary pharmacoeconomic analyses have shown dexrazoxane to be a cost-effective agent in women with advanced breast cancer, they require confirmation. CONCLUSIONS Dexrazoxane is a valuable drug for protecting against cardiac toxicity in patients receiving anthracycline-based chemotherapy. Whether it offers protection against late-onset cardiac toxicity in patients who received anthracycline-based chemotherapy in childhood or adolescence remains to be determined. Further clinical experience is required to confirm that it does not adversely affect clinical outcome, that it is a cost-effective option, and to determine the optimal treatment regimen.

Daclizumab : A review of its use in the prevention of acute rejection in renal transplant recipients

UNLABELLED The humanised monoclonal antibody daclizumab is an immunosuppressive agent that reduces acute rejection in renal transplant recipients. It is specific for the alpha subunit (Tac/CD25) of the interleukin-2 (IL-2) receptor on activated T cells and achieves immunosuppression by competitive antagonism of IL-2-induced T cell proliferation. Daclizumab has advantages over murine antibodies to the IL-2 receptor, including improved effector function, a low potential for immunogenicity and long elimination half-life. When added to standard cyclosporin-based immunosuppressive therapy with or without azathioprine, daclizumab (1 mg/kg prior to surgery and once every 2 weeks thereafter for a total of 5 doses) significantly reduced the 6-month rate of acute rejection compared with placebo in 2 phase III studies. The mean number of rejection episodes was significantly reduced and the time to first acute rejection significantly increased in daclizumab versus placebo recipients. Patient survival at 1 year after transplantation was significantly higher with daclizumab than placebo in 1 study and showed a trend in favour of the drug in the other study. The 1-year graft survival rate tended to be greater in daclizumab than in placebo recipients in both studies, In a phase II study, acute rejection rates in patients treated with both daclizumab and mycophenolate mofetil (plus standard cyclosporin-based immunosuppression) were lower than those achieved with mycophenolate mofetil alone. Preliminary results indicate that daclizumab is also a useful agent in paediatric renal transplant recipients. Further investigation of the efficacy and tolerability of the drug in this patient group is clearly warranted. Daclizumab does not increase the incidence of adverse events when added to standard cyclosporin-based therapy. The incidence of opportunistic infections, lymphoproliferative disorders and malignancies was not increased above that seen with placebo. CONCLUSIONS Although the effects of daclizumab on long term graft and patient survival require further investigation, available data indicate that daclizumab is an important advance in renal transplant immunosuppression, reducing acute graft rejection without affecting the tolerability of standard cyclosporin-based immunosuppression.

Secnidazole: A Review of its Antimicrobial Activity, Pharmacokinetic Properties and Therapeutic Use in the Management of Protozoal Infections and Bacterial Vaginosis

Secnidazole is structurally related to the commonly used 5-nitroimidazoles metronidazole and tinidazole. These drugs share a common spectrum of activity against anaerobic micro-organisms and they appear particularly effective in the treatment of amoebiasis, giardiasis, trichomoniasis and bacterial vaginosis. Secnidazole is rapidly and completely absorbed after oral administration and has a longer terminal elimination half-life (approximately 17 to 29 hours) than commonly used drugs in this class. in patients with intestinal amoebiasis or giardiasis, clinical or parasistological cure rates of 80 to 100% are achieved after treatment with a single dose of secnidazole 2g (30 mg/kg in children), similar to the response rates achieved with multiple dosage regimens of metronidazole or tinidazole. Patients with hepatic amoebiasis appears to respond well to 5- to 7-day therapy with secnidazole, but the efficacy of this drug regimen requires further evaluation in larger numbers of patients. After administration of a single dose of secnidazole, parasitological eradication was achieved in approximately 92 to 100% of patients with urogenital trichomoniasis. Patients with bacteria vaginosis respond at least as well to a single dose of secnidazole as to single-dose tinidazole, or single- or 7-day treatment with metronidazole; clinical improvement and/or microbiological evidence of cure was attained in approximately 59 to 96% of patients. In the clinical trials reviewed, secnidazole was well tolerated; most adverse events were gastrointestinal in nature and did not require treatment intervention or withdrawal from therapy. In summary, available evidence suggests that secnidazole is as efficacious as other 5-nitroimidazole drugs in the treatment of protozoal infections and bacterial vaginosis. The convenience and ease of administration associated with single-dose therapy, combined with a good tolerability profile, make secnidazole a suitable option to other single-dose treatments and an attractive alternative to multiple dosage regimens with other drugs in this class.

Paclitaxel : An update of its use in the treatment of metastatic breast cancer and ovarian and other gynaecological cancers

UNLABELLED The antitumour agent paclitaxel has proved to be effective for the treatment of patients with metastatic breast or ovarian cancer, and limited data also indicate its clinical potential in patients with cervical or endometrial cancer. The regimen of paclitaxel administration has varied in clinical trials, the most common including a dosage of between 135 and 250 mg/m2 administered over an infusion period of 3 or 24 hours once every 3 weeks. Promising results have been achieved in phase I/II trials of a weekly regimen of paclitaxel (60 to 175 mg/m2). The objective response rate in patients with metastatic breast cancer (either pretreated or chemotherapy-naive) is generally between 20 and 35% with paclitaxel monotherapy, which compares well with that of other current treatment options including the anthracycline doxorubicin. Combination therapy with paclitaxel plus doxorubicin appears superior to treatment with either agent alone in terms of objective response rate and median duration of response. However, whether combination therapy also provides a survival advantage remains unclear; recent results of a phase III study indicate that it does not. Paclitaxel is also a useful second-line option in some patients with anthracycline-resistant disease. Combination therapy with paclitaxel and cisplatin has proved highly effective as first-line therapy for patients with advanced ovarian cancer, showing superior efficacy to cyclophosphamide/cisplatin in terms of progression-free survival time and median duration of survival. Combination therapy with paclitaxel and carboplatin has also shown promising results. Paclitaxel monotherapy is a useful second-line option for patients with platinum-refractory metastatic ovarian cancer (objective response rates have ranged from 15 to 48%). The major dose-limiting adverse events associated with paclitaxel include myelotoxicity and peripheral neuropathy. Paclitaxel has acceptable tolerability in most patients, although adverse events are common. CONCLUSION Paclitaxel generally appears to be as effective as other antineoplastic agents used in the treatment of metastatic breast cancer, including doxorubicin. Importantly, it is a useful second-line option for some patients with anthracycline-resistant disease. Combination therapy with both paclitaxel and doxorubicin is a highly effective first-line option for metastatic breast cancer; however, recent results indicate no survival advantage versus monotherapy. Paclitaxel is a valuable agent for second-line treatment of patients with platinum-refractory metastatic ovarian cancer and, when combined with cisplatin or carboplatin, is recommended as first-line therapy for this disease.