26. Jahrgang Heft 06, Juni 2008

Trabectedin – therapy of advanced soft tissue sarcoma in adult patients

Soft tissue sarcoma (STS) is a relatively rare type of cancer, accounting for approximately 1 % of all adult cancers. Chemotherapy is used to achieve systemic control in patients with metastatic disease, but most types of STS are relatively insensitive to chemotherapy. Current first-line therapies are doxorubicin and ifosfamide, which induce response rates of approximately 10 to 20 % as single agents, and overall survival is approximately 12 months. Virtually all patients will experience progression of the STS in spite of these standard-of-care agents.

Trabectedin has recently emerged as the first efficacious drug developed against soft tissue sarcoma in the last three decades. Trabectedin is a novel DNA-binding agent originally derived from the marine tunicate, Ecteinascidia turbinata, and now manufactured synthetically. Trabectedin has a unique mode of action: it binds to the minor groove of DNA interfering with cell division and genetic transcription processes and DNA repair machinery. These inhibitory effects of Trabectedin are highly dependent on the presence of two specific DNA repair systems.

Phase I studies investigating different dosing schedules identified 3-hour and 24-hour infusions given 3-weekly, and 3-hour infusions given weekly for 3 out of 4 weeks, to be the most appropriate schedules for further study. The pharmacokinetics for these dosing schedules were linear over the dose range investigated. In addition, Trabectedin was found to have a high apparent volume of distribution and a long elimination half-life. Trabectedin undergoes extensive hepatic metabolism involving cytochrome P450 3A4 and other cytochrome P450 isozymes. Drugs that inhibit cytochrome P450 increase the cytotoxic activity of Trabectedin and may increase hepatotoxicity. However, cytochrome P450 inducers and inhibitors of uridine diphosphoglucuronosyl transferase and glutathione S-transferase do not affect the activity of trabectedin.

The efficacy of trabectedin monotherapy in patients with STS has been well established in the results of a randomised study involving 270 patients and in three single-arm phase II studies. When given at the recommended regime – 1.5 mg/m2 as a 24-hour infusion 3-weekly – trabectedin increases time to progression (TTP); in the randomised study a median TTP of 3.7 months was achieved with the recommended regime. This represented a significant 27 % reduction in the risk of progression relative to the weekly schedule (p = 0.0302), and was also efficacious compared with suitable historical controls. The overall survival (OS) of patients treated with trabectedin – as is evident from the median OS (all randomised patients) of 13.8 months, and the percentage of patients alive at 12 months (i. e. 60.6 %) in the randomised study – appears unusually long relative to historical controls for such a heavily pretreated patient population. This may reflect the high proportion of patients who benefit from the drug in terms of achieving prolonged tumour control. Data from the three single-arm phase II studies and the randomised study in patients with STS have shown that trabectedin is generally well tolerated when administered at the recommended dose of 1.5 mg/m2 given as a 24-hour infusion 3-weekly. Toxicities are non-cumulative, reversible and manageable. The most common adverse events associated with trabectedin therapy are neutropenia, transient elevation in plasma liver enzymes (AST, ALT), nausea, vomiting and fatigue. The majority of these events were mild or moderate in severity.

In the randomised study severe, treatment-related (grade 3/4) events in patients receiving the recommended regime consisted of: neutropenia (47 %), AST/ALT (32/48 %), nausea (4 %), vomiting (2 %) and fatigue (6 %).

In the randomised study in patients receiving the recommended regime, 8 (6.2 %) patients discontinued treatment due to treatment-related adverse events, and there were 2 deaths (1.5 %) regarded as being possibly treatment-related. Particularly remarkable is the rarity of many of the unpleasant and/or life-threatening effects typical of commonly used anticancer chemotherapeutic agents, such as alopecia, mucositis, skin/nail toxicities, neurotoxicity, cardiac toxicity or other major organ-related toxicities. Likewise, and in contrast with the most commonly used agent in STS, doxorubicin, the lack of any evidence of cumulative toxicities with trabectedin is noteworthy.

Premedication with dexamethasone ameliorates nausea and vomiting induced by trabectedin, and is also used because of its hepatoprotective effects. Use of dexamethasone premedication is thus mandatory.

No relevant differences in the safety profile of trabectedin have been seen in elderly patients (> 65 years) compared with younger patients.

Studies including patients with severe renal insufficiency (creatinine clearance < 30 ml/min) have not been conducted. Therefore trabectedin should not be used in this patient population.

Patients with clinically relevant liver diseases, such as active chronic hepatitis, must be closely monitored since dose adjustment may be necessary.

Trabectedin is indicated for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. In addition, patients must meet specific criteria with respect to laboratory parameters both prior to initiating trabectedin therapy and prior to administration of each dose.

The recommended dose and schedule for trabectedin is 1.5 mg/m2 administered as an IV infusion over 24 hours with a three-week interval between cycles. All patients should also receive 20 mg of dexamethasone intravenously, 30 minutes prior to trabectedin, as anti-emetic prophylaxis. Trabectedin doses should be reduced to 1.2 mg/m2 or 1.0 mg/m2 in cases of defined toxicities.

Trabectedin is supplied as 0.25 mg or 1 mg powder concentrate, which is reconstituted with sterile water for injections to give a concentration of 0.05 mg/ml. This solution is further diluted for IV infusion. The reconstituted solution should be diluted and used immediately.

It is strongly recommended to administer trabectedin through a central venous line. Treatment may be given in an inpatient or ambulatory setting.

Keywords: Trabectedin, soft tissue sarcomas

Pharmacotherapy of functional gastrointestinal disorders

Functional gastrointestinal disorders are among the most frequent disorders seen in hospital and clinical practice. They comprise different disorders without structural or biochemical abnormalities as detected by routine evaluation. In adults, functional gastrointestinal disorders are classified into six different subclasses (A. Functional esophageal disorders, B. Functional gastroduodenal disorders, C. Functional Bowel Disorders, D. Functional abdominal pain syndrome, E. Functional gallbladder and sphincter of oddi disorders, F. Functional anorectal disorders) according to the Rom-III-consensus. The therapy of functional gastrointestinal disorders is symptome-based and should be only temporary after exclusion of organic diseases. There might be a great overlap of symptoms (pain, “discomfort“, dyspepsia, nausea, vomiting, meteorism, constipation, straining, diarrhea) very often associated with visceral hypersensitivity. In addition, symptoms and altered function may show only poor correlation. Despite the frequent demand of pharmacotherapy most drugs are not approved for the treatment of functional gastrointestinal disorders.

Keywords: Functional gastrointestinal disorders, visceral hypersensitivity, dyspepsia, meteorism, constipation, straining, diarrhea, pharmacotherapy