A phase II trial of continuous 5-fluorouracil in recurrent or metastatic transitional cell carcinoma of the urinary tract.

AIMS: To assess the activity of a continuous infusion of 5-fluorouracil in patients with recurrent locally advanced or metastatic transitional cell carcinoma of the urinary tract. MATERIALS AND METHODS: Eight centres within the UK entered 50 patients into the study. Twenty-four weeks of continuously infused 5-fluorouracil, 300mg/m(2)/day through a mini-pump, were planned. The primary outcome was tumour response at 8 weeks after the start of treatment. RESULTS: The median age of the patients was 68 years and 37 (80.4%) had a World Health Organization performance status of 0 or 1. The overall response rate at 8 weeks, according to the response evaluation criteria in solid tumors (RECIST) criteria in 46 evaluable patients, was 15% (95% confidence interval 5-26%) and 20% (95% confidence interval 8-31%) when assessments at all time points were included. The median progression-free survival was 1.9 months (95% confidence interval 1.8-2.7 months) and the median overall survival was 6.5 months (95% confidence interval 4.1-8.5 months). The most frequent grade 3/4 toxicities were mucositis and diarrhoea (each in 6.5% of patients) and nausea/vomiting and hand-foot syndrome (each in 4.3% of patients). CONCLUSIONS: Continuous infusional 5-fluorouracil has activity in transitional cell carcinoma of the urinary tract. Prolonged fluoropyrimidine administration may be a useful component of future combination regimens for this disease, particularly in patients with poor renal function.

Weekly cisplatin with oral etoposide: a well-tolerated and highly effective regimen in relapsed ovarian cancer.

The optimal treatment of progressive ovarian cancer after first-line platinum-based therapy remains a challenge. We collected prospectively data on patients with relapsed or progressive ovarian cancer treated with weekly cisplatin and oral etoposide in our institution to evaluate the feasibility, efficacy, and toxicity of this regimen. Patients (n = 34) had stage IIIC/IV ovarian cancer, which was recurrent or progressive following previous treatment with carboplatin and a taxane. Cisplatin (50 mg/m(2)) was given days 1, 8, 15, 29, 36, and 43, with oral etoposide (50 mg daily) on days 1-15 and 29-43. Responders and those with stable disease then received oral etoposide (50 mg daily for 21 days of a 28-day cycle) until disease progression. The overall CA125 response rate was 88%. The overall radiological response rate was 57%: 78% in the platinum-sensitive group, 50% in the intermediate-sensitive group, and 46% in the platinum-resistant group. Treatment was well tolerated. Median survival in the overall group was 14 months: in the platinum-sensitive group 16.5 months, in the intermediate-sensitive group 11 months, and 10.5 months in the platinum-resistant group. We conclude that weekly cisplatin/etoposide, followed by maintenance oral etoposide, is an active and well-tolerated regimen in relapsed or progressive ovarian cancer, even in platinum-resistant patients.

Hyphenated techniques in anticancer drug monitoring. I. Capillary gas chromatography-mass spectrometry.

Most anticancer agents are relatively unstable substances and are subjected to intensive metabolism in vivo and radiation during sample pretreatment. Hyphenated techniques including a separation technique and, most frequently, mass spectrometry are therefore chosen to obtain insight into the in vivo behavior of anticancer agents. Once established, simpler assays can be derived from those based on hyphenation, which are less expensive. Capillary gas chromatography (cGC)-mass spectrometry (MS) is amongst the most frequently applied hyphenated analytical technologies in anticancer drug monitoring. Here a selection has been made of: (i) cGC-MS applied to the analysis of agents frequently used in clinical oncology (e.g. tamoxifen, oxazaphosphorines); (ii) cGC-MS applied to the development of new agents (Swainsonine and Brefeldin); (iii) cGC-MS applied to the analysis of agents for which comparisons with other frequently applied hyphenation technologies are possible (see Part I of this series). cGC-MS played a key role in the elucidation of the in vivo behavior of the oxazaphosphorine cyclophosphamide, historically the most frequently applied anticancer agent. cGC-MS appeared to be of special interest in the analysis of cyclophosphoramide and congeners in human erythrocytes by coupling of the hyphenated technique with a measurement of sediment technique. This resulted in the quantitative and qualitative analysis of oxaphosphorine-related mustard gas moieties in human erthrocytes for the first time.

Hyphenated techniques in anticancer drug monitoring. II. Liquid chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry.

High-performance liquid chromatography has become the separation technique of choice for the monitoring of generally thermolabile anticancer agents. With the introduction of electrospray mass spectrometry, the coupling of liquid chromatogaphy and mass spectrometry has opened the way to widely and routinely applied anticancer drug monitoring. Real-time metabolism versus degradation can now be distinguished, since derivatization is no longer obligatory. This is important for the monitoring of the anabolic and catabolic pathways of the same agent, such as 5-fluorouracil. Detection limits almost equal to those obtained with capillary gas chromatography-mass spectrometry are realistic with the latest generation of mass spectrometers, enabling quantitative analysis of various anticancer agents and their metabolites down to the low ng/ml level. Furthermore, sample clean-up and chromatography can be downscaled markedly using the latest column technologies, such as the generally applied 10 cm x 2.8 mm I.D. RP 18 columns. The coupling of capillary electrophoresis to mass spectrometry is today far from a routine application in anticancer drug monitoring. Nevertheless, interesting applications have been reported and are selected for the present review.

Multicenter phase II study of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer.

Gemcitabine has activity in advanced ovarian cancer, with responses in platinum-resistant disease. This study assessed the activity of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer. All patients had histologically verified invasive epithelial ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease and no prior chemotherapy. Patients received gemcitabine 1250 mg/m(2) on days 1, 8 and 15 of a 28-day cycle. Radiological response was assessed after two cycles. Between December 1992 and October 1995, 35 patients were enrolled. Of 33 evaluable patients, there was one complete response and five partial responses, for an overall response rate of 18% (95% confidence interval 7-36%). Forty-two percent of patients had a greater than 50% decrease in their CA-125 levels. Of the 25 patients who received platinum-based chemotherapy following treatment with gemcitabine, 12 achieved an overall response rate of 48%. Toxicity was mild, with two episodes of WHO grade 4 neutropenia (not associated with fever) and two episodes of grade 4 thrombocytopenia (not associated with bleeding). Gemcitabine has single-agent activity for poor-prognosis patients with advanced ovarian cancer. Similar results with subsequent platinum-based therapy indicate a lack of cross-resistance. This, combined with gemcitabine's favorable toxicity profile, warrants testing in comparative trials.

Treatment of invasive thymoma with single-agent ifosfamide.

PURPOSE: To evaluate single-agent ifosfamide in the treatment of invasive thymoma. PATIENTS AND METHODS: Fifteen patients (eight male and seven female) with histologically confirmed invasive thymoma were treated. The median age was 48 years (range, 23 to 76 years). Four patients had stage III disease, seven patients had stage IVa disease, and four patients had stage IVb disease. The most common histologic type was lymphoepithelial. Seven patients had received prior treatment, including one patient who received chemotherapy. Ifosfamide 1.5 g/m(2) was given on days 1 to 5, with mesna as a uroprotector. RESULTS: Thirteen patients were assessable for response. Five complete responses (38.5%; 95% confidence interval [CI], 17.7% to 64.5%) and one partial response (7.7%; 95% CI, 1.4% to 33.3%) were seen. The median duration of complete response was 66+ months (range, 25 to 87 months), and the estimated survival rate 5 years after ifosfamide treatment was 57% (SE, 32% to 79%). The most frequent toxicities were nausea, vomiting, and leucopenia, but these were well tolerated. CONCLUSION: Single-agent ifosfamide possesses significant activity against invasive thymoma and is comparable to currently used combination regimens. The inclusion of ifosfamide in combination therapy, particularly in place of cyclophosphamide in regimens such as cisplatin, doxorubicin, and cyclophosphamide, needs to be evaluated.

Intravesical drug delivery. Pharmacokinetic and clinical considerations.

Intravesical drug administration is widely used in the treatment of patients with superficial bladder cancer, and aims to optimise drug delivery in the vicinity of the tumour and reduce systemic availability. The most commonly employed intravesical agents in patients with superficial bladder cancer are mitomycin (mitomycin C), thiotepa, ethoglucid (ethoglucid), anthracyclines such as doxorubicin, bacille Calmette-Guérin (BCG) and, more recently, taxol and the new mitomycin derivative KW-2149. Recurrence rates in patients with superficial bladder cancer have been substantially reduced by combined transurethral resection and intravesical pharmacotherapy. The high concentration of cytotoxics in urine and tumour tissue explain the high efficacy rates. Furthermore, the low systemic availability of most intravesical agents is consistent with the low frequency of acute and delayed systemic adverse effects. Systemic toxicity is almost negligible, except in the case of thiotepa, and local toxicity is transient and tolerable. Pharmacokinetic models of drug absorption from the bladder have been developed, both in animals and humans. These have led to the identification of optimal intravesical treatment regimens.

Pharmacokinetics and bioavailability of oral 5'-deoxy-5-fluorouridine in cancer patients.

AIMS: Oral administration of 5-fluorouracil (FUra), an important cytotoxic agent, is limited by a wide variation in bioavailability. 5'-deoxy-5-fluorouridine (dFUrd), a masked form of FUra, has shown promise clinically when given intravenously or orally as a solution or tablet. This study investigates the efficacy of an oral capsule formulation of dFUrd in generating continuous systemic levels of this compound in cancer patients. METHODS: Six patients with advanced intestinal or ovarian malignancies were given three cycles of dFUrd, days 1-5, at intervals of 4 weeks. The doses of dFUrd were 600 mg m-2 three times daily, 800 mg m-2 three times daily, and 1000 mg m-2 three times daily, on cycles one, two and three, respectively (total dose 36 g m-2 ). The initial dose in each cycle was given as a slow intravenous injection over 10 min, and the remainder orally. Plasma and urine levels of dFUrd and two of its metabolites, FUra and 5,6-dihydro-5-fluorouracil (FUraH2 ), were monitored in six patients at each dose level. RESULTS: All six patients completed the study, receiving three different doses over a 3 month period, following which one had achieved a partial response, one had stable disease, and four had developed progressive disease. Side-effects were negligible, and only two instances of transient diarrhoea WHO grade 1 were seen. Total body clearance (CLtot) of intravenous dFUrd decreased with increasing dose; 2.7, 2.0 and 1.3 l min-1 m-2, following doses of 600, 800 and 1000 mg m-2, respectively. The mean elimination half-life of intravenous dFUrd increased with the dose from 15 to 22 min. Oral dFUrd was rapidly absorbed with a lag time of less than 20 min. The mean elimination half-life (t1/2, z ) of oral dFUrd was 32-45 min in the dose range 600-1000 mg m-2. The AUC of FUra and FUraH2 increased overproportionally with increasing intravenous doses of dFUrd. The mean systemic bioavailability of oral dFUrd was 34-47%. CONCLUSIONS: dFUrd, which selectively releases the antimetabolite FUra in tumour cells, can be given orally at doses of 600-1000 mg m-2 three times daily for 5 days. The systemic levels achieved are equivalent to those seen following continuous infusions of dFUrd or FUra. Toxicity is tolerable, and further clinical investigation of oral dFUrd is warranted.

Activated oxazaphosphorines are transported predominantly by erythrocytes.

PURPOSE: Oxazaphosphorines are metabolised by a variety of pathways, one of which leads to activation and the formation of alkylating compounds. However, the transport forms conveying activated oxazaphosphorines to the tumour cell have not been fully characterised. There is increasing recognition of the importance of the erythrocyte as a carrier of compounds in the circulation, and we have recently described higher concentrations of 4-hydroxycyclophosphamide within the erythrocyte compartment compared to plasma. We have now determined the concentrations of ifosfamide and seven of its metabolites in the plasma and erythrocytes of patients receiving a six-hour intravenous infusion of ifosfamide. PATIENTS AND METHODS: Red cells from five patients, receiving a total of eight cycles of ifosfamide, were separated from plasma using the MESED instrument, and analysis of red cells and plasma performed using Gas Chromatography-Mass Spectrometry (GC/MS). RESULTS: The concentration of all compounds in the erythrocyte compartment was higher than or equal to those in plasma, and isophosphoramide mustard and carboxyifosfamide showed a particular affinity for the erythrocyte. The red cell fraction can contain as much as 77% of the total blood concentration of isophosphoramide mustard. CONCLUSIONS: Erythrocyte associated isophosphoramide mustard is an important transport form of activated ifosfamide. Red cells may have a role in the delivery of activated oxazaphosphorines to tissues.

Partitioning of ifosfamide and its metabolites between red blood cells and plasma.

A recently developed GC-MS analytical method for the quantitative determination of oxazaphosphorines and their metabolites in blood plasma, using stable trifluoroacetyl derivatives and electron capture negative chemical ionization detection, was applied to measure the partitioning of the antitumor drug ifosfamide and its metabolites between plasma and red blood cells for four cancer patients. The separation of a constant volume of red blood cells was performed using a special instrument, MESED, through centrifugation of blood samples. The measured compounds were ifosfamide, 2- and 3-dechloroethylifosfamide, 4-ketoifosfamide, carboxyifosfamide, ifosfamide mustard, 2-chloroethylamine and 1,3-oxazolidin-2-one. Concentration-time profiles for the metabolites in the two blood fractions and partitioning factors between erythrocytes and plasma were obtained. For ifosfamide itself, and metabolites with an intact ring system, a partitioning factor between 1 and 2 was observed for the concentration ratio between red blood cells and plasma in the patients studied. However, for the compounds with an open structure, carboxyifosfamide and ifosfamide mustard, partitioning factors higher than 3 were obtained. The active antitumor metabolite ifosfamide mustard showed a strong preference for the red blood cells in the measured patient samples. This means that erythrocytes may play an important role in the transport and the subsequent release of the active alkylating agent to the tumor cells.

Erythrocytes and the transport of drugs and endogenous compounds.

This review considers the significance and measurement of endogenous compounds and drugs on erythrocytes. Part I examines literature examples where a direct measurement of hydrocortisone, phenytoin and valproate was performed on unwashed red cells in vitro and in vivo, showing a consistent contribution of the erythrocyte fraction to the transport of these compounds. In vitro partition experiments using systems composed of plasma water, plasma proteins and erythrocytes are discussed. When spiked blood is diluted with blank autologous plasma water, erythrocytes always discharge the compound over-proportionally compared to plasma proteins. In vivo, during the distribution phase, the elimination half-life from the erythrocyte is the same as or shorter than that from plasma water, and substantial amounts of drug leaving the circulation originate from erythrocytes. In Part II, the transfer of compounds is considered and evidence for the facilitated exchange of red cell associated substances between the erythrocyte and capillary endothelium presented. Situations where a failure to analyse the erythrocyte compartment leads to the loss of vital information are identified. Part III explores methods for analysing erythrocyte associated substances, most commonly indirect calculation, or analysis of washed erythrocytes. A direct determination is rarely performed, but one such method, allowing concurrent plasma analysis, is discussed. An instrument collects a fixed and known quantity of a maximally compressed cell mass, without disturbing the equilibrium between cells and plasma. To isolate compounds associated with the mass of erythrocytes, the red cell sediment can often be extracted quantitatively into a blank protein solution.

Combination chemotherapy with epirubicin, cisplatin and 5-fluorouracil for the palliation of advanced gastric and oesophageal adenocarcinoma.

The palliative efficacy of laser therapy with combination chemotherapy (cisplatin, epirubicin and continuous infusion of 5-fluorouracil) was assessed in 34 patients with inoperable gastro-oesophageal cancer. Comparison was made with a group of 30 patients treated previously by laser alone. Twenty patients responded to chemotherapy. There was a significant improvement in dysphagia, as measured by a decreased laser requirement to maintain satisfactory swallowing. In this non-randomized prospective phase II trial, palliation was attained and some responses were long-lasting (median duration of response 8.7 (range 2.3 to more than 29.2) months).

Drugs prescribed for self poisoners.

Of 230 adults admitted for self poisoning over two months, 153 (67%) had previously been taking a total of 309 prescribed drugs. Of these patients, 119 (78%) had been given psychotropic drugs (usually benzodiazepines), 81 (53%) obtained them on repeat prescription, and 47 (31%) had been prescribed multiple psychotropic drugs, often in seemingly illogical combinations. The use of these drugs increased progressively with age and most patients took the same drugs in overdosage as they had been prescribed. Psychotropic drugs were prescribed for more than a third of patients with no psychiatric illness and a normal personality, nearly half of those with existing alcohol or drug abuse problems, and for most of the unemployed. Fewer than a third of the patients suffering from depression were prescribed antidepressants but half had been given benzodiazepines and other potentially depressing drugs. Psychotropic drug use, psychotropic polypharmacy, and the repeat prescribing of these drugs were strongly associated with repeated overdosage and, under certain circumstances, with personality disorder, alcohol or drug abuse, unemployment, and conflict with the law. In the long term psychotropic drugs are unlikely to benefit most self poisoners, and they may do positive harm by inducing apathy and depression and predisposing to self poisoning. The incidence of self poisoning (and repeat overdosage in particular) might be reduced by more care and restraint in the prescribing of these drugs.