Long-term oral etoposide in metastatic breast cancer: clinical and pharmacokinetic results.

To evaluate the activity of long-term, single-agent oral etoposide against advanced breast cancer, this study employed etoposide 50 mg/day and 100 mg/day (given over 14 days) in previously treated and chemotherapy-naive patients with histologically confirmed, recurrent or metastatic breast cancer. Of 38 patients, 24 had had chemotherapy, 34 had prior radiotherapy, and 31 had received hormone therapy. Etoposide courses in both treatment groups were repeated every 4 weeks for at least two courses; delays were instituted when patients' total leukocyte nadir fell to or below 3.0 x 10(9)/l. Dose reductions were made in the 100-mg group (to 50 mg/day) if World Health Organization leukopenia grade 3 or higher was present. Plasma pharmacokinetic profiles were measured in selected patients to assess inter- and intrapatient variability in etoposide's oral bioavailability. No complete responses were achieved among the 36 patients evaluable for response, but eight patients had a partial response. Responses were more frequent at the 100-mg dose and in previously untreated patients (seven of eight partial responders had not had previous chemotherapy). Median duration of response was 16 weeks (range, 7 to 46). Myelosuppression (variable and unpredictable) and alopecia (universal) were the notable toxicities. Pharmacokinetic analyses of oral bioavailability revealed significant interpatient variability, but much less intrapatient variability when successive etoposide courses in individual patients were evaluated. Despite the relatively small number of patients in this study, the responses achieved by previously untreated patients suggest etoposide's value against breast cancer. Further trials should use pharmacokinetic studies to assess bioavailability as well as to help define 'target' etoposide doses, based on plasma etoposide levels, during treatment.

Low-dose aminoglutethimide in postmenopausal breast cancer: effects on adrenal and thyroid hormone secretion.

Aminoglutethimide is effective in the treatment of breast cancer in postmenopausal patients as a result of its inhibition of aromatase. Its use is complicated by a number of endocrine side-effects which include the inhibition of thyroxine synthesis and inhibition of 11-steroid and 21-steroid hydroxylases. When aminoglutethimide is used at the conventional daily dose of 1000 mg in combination with 40 mg of hydrocortisone these effects can result in clinically significant hypothyroidism and increases in the serum levels of oestrone in response to stimulation of adrenocorticotropic hormone (ACTH). In the current study it was found that with twice daily treatment at the low dose of 125 mg aminoglutethimide plus 20 mg hydrocortisone there was no significant increase in oestrone levels after ACTH stimulation. In addition there was little effect on thyroid function: serum levels of triiodothyronine and thyroxine were unaffected whilst there was a marginally significant (P less than 0.05) increase in thyroid-levels were confined to those patients with pretreatment values greater than 2.5 mU/L, the most marked effect being in 1 patient whose pretreatment level was already outside the normal range.

Intermittent high-dose tamoxifen as a potential modifier of multidrug resistance.

In vitro tamoxifen reverses multidrug resistance (MDR). To evaluate the clinical potential of using tamoxifen in this way, intermittent high-dose tamoxifen was combined with oral etoposide in 86 patients. At 320 mg/day tamoxifen for 6 days, mean plasma levels of tamoxifen in 11 patients increased from 453 ng/ml (range 269-664) on day 2 to 984 ng/ml (578-1336) on day 6. Of 31 patients who had plasma tamoxifen measured during the time of etoposide administration (days 4-6), 13(43%) were over 1111 ng/ml (3 mumol/l), an active in vitro level. Potentially active levels of the principal metabolite, N-desmethyl tamoxifen, were also obtained but accumulation was slower. Emesis and thromboembolism were toxicities. Tamoxifen is a modifier of MDR, a role that warrants further clinical studies.

Parallel changes in the blood levels of abnormally-fucosylated haptoglobin and alpha 1,3 fucosyltransferase in relationship to tumour burden: more evidence for a disturbance of fucose metabolism in cancer.

Levels of an abnormally-fucosylated form of the serum glycoprotein, haptoglobin (FHp) and an enzyme, alpha 1,3 fucosyltransferase (FT) have been measured in blood specimens from women with carcinoma of the ovary or breast who are undergoing chemotherapy. The levels of FHp and FT increased if the women had progressive disease and decreased if they showed complete response to therapy. The statistical correlation between the blood concentrations of these two substances is very strong (P less than 0.0001, chi 2 test). These results and recent studies of fucosyltransferases and cell adhesion molecules from other laboratories, suggest that there are important changes in fucose metabolism in cancer which are worthy of further investigation.

A phase II study of the platinum analogues JM8 and JM9 in malignant pleural mesothelioma.

The platinum analogues JM8 and JM9 were assigned randomly to 16 patients with pleural mesothelioma. Nine patients received JM8 and seven received JM9. Two of nine (22%) JM8-treated patients had objective responses (confidence limits 2.8%-60.0%, 95% confidence level). JM9 was more emetogenic than JM8, but not to a significant level. However, patients who received JM9 significantly preferred this drug to be given on an inpatient basis, in contrast with patients receiving JM8, who received the majority of courses as outpatients. Primary cytotoxic drug resistance is a major obstacle to successful treatment of mesothelioma, and phase II studies of novel agents should continue in an effort to circumvent this problem.

A phase II study of ifosfamide/mesna with doxorubicin for adult soft tissue sarcoma.

In a phase II study, 16 adult patients with locally advanced or metastatic soft tissue sarcomas were treated with i.v. infusions of ifosfamide/mesna 5 g/m2 plus i.v. doxorubicin 40 mg/m2. Courses were given every 3 weeks up to a maximum of six courses in responding patients. Six patients (37.5%) had either complete (1 patient) or partial responses (5 patients). Confidence limits for this response rate were 15.2%-64.5% (95% confidence level). There was one toxic death in association with encephalopathy, renal and bone marrow failure. Unilateral pneumothoraces occurred in 2 patients with large pulmonary metastases. Recurrent severe ifosfamide/mesna encephalopathy occurred in 2 patients at risk for this complication; patients who develop severe ifosfamide/mesna encephalopathy should not be retreated with this drug. Ifosfamide/mesna with doxorubicin is an active combination to treat adult soft tissue sarcoma but, despite the feasibility of the combination, sequential monotherapy with these drugs might provide similar or better clinical benefit.

Experience with 24-h infusions of ifosfamide/mesna in small cell lung cancer.

Two studies were carried out (A and B) in order to assess the effectiveness of ifosfamide administered with mesna (IFO/M) in the treatment of small cell lung cancer. The first study (A) was a cross-over study; the second (B) was a randomized trial, and in B IFO/M was evaluated earlier in the course of the disease. IFO/M given be infusion is effective as second-line therapy and can be administered with other cytotoxics at the doses reported here earlier in the course of the disease. The complete remission rates were high.

Phase 1 study of high-dose hydroxyurea in lung cancer.

The in vitro chemosensitivity of a human lung cancer cell line to hydroxyurea (HU) was measured, and concentrations of 1 mM HU effected 99% inhibition of cell growth. Therefore, infusions designed to achieve serum levels of over 1 mM HU were assessed by escalating doses of hydroxyurea (HU) administered by continuous i.v. infusion at 3-weekly intervals in 18 patients with lung cancer. Dose increments from 24 g in 24 h to 48 g in 48 h were achieved. The dose-limiting toxicity at 48 g in 48 h was myelosuppression. Oral administration of HU did not result in sustained levels comparable to those achieved with continuous infusion. Two patients showed evidence of radiological response after three courses of treatment. Serum HU profiles were monitored after administration i.v. in 26 courses and after administration p.o. in 5 courses of treatment. A mean serum level of greater than 1 mM was achieved by 6 h and then maintained during treatment. The standard error of the mean area under the curve showed an overall 5% variation. HU can be given in doses up to 48 g in 48 h 3-weekly with manageable tissue and bone marrow toxicity, and the in vivo blood levels attained are equal to those necessary for effective cell inhibition in an appropriate in vitro model. This schedule provides a basis for combination studies with other cytotoxics or for use of HU as a DNA repair inhibitor.

Cisplatin with high-dose infusions of hydroxyurea to inhibit DNA repair. A phase II study in non-small-cell lung cancer.

A total of 45 patients with locally advanced and/or metastatic non-small-cell lung cancer (NSCLC) were treated in a phase II trial with high-dose i.v. infusions of 24 g hydroxyurea over 24 h, with 50 mg/m2 i.v. cisplatin 8 h after the start of hydroxyurea infusion. Hydroxyurea, a cell-cycle-specific inhibitor of ribonucleotide reductase, inhibits DNA repair by depleting nucleotide pools. We gave hydroxyurea to achieve steady-state levels of greater than or equal to 1 mM and to potentiate therapy by inhibiting repair of DNA damage produced by cisplatin. Among 21 patients with squamous cell lung cancer, there were 1 complete response (CR), 2 partial responses (PR) and 3 minor responses (MR). Of 13 patients with adenocarcinoma of the lung, 2 had MRs; of 11 patients with large-cell anaplastic lung cancer, none responded. The dominant toxicity was nausea and vomiting, which was manageable and mainly related to cisplatin. The response rate in squamous cell lung cancer was similar to responses obtained with cisplatin alone. The relative ineffectiveness of high-dose 24-h infusions of hydroxyurea in inhibiting repair of DNA damage produced by cisplatin may be due to the low growth fraction of human NSCLC. The high-dose hydroxyurea approach may be more applicable in tumours with a high growth fraction.

A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response.

As part of an open dose-ranging study, the pharmacokinetics of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist given by the i.v. route, was studied in 18 patients receiving highly emetogenic cytotoxic drugs, predominantly cisplatin, either alone or in combination with other cytostatic agents. All patients received 30-min infusions of granisetron at a dose of 40 micrograms/kg. Nine showed complete absence of the gastrointestinal side effects normally associated with cisplatin, and in the majority of the remaining patients, the onset and severity of nausea was significantly modified. No acute side effects were observed at this dose and the drug was well tolerated in all cases. Peak plasma concentrations and area under the curve (AUC) values for granisetron showed considerable inter-patient variation. Higher plasma levels of granisetron were observed at 5 h in responding patients compared with those in whom the drug was ineffective in controlling emesis (P less than 0.05). AUC values were higher in responding patients, but this difference was not statistically significant. There was apparently no defined plasma concentration threshold for the drug's anti-emetic effect in these patients. Granisetron seems to be an effective and safe anti-emetic in patients receiving cytotoxic chemotherapy. Further exploration of its dose scheduling and pharmacokinetic profile is warranted.

Urinary protein and enzyme excretion in patients receiving chemotherapy with the cis-platinum analogs carboplatin (CBDCA, JM8) and iproplatin (CHIP, JM9).

Urinary protein and enzyme excretion was measured in 33 patients with solid tumours receiving chemotherapy with the cis-platinum analogs carboplatin (JM8, CBDCA) and iproplatin (JM9, CHIP). The patients were given up to six courses of the drugs at 4-week intervals, and serial urine samples were collected weekly for periods up to 28 weeks. Overall there was no significant increase in the alkaline phosphatase (ALP), lactate dehydrogenase (LD), and N-acetyl glucosaminidase (NAG) excretion of the first posttreatment samples compared with the pretreatment samples. During the course of treatment there were transient increases in all three enzymes, some quite marked. There was no consistent increase in urinary protein or enzyme excretion during the period of treatment, suggesting that there was no cumulative nephrotoxicity. There was no change in creatinine clearance or urinary beta 2-microglobulin content. Iproplatin appeared marginally more toxic on the basis of elevated NAG and ALP during the second half of the treatment periods compared with the first (P less than 0.01 and less than 0.025, respectively).

Assessment of renal toxicity by urinary enzymes in patients receiving chemotherapy with 8-methyl-8-acetylenic-putrescine.

Renal toxicity was assessed in 19 patients receiving methyl acetylenic putrescine (MAP), an irreversible inhibitor of ornithine decarboxylase. Patients received 250 mg t.d.s. for up to 13 weeks. This dose effectively inhibited the target enzyme, as shown by elevations in decarboxylated S-adenosyl methionine levels. No significant nephrotoxicity was observed in these patients as determined by plasma urea, creatinine and creatinine clearance measurements, although minor elevations of the urinary enzymes lactate dehydrogenase, N-acetyl-beta-glucosaminidase, alkaline phosphatase and alanine aminopeptidase were observed. As this could represent sub-clinical renal damage, caution should be exercised when using MAP in combination with other cytotoxic drugs.

Serum alpha-1-proteinase inhibitor with abnormal properties in ovarian cancer.

It was previously reported that sera from ovarian cancer patients contained abnormal forms of alpha-1-proteinase inhibitor (API) that predicted unresponsiveness to chemotherapy. These molecules were detected by extracting the sera with the fucose-specific lectin, lotus tetragonolobus, and analysing the extracts by electrophoresis. In a new study of ovarian cancer, we report that API cannot be extracted by lotus from fresh sera, unless the specimens are subjected to repeated cycles of freezing and thawing. Furthermore, increases in lotus-extractable API in the pretreated sera are also associated with a poor response to chemotherapy. This would suggest that lotus is extracting the same molecules in both studies. It seems likely that the discrepancy between the two studies is due to the length of time the specimens were stored prior to analysis. We present evidence suggesting that the API extracted by lotus is present in serum as soluble complexes, the detailed composition of which is unclear. The change in the properties of API in cancer may be very important with respect to tumour spread.