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Acivicin, an antimetabolite which inhibits enzymes necessary for glutamine utilization, was administered to 16 patients with recurrent high grade astrocytoma. The dose was 12 mg/m(2)/day intravenously over 30 min, daily for 5 days to be repeated every 3 weeks. All patients had previously received cranial irradiation. There were no objective responders, two patients remained stable, two were not evaluable for response and the other 12 progressed on treatment. The median survival of the patients was 128 days. The major toxicity was reversible neurological toxicity, with episodes of WHO grade 3 symptoms in two patients, grade 2 in 19 and grade 1 in six patients. Non-neurological toxicities were infrequent with two patients with grade 2 vomiting and two patients developing infections on treatment, although no severe myelosuppression occurred. Three patients developed mild rashes. The lack of activity and the neurological toxicity makes a daily for 5 days schedule of acivicin unsuitable for further study in central nervous system tumours.

Induction therapy of acute myeloid leukemia (AML) with standard dose chemotherapy will result in approximately 55-75% of patients achieving a complete remission (CR). Intensification of induction treatment with etoposide and high dose cytarabine does not alter the CR rate but appears to significantly improve the subsequent outcome. Updated results of the comparison of high dose cytarabine with daunorubicin and etoposide in induction (HIDAC-3-7) versus a standard dose combination (7-3-7) demonstrated a highly significant increase in relapse free survival, (RFS) on the high dose arm (p = 0.007) with RFS of 48% at 5 years with HIDAC-3-7 and 25% on 7-3-7. The high dose arm had a more modest survival advantage at 5 years of 33% compared with 25% on standard treatment, possibly because of a higher initial death rate with HIDAC-3-7. The improvement seen in patients with CR after high dose induction appear to parallel results obtained with post-remission therapies intensified with high dose cytarabine. These studies provide clinical evidence that a dose-response effect is present for cytarabine in AML. Intensified treatment is more toxic, gives more profound myelosuppression post-remission and has been shown to benefit younger patients only. Issues of patient selection and the optimal placement of intensification in the treatment sequence require further study. In the future, it is likely that remission duration may be a useful clinical tool to study the influence of new induction therapies on residual resistant leukemia.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a taxane with a wide spectrum of antitumor activity. Combination chemotherapy with paclitaxel plus cisplatin has been shown to be more active than older drug combinations in the treatment of ovarian cancer and non-small cell lung cancer. Paclitaxel also appears to be as active as other therapies for the first-line treatment of breast cancer, and an established salvage treatment after platinum therapy for ovarian cancer and after anthracycline therapy for breast cancer. Ongoing clinical trials are evaluating the role of paclitaxel in the adjuvant treatment of breast cancer and in early stage lung cancer. Cost analysis of combination paclitaxel/cisplatin treatment for ovarian cancer indicated drug costs represented a low proportion of inpatient costs, making it cost effective per life-year gained in both the inpatient and outpatient settings. In extensive cost analyses of lung cancer therapies in Canada, best supportive care for stage IV lung cancer was shown to cost more than Can$28,000. In this setting, with an expected increase in survival, the cost of treating stage IV lung cancer with paclitaxel appears to be cost effective. Furthermore, in a large randomized study of paclitaxel versus cyclophosphamide/methotrexate/5-fluorouracil/prednisone in breast cancer, preliminary results suggested that paclitaxel may be associated with equivalent cancer control, quality of life, and less side effects. Thus, future research will consider the cost-benefit of improved quality of life with paclitaxel therapy and evaluate the comparative cost-benefit when taxanes are used to treat earlier-stage disease.

Brain-derived neurotrophic factor (BDNF) has potent trophic and protective actions on CNS neurons, including mesencephalic dopaminergic neurons, ventral forebrain cholinergic neurons and spinal motor neurons. To evaluate the effects of calcium and other second messengers on BDNF gene transcription, C6 glioma cells were treated for 4 h with the calcium ionophore A23187, forskolin + isobutyl-methyl-xanthine (IBMX), or the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate. Semi-quantitative RT-PCR analysis revealed that A23187 treatment increased BDNF transcripts containing the protein coding exon by 4.4-6.4-fold. Alternate BDNF transcripts were elevated to varying degrees after treatment with this ionophore and a subset of these transcripts was elevated following forskolin + IBMX treatment. When co-incubated with the RNA polymerase inhibitor, actinomycin D, A23187-induced increases were reduced or abolished, suggesting that calcium-mediated regulation of BDNF mRNA expression occurs at transcriptional as well as post-transcriptional levels. Transient transfection experiments employing reporter constructs containing serial 5' deletions of alternate BDNF promoters suggested that A23187-induced elevations in BDNF exon 1b, 1d and 1e containing transcripts are mediated by putative calcium-responsive regions flanking all three of these exons.

When administered as a single agent to previously treated patients with advanced breast cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has good activity. This trial was undertaken to compare paclitaxel with standard chemotherapy as front-line treatment for this disease. Patients with measurable or evaluable metastatic breast cancer, no prior chemotherapy for metastatic disease, and Eastern Cooperative Oncology Group performance status of 0 to 2 were randomized to receive either paclitaxel 200 mg/m2 intravenously over 3 hours for eight cycles over 24 weeks or standard treatment with oral cyclophosphamide 100 mg/m2/d days 1 to 14, intravenous methotrexate 40 mg/m2 days 1 and 8, intravenous 5-fluorouracil 600 mg/m2 days 1 and 8, and oral prednisone 40 mg/m2 daily days 1 to 14 (CMFP) for six cycles over 24 weeks. Patients whose disease progressed or relapsed were recommended for second-line therapy with epirubicin. Accrual has been completed with 209 patients randomized, and an interim analysis of the first 100 patients is reported here. Analysis of quality of life, assessed by the linear analogue scale and overall quality of life indices, is ongoing. Objective response occurred in 31% (confidence interval, 19% to 45%) with paclitaxel and 35% (confidence interval, 22% to 51%) with CMFP, with stable disease in an additional 33% and 29%, respectively. Median time to progression was 5.5 months with paclitaxel and 6.4 months with CMFP, with a median survival of 17.3 months for patients treated with paclitaxel and 11.3 months for those given CMFP. Grades 3 and 4 neutropenia occurred in 64% of patients with paclitaxel and 63% with CMFP. However, febrile neutropenia was the primary reason for hospitalization in 1% of paclitaxel courses, compared with 8% with CMFP. Major infections (World Health Organization grade 4) were seen in 7% of patients treated with CMFP, but in none of those given paclitaxel. Moderate or severe mucositis occurred in 13% of paclitaxel and 27% of CMFP patients. Alopecia and peripheral neuropathy were more common with paclitaxel. Quality of life assessments in the first 100 patients suggest better overall results for those treated with paclitaxel compared with CMFP. Preliminary analyses suggest that single-agent paclitaxel is well tolerated and provides control of metastatic cancer comparable to that of CMFP combination therapy when used as front-line therapy in an outpatient setting.

Twenty-two patients with advanced transitional cell bladder cancer were treated in a phase II trial exploring the possible synergy of cisplatin and interferon alpha 2b. Of the 20 evaluable patients, 7 (35%) had a partial response to the treatment, and only 6 patients were able to complete the full planned six cycles of treatment. Response rates, duration of responses, and overall survival of our patients are not superior to those expected by cisplatin alone.

This study investigated dose intensification of epirubicin administered as a 2-weekly regimen with granulocyte-macrophage colony-stimulating factor (GM-CSF) support. The aim was to define the maximally tolerated dose of epirubicin and to assess the efficacy of GM-CSF to ameliorate its toxicity. Patients with anthracycline-responsive advanced malignancies were eligible. Six dose levels, commencing at 90 mg/m2, of epirubicin administered every 2 weeks for four courses were planned with GM-CSF 10 micrograms/kg/day administered for 10 days from the second day of each course. Six patients were to be entered at each dose level, and escalation to the next level was based upon toxicity criteria. Twelve patients were entered, six at dose level 1 (90 mg/m2) and six at dose level 2 (120 mg/m2). Prospectively defined haematological dose-limiting toxicities were noted in one patient at dose level 1 and in five patients at dose level 2. Further dose escalation was not attempted. Significant nonhaematological toxicities included febrile neutropenia in two and four patients at dose levels 1 and 2, respectively. This study has demonstrated that epirubicin can be safely administered at 2 week intervals with GM-CSF at a dose of 90 mg/m2, equivalent to the previously reported maximum tolerated dose intensity of 45 mg/m2/week. Neutropenia was dose-limiting despite the use of GM-CSF.

Objective: To determine the efficacy and safety of paclitaxel given as a three-hour infusion in patients with metastatic breast cancer which had progressed despite hormonal therapy and/or chemotherapy., Design and Setting: Multicentre phase it trial undertaken in five major centres or hospitals in Sydney, Melbourne and Adelaide., Patients and Methods: 50 patients with clinically or radiologically measurable or evaluable metastatic breast cancer recruited between March and July 1993. All had received prior chemotherapy, with subsequent disease progression., Intervention: Paclitaxel (Anzatax, Faulding) was given at a dose of 175 mg/m2 intravenously over three hours every three weeks for up to nine courses., Main Outcome Measures: Response rate (partial or complete); duration of progression-free survival; duration of survival; and adverse reactions., Results: Patients had a median age of 51 years; 62% had received at least two prior drug regimens for metastatic breast cancer and 48% had anthracycline-resistant tumours. A median of six paclitaxel courses was given per patient. Overall response rate was 18% (95% confidence interval [95% CI], 9%-31%), with complete responses in four patients (8%). In patients with anthracycline-resistant tumours, response rate was 25% (95% CI, 10%-47%). Response was not influenced by extent of prior treatment. Estimated median progression-free survival was 4.1 months (95% CI, 3.2-6.0 months) and estimated median survival was 6.3 months (95% CI, 6.2-10.3 months). Treatment was well tolerated, with neutropenia the major toxic effect., Conclusions: Paclitaxel (three-hour infusion) has significant activity in heavily pretreated patients with metastatic breast cancer, including anthracycline-resistant tumours.

When administered as a single agent in pretreated patients with advanced breast cancer, paclitaxel (Taxol) exhibits remarkable antitumor activity. This trial was undertaken to compare paclitaxel with standard chemotherapy as front-line therapy for this disease. Patients with measurable or evaluable metastatic breast cancer, no prior chemotherapy for metastatic disease, and an Eastern Cooperative Oncology Group performance status of 0 to 2 were randomized to receive paclitaxel 200 mg/m2 intravenously over 3 hours for eight cycles (6 months) or standard treatment with oral cyclophosphamide (Cytoxan) 100 mg/m2/d days 1 through 14, intravenous methotrexate 40 mg/ m2 days 1 and 8, intravenous 5-fluorouracil 600 mg/m2 days 1 and 8, and oral prednisolone 40 mg/m2/d (CMFP) days 1 through 14 for six cycles (6 months). Patients whose disease progressed or relapsed were recommended to receive second-line epirubicin. Accrual has been completed with 208 patients randomized, but a preplanned interim analysis of the first 100 patients is reported here. Analysis of quality of life, assessed by a linear analogue scale and overall quality of life indices, is ongoing. Objective response occurred in 31% (confidence interval, 19% to 45%) with paclitaxel and 35% (confidence interval, 22% to 51%) with CMFP with stable disease in an additional 33% and 29%, respectively. Median time to progression was 5.5 months for paclitaxel-treated patients and 6.4 months for those given CMFP, with median survival durations of 17.3 and 11.3 months, respectively. Grades 3 and 4 neutropenia occurred in 64% of patients treated with paclitaxel and in 63% treated with CMFP. However, febrile neutropenia was the primary reason for hospitalization in 1% of paclitaxel courses, compared with 8% of CMFP courses. Nine percent of the patients had major infections with CMFP, but none were seen with paclitaxel. Moderate or severe mucositis occurred in 13% of paclitaxel-treated and 27% of CMFP-treated patients. Alopecia and peripheral neuropathy were more common with paclitaxel. Quality of life assessments in the first 100 patients suggest better overall results on paclitaxel treatment as compared with CMFP. Preliminary analyses suggest that single-agent paclitaxel is well tolerated and provides comparable control of metastatic cancer to CMFP combination therapy when used as front-line treatment.

Induction therapy of acute myeloid leukemia (AML) with standard-dose chemotherapy will result in 52% to 72% of patients achieving a complete remission (CR) on bone marrow morphology. Newer agents that appear to improve the outcome of induction therapy are etoposide, idarubicin, and high-dose cytarabine. New studies are now required to define new induction combinations and the place of these and other promising new drugs in the treatment. Standard attenuated postremission therapy is required after standard induction to maintain remission. However, new intensified postremission therapies have significantly improved outcome in de novo AML. This development has required re-examination of the value of intensive treatment. There is now clear clinical evidence that a dose-response effect is present for cytarabine in AML. The optimal placement of intensified treatment and marrow transplantation requires further study. In the future, it is likely that new treatment strategies will be defined by identifying new prognostic subgroups. To identify new successful induction treatments in AML, more precise measures of CR are required including an attempt to define cytogenetic CR and molecular CR wherever it can be applied. A theoretical model of blast cell kill would suggest that remission duration may be a useful clinical end point to study the influence of new induction therapies on residual resistant leukemia.

Purpose: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies., Patients and Methods: Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery., Results: Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs., Conclusion: Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.

The aim of the present study was to investigate whether cisplatin would enhance the radioresponse of a human tumour xenograft when given in different schedules combined with accelerated fractionated radiation therapy. A human squamous carcinoma of the hypopharynx, FaDu, was grown in the thigh of athymic nude mice. Tumours were exposed to twice-daily 2-Gy fractions, applied 6 h apart over 2 weeks, 5 days a week, alone or combined with cisplatin given at maximally tolerated doses in three different schedules: (1) i.p. as a single bolus (SB) or (2) i.p. as a daily bolus at 30 min before the first daily radiation fraction or (3) s.c. as a continuous infusion through a mini-osmotic pump over 13 days, commencing 24 h prior to the first daily radiation fraction. The end point for the study was tumour growth delay (TGD), calculated as the difference between the delay in regrowth to 200% of the initial tumour size in treated versus control mice. SB cisplatin plus radiation showed only an additive effect on TGD, whereas daily-bolus and continuous-infusion cisplatin demonstrated a greater than additive effect when combined with accelerated fractionated radiation in this human tumour model. Cisplatin appears to be especially beneficial as a radiation enhancer when given throughout the course of radiation.

Background: Paclitaxel (Taxol) is a new drug with efficacy against a variety of malignant tumors. The clinical formulation of paclitaxel contains 50% Cremophor EL, a polyethoxylated castor oil vehicle (carrier) that can reverse multidrug resistance (MDR) mediated by P-glycoprotein. Three-hour intravenous infusions of paclitaxel can yield end-of-infusion plasma Cremophor concentrations of 1 microL/mL or more, which are sufficient to reverse MDR in vitro by at least 50%. Despite extensive clinical use, the pharmacokinetics of Cremophor have not been described., Purpose: We studied the pharmacokinetics of Cremophor in patients with ovarian cancer who were undergoing treatment with paclitaxel to determine whether plasma Cremophor concentrations achieved during and following 3-, 6-, and 24-hour drug infusions were similar to those shown to modulate MDR in vitro., Methods: Eleven patients with previously treated (i.e., with platinum-containing chemotherapy regimens) ovarian cancer were randomly assigned to receive one 3-hour, one 6-hour, and one 24-hour infusion of paclitaxel in varied sequences during their first three cycles of treatment with this drug. Blood samples were collected both during and following the three infusion periods, and Cremophor concentrations in these samples were measured by use of a bioassay based on the ability of Cremophor in plasma samples to reverse cellular resistance to daunorubicin in vitro., Results: Ten patients were treated with paclitaxel at a dose level of 175 mg/m2, and one patient was treated at a dose level of 135 mg/m2. At the 175-mg/m2 dose level, peak plasma Cremophor concentrations of 1 microL/mL or more were achieved in eight of 10 patients during both the 3-hour and the 6-hour infusions; with the 24-hour infusion, only one patient achieved a peak plasma Cremophor concentration of 1 microL/mL or more. The eight patients who achieved plasma Cremophor concentrations of 1 microL/mL during the 3-hour infusion were above this level 30 minutes into the infusion; the total time that the plasma concentration was greater than 1 microL/mL was 8.9 +/- 5.0 hours (mean +/- standard deviation; range, 4.1-15.6 hours). For the eight patients who achieved plasma Cremophor concentrations of 1 microL/mL during the 6-hour infusion, the total time that the concentration was greater than 1 microL/mL was 10.2 +/- 9.0 hours (range, 0.3-21.9 hours). The patient who received paclitaxel at a dose of 135 mg/m2 achieved a peak plasma Cremophor concentration of 1 microL/mL or more only during the 3-hour infusion., Conclusions: Paclitaxel infusions of 3 and 6 hours can result in sustained plasma Cremophor concentrations sufficient for substantial reversal of P-glycoprotein-mediated MDR in vitro. These plasma Cremophor concentrations are not achieved during 24-hour infusions of paclitaxel.

The effects of 14 days neuroleptic treatment on the expression of the D3 dopamine receptor gene was investigated in rats using a sensitive polymerase chain reaction assay. In olfactory tubercle, D3 mRNA levels increased following haloperidol (40%), pimozide (56%), and sulpiride (63%) administration, and in nucleus accumbens, levels increased after haloperidol (50%) and sulpiride (50%). D3 expression in the motor striatum did not change with any antagonist tested. Clozapine did not affect D3 expression in any brain region. These data suggest that dopamine antagonists can regulate the expression of the D3 receptor in a brain region selective manner. The findings also suggest that the motor complications of chronic antipsychotic therapy are not due to D3 receptor up-regulation in the striatum.

Background: Carboplatin is used in treating many types of cancer. Because renal excretion is the major variable determining the pharmacokinetics of this drug, a dosing formula based on glomerular filtration rate (GFR) has been proposed and is being increasingly used in carboplatin dosing. This method of dosing is critically dependent on accurate measurement of GFR., Aims: To report the experience at a single major oncology centre of carboplatin dosing based on GFR, and comparisons of different methods of measuring renal function for use in this dosing method., Methods: An initial group of patients (n = 24) was studied where GFR was measured by Cr51EDTA clearance and compared to Tc99mDTPA clearance, measured 24 hour urine creatinine clearance and the Cockcroft and Gault formula. The carboplatin area under the plasma concentration versus time curve (AUC) was calculated using total platinum measured in a single blood sample assayed by flameless atomic absorption spectrophotometry. A subsequent patient group (n = 16) was then studied using Tc99mDTPA clearance to measure GFR., Results: Carboplatin dosing using Cr51EDTA clearance to measure GFR was accurate (< 25% difference between planned and measured AUC) in 87% of samples. Estimation of renal function using the Cockcroft and Gault formula correlated with Cr51EDTA clearance only in patients with GFR < 100 mL/minute. The measured 24 hour urine creatinine clearance did not correlate with Cr51EDTA clearance. Using Tc99mDTPA clearance to measure GFR, carboplatin dosing was accurate in 81% of samples. Across a GFR range of 42-239 mL/minute, the Cr51EDTA and Tc99mDTPA clearance were closely correlated (r = 0.98, slope of regression line = 1.02)., Conclusions: Carboplatin dosing using a pharmacological formula based on GFR produces accurate targeting of the carboplatin AUC. Tc99mDTPA clearance can be used to measure GFR instead of Cr51EDTA clearance, which is both more convenient and has potential cost savings. Estimates of renal function using the Cockcroft and Gault formula or measured 24 hour creatinine clearance are insufficiently accurate to use for carboplatin dosing.

Background: Loss of heterozygosity (LOH) studies have been pivotal in identifying tumor suppressor genes involved in the pathogenesis of a number of cancers. In squamous cell carcinomas of the head and neck region (SCCHN), LOH studies using the Southern blot technique are scarce., Methods: SCCHNs were obtained immediately after surgical resection from 78 patients. Histologic confirmation was made by frozen section and tumors with less than 50% malignant cells were excluded. DNA was digested with restriction enzymes, and after Southern blotting the membranes were hybridized with radio-labeled probes. Chromosome arms analyzed included 1p, 3p, 4p, Sq, 8p, lOp, 11p, 11q, 13q, 17p, 17q, 18q, 21q, and 22q., Results: The average rate LOH was 25% per chromosome arm. Significantly higher rates of LOH were observed for chromosome arms 5q (56%) and 17p (45%). Other investigators have reported high rates of LOH for the H- ras-1 locus, and chromosome arms 11p, 11q, and 13q. However, these results were not confirmed in this study. For patients with stage 1 or 2 tumors, the overall LOH rate was 13%, and for patients with stage 3 or 4 disease the rate was 23%. This difference was statistically significant (p < 0.025)., Conclusions: tumors progress to higher stages, they appear to accumulate an increasing number of genetic abnormalities. Chromosome arms 5q and 17p contain tumor suppressor genes which are likely to be involved in the pathogenesis of SCCHN:

Patients fail to be cured of acute myeloid leukemia (AML) because they develop absolute or relative resistance to antileukemic drugs such as ara-C (cytarabine) or because they die of complications of bone marrow failure. The Australian Leukemia Study Group (ALSG) has been investigating strategies to improve leukemia control by changing the methods of induction treatment. High-dose ara-C (HIDAC) may overcome ara-C resistance in leukemic blasts, and it has been used as a successful salvage regimen and in postremission therapy. The data from ALSG suggest that a dose-effect relationship exists for ara-C in AML, that the use of HIDAC prolongs remission duration and disease-free survival and that it is tolerable when used as initial induction therapy in patients with de novo AML. A fundamental question still to be answered in ongoing clinical trials is: When should AML treatment be optimally intensified--during the induction phase, immediately after remission, or after 2 to 3 months of preparative regimens, as in some transplantation programs?

Patients with locally advanced stage 3 or 4 recurrent squamous cell carcinoma of the head and neck received 5-fluorouracil (5-FU) 200 or 300 mg/m2/day by prolonged ambulatory infusion concomitantly with radiotherapy (60-66 Gy) to the primary site and neck nodes in 30-33 fractions at five fractions per week, boosting to smaller volumes after 60 Gy. Of 39 patients, the complete response rate was 82% (95% CI: 67-93%). The estimated percentage without failure at 2 years was 59% (S.E. 8%) and at 4 years was 50% (S.E. 8%). Estimated head and neck cancer specific survival was 64% (S.E. 8%) at 2 years and 52% (S.E. 8%) at 4 years. Acute toxicities included moist desquamation in 49% and dry desquamation in 28%, confluent mucositis in 56% and patchy mucositis in 44%. Late effects, more than 6 months after completing treatment, assessed in 35 patients, included severe salivary dysfunction in 3 patients and moderate in 21, severe osteonecrosis in 4 patients and moderate toxicity in subcutaneous tissues in 13, skin in 3 and mucosa in 2 patients. It is feasible to give continuous 5-FU concurrently with radiotherapy in locally advanced or recurrent head and neck cancer, albeit with increased toxicity. The response rate and survival obtained in this trial justify further investigation of the combined treatment in a randomised trial.

Standard induction therapy of acute myeloid leukemia (AML) with standard dose chemotherapy will result in 52-72% of patients achieving a complete remission (CR) and only 20% long term survivors. Newer agents which intensify induction therapy appear to improve the outcome of induction include etoposide, idarubicin and high dose cytarabine. New studies are now required to define new induction combinations and the place of these and other promising new drugs in the treatment. Standard attenuated post-remission therapy is required after standard induction to maintain remission. However, new intensified post-remission therapies have significantly improved outcome in de novo patients. This development has required re-examination of the value of intensive treatment. There is now clear clinical evidence that a dose-response effect is present for cytarabine in AML. The optimal placement of intensified treatment and marrow transplantation requires further study.

Purpose: To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Fifty-one patients with advanced measurable or assessable NSCLC and performance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mg/m2 over 3 hours with premedication. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57%), extrathoracic metastatic disease (65%), and measurable disease (75%). Twenty-two percent had previously untreated stage III disease., Results: The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organization (WHO) grade IV neutropenia in only 16% of patients. Grade III/IV myalgia/athralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred., Conclusion: The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase II trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.

The influences of bilateral or unilateral injuries within the posterior parietal cortex (PPC) upon spatial learning in a water maze were examined in three experiments. Place-learning and response-learning were investigated in a four-alley 'Greek-cross' shaped water maze with extra-maze visual cues available. No differences were detected on any of several measures sensitive to learning between the lesion groups on the place-learning task. Microanalysis of behavior within trials revealed that animals with either bilateral or right unilateral PPC injuries committed significantly more total errors, initial alley entrance ('reference memory') errors, and re-entry ('working memory') errors in the response-learning paradigm than did either the control or left PPC-injured rats. No differences were detected between the latter two groups on these measures. Unilateral lesions resulted in asymmetrical placing responses ipsilateral to the injury 10 days after surgery whereas bilateral injuries resulted in asymmetrical placing with mixed directionality. The acquisition of the response-learning problem in the absence of visual cues was studied on animals prepared with unilateral lesions and housed post-operatively either in isolation or in a 'complex environment.' In the absence of visual cues both right and left PPC-injured rats committed more errors than sham controls, and differential post-surgical housing did not attenuate these impairments. These same animals were trained on the landmark navigation task. Although no differences appeared between the lesion groups, a generalized but transient facilitation of learning was observed in animals housed in the 'complex' environment. Unilateral injuries placed in sham controls failed to disturb retention of the landmark navigation strategy. Because none of the PPC-injured animals were deficient in the landmark task, a result which is contrary to observations in other laboratories, the influence of post-surgical recovery interval upon acquisition of the landmark navigation strategy was explored. Animals were prepared with right PPC injuries and trained following either a 5 or 35 day recovery interval. Only those animals limited to the short recovery interval proved to have a spatial deficit in the landmark task. It is concluded that injuries in the PPC of either hemisphere disturb egocentric spatial functions. However, animals with left PPC injuries are able to compensate by using allocentric visual cues if they are available. It is due to the special role played by the right PPC in complex visuospatial functions that animals with this injury are unable to compensate.

In scheduling chemotherapy and radiotherapy for locally advanced non-small cell lung cancer (NSCLC), chemotherapy can be given pre-radiotherapy or concurrently as a single agent or in combination. Optimal scheduling has yet to be established. Optimal pre-radiotherapy for NSCLC requires further development but cisplatin with vinblastine, vindesine, etoposide or navelbine appear the best currently available. A number of new drugs show potential for enhancing radiation effects. Concurrent chemotherapy and radiotherapy has been tested in a number of experimental tumours in cell culture. In these systems cisplatin, carboplatin, 5-fluorouracil, mitomycin-C and other agents appear to improve cell kill compared to chemotherapy alone. Mouse xenograft models allow the study of various concurrent drug and radiation schedules including the effect of radiation with cisplatin, carboplatin, paclitaxel and gemcitabine. In these systems, cisplatin in divided doses shows optimal enhancement with fractionated radiotherapy. There are a number of drug candidates for concurrent chemotherapy and radiotherapy programs. Clinical studies in head and neck cancer, esophageal cancer, small cell lung cancer and NSCLC show promising results with concurrent chemotherapy and radiotherapy. Cisplatin given daily with radiotherapy improved survival in NSCLC compared to cisplatin given weekly with radiotherapy or to radiotherapy alone. To study the toxicity of radiation and concurrent carboplatin, we have studied 170 patients with unresectable locally advanced NSCLC in a 4-arm randomized trial. An analysis of the first 100 patients entered revealed significantly more neutropenia (P < 0.0001) and thrombocytopenia (P < 0.004) with the combined modality arms. Esophagitis was worse on all three experimental arms but was significantly more prolonged with accelerated radiotherapy arms.(ABSTRACT TRUNCATED AT 250 WORDS)

A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m2 per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m2, three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m2, two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58 +/- 0.24 microM. Renal excretion of platinum accounted for 70 +/- 12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83-603 ml/min) and renal clearance (range, 67-390 ml/min). A terminal elimination half-life of 13-27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-state UFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m2 per day.

Brain-derived neurotrophic factor (BDNF) enhances the survival of dopaminergic neurons and protects them from neurotoxins in vitro. This trophic factor might thus be of therapeutic value for the treatment of Parkinsonian syndromes. The rat BDNF gene consists of several upstream noncoding exons that are alternatively spliced to a common coding exon. To investigate BDNF 5' exons expressed in the adult rat brain, we subjected RNA from cerebellum to 5'-RACE analysis and compared the resulting clones to previously reported 5' exon sequences from rat brain and hippocampus. In addition to known 5' exons, we isolated a BDNF transcript with a novel 5' sequence representing yet another alternate upstream exon in this gene. Quantitative PCR analysis of BDNF mRNAs containing each of the five upstream exons indicated that each of the alternate transcripts is most abundant in the hippocampus, intermediate in the substantia nigra and cerebellum and least abundant in the striatum. However, the magnitude of these differences in expression varied considerably suggesting that BDNF gene transcription in the mature brain is regulated by alternate promoters that are differentially active across regions.

To determine the incidence and prognostic significance of mutation in the N-ras gene in de novo acute myeloid leukemia (AML) we performed an analysis of bone marrow smears from 219 patients with de novo AML treated between 1984 and 1986 and followed for at least six years. DNA extracted from bone marrow smears taken at diagnosis was screened for the presence of mutations in codons 12 and 13 of exon 1 by using the polymerase chain reaction to insert an Hph1 restriction enzyme site into DNA. Presumptive mutations were confirmed by direct sequencing. Mutations were detected in a total of 26 patients (12%); in nine patients (4%) in codon 12 only, in ten patients (5%) in codon 13 only, and in seven patients (3%) in both codons. Mutations in codon 12 or codon 13 were not associated with any clinical features. Mutations in codon 12 had no prognostic significance but mutations in codon 13 were associated with an increased remission rate, a more durable remission, and a significantly prolonged survival which appeared to be independent of other prognostic factors.

The aim of this study was to assess the influence of dose and dose intensity (DI) of induction and consolidation chemotherapy on relapse rates in 264 de novo patients with acute nonlymphocytic leukemia (ANLL). Patients were randomised to receive cytosine arabinoside (ARAC) 100 mg/m2 continuous infusion for 7 days and daunorubicin (DNR) 50 mg/m2 IV day 1-3 (7-3) or the same drugs with the addition of etoposide 75 mg/m2 IV days 1-7 (7-3-7). Cox proportional hazards regression models were used throughout to identify prognostic factors, including dose delivery parameters, influencing the rate of relapse. Of 152 patients who achieved a complete remission (CR), 104 have relapsed with a median duration of CR of 15.8 months. Actual dose delivered was prospectively documented. Cox regression analysis identified the most significant prognostic factors jointly influencing duration of CR as performance status groups (p < 0.0001), percentage peripheral blasts (p = 0.0015), 7-3-7 arm (p = 0.0075), age < 40 years (p = 0.022) and induction dose ARA-C plus DNR (p = 0.029). In this analysis patients randomized to the 7-3-7 arm had an estimated 43% reduction in the relapse rate and each 10% reduction of doses ARA-C and DNR was associated with an estimated 45% increase in the relapse rate. The number of induction courses, delays in treatment and induction dose intensity did not significantly influence the duration of CR nor did any of the consolidation treatment parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To report three cases of cardiotoxicity related to the administration of 5-fluorouracil (5-FU) in patients with cancer., Clinical Features: Three patients with gastrointestinal malignancies were being treated with combined radiotherapy and chemotherapy regimens. Two patients developed myocardial ischaemia and the other a ventricular arrhythmia in association with 5-FU administration., Intervention and Outcome: All patients survived the cardiac event. No patient was rechallenged with 5-FU. Radiotherapy was continued, achieving a good tumour response., Conclusion: Cardiotoxicity is rarely reported with 5-FU. The cardiac events can be life threatening. It is difficult to predict which patients will be affected. Clinicians need to be aware of this potential toxicity and monitor patients appropriately.

Severe thrombocytopenia and clinical bleeding remain major clinical problems in leukemic patients undergoing remission induction and those receiving high dose chemotherapy. Prophylactic platelet transfusions have made a major impact on hemorrhagic deaths over the last 20 years. The effectiveness of platelet transfusions is influenced by a number of clinical factors including the status of the spleen, prior bone marrow transplantation, the presence of disseminated intravascular coagulation and the presence of HLA antibodies. Optimal platelet transfusion therapy requires that transfusions be monitored routinely by post-transfusion counts and that a refractory group be clearly defined. The cytokine granulocyte colony stimulating factor (G-CSF) has not had a clinically significant impact on thrombocytopenia. Granulocyte-macrophage colony stimulating factor (GM-CSF) also probably has little clinical relevance, although in a randomized study, thrombocytopenia was worse in GM-CSF-treated patients. Interleukin-3 (IL-3) can increase platelet count and has the potential to protect against thrombocytopenia in patients receiving chemotherapy. This hypothesis is currently being tested in on-going clinical trials.

Previously untreated patients with stages I to IV, N0-3, M0 unresectable non-small cell lung cancer were randomized to arm I (conventional radiotherapy [RT], 60 Gy in 30 fractions over 6 weeks), arm II (accelerated RT, 60 Gy in 30 fractions over 3 weeks), arm III (conventional RT, as in arm I, plus carboplatin 70 mg/m2/d on days 1 to 5 during treatment weeks 1 and 5), or arm IV (accelerated RT, as in arm II, plus carboplatin 70 mg/m2/d on days 1 to 5 of week 1 only). An intensive analysis of toxicity in the first 92 patients entered revealed significantly more neutropenia (P < .0001) and thrombocytopenia (P = .004) in the combined-modality arms. Esophagitis was worse on arms II, III, and IV, but was more prolonged in the accelerated RT arms. Overall, however, the treatment on all study arms was well tolerated.

Patients receiving outpatient chemotherapy, without cisplatin, were randomised to receive four doses of either domperidone 60 mg or prochlorperazine 25 mg suppositories every 4 h, starting 30 min before the chemotherapy. They were crossed over for the next chemotherapy cycle. To enable analysis of 100 patients who had received identical chemotherapy in each course, 136 patients were randomised. Patients experienced a higher grade of nausea on domperidone (P = 0.05). Only 18% of patients vomited on domperidone and 14% on prochlorperazine, but the number of vomits was higher on domperidone (P = 0.003) and the duration was significantly increased (P = 0.02). Patients experienced significantly more diarrhoea on domperidone (P < 0.0001), although it was predominantly mild. Patients were significantly more sedated on prochlorperazine on the second course (P = 0.006), but not on the first course (P = 0.9). More patients preferred their second course (P < 0.0001), and were significantly less anxious (P = 0.0002). Patients reported tolerating their treatment similarly for both antiemetics, but more patients preferred prochlorperazine (P = 0.003), mainly due to reductions in nausea and vomiting and other side-effects, particularly diarrhoea.

The endpoints assessed by both patients and nurses were compared in three anti-emetic studies. In a parallel subjects study, there was no significant difference between the patients' and nurses' assessment of the number of vomiting episodes, but the duration of vomiting, the severity and duration of nausea, and the side-effects of the anti-emetic were given higher scores by the nurses. In two cross-over studies, the patients recorded more vomiting episodes than the nurses, while the nurses recorded more anxiety and sedation than the patients. This resulted in the patients detecting a difference between the side-effects of the anti-emetics being compared that was not apparent from the nurses' forms. Many of the differences reflect differences in the timing and frequency of data collection. Nurses collected data regularly during the assessment period whereas patients reported their experiences only at the completion of 24 h. Both assessments provide useful perspectives on the study outcomes.

The most potent, physiologic activator of proopiomelanocortin (POMC) gene transcription is corticotropin releasing hormone (CRH) and increased intracellular cAMP is critical for this effect. The 5'-flanking region of the murine POMC gene has several potential binding sites for regulatory proteins. To characterize the region between nucleotides -141 and -106, which includes a TRE-like site and an adjacent AP-2 consensus sequence, and to study its role in signal-transcription coupling, gel mobility shift assays and transient expression of CAT chimeras were performed. In transient transfections of AtT-20 cells with pCATp-141/-106, CRH treatment led to significant increases in CAT expression compared with CRH treatment of cells transfected with the enhancerless vector. However, no response to direct activation of cAMP dependent protein kinase or protein kinase C was detected. Despite the high homology of the sequence -137/-131 to the consensus AP-1 binding site (TRE), the nuclear factor(s) in AtT-20 cells binding to this region appears to be different than authentic AP-1 since neither a competitor oligonucleotide having the authentic TRE sequence nor antibodies against Jun or Fos affected the gel shift pattern of a probe having the -137/-131 sequence. We conclude that the -141 to -106 region of the murine POMC gene contains a functional CRH responsive element and that second messenger systems that transduce the CRH signal to this element do not exert their actions solely through activation of PKA or PKC.

A total of 22 patients with superficial transitional cell carcinoma of the bladder, uncontrolled cystoscopically and unsuitable for or having failed intravesical therapy, received 50 mg. oral methotrexate per week for 12 months. Of the patients 7 (32%) achieved or remained in complete remission and 5 achieved a partial response, while 4 remained stable, 3 had progression and 3 were not evaluable. Patients who were still alive had a median followup of 2.5 years. Two patients with complete remission had relapse at 16 and 26.4 months, and 5 were disease-free at 34.5, 31.3, 18.6, 17.8 and 16.8 months, respectively. The methotrexate was generally well tolerated but 2 patients discontinued therapy because of dyspnea (1 subsequently died of respiratory failure that was possibly related to the methotrexate) and 1 because of persistent grade 2 mucositis. Grade 3/4 toxicities occurred in 3 patients: 1 each with reversible increases in creatinine and aspartate aminotransferase, and 1 with gastric bloating. There was little hematological toxicity. Reversible skin lesions developed in 4 patients. This oral treatment may provide an effective alternative to intravesical therapy but can be associated with severe toxicity.

To assess the effect of danazol in advanced breast cancer 183 patients were randomised to receive either tamoxifen plus danazol or tamoxifen plus placebo. Patients underwent systemic work-up pretreatment then every 12 weeks or sooner if they clinically progressed. There were no differences in objective response rates with tamoxifen plus danazol vs. tamoxifen plus placebo (27% vs. 24%), time to progression (median 6.4 vs. 6.2 months) or survival (median 22.6 vs. 23.5 months) when the two arms were compared (all P > 0.5). The addition of danazol to tamoxifen had no effect on time to progression when adjusted for significant prognostic factors in a multivariate analysis. However, it was found incidentally that weight was stable on tamoxifen plus danazol (average gain 0.6 kg, S.E. 0.6 kg) compared with a significant loss on tamoxifen plus placebo (average loss 2.0 kg, S.E. 0.6 kg, P = 0.003). The average weight was maintained on tamoxifen plus danazol even in patients who did not respond to treatment.

Toremifene is a triphenylethylene antioestrogen with significant antitumor activity. It is structurally very similar to tamoxifen. Both drugs undergo extensive hepatic metabolism, and tamoxifen is known to inhibit hepatic mixed-function oxidases (MFO). Using the isolated perfused rat-liver model, we investigated the effect of toremifene on the elimination of antipyrine, a standard marker of MFO activity. Perfusate consisted of 20% red cells in a modified Krebs-Henseleit buffer, and 80 ml was recirculated at 14 ml/min for 3 h. High but clinically relevant steady-state toremifene levels of 3 and 10 micrograms/ml were achieved using bolus plus constant infusion into the reservoir. Elimination of 2.5 mg antipyrine was not inhibited by steady-state toremifene, but methanol (maximal perfusate concentration, 1.29%), the vehicle used for toremifene administration, caused a statistically significant increase in the antipyrine elimination half-life (mean, 1.4 +/- 0.2 h for controls vs 2.2 +/- 0.3 h for methanol; P < 0.05, n = 4). Whereas the methanol had no apparent effect on liver viability as assessed by bile flow and perfusate back-pressure, toremifene at a steady-state concentration of 10 micrograms/ml caused a statistically significant decrease in bile flow (value at 180 min, 0.22 +/- 0.05 ml/h as compared with 0.52 +/- 0.06 ml/h in the methanol control; P < 0.05) and a statistically significant increase in perfusate back-pressure (value at 180 min, 17.5 +/- 1.8 cm vs 11.0 +/- 2.6 cm in the methanol control; P < 0.05). Therefore, toremifene used at high doses can impair liver function in the isolated perfused rat liver, but it does not have any effect on antipyrine elimination.

Advanced or metastatic melanoma responds poorly to chemotherapy, which has no impact on survival. Responses have been recorded using cisplatinum as a single agent. This study tested the established combination of cisplatinum 100 mg/m2 and 5-fluorouracil 1 g/m2/day continuously intravenously for 5 days repeated every 3 weeks in patients with disseminated melanoma. Twenty-nine patients, 13 having received no prior systemic chemotherapy, received 49 cycles of therapy (median 1, range 1-4). Only one previously untreated patient achieved a partial response with a failure-free survival of 6.5 months and an overall survival of 7.7 months from the commencement of therapy. The major toxicities were nausea and vomiting, (grade 3 in eight patients), stomatitis (grade 4 in two patients, grade 3 in two patients), and myelosuppression. The study showed that cisplatin and 5-fluorouracil have a low order of activity in patients with advanced or disseminated melanoma.

Etoposide (VP16-213), a topoisomerase II inhibitor, has produced complete responses in 17% of previously treated patients with acute nonlymphocytic leukemia (ANLL) but has little activity in acute lymphoblastic leukemia. As salvage therapy for relapsed ANLL etoposide produces 28% complete responses in combination with amsacrine, 49% with 5-azacytidine, and 51% with anthracycline. It has been successfully combined with high-dose cytarabine as a salvage treatment. In a randomized trial in previously untreated patients with ANLL, etoposide significantly prolonged remission duration. Etoposide has been used to intensify postinduction therapy with or without bone marrow rescue, but its exact role in that setting has not been clarified. Because of its schedule dependency in other tumors, etoposide should be investigated using different schedules in ANLL.

Sixty-seven patients with advanced breast cancer were prospectively entered into a Phase II trial of cyclophosphamide 100 mg/m2 orally on days 1-14, methotrexate 40 mg/m2 intravenously (i.v.) on day 1, 5-fluorouracil 600 mg/m2 i.v. on day 1, and prednisolone 40 mg/m2 orally on days 1-14 (CMFP) rapidly alternating with doxorubicin 25-30 mg/m2 i.v. on day 8 and vincristine 1.4 mg/m2 i.v. on day 8 (AV). Complete responses (CR) were seen in 7 patients, partial responses (PR) in 25 (CR + PR, 48%), stable disease in 24, and progressive disease in 9. The median time to disease progression was 9.8 months, and the median survival 19.4 months. Neutropenia was the major toxicity with WHO grade 3 or 4 neutropenia in 50% of patients. CMFP/AV is a well-tolerated, effective regimen in advanced breast cancer but does not appear to be superior to CMFP alone.

A series of 21 consecutive patients with carcinoma of the breast and symptomatic choroidal metastases was reviewed. All patients were symptomatic of choroidal metastases at presentation. Most patients had disease progression at other sites at the time of diagnosis. The incidence of cerebral metastases was not increased in this group compared to that in patients with metastatic breast cancer at other sites. Radiotherapy using a direct anterior field proved effective palliation for this disease site. Of the 32 eyes treated, serial visual acuity was documented in 23. Seventeen showed objective improvement and six showed stabilisation. The median duration of improvement was 11.5 months.

The relationship between the 1 and 20 h post-transfusion platelet count and three parameters used to define refractory transfusions, namely the corrected increment (CI), platelet increment (PI), and percentage platelet recovery (%REC), was studied in 437 non-HLA matched platelet transfusions given to 102 patients with bone marrow failure. The percentage agreement between common definitions of refractoriness was calculated based on these parameters. As the maintenance of platelet counts above 20 x 10(9)/l is a relevant clinical goal for platelet support, the values of the CI, PI and %REC, which best corresponded to 1- and 20-h post-transfusion counts of 20 x 10(9)/l, were identified. A 1-h post-transfusion CI < 3 (PI < 7 x 10(9)/l or % REC < 8%) corresponded to clinically unsuccessful transfusions with a 1-h platelet count < 20 x 10(9)/l. A 1-h CI > or = 5.5 (PI > or = 12 x 10(9)/l or %REC > or = 14%) corresponded to clinically successful transfusions with a 20-h post-transfusion count of > or = 20 x 10/l. These data tie together the end points reported in the literature for defining refractory transfusions.

Carboplatin is well suited to dose escalation because its major dose-limiting toxicity is myelosuppression when given in 1,200 mg/m2 doses without marrow support. Repeated 800 mg/m2 doses can be given in an investigational setting. With autologous bone marrow rescue the maximum tolerated single-agent dose is approximately 1.8 to 2 g/m2, with dose-limiting toxicities being hepatitis, renal dysfunction, and ototoxicity. Combinations of carboplatin with other agents plus bone marrow rescue are now being investigated in germ cell tumors, ovarian cancer, breast cancer, and small cell lung cancer. High-dose carboplatin plus etoposide combinations are being evaluated with colony-plus stimulating factors in an effort to ameliorate myelosuppression. Future high-dose carboplatin studies could be designed with more predictable toxicity, using an assessment of carboplatin renal clearance. Carboplatin is an important new drug warranting further investigation at escalated doses.

The efficacy and toxicity of two regimens based on etoposide/carboplatin with or without cyclophosphamide/vincristine in the management of small cell lung cancer (SCLC) were assessed by the Australian Lung Cancer Study Group. Response rates of 77% and 85% were noted for the two- and four-drug regimens, respectively, among patients with limited disease (LD). Response rates among patients with extensive disease (ED) were 58% and 79%, respectively. The profiles of nonhematologic toxicity were modest; myelosuppression was dose-limiting when colony-stimulating factors were not used. Twenty-six patients (14%) were older than 70 years of age. Although hematologic toxicity was more severe in the elderly group, there was no significant difference in nonhematologic toxicity, response rate, or overall survival between the geriatric and younger groups. When LD only was considered, 33% of those younger than 70 were alive at 2 years; no patients aged 70 years or older with LD were alive beyond 2 years. In patients with ED, there was no age-related difference in survival. Cytotoxic regimens based on etoposide/carboplatin constitute useful treatment for SCLC, with high response rates and manageable toxicity, irrespective of patient age.

To define further the place of dexamethasone in antiemetic combinations, lorazepam, prochlorperazine and placebo (LP) were compared with lorazepam, prochlorperazine and dexamethasone (DLP) in a randomised, double-blind, crossover study. Both patient and observer assessments were documented in 84 patients receiving both cisplatin and non-cisplatin chemotherapy. The addition of dexamethasone significantly reduced the severity of nausea (P = 0.002) and vomiting (P less than 0.0001), duration of nausea (P = 0.01) and vomiting (P = 0.002) and the number of vomiting episodes (P = 0.003). DLP was the superior regimen in subsets of patients receiving cisplatin and the non-cisplatin chemotherapy. The improvements produced by the dexamethasone regimen were large and of major benefit to our patients. Patients documented significantly improved tolerance to chemotherapy with DLP courses (P = 0.0006). Overall, significantly more patients preferred DLP (P less than 0.0001). Patient assessments produced results similar to observer assessments but gave a broader understanding of their experience. The addition of dexamethasone to prochlorperazine and lorazepam significantly improved our patients' experience while receiving chemotherapy.

This phase I study investigated flavone acetic acid (FAA) given as a 12-h intravenous infusion every 3 weeks in the absence of urinary alkalinisation. Cohorts of three patients were treated at doses of 7, 10 and 13 g/m2. One subject had colon cancer; 5, renal cancer; and 3, lung cancer. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in four patients, 1 in two subjects and 2 in three cases. The maximum tolerated dose was 13 g/m2. The dose-limiting toxicities were WHO grade 3 hypotension and grade 3 diarrhoea. Other toxicities included lethargy and dizziness, nausea, temperature fluctuation, myalgia and dry mouth, but no significant myelosuppression was encountered. One patient receiving 10 g/m2 for renal cancer showed a partial response that lasted for 3 months and included the resolution of pulmonary and cutaneous metastases. The pharmacokinetics showed large interpatient variability. At 12-16 h post-infusion, the plasma elimination profile entered a plateau phase, with frequent increases in concentration suggesting enterohepatic recycling. Neither peak FAA levels nor AUC values were dose-dependent at the doses studied. Peak plasma levels were 101-402 micrograms/ml and AUC (0-48 h) values were 75-470 mg ml-1 min. Plasma protein binding varied with total concentration. Two metabolites were detected in the plasma, and both also underwent apparent enterohepatic recycling. Repeat dosing resulted in decreases of up to 48% in peak levels and AUC values for FAA in three of six patients. Of the total FAA dose, 39%-77% was excreted in the urine as FAA or metabolites within 2 days. The dose recommended for further phase II studies is 10 g/m2.

Carboplatin/etoposide is an active combination in small cell lung cancer. In phase II studies, it produces results that appear equivalent to cisplatin/etoposide, but it has not been compared in a randomized study. It has a better toxicity profile than cisplatin/etoposide when compared in non-small cell lung cancer. The combination of carboplatin/etoposide is very well tolerated by elderly patients. Carboplatin/etoposide lacks important nonhematologic side effects, which has led to its assessment in dose escalation studies with colony-stimulating factors and autologous bone marrow transplantation.

High-dose prochlorperazine 0.8 mg/kg administered intravenously 30 min pre and 7 h 30 min post the initial dose of emetogenic chemotherapy was compared to high-dose metoclopramide 2 mg/kg over 20 min every 2 h for five doses starting 30 min prior to chemotherapy in a randomised, double-blind, parallel subjects design study. On the prochlorperazine arm intravenous dextrose placebos every 2 h maintained blinding. Complete suppression of vomiting occurred in 42% on metoclopramide (53% with non-cisplatin regimens) and 36% on prochlorperazine (52% with non-cisplatin-containing regimens) while major responses (2 or less vomits) occurred in 58% on metoclopramide and 54% on prochlorperazine. In patients who vomited after cisplatin, prochlorperazine achieved a significantly shorter duration of vomiting, a median of 5 h compared to 15 h on metoclopramide (P = 0.03). The response rate to prochlorperazine for cisplatin-induced emesis between 12 and 24 h was significantly better than for metoclopramide (prochlorperazine = 0.02). Toxicities were equivalent except for significantly greater sedation and dry mouth on prochlorperazine. Extrapyramidal reactions were recorded equally on both arms but were only severe enough to stop treatment on metoclopramide. The metoclopramide regimen was five times as expensive as prochlorperazine. High-dose prochlorperazine is an active and cost-effective antiemetic.

A high-performance liquid chromatographic method has been developed for the measurement of toremifene and its major human metabolites in plasma and urine. We have simplified other published methods, such that our assay uses protein precipitation in place of organic extraction, and ultraviolet detection instead of photochemical activation followed by fluorescence detection. In a stability study toremifene and metabolites remained unchanged for up to seven weeks at -70 degrees C. This simple and specific assay allowed toremifene and three metabolites to be quantitated for pharmacokinetic analyses in a high-dose Phase I trial.

Single-agent etoposide (VP16-213, NSC 141540) induces complete response (CR) in 15% to 25% of previously treated patients with acute nonlymphocytic leukemia (ANLL). Etoposide has been used successfully in combination with cytarabine, daunorubicin, and amsacrine as salvage and consolidation therapy. Patients aged 15 to 70 years with previously untreated ANLL were randomized to therapy with either 7-3 (cytarabine 100 mg/m2/d days 1 to 7 and daunorubicin 50 mg/m2/d days 1 to 3) or 7-3-7 (7-3 plus etoposide 75 mg/m2/d days 1 to 7). Patients achieving CR received two consolidation courses of the same drugs for shorter duration (5-2 or 5-2-5). Of 264 eligible patients, 7-3 induced CR in 56%, 7-3-7 in 59%. Remission duration was significantly improved with 7-3-7 (median, 12 months 7-3, 18 months 7-3-7, P = .01) but not survival. Subset analysis in patients under 55 years of age revealed prolonged remission (median, 12 months 7-3 v 27 months 7-3-7, P = .01) and survival (median, 9 months 7-3 v 17 months 7-3-7, P = .04) with 7-3-7. Hematologic toxicity was similar during induction but significantly more severe in consolidation. Etoposide is active in ANLL and prolongs remission when used as induction therapy.