Antiemetic therapy--where do we go from here?
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Antiemetics↗
Biomedical subjects
S B Kaye
Publications and source records attributed to S B Kaye.
Prognostic factors in metastatic non-seminomatous germ cell tumours: an interim analysis of the EORTC GU-Group experience.
Univariate and multivariate analyses were performed in 632 patients treated with cisplatin combination chemotherapy for metastatic non-seminomatous testicular germ cell tumours. Multivariately, the most important poor prognosis factors for the prediction of survival were: HCG > or = 10,000 IU/l, lung metastases > or = 10, abdominal metastases with a horizontal diameter of > or = 5 cm and the presence of supraclavicular metastases. If patients had 2 or more of these factors the death rates increased from 30% for patients with 2 factors to 65% for patients with 3 or 4 factors. The patients studied here are not a random sample of the metastatic testicular cancer patients in general, as the population studied comprised a large proportion of low volume metastatic disease patients. Therefore, the final analysis will include patients from all the recently completed trials.
Analysis of Variance↗
New approaches in preclinical and clinical pharmacokinetics.
Pharmacokinetic studies are now playing an increasingly important part in the preclinical and clinical development of new anti-tumour agents. Preclinically, pharmacokinetic, metabolism and toxicological investigations are being integrated and used for the rational selection of new agents with a favourable pharmacological profile. More importantly, this approach should reduce the chance of developing a lead compound that may display idiosyncratic and unpredictable behaviour in patients. Pharmacokinetic studies are also invaluable in identifying potential problems due to species differences in drug handling and should help improve the quality, reliability and predictability of toxicokinetic investigations in experimental animals. Importantly, pharmacokinetic studies involving PGDE, MTSE and Bayesian approaches are increasingly being used to guide dose escalation in early clinical trials. It is likely that these methodologies will evolve further as experience with them develops, and this should lead to improvements in the conduct and scientific quality of phase I/II trials. It therefore behooves the clinician and clinical pharmacologist to pay special attention to the design and implementation of pharmacokinetic studies in early clinical trials.
Antineoplastic Agents↗
Pharmacokinetics and early clinical studies of selected new drugs.
The five examples given here illustrate new cytotoxic agents at different stages of evaluation. In all cases, considerable effort has gone into detailed pharmacokinetic studies conducted before and during the clinical phase I studies. Has this effort contributed significantly to the development of these agents? At present, it has to be said that the contribution made in the case of these particular agents has been modest. For the anthrapyrazoles, the availability of the pharmacokinetic data did not permit a pharmacokinetically guided dose escalation to be performed because of non-linear kinetics, and a similar comment can be made for rhizoxin, since the human plasma AUC values at the MTD were much lower than in the mouse. For the camptothecin analogues, a detailed knowledge of the kinetics of the closed and open forms of the various agents did not influence the way in which the studies were conducted, nor did pharmacokinetic information appreciably do so for EO9, although some comfort was gained by clinical investigators when the short half-life seen in preclinical species was also observed in humans. For suramin, therapeutic drug monitoring is clearly essential, although toxicity remains a problem. Of course, a proper understanding of the pharmacokinetics and metabolism of these agents greatly improves the interpretation of the clinical observations made and is often critical in planning the next stages of development. This is more clearly seen with agents that have unusual forms of toxicity, such as flavone acetic acid, for which the achievement of notional target concentrations is a key element in clinical trials (Kerr et al, 1987; Maughan et al, 1992). Moreover, as reviewed elsewhere (Graham and Workman, 1992; see also Graham and Kaye, this volume), there are several other instances where pharmacokinetically guided dose escalation has greatly improved the conduct of a phase I study. Good examples of this are iododoxorubicin (Gianni et al, 1990), mitotic inhibitor CI-980 (Brodfuehrer et al, 1992) and DNA intercalator CI-958 (Whitfield et al, 1992). Not surprisingly then, pharmacokinetics can help guide early clinical studies of some compounds but not others and whether they will be of value can only be determined by carrying out the pharmacokinetic measurements. The real value of the pharmacokinetic studies for the five compounds reviewed may not yet have been seen. Interpatient variations in drug handling can play a major part in determining levels of anti-tumour activity as well as toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Potential contribution of therapy to cancer mortality reduction.
Reductions in cancer mortality may come about for a number of reasons, including improvements in treatment. The impact will vary from cancer to cancer. For some, expert curative surgery is crucial, whereas for others, the use of appropriate chemotherapy is a key factor. Examples of the latter, in which there are already discernible reductions in national cancer mortality data resulting from chemotherapy, include testicular cancer and Hodgkin's disease. For more common diseases, such as ovarian cancer, reductions also are being seen. For others, such as breast and colorectal cancer, the current more widespread use of adjuvant chemotherapy may lead to overall mortality reduction in the future. It should be recognized that chemotherapy should be given only by those experienced in its use, and that this facility should form part of a larger provision for health care in relation to cancer, ranging from public education to population screening and from better oncology training for clinicians to greater encouragement to participation in clinical trials. New drug development is clearly a priority, but further advances can be made in many countries already using available forms of chemotherapy if treatment facilities are organized appropriately.
Adult↗
Advanced ovarian cancer. Carboplatin versus cisplatin.
BACKGROUND: Since the introduction of the second generation platinum compound carboplatin, debate has taken place about whether this analogue can replace cisplatin in combination chemotherapy regimens for the treatment of ovarian cancer patients. MATERIALS AND METHODS: In the present review the pharmacologic characteristics of carboplatin and cisplatin and the results of comparative studies are described. RESULTS: Many of the trials performed comparing carboplatin with cisplatin, either as single agent first-line therapy or in combination chemotherapy suggest equivalent results. However, most of these trials are characterized by an inadequate patient number to detect small but important differences, inadequate carboplatin doses, ratios < 4:1, and crossover to the other analogue which makes survival comparisons difficult. Superior results in terms of either progression-free survival or overall survival have been obtained with cisplatin in two larger randomized studies of combination chemotherapy. Furthermore, another randomized study indicates substantial differences in favour of cisplatin in the subgroup of patients with < 1 cm residual tumour. Generally, there is a lack of long-term follow up. CONCLUSIONS: Based on the presently available data it is recommended that carboplatin should not routinely replace cisplatin in the management of patients with potentially curable small volume disease.
Antineoplastic Combined Chemotherapy Protocols↗
Who should receive a 5-HT3 antagonist?
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Acute Disease↗
Randomised study of two doses of cisplatin with cyclophosphamide in epithelial ovarian cancer.
Cisplatin is generally accepted to be the most active cytotoxic agent for the treatment of ovarian cancer but the optimum dose remains unclear. We have performed a randomised trial to assess the importance of cisplatin dose in the treatment of advanced epithelial ovarian cancer. Patients were randomly assigned treatment with 50 mg/m2 (low dose) or 100 mg/m2 (high dose) cisplatin plus 750 mg/m2 cyclophosphamide, for a maximum of six cycles with intervals of 3 weeks. We planned to recruit 300 patients, but an interim analysis on the first 165 indicated a highly significant survival difference (p = 0.0008). Recruitment was therefore stopped and the trial patients were followed-up for 12 months longer. The relative progression rate (high-dose/low-dose) after 12 months' extra follow-up was 0.55 (95% confidence interval 0.37-0.81, p = 0.003) and the relative death rate 0.53 (0.34-0.81, p = 0.003). Overall median survival was 69 weeks in the low-dose group and 114 weeks in the high-dose group. Residual disease extent before chemotherapy had an important influence--patients with lesions of less than 2 cm did best; if given high-dose cisplatin their median survival was 3 years. 56 low-dose and 45 high-dose patients completed six cycles of chemotherapy; 15 and 9 patients, respectively, were withdrawn early because of progressive disease and treatment was stopped in 6 and 25, respectively, because of unacceptable side-effects or patient refusal. Toxic effects were significantly greater in the high-dose group, especially those on the nervous system and ears, alopecia, vomiting, and anaemia. Although the higher dose of cisplatin clearly leads to better results in terms of survival, its overall clinical benefit in the management of ovarian cancer will depend on further improvements in measures to alleviate toxic effects.
Adult↗
Phase I and pharmacokinetic study of rhizoxin.
Rhizoxin is a tubulin-binding cytotoxic compound, isolated from the fungus Rhizopus chinensis, with significant antineoplastic activity in several murine and human tumor models. In this Phase I study, the drug was administered by i.v. bolus injection at 3-wk intervals. Twenty-four patients with refractory solid tumors were treated; 60 courses of rhizoxin were given, at doses ranging from 0.8 to 2.6 mg/m2. Grade 3 mucositis, Grade 4 leukopenia, and Grade 3 diarrhea were dose limiting but reversible at 2.6 mg/m2, the maximum tolerated dose for both previously untreated and heavily pretreated patients. Alopecia and moderate discomfort at the injection site occurred at all doses. Other sequelae, including peripheral neuropathy, phlebitis, and nausea and vomiting, were sporadic and mild. Two heavily pretreated patients with recurrent breast cancer had minor responses to rhizoxin, one at 1.6 mg/m2 and the other at 2.6 mg/m2. Plasma concentrations of rhizoxin were measured by high-performance liquid chromatography. The drug was not detectable (less than 5 ng/ml) at doses of 0.8 mg/m2 and 1.6 mg/m2 and was not measurable 10 min after injection at 2.0 mg/m2. At 2.6 mg/m2, there was considerable intersubject variation in the plasma concentration-time profiles; the area under the curve ranged from 0.29 to 0.96 microgram/ml.min. Rhizoxin has shown some clinical activity in this Phase I study, and a dose of 2.0 mg/m2 is recommended for Phase II studies using this schedule.
Adult↗
Preclinical and phase I studies with rhizoxin to apply a pharmacokinetically guided dose-escalation scheme.
BACKGROUND: Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis which displays broad-spectrum antitumor activity against murine and human tumor xenografts and has activity against a number of vincristine-resistant tumors in vitro and in vivo. PURPOSE: This study describes the preclinical and clinical pharmacology of rhizoxin to apply a pharmacokinetically guided dose-escalation (PGDE) strategy during the phase I trial. METHODS: Rhizoxin was administered by a single intravenous bolus injection to female BALB/c mice over the dose range 7.5-18 mg/m2 from which we derived the dose that was lethal to 10% and 50% of the mice (i.e., LD10 and LD50, respectively). The LD10 was 11.7 +/- 0.7 mg/m2 (mean +/- SD), and the LD50 was 14.7 +/- 0.6 mg/m2. Pharmacokinetic studies were integrated with the toxicity study in female BALB/c mice at one-tenth the LD10, one-half the LD10, and the LD10 (i.e., 1.2, 6, and 12 mg/m2, respectively). From these data, a target area under the plasma drug concentration versus time curve (AUC) (i.e., 40% of the LD10 AUC) was calculated for clinical studies. Phase I studies were initiated at 0.8 mg/m2 (one-tenth the equivalent LD10 in male CD1 mice), with the intent of escalating the dose by an extended factor-of-two method until the target AUC and/or maximum tolerated dose (MTD) was reached. RESULTS: The major drug toxic effects in mice were body weight loss, sluggishness, ataxia, transient changes in hematological parameters, and hematuria. Diarrhea was universal at doses greater than 9 mg/m2, and hind limb paralysis was observed in one of 10 mice, but only at supralethal doses (18 mg/m2). Rhizoxin pharmacokinetics were best described by a two-compartment open model (half-life [t 1/2] alpha = 4.4 minutes +/- 0.9 minute [mean +/- SD], and t 1/2 beta = 84 minutes +/- 20 minutes at 12 mg/m2) and found to be nonlinear with respect to dose. At doses of 1.2, 6, and 12 mg/m2, the respective AUC values were 1.3, 22.4, and 70.6 microM x minute. From these data, a target AUC value of 28 microM x minute (40% of the LD10 AUC) was derived. Rhizoxin was not detectable in patient plasma (less than 5 ng/mL at 0.8 and 1.6 mg/m2), and doses had to be escalated by conventional methods. Myelosuppression was dose limiting in patients: Seven of eight treated at 2.6 mg/m2 experienced World Health Organization grade 3-4 neutropenia, and five of eight developed mucositis. The AUC values at the human MTD (2.6 mg/m2) were in the range of 0.41-1.01 microM x minute, considerably lower than the target AUC of 28 microM x minute. CONCLUSION AND IMPLICATIONS: Although PGDE schemes have been successfully employed for other antitumor agents, this methodology could not be applied during the phase I trial of rhizoxin. PGDE studies in the future may incorporate comparative murine versus human metabolism studies in vitro with phenotyped liver microsomes. It may also be useful to assess the comparative myelotoxicity of a new drug by performing in vitro cytotoxicity studies on mouse and human bone marrow stem cells.
Adolescent↗
Cigarette smoking is a risk factor for bleomycin-induced pulmonary toxicity.
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Adolescent↗
Adequate tumour quinidine levels for multidrug resistance modulation can be achieved in vivo.
The multidrug resistance (MDR) phenotype can be reversed in vitro by a number of agents thought to interact with P-glycoprotein (P-gp). Although plasma levels, adequate for MDR modulation, can be achieved with certain modulators, concern has been expressed that tumour levels may be inadequate due to high plasma protein binding. Mice bearing an MDR-positive human tumour xenograft were injected intraperitoneally with quinidine (150 mg/kg). After 2 h the mean plasma quinidine level was 1.9 micrograms/ml (5.1 mumol/l) and the mean tumour quinidine effective in vitro. Three tumour biopsy specimens were obtained from patients who had received oral quinidine prior to surgery. Plasma and tumour levels were similar and were comparable with those measured in mice. This study should dispel fears of inadequate tumour levels of this and other modulators due to high plasma protein binding and encourage future clinical trials of modulators in MDR-positive human tumours.
Animals↗
Training for clinical oncology: experience in Glasgow 1987-1992.
This paper describes how a joint core training course in clinical oncology was set up at the Beatson Oncology Centre in Glasgow. The course extends over a period of two years and modules are taught in cancer basic sciences, physics and surgical oncology, pathology and natural history of malignant disease, and statistics. The structure and content of the course are described, together with an analysis of the problems encountered. There is an assessment of effectiveness. Proposals are made for a scheme for joint accreditation in oncology.
Cancer Care Facilities↗
Phase I trial of the anthrapyrazole CI-941: prospective evaluation of a pharmacokinetically guided dose-escalation.
The development of new drugs in early clinical trials is currently based upon the results of preclinical antitumour and toxicity studies in animals. More recently, the use of preclinical pharmacokinetic information in mice has been proposed to also provide information that might expedite early clinical trials and more specifically phase I studies. The anthrapyrazole CI-941 was one of three chosen for phase I anticancer drug development. In addition, because of the predictability of the preclinical dose limiting toxicity and linear CI-941 pharmacokinetics in mice; a pharmacokinetically guided dose escalation scheme was attempted during the phase I trial, but had to be abandoned. 44 patients were entered who received 95 courses of treatment using a bolus injection every 21 days. The dose range was 5-55 mg/m2. The dose limiting toxicity was leucopenia and other toxicities, which included nausea and vomiting, mucositis, diarrhoea, alopecia and skin discolouration were either mild or manageable. Pharmacokinetic studies were performed with 27 courses. There were wide interpatient variations in the dose-AUC relationship (r = 0.7496) that hampered application of the proposed pharmacokinetically guided dose escalation scheme as planned. No complete or partial responses were observed. The recommended phase II dose using this schedule is 50 mg/m2.
Adult↗
An independent evaluation of the potential clinical usefulness of proposed CA-125 indices previously shown to be of prognostic significance in epithelial ovarian cancer.
CA-125 levels were assessed prior to each of the first three cycles of chemotherapy, in 81 patients with epithelial ovarian cancer receiving first-line chemotherapy. All patients have at least 1 year's follow-up. Thirty-nine patients (48%) have progressed clinically or have died within 1 year of treatment (treatment 'failures'). Three CA-125 indices previously shown to be of prognostic value are assessed for their ability to pick-out these 'failures'. When the indices examined are modified to obtain a specificity for picking out failures just exceeding 90%, the maximum sensitivity obtained was 46%. The use of CA-125 for clinical decision making in ovarian cancer requires further investigation to determine and validate a prognostic index with acceptable sensitivity and specificity, and to determine the clinical impact of treatment decisions made using such an index.
Antigens, Tumor-Associated, Carbohydrate↗
Phase II trials of fosquidone, (GR63178A), in colorectal, renal and non-small cell lung cancer. CRC Phase II Clinical Trials Committee.
A total of 61 eligible patients with metastatic cancer have been treated in a series of Phase II trials of the novel pentacyclic pyrroloquinone, fosquidone. Tumour types were colorectal (23), renal (21), and non small cell lung (17). No patient had received prior chemotherapy. The drug was given intravenously as a 20 min infusion at the dose of 120 mg-2 on days 1 to 5 every 3 weeks. Treatment was well tolerated; the only significant side effects being mild nausea and generalised musculo-skeletal pains. Response was assessed after two cycles of therapy. No patient achieved an objective partial response. A total of nine patients demonstrated stable disease for a median duration of 11 weeks. Using this schedule of administration, fosquidone has no significant antitumour activity in this group of tumours.
Adult↗
The changing role of surgery in metastatic non-seminomatous germ cell tumour.
In the last 2 years (1989-1990) we have treated a total of 53 patients with metastatic nonseminomatous germ cell tumours (teratoma). In ten cases surgery to remove residual abdominal masses was required on completion of chemotherapy and normalisation of tumour markers (HCG and AFP). In a further three patients with large intra-abdominal masses and little or no other sites of disease surgery was performed as a therapeutic intervention, in the context of plateauing or rising tumour markers despite intensive chemotherapy. In all three, this approach resulted in a rapid fall in tumour markers, and following further chemotherapy all three remain disease free at 7, 12 and 25 months. For this small sub-group of patient failing to respond to chemotherapy who have resectable lesions, interventional surgery should be considered as part of a combined approach to treatment.
Adult↗
A randomised study comparing standard dose carboplatin with chlorambucil and carboplatin in advanced ovarian cancer.
A total of 161 previously untreated patients with FIGO stage III or IV epithelial ovarian cancer were randomised after surgery to receive six courses of either carboplatin 400 mg m-2 alone (Arm A) or carboplatin 300 mg m-2 with chlorambucil 10 mg day-1 for 7 days (Arm B). The median progression free survival (PFS) was similar: arm A: 45 weeks; arm B: 61 weeks (P = 0.830). Multivariate Cox regression analysis showed that the extent of residual disease and performance status were the most important prognostic factors for PFS. Fifty-two per cent of patients received dose escalations based on nadir blood counts, and 89% of all dose adjustments were made according to protocol. Failure to achieve a significant degree of leucopenia was associated with worse progression free survival (P less than 0.001). A total of 29.4% of patients fall into this category. The median survival was similar in both arms, i.e. 75 weeks. It is unlikely that there is any major clinical advantage to adding chlorambucil to single agent carboplatin for the management of advanced ovarian cancer, but whether used in combination or a single agent, the dose of carboplatin should be sufficient to cause at least grade I leucopenia. This may best be achieved by determining the initial dose based on renal function, and then adjusting subsequent doses according to nadir blood counts.
Adult↗