Who should receive a 5-HT3 antagonist?
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Acute Disease↗
Biomedical subjects
S B Kaye
Publications and source records attributed to S B Kaye.
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56 low-dose and 45 high-dose patients completed six cycles of chemotherapy; 15 and 9 patients, respectively, were withdrawn early because of progressive disease and treatment was stopped in 6 and 25, respectively, because of unacceptable side-effects or patient refusal.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↗
Phase II trial with Flavone Acetic Acid (NSC.347512, LM975) in patients with non-small cell lung cancer.
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Aged↗
5-Aza-2'-deoxycytidine (NSC 127716) in non-seminomatous testicular cancer. Phase II from the EORTC Early Clinical Trials Cooperative Group and Genito-Urinary Group.
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Adult↗
Phase II trials of fosquidone (GR63178A) in carcinoma of the breast, head and neck, ovary and melanoma.
A total of 91 eligible patients with metastatic cancer have been treated in a series of phase II trials of the novel pentacyclic pyrroloquinone, fosquidone. Tumour types were breast (24), ovary (25), head and neck (21) and melanoma (21). All patients, except those with melanoma had received prior chemotherapy. The drug was given intravenously as a 20 min infusion, at the dose of 120 mg/m2 on days 1 to 5 of a 3 week cycle. Treatment was well tolerated; the only significant side-effects being mild headaches and generalised musculo-skeletal pains. Response was assessed after 2 cycles of therapy. Only one patient (with head and neck cancer) achieved an objective partial response, lasting 6 weeks. A total of 12 patients demonstrated stable disease for a median duration of 15 to 20 weeks. Using this schedule of administration, fosquidone has no significant antitumour activity in this group of tumours.
Adult↗
High-dose epirubicin in chemotherapy refractory non-seminomatous germ cell cancer: a phase II study. EORTC Genito-Urinary Tract Cancer Co-operative Group. EORTC Early Clinical Trials Group.
Eighteen patients with progressive disseminated, platinum-resistant germ cell tumors were treated with epirubicin 135 mg/m2, every 3 weeks. One patient had stable disease, 17 developed progression. Myelosuppression was dose-limiting. One patient died of neutropenic septicemia. High-dose epirubicin is not active against platinum-resistant germ cell cancer.
Adolescent↗
Laboratory and phase I studies of new cancer drugs.
New drug discovery continues to follow the time-honored paths of screening and novel target identification combined with analogue development and serendipity. The agents selected here reflect these various approaches. They include drugs already showing significant antitumor activity, eg, anthrapyrazoles, temozolomide, camptothecin analogues, and taxotere, and updated information is provided on their development. Other drugs just entering or currently in phase I trials include rhizoxin, which seems capable of overcoming multidrug resistance; the novel bioreductive agent EO9 [corrected]; and bryostatin, a highly potent protein kinase C agonist. Sequence specificity could well prove to be an important factor in the development of DNA-interactive agents, and information is provided on the progress with distamycin mustard and the new cyclopropylpyrroloindole analogues carzelesin and adozelesin.
Antineoplastic Agents↗
Initial combination chemotherapy with cisplatin, methotrexate and vinblastine in locally advanced transitional cell carcinoma--response rate and pitfalls. MRC Subgroup in Advanced Bladder Cancer (on behalf of the MRC Urological Working Party).
A total of 51 patients with locally advanced transitional cell carcinoma of the bladder were entered into a phase II study to evaluate the effect of initial cisplatin (100 mg/m2, Day 2) combined with methotrexate (30 mg/m2, Days 1 and 8) and vinblastine (4 mg/m2, Days 1 and 8). Of 44 evaluable patients, 25 (57%) achieved an objective response of their primary bladder tumour (complete response (CR): 4 patients; partial response (PR): 21 patients); 30 of the 36 patients with micturition disturbances obtained relief. Toxicity was acceptable, but dose modifications due to haematological or renal toxicity were required in 153 of the 690 drug courses. Non-protocol dose modifications were performed 45 times. The experience gained in this trial emphasises the need for improved co-operation between urologists, radiologists and clinical oncologists in such multicentre phase II studies. Difficulties were observed in adhering to dose modification rules, assessing pre-treatment tumour size (due to variation in quality of measure and in timing relative to initial transurethral resection (TUR)) and defining response to chemotherapy (due to failure to perform mandatory investigations at the right time). This study also illustrates that the accepted criteria for assessing response in the primary bladder tumour are difficult to apply in practice and that the results of any study using this indicator lesion require caution in their interpretation.
Aged↗