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Biomedical subjects

C J Twelves

Publications and source records attributed to C J Twelves.

At least 19 recordsLinked to original sources
PubMed2004

A cancer research (UK) randomized phase II study of idoxifene in patients with locally advanced/metastatic breast cancer resistant to tamoxifen.

Idoxifene is a novel selective oestrogen receptor modulator (SERM) which had greater binding affinity for the oestrogen receptor (ER) and reduced agonist activity compared with tamoxifen in preclinical studies. In a randomized phase II trial in 56 postmenopausal patients with progressive locally advanced/metastatic breast cancer we assessed whether idoxifene showed evidence of activity compared with an increased 40 mg/day dose of tamoxifen in patients who had previously demonstrated resistance to the standard 20 mg/day dose of tamoxifen. Of 47 patients eligible for response (25 idoxifene, 22 tamoxifen), two partial responses and two disease stabilizations (SD) for >6 months were seen with idoxifene (overall clinical benefit rate 16%, 95% CI 4.5-36.1%). The median duration of clinical benefit was 9.8 months. In contrast, no objective responses were seen with the increased 40 mg/day dose of tamoxifen, although two patients had SD for 7 and 14 months (clinical benefit rate 9%, 95% CI 1.1-29.2%). Idoxifene was well tolerated and the reported possible drug-related toxicities were similar in frequency to those with tamoxifen (hot flushes 13% vs 15%, mild nausea 20% vs 15%). Endocrine and lipid analysis in both groups showed a similar significant fall in serum follicle-stimulating hormone and luteinizing hormone after 4 weeks, together with a significant rise in sex hormone binding globulin levels and 11% reduction in serum cholesterol levels. In conclusion, while idoxifene was associated with only modest evidence of clinical activity in patients with tamoxifen-resistant breast cancer, its toxicity profile and effects on endocrine/lipid parameters were similar to those of tamoxifen.

Adult↗
PubMed2004

Improvements in survival for women with breast cancer in Scotland between 1987 and 1993: impact of earlier diagnosis and changes in treatment.

We investigated changes in survival, and their causes, in women with early breast cancer diagnosed in Scotland. The Scottish Cancer Registry identified 1617 and 2077 such women, without metastases at diagnosis who underwent surgery as part of their primary treatment, diagnosed in 1987 and 1993, respectively. There was a statistically significant 11% improvement in 8-year survival between 1987 and 1993. Survival improved across almost all clinical/pathological, treatment and health care delivery/deprivation categories; improvement was not limited to those women diagnosed through the screening programme. In a multivariate model, improved survival appeared to be explained largely by screening and clinical/pathological prognostic factors. Deprivation also had an adverse effect on survival; however, the geographical variation in survival observed for women diagnosed in 1987 was not apparent by 1993. We did not demonstrate a significant independent effect of surgical caseload on survival. We conclude that survival has increased partly as a consequence of screening and earlier diagnosis, but also due to improvements in the organisation and delivery of care.

Adult↗
PubMed2003

Epirubicin in patients with liver dysfunction: development and evaluation of a novel dose modification scheme.

This study aimed to develop an epirubicin dose modification scheme in women with breast cancer and liver dysfunction. We first identified target areas under the concentration-time curve (AUCs) of 2400 and 1600 ng/ml.h from pharmacokinetic studies in 15 women with normal liver tests. In a second group of 16 women with abnormal liver biochemistry, the relationship between raised asparate aminotransferase (AST) and epirubicin clearance was: dose=AUC (97.5-34.2xlog AST). Adaptive dosing was evaluated prospectively in a third group of 41 women with serum AST > or =2xnormal+/-raised bilirubin. The median AUCs were 2444 and 1608 ng/ml.h, close to the high and low target AUCs, respectively. Variability in AUC was lower with adaptive dosing than in a fourth group given an unadjusted dose of epirubicin (coefficient of variation=25.8, 30.0 and 46.5%, respectively; P=0.06). Epirubicin dosing based on AST is safe and may reduce pharmacokinetic variability.

Adult↗
PubMed2003

Protein kinase C: a target for anticancer drugs?

Protein kinase C (PKC) is a family of serine/threonine kinases that is involved in the transduction of signals for cell proliferation and differentiation. The important role of PKC in processes relevant to neoplastic transformation, carcinogenesis and tumour cell invasion renders it a potentially suitable target for anticancer therapy. Furthermore, there is accumulating evidence that selective targeting of PKC may improve the therapeutic efficacy of established neoplastic agents and sensitise cells to ionising radiation. This article reviews the rationale for targeting PKC, focuses on its role in breast cancer and reviews the preclinical and clinical data available for the efficacy of PKC inhibition.

Animals↗
PubMed2002

Phase I study of docetaxel in combination with cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

This phase I was study conducted to establish the maximum tolerated dose, dose-limiting toxicity, and recommended dose of docetaxel in combination with cyclophosphamide as first-line chemotherapy for metastatic breast cancer. Twenty-six patients were treated with cyclophosphamide (600 mg m(-2), intravenous bolus) followed by docetaxel (60, 75 or 85 mg m(-2), 1-h intravenous infusion) every 3 weeks. The maximum tolerated dose was docetaxel 85 mg m(-2) with cyclophosphamide 600 mg m(-2), the dose-limiting toxicity being febrile neutropenia. Grade 4 neutropenia was experienced by all patients, but was generally brief. Otherwise, the combination was well tolerated with few acute and no chronic non-haematological toxicities of grade 3/4. Activity was observed at all dose levels and disease sites, and the overall response rate was 42% (95% confidence interval 22-61%). The pharmacokinetics of docetaxel were not modified by cyclophosphamide coadministration. These findings establish a recommended dose of docetaxel 75 mg m(-2) in combination with cyclophosphamide 600 mg m(-2) every three weeks for phase II evaluation.

Adult↗
PubMed2002

Oral cancer treatment: developments in chemotherapy and beyond.

Oncology is one of the few areas of medicine where most patients are treated intravenously rather than receiving oral drugs. Recently, several oral anti-cancer drugs have been approved and there are many more in development. Oral chemotherapy is attractive because of its convenience and ease of administration, particularly in the palliative setting. With an increasing number of oral agents emerging, we can expect to see a rapid rise in the use of oral chemotherapy in years to come. This article reviews recent developments in oral chemotherapy, both of traditional cytotoxics and novel, targeted agents, from the viewpoint of patients, physicians, drug developers and health-care providers.

Administration, Oral↗
PubMed2002

Which endpoints should we use in evaluating the use of novel fluoropyrimidine regimens in colorectal cancer?

Although significant advances have been made in the treatment of advanced/metastatic colorectal cancer, 5-fluorouracil (5-FU) still forms the basis of chemotherapy. Recently, new 5-FU schedules and novel fluoropyrimidines have been developed, but there are no trials directly comparing these regimens. The current review describes the mechanisms of action, pre-clinical and phase I/II studies of two oral fluoropyrimidine therapies, capecitabine and uracil with tegafur plus leucovorin. It also compares the phase III studies of these agents with those of the two most popular infusional 5-FU-based regimens: de Gramont and German AIO (The Association of Medical Oncology (AIO) of the German Cancer Society). Both oral and infusional regimens demonstrated similar survival to the Mayo Clinic regimen, a standard treatment for colorectal cancer. Therefore, other endpoints must be examined to decide optimum therapy, including response rates, time to disease progression, tolerability and patients' convenience. All four new therapies demonstrated superior safety profiles compared with the Mayo Clinic regimen. However the uracil with tegafur plus leucovorin regimen was associated with severe diarrhoea and capecitabine with hand-foot syndrome. Patients will not sacrifice efficacy for the convenience of oral therapy alone, therefore the fact that capecitabine achieved superior response rates and equivalent time to disease progression compared with the Mayo Clinic regimen, while uracil with tegafur plus leucovorin produced lower response rates and significantly inferior time to disease progression, is highly relevant in choosing treatment.

Antimetabolites, Antineoplastic↗
PubMed2002

Follow-up in women with breast cancer: the patients' perspective.

We surveyed the opinions of patients on routine follow-up for early breast cancer to assess their satisfaction with current breast cancer follow-up arrangements, establish the issues that are important to patients in this setting and to assess their opinions on different models of care in breast cancer follow-up. A self-completion questionnaire was issued to 134 women attending an outpatient breast cancer follow-up clinic at a central teaching hospital in Glasgow. Most women (84%) considered follow-up 'important' and 90% were satisfied with current follow-up practice. Almost all patients (91%) were content with both the current frequency and duration of their appointments. Risk of recurrence and effects of treatment were considered the most important topics for discussion. Two-thirds of patients felt it was important to see the same member of staff at each follow-up appointment. The majority (64%) would have been satisfied with a nurse-led system of follow-up, whereas only 38% would be happy with General Practitioner-led care. Although patients are generally satisfied with current follow-up arrangements, most would accept the involvement of specialist nurses in conjunction with a consultant.

Journal Article↗
PubMed2002

Adjuvant ovarian ablation vs CMF chemotherapy in premenopausal breast cancer patients: trial update and impact of immunohistochemical assessment of ER status.

This trial, initiated in 1980, examined the relative values of adjuvant ovarian ablation and chemotherapy comprising cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in premenopausal women with pathological stage II breast cancer. With median follow-up for patients still alive of 13.9 years, there is no difference in survival between women receiving ovarian ablation and CMF (hazard ratio 1.01; 95% CI: 0.74, 1.37). Tumour oestrogen receptor (ER) status was assessed at the time using biochemical ligand-binding assay and retrospectively by immunohistochemistry (IHC). Agreement between these two methods was only fair, but both confirmed the importance of ER status in determining appropriate adjuvant systemic therapy. A statistically significant interaction between IHC quick score and treatment (P=0.001) showed ovarian ablation was more beneficial for patients with a positive quick score, whereas women with a quick score of 0 had a significantly higher risk of death with ovarian ablation (2.33; 95% CI: 1.30, 4.20). We have shown that IHC identifies women with ER 'poor' tumours for whom endocrine manipulation is not appropriate.

Journal Article↗
PubMed2002

Topotecan in combination with carboplatin: phase I trial evaluation of two treatment schedules.

BACKGROUND: Topotecan and cisplatin combinations have shown schedule-dependent toxicity, which may in part be due to cisplatin nephrotoxicity. As carboplatin is less nephrotoxic and increasingly replacing cisplatin in clinical practice, the aim of this study was to define the optimal sequence and dose for topotecan in combination with carboplatin. PATIENTS AND METHODS: Two parallel phase I trials, with pharmacokinetic studies, were conducted administering carboplatin on day 1 with topotecan on days 1-5 (schedule A) or days 8-12 (schedule B). repeated every 3 weeks. RESULTS: Twenty-one patients were treated over two dose levels, carboplatin AUC 4 [glomerular filtration rate (GFR) calculated from 51Cr-EDTA clearance] with topotecan 0.5 or 0.75 mg/m2. At the first dose level, six patients were evaluable for each schedule. With schedule A, from 34 cycles, there were two dose reductions and 10 treatment delays due to myelosuppression. With schedule B from 25 cycles, there was one reduction and 10 delays. At dose level 2, both patients in schedule A had dose-limiting neutropenia. In contrast, there was no dose-limiting toxicity with schedule B in six patients, although the majority of cycles were delayed. CONCLUSION: The combination of topotecan and carboplatin using these 3-weekly schedules lead to significant myelotoxicity with attendant dose reductions and delays; the optimal scheduling of these agents remains to be defined.

Adult↗
PubMed2001

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver.

PURPOSE: Although oral fluoropyrimidine prodrugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. METHOD: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m2) OGT 719. RESULTS: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. CONCLUSION: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Administration, Oral↗
PubMed2001

The oral fluorinated pyrimidines.

The fluorinated pyrimidines have played a major role in the treatment of many common tumors since 5-fluorouracil (5FU) was first introduced. Studies of the cellular and clinical pharmacology of 5FU have led to an improved understanding of the mechanisms of action of this agent. This knowledge has allowed the optimal and rational development of fluoropyrimidine therapy, with significant therapeutic advances in recent years. Efforts to improve the therapeutic index of 5FU have included alteration of schedule, and the addition of biochemical modulators such as folinic acid. Although protracted continuous infusion of 5FU has led to better response rates and decreased toxicity, the administration of 5FU by protracted infusion is not only costly, but also inconvenient to the patient. Furthermore it is often associated with infectious and thrombotic complications related to the required indwelling intravenous catheter. Protracted oral administration is a rational route for administering 5FU, being preferred by the patient and the pharmaco-economist. The unpredictable and low oral bioavailability of 5FU initially discouraged this form of treatment. This problem has now been overcome by the new generation of oral fluoropyrimidines. Two main strategies have been pursued: 1) The administration of an inactive prodrug of 5FU, which is absorbed intact, and subsequently converted to 5FU. Capecitabine is converted to 5FU by a 3 step enzymatic process. 2) The administration of 5FU with an inhibitor of dihydropyrimidine dehydrogenase (DPD) to minimise the erratic absorption and variable clearance of 5FU: the preparations UFT, S1, and ethinyluracil/5FU contain an oral fluoropyrimidine co-administered orally with inhibitors of this enzyme. The development and characteristics of these agents are discussed.

Administration, Oral↗
PubMed2001

Matrix metalloproteinase inhibitors: past lessons and future prospects in breast cancer.

The matrix metalloproteinases (MMPs) play a central role in invasion and metastasis. However, despite striking activity in preclinical models, the clinical development of the matrix metalloproteinase inhibitors (MMPIs) has been difficult. The results of important phase III trials are now emerging and it is therefore opportune to review the current state of the MMPIs. In this article the evidence for the role of MMPs in the progression of breast cancer, the development of the MMPIs and the recent phase III results are discussed. Despite the problems encountered it is hoped that the MMPIs may yet provide another mechanism for the long-term control of micrometastatic disease. Furthermore, important lessons can be learnt from their development that are relevant to the development of other biological agents.

Journal Article↗
PubMed2001

Prognostic factors in women with breast cancer: distribution by socioeconomic status and effect on differences in survival.

STUDY OBJECTIVE: To quantify and investigate differences in survival from breast cancer between women resident in affluent and deprived areas and define the contribution of underlying factors to this variation. DESIGN: Analysis of two datasets relating to breast cancer patients in Scotland: (1) population-based cancer registry data; (2) a subset of cancer registration records supplemented by abstraction of prognostic variables (stage, node status, tumour size, oestrogen receptor (ER) status, type of surgery, use of radiotherapy and use of adjuvant systemic therapy) from medical records. SETTING: Scotland. PATIENTS: (1) Cancer registration data on 21,751 women aged under 85 years diagnosed with primary breast cancer between 1978 and 1987; (2) national clinical audit data on 2035 women aged under 85 years diagnosed with primary breast cancer during 1987 for whom adequate medical records were available. MAIN RESULTS: Survival differences of 10% between affluent and deprived women were observed in both datasets, across all age groups. In the audit dataset, the distribution of ER status varied by deprivation group (65% ER positive in affluent group v 48% ER positive in deprived group; under 65 age group). Women aged under 65 with non-metastatic disease were more likely to have breast conservation than a mastectomy if they were affluent (45%) than deprived (32%); the affluent were more likely to receive endocrine therapy (65%) than the deprived (50%). However, these factors accounted for about 20% of the observed difference in survival between women resident in affluent and deprived areas. CONCLUSIONS: Deprived women with breast cancer have poorer outcomes than affluent women. This can only partly be explained by deprived women having more ER negative tumours than affluent women. Further research is required to identify other reasons for poorer outcomes in deprived women, with a view to reducing these survival differences.

Adult↗
PubMed2001

DNA: still a target worth aiming at? A review of new DNA-interactive agents.

DNA acts as the final target for most clinically effective cytotoxic agents, but the lack of selectivity for tumor cells has raised questions about the value of developing new DNA-interactive agents. Three new classes of cytotoxic agents are reviewed; each interacts directly with DNA but cytotoxicity appears to be mediated through novel mechanisms, including the interaction with specific proteins by DNA-bound drug molecules. Irofulven is the lead compound of the illudin family of molecules. It causes a novel type of DNA damage whose repair is dependent on functioning DNA helicases. Pre-clinical and clinical synergy between irofulven and agents which inhibit topoisomerases has been observed. Clinical trials with irofulven have shown significant activity and phase II studies in pancreatic, ovarian and prostatic cancer are ongoing. Toxicity in the form of myelosuppression and fatigue have been shown to be schedule dependent, with intermittent administration appearing to significantly reduce toxicity. DNA-interacting agents which alkylate bases exposed in the minor groove have been derived from a number of natural sources. The minor groove alkylation appears to be sequence specific; although the significance of this specificity for cytotoxicity is unclear, one proposed mechanism is through inhibition of expression of particular genes. Three cyclopropylpyrroloinole analogues which cause sequence specific minor groove alkylation are currently under clinical assessment. Myelosuppression is the dose limiting toxicity and is biphasic in its time course. Moderate activity in phase I trials has been observed. Ecteinascidins represent one of the increasing number of groups of drugs isolated from marine organisms. Ecteinascidin-743 (ET-743) is the most advanced in its clinical development. Binding to the minor groove of DNA occurs, although with a different base specificity from other compounds. The cytotoxic effects of ET-743 may occur by inhibition of the inducible transcription of a number of genes by sequestration of specific transcription factors. Clinical trials of ET-743 have shown significant activity, and phase II trials are underway in soft tissue sarcoma and breast cancer. Hepatic toxicity and myelosuppression are predictable and appear associated with peak plasma concentrations, whereas efficacy seems to be improved with prolonged infusion.

Alkylation↗