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Biomedical subjects

R C Leonard

Publications and source records attributed to R C Leonard.

At least 19 recordsLinked to original sources
PubMed1996

Definition and refinement of a region of loss of heterozygosity at 11q23.3-q24.3 in epithelial ovarian cancer associated with poor prognosis.

Previous cytogenetic and loss of heterozygosity (LOH) data suggest that disruption of chromosome 11q23-qter occurs frequently in epithelial ovarian cancer and is associated with an adverse clinicopathological phenotype. Ten polymorphic microsatellite repeat loci were analyzed by PCR from the 11q22-q25 region between D11S35 and D11S968 in 40 ovarian tumors (including 31 epithelial ovarian cancers). Two distinct regions of loss were detected, suggesting possible sites for genes involved in epithelial ovarian neoplasia: a large centromeric region between D11S35 and D11S933 (11q22-q23.3) and a telomeric 8.5-Mb region lying between D11S934 and D11S1320 (11q23.3-24.3) not previously defined. LOH of the latter region but not the former one was significantly associated with poor survival, despite all tumors in this study having LOH somewhere on chromosome 11. This analysis provides a starting point for positional cloning.

Carcinoma↗
PubMed1996

High-dose chemotherapy for breast cancer.

What can we conclude and hope to see in the next few years? Laboratory studies and imperfect retrospective analysis of conventional chemotherapy have created a climate of active interest to experiment with dose-intensive chemotherapy. There seems to be a consensus in favour of combination alkylating agents to maximise anticancer and rescuable antimarrow stem cell effects, whilst producing sublethal second-organ toxicity. PBPC has replaced ABMT as the routine rescue technique, on grounds of cost and recovery time. The mature results of this changed technology for support have yet to be seen in terms of the risks of late, poor engraftment and the potential benefits in terms of acute complications (faster engraftment) and tumour kill (reduced tumour contamination?). Whilst experiments continue to examine the impact of tumour contamination of blood harvests or BM harvests, inadequate attention has been paid in metastatic disease to patient selection. There seems to be a continuing growth of interest in multiple high-dose therapy regimens using stem cells collected earlier in the therapy to rescue sequential myeloablative treatments. This possibility has been realised by the stem cell technology and is being pursued with enthusiasm and with promising early results. Media-driven public interest in this increasingly political disease is pushing us to 'do more'. In future years, our worst nightmares may be realised if this means aping the experience of Halsted's disciples, "don't test, just believe"--the economic and human costs of high-dose treatment cannot justify our avoiding the rigorous examination of controlled trials.

Antineoplastic Agents↗
PubMed1996

The case for high-dose adjuvant chemotherapy in breast cancer: (II) clinical experience.

Recent Phase II studies on the use of myelo-ablative chemotherapy in breast cancer have confirmed that this approach is associated with low mortality and apparent efficacy. In a preceding article the theoretical arguments were presented for testing this approach in the high-risk adjuvant setting; in the current article the clinical data justifying the present approaches for this type of treatment are reviewed. The evidence suggests that peripheral blood stem cell supported myelo-ablative chemotherapy should be tested against conventional regimens in order to determine whether or not the increased expense and toxicity of such an approach is associated with improved survival for women whose axillary node status places them at high risk of disease relapse and subsequent death.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

The case for high-dose adjuvant chemotherapy in breast cancer: (I) theoretical considerations.

Adjuvant systemic therapy of breast cancer is now a well-established treatment resulting in improved survival. However, the available evidence suggests that it is most unlikely that an individual woman will be cured as a consequence of such treatment. There is, therefore, a pressing need for more effective therapy, particularly for younger women whose degree of axillary nodal involvement indicates a high risk of subsequent relapse. The case for using myelo-ablative chemotherapy for such women is presented in this article. In a subsequent publication we will discuss the clinical data to suggest that such an approach is not only possible with acceptable toxicity, but also could actually offer the increased cure rate sought by clinicians and patients alike.

Antineoplastic Agents↗
PubMed1996

Mathematical modelling of tumour response in primary breast cancer.

Although breast cancer is perceived to be relatively chemosensitive, cytotoxic drug therapy only leads to cure in the adjuvant setting. In advanced disease, primary resistance and inadequate cell kill may be important in determining the lack of a durable response to cytotoxics, but for an individual patient's tumour there is no consistent way of determining the importance of these two factors. An adaptation of Skipper's log cell kill model of tumour response to chemotherapy was applied to serial tumour measurements of 46 locally advanced primary breast carcinomas undergoing neoadjuvant chemotherapy. Assuming a log-normal distribution of errors in the clinically measured volumes, the model produced, for each tumour separately, in vivo estimates of proportional cell kill, initial resistance and tumour doubling times during therapy. After 4 weeks' treatment, these data could then be used to predict subsequent tumour volumes with good accuracy. In addition, for the 13 tumours that became operable after the neoadjuvant chemotherapy, there was a significant association between the final volume as predicted by the model and the final pathological volume (P < 0.05). This approach could be usefully employed to determine those tumours that are primarily resistant to the treatment regimen, permitting changes of therapy to more effective drugs at a time when the tumour is clinically responding but destined to progress.

Antineoplastic Agents↗
PubMed1996

Weekly doxorubicin and continuous infusional 5-fluorouracil for advanced breast cancer.

Drug scheduling alterations can improve the therapeutic index of both 5-fluorouracil and anthracyclines. We investigated a regimen of weekly doxorubicin and continuous infusional 5-fluorouracil (AcF) in loco-regionally recurrent and metastatic breast cancer. The aims of this phase II study were to use low-dose weekly anthracyclines in a patient group where liver metastases are a frequent problem, to optimise scheduling of 5-fluorouracil using continuous infusion and to conserve alkylating agent use for late intensification in responding patients. Fifty-six patients received 5-fluorouracil 200 mg m-2 day-1 and doxorubicin 20-30 mg m-2 week-1 for at least 6 weeks. Sixty-two percent were chemonaive. Patients were evaluated for dose intensity, response, toxicity and survival. Of the assessable patients, 76% achieved UICC response criteria (20% complete response, 56% partial response). WHO grade 3+ toxicities were: alopecia, 98%; mucositis, 62%; neutropenia, 22%; and grade 3 palmar-plantar syndrome, 24%. Median survival was 13 months, with visceral metastasis conferring a significantly worse outcome (P = 0.03). Grade 3+ mucositis was more frequent with planned doxorubicin dose intensity > or = 25 mg m-2 week-1 (P = 0.04). AcF is highly active in breast cancer with acceptable toxicities and can be used before alkylating agent-based high-dose therapy.

Adult↗
PubMed1996

High-dose chemotherapy supported by peripheral blood progenitor cells in poor prognosis metastatic breast cancer--phase I/II study. Edinburgh Breast Group.

Current treatments for metastatic breast cancer are not associated with significant survival benefits despite response rates of over 50%. High-dose therapy with autologous bone marrow transplantation (ABMT) has been investigated, particularly in North America, and prolonged survival in up to 25% of women has been reported, but with a significant treatment-related mortality. However, in patients with haematological malignancies undergoing autologous transplantation, haematopoietic reconstruction is significantly quicker and mortality lower than with ABMT, when peripheral blood progenitor cells (PBPCs) are used. In 32 women with metastatic breast cancer, we investigated the feasibility of PBPC mobilisation with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) after 12 weeks' infusional induction chemotherapy and the subsequent efficacy of the haematopoietic reconstitution after conditioning with melphalan and either etoposide or thiotepa. PBPC mobilisation was successful in 28/32 (88%) patients, and there was a rapid post-transplantation haematopoietic recovery: median time to neutrophils > 0.5 x 10(9) l-1 was 14 days and to platelets > 20 x 10(9) l-1 was 10 days. There was no procedure-related mortality, and the major morbidity was mucositis (WHO grade 3-4) in 18/32 patients (56%). In a patient group of which the majority had very poor prognostic features, the median survival from start of induction chemotherapy was 15 months. Thus, PBPC mobilisation and support of high-dose chemotherapy is feasible after infusional induction chemotherapy for patients with metastatic breast cancer, although the optimum drug combination has not yet been determined.

Adult↗
PubMed1996

Pharmacokinetics, metabolism and tumour disposition of 8-chloroadenosine 3',5'-monophosphate in breast cancer patients and xenograft bearing mice.

BACKGROUND: 8-Chloroadenosine 3',5'-monophosphate (8-Cl-cAMP) is undergoing phase I clinical trials as an anticancer drug. However, there is debate as to whether it is a prodrug for its 8-Cl-adenosine metabolite. DESIGN: Pharmacokinetics, metabolism and tumour disposition studies have been performed in 7 breast cancer patients receiving continuous infusion (28 day) 8-Cl-cAMP (0.54 or 1.08 mg/kg/day) and tumour biopsies were obtained before and on the last day of infusion. Parallel studies were performed in nude mice bearing the HT29 human colon cancer xenograft after continuous infusion (7 day) of active drug doses (50 or 100 mg/kg/day). RESULTS: Steady state plasma levels (Css) of 8-Cl-cAMP in patients ranged from 0.15-0.72 microM but 8-Cl-adenosine was not detected in plasma. In contrast, 8-Cl-cAMP was not detectable in 3 tumour biopsies but 8-Cl-adenosine was present in 2 samples at high concentrations (1.33 and 2.02 microM). In mice, Css of 8-Cl-cAMP ranged from 3.2-4.6 microM and 8-Cl adenosine was present in plasma only at the higher dose (100 mg/kg/day, peak concentration of 2.3 microM). In the HT29 xenograft, 8-Cl-cAMP levels were considerably lower than in plasma (0.37-1.22 microM) while 8-Cl-adenosine was present at 5.3-21.0 microM and 8-Cl-AMP was found at 11.3-35.7 microM. CONCLUSIONS: The fate of 8-Cl-cAMP in human tumours is characterised by extensive metabolism to products which are not generally observed in plasma. These data raise the possibility that 8-Cl-cAMP is a prodrug for a product of its metabolism in human tumours.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

A pilot study of infusional CMF (CMF-inf): active and well tolerated in breast cancer. The Edinburgh Breast Group.

BACKGROUND: We have previously shown that 5-fluorouracil (5-FU) given by continuous infusion is well tolerated and active in the treatment of breast cancer [1, 2]. We found that given infusional 5-FU could produce responses in patients whose disease was resistant to bolus 5-FU and speculated that it could be combined safely with methotrexate/cyclophosphamide in a manner analogous to i.v. CMF bolus. Using a modification of the i.v. CMF regimen, comprising a standard dosage of bolus cyclophosphamide at 750 mg/m2 and bolus methotrexate at 50 mg/m2 given every 3 weeks we altered the continuously infused 5-FU schedule to 200 mg/m2/24 hours and treated 28 patients of whom 23 had had previous chemotherapy (18 containing anthracycline, 4 bolus CMF and 19 infusional 5-FU alone or in combination with other drugs) and 4 post menopausal patients with locally advanced breast cancer. RESULTS: Fourteen responded (2 CR, 12 PR) out of 27 evaluable patients with onset of response between 3 and 9 weeks. Toxicity was relatively mild in the 28 evaluable patients and did not require cessation of treatment, with one exception (vomiting leading to dehydration at home and moderate transient uraemia). The main toxicities seen were WHO grade 3 neutropenia in 13/28 patients and grade 2 mucositis in 2 further patients. Grade 2 palmar/planter syndrome was reported in 4/28 patients and grade 2 or 3 nausea/vomiting was reported in 7/28 patients. CONCLUSION: This well tolerated regimen is clearly active in patients with heavily pretreated breast cancer and should be tested against intravenous or classical CMF in a randomised trial.

Adult↗
PubMed1996

High dose chemotherapy for breast cancer: the case for trials in adjuvant therapy.

Adjuvant polychemotherapy reduces the annual mortality for breast cancer, the effect being seen for at least the first decade after primary treatment for stage II disease. However, the overall benefit is modest with an annual reduction in the odds of death of the order of 20%-30%. For patients at standard or low risk of recurrence this appears to be an acceptable benefit given low toxicity of treatment. However, some patients have a very much worse prognosis identifiable on the basis of the number of involved axillary nodes at surgery. Patients with more than 10 lymph nodes, for example, have a predicted survival of less than 30% at 5 years and around 10% at 10 years. High dose chemotherapy has shown immediate benefits in terms of complete response rates in advanced breast cancer. Potential benefits of this treatment could be even higher in the adjuvant setting given the patient's fitness and the fact that micrometastatic disease represents the best clinical analogue of the successful laboratory experimental conditions. Now that the safety factors appear to be favourable with a treatment-related mortality of less than 5% it would appear that stage II poor risk disease is an appropriate setting to test high dose chemotherapy against the best conventional therapy in randomized trials.

Antineoplastic Agents↗
PubMed1995

Prospective randomized study of surgical morbidity following primary systemic therapy for breast cancer.

The influence of primary systemic therapy in treating operable breast cancer on postmastectomy morbidity rates was investigated. The contribution of other risk factors was assessed by multiple logistic regression. Seventy-nine eligible patients were randomly allocated, 39 to undergo immediate modified radical mastectomy, and 40 to receive initial cytotoxic or endocrine treatment followed by mastectomy. Postoperative wound seroma, infection and necrosis were recorded prospectively. Fourteen minor and six major complications occurred in 17 patients treated conventionally, while 14 patients developed 11 minor and six major complications after systemic therapy (P > 0.4). Median hospital stay was 8 days for both groups. Age, smoking, immediate breast reconstruction and the type of primary systemic treatment given were not independent predictors of complication risk. Obesity emerged as a significant risk factor for postmastectomy complications (P = 0.015). Primary systemic therapy does not increase the rate of morbidity after mastectomy.

Adult↗
PubMed1995

Chromosome 11 allele imbalance and clinicopathological correlates in ovarian tumours.

Allele imbalance on chromosome 11 loci in ovarian cancer is a frequent event, suggesting the presence of tumour-suppressor genes for ovarian carcinogenesis on this chromosome. Ten highly polymorphic (CA) repeat microsatellites were used to determine allele imbalance in 60 primary ovarian tumours, including 47 epithelial ovarian cancers (EOCs). Forty EOCs (85%) showed allele imbalance at one or more loci, and in 39 of these (83%) the data suggested subchromosomal deletions: eight of 11p only; six of 11q only; and 25 of both 11p and 11q. Three consensus regions of deletion were indicated at 11p15.5-p15.3, 11q12-q22 and 11q23.3-q24.1. Allele imbalance at the 11q subtelomeric region (D11S912) correlated significantly with adverse survival, while imbalance at 11q14.3 and retention of heterozygosity at 11q22 (close to the site of the progesterone receptor gene) were associated with favourable clinicopathological features. The findings allow development of a preliminary model for the molecular evolution of epithelial ovarian cancer.

Adenocarcinoma↗
PubMed1995

The importance of dose and schedule in cancer chemotherapy: breast cancer.

For a variety of reasons, sociopolitical as well as biological, breast cancer therapy has become an area of great public and professional interest over the last decade. Studies in the US have focused on intensive and high-dose chemotherapy, both in advanced and in high-risk adjuvant settings. In the UK more attention has been paid to primary medical therapy and lessons have been learned on the value of scheduling as well as dose. With peripheral blood stem cell transplantation technology established we are now in a position to examine intensive chemotherapy in high-risk and in advanced disease and must take the opportunity to establish its relative benefit in randomised clinical trials.

Antineoplastic Agents↗