R C Leonard

Western General Hospital, Edinburgh, Scotland, United Kingdom

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Publications (124)690.15 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of 'ifosfamide at a dose of 9g/m2 over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M18F) with a median age of 28 years (range 13–45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and 61 months. Median overall survival for the whole group is 36 months. Hae-matological toxicity, particularly neutropenia (WHO grade IV), was observed in all cases but improved over the 3 courses of treatment in all patients. Non-haematological toxicity was not a major problem; no significant cardiac, hepatic, renal, pulmonary or neuro toxicity was observed and there were no deaths on treatment. This regime shows promise in patients with diffcult Hodgkin's disease and warrants further study.
    Leukemia & Lymphoma. 07/2009; 37(5-6).
  • R. J. Prescott, R. C. F. Leonard
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    ABSTRACT: This report compares a pilot study followed by a trial of the combination of mitozantrone and ifosfamide for relapsed lymphoma. In the pilot study (15 patients) toxicity and activity of the combination was tested on a variety of relapsed non-Hodgkin's lymphoma. In the trial (19 patients) the therapy was confined to patients with high and intermediate grade non-Hodgkin's lymphoma in which the combination was compared against single agent mitozantrone. The median survival of patients on the pilot and trial was very poor at around six months, but some individuals survived for several years from both groups. The main toxicities of treatment were, predictably, nausea and vomiting and bone marrow suppression on the combination, and bone marrow suppression alone on the single agent mitozantrone. There was no obvious disadvantage of the single agent treatment when compared with the combination, but this statement has to be interpreted with caution given the high death rate amongst all patients and the very small numbers who entered the randomised trial.
    Leukemia & Lymphoma. 07/2009; 11(1-2).
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    ABSTRACT: Follicular lymphoma is often seen as an indolent disease with a reasonable medium-term survival. We have used the information in the Scotland and Newcastle Lymphoma Group database to devise an index which is easily calculated and differentiates patients into poor, intermediate and good prognostic groups with 5 year survivals of 24%, 61% and 86% respectively. The key factors at presentation are age, ECOG performance status, stage and the presence or absence of B symptoms or gastro-intestinal tract involvement. The use of such an index permits early identification of patients with a poor prognosis for whom more intensive treatment could be offered.
    Leukemia & Lymphoma. 07/2009; 10(1-2).
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    ABSTRACT: Exemestane is a potent steroidal aromatase inhibitor (AI) with activity in post-menopausal women with metastatic breast cancer, with a reported clinical benefit (CB) rate of 24.3% after prior AI therapy. Data on 114 patients (112 female, 2 male) were obtained retrospectively at two cancer centres. Sixty-five percent of patients were confirmed as oestrogen receptor (ER) positive. All patients had received prior third-generation AI therapy. Responses were seen in 5% and the overall CB rate (CR+PR+SD24 weeks) was 46%. Median PFS and OS were 18 and 61 weeks, respectively. In patients with visceral disease, the CBR was 33%. Patients with known ER-positive disease had a CBR of 47%, and a median TTP of 19 weeks. No benefit was seen in patients with known ER-negative disease. Survival was better in those with CB (median survival not reached in those with CB, 28 weeks in those without CB P<0.0001). Efficacy persisted in those patients who had received 3 prior lines of hormonal therapy, including adjuvant treatment. These data confirm exemestane to be an effective therapy after third-generation non-steroidal AI in post-menopausal ER-positive metastatic breast cancer, including visceral disease.
    The Breast 06/2006; 15(3):430-6. · 2.49 Impact Factor
  • Breast. 01/2003; 12.
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    ABSTRACT: Mutation of the p53 tumor suppressor gene is the most commonly observed genetic abnormality in human tumors and associations between p53 aberration and patient survival have been shown for several tumor types. Previous studies have found that approximately 50% of epithelial ovarian carcinomas exhibit abnormalities in the p53 gene. The aim of this study, therefore, was to examine the potential prognostic significance of aberrant p53 in patients with primary epithelial ovarian carcinoma. Using immunohistochemistry (IHC) and the anti-p53 antibodies CM1, PAb240 and PAb1801, p53 over-expression was observed in 20/39 (51%) tumors. When these results were combined with previously reported IHC and sequencing analyses, 37/61 (61%) tumors exhibited a p53 aberration. Although there was no significant difference between sequencing and IHC results, several cases gave discordant results, indicating that a combination of both methods may be required to estimate accurately the proportion of tumors with p53 aberrations. Univariate statistical analysis showed that p53 aberrations were significantly associated with tumor grade 3/4, FIGO stage III/IV, serous tumors and the presence of bulk (>2 cm) residual disease following surgery. In univariate survival analysis, tumor grade and stage, ascites and post-surgical residual tumor> 2 cm were associated with both overall survival (OS) and disease-free survival (DFS). p53 status, however, was not a predictor of either OS or DFS. Using the Cox proportional hazards model, only FIGO stage and post-surgical residual disease> 2 cm had an independent effect on OS and only stage was found to be an independent predictor of DFS. In conclusion, p53 mutation and overexpression does not appear to be a significant indicator of patient survival in this series of ovarian carcinomas.
    International Journal of Gynecological Cancer 02/2002; 6(6):483 - 490. · 1.94 Impact Factor
  • D.A. Cameron, C. Massie, G. Kerr, R.C.F. Leonard
    European Journal of Cancer 01/2002; 38. · 5.06 Impact Factor
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    ABSTRACT: One hundred and seven patients (61 with diffuse large B-cell non-Hodgkin's lymphomas and 46 with Hodgkin's disease) in relapse or following of primary therapy received ifosfamide 3 g/m2 i.v. daily for 3 days in combination with epirubicin 50 mg/m2 i.v. day 1 and etoposide 200 mg/m2 i.v. days 1-3. Of the 46 patients with Hodgkin's disease (28 male, 18 female, and a median age of 28 years) 85% of patients had a response to treatment, with 17 achieving complete remission and 11 good partial remission. Twenty-eight proceeded to autologous bone marrow or peripheral blood stem cell transplantation. Twenty-three patients remain alive in continuous remission with a follow-up of 12-61 months. The median overall survival time for all patients in this group is 36 months. Haematological toxicity, particularly WHO Grade IV neutropenia, occurred in all patients but improved over the three courses of treatment. There was no major non-haematological toxicity. Further trials of this regimen in this clinical situation are indicated. The patients with non-Hodgkin's lymphomas in this study had diffuse large B-cell lymphomas and had only received first-line treatment. Twenty had primarily refractory disease, 15 had only achieved partial remissions (PR), and 26 had developed relapse following primary treatment. The overall response rate was 43%; it was 60% for those who had achieved initial PR, 58% for those in relapse after an initial CR or very good PR following initial therapy, but only 10% for those with primarily refractory disease. Tolerance to the regimen was similar to that observed in treatment of the patients with Hodgkin's disease and many were able to undergo stem cell collection, following mobilization with this regimen. The 2-year overall survival result was 22% for patients with some response to first-line treatment but 0% for primary refractory patients.
    European journal of haematology. Supplementum 08/2001; 64:28-32.
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    Journal of Clinical Oncology 06/2001; 19(10):2767. · 18.04 Impact Factor
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    ABSTRACT: To investigate the efficacy of letrozole 2.5 mg and 10 mg used as primary neoadjuvant therapy for patients with locally advanced and large operable breast cancer. Twenty-four postmenopausal patients with locally advanced or large operable breast cancer were treated in two consecutive series with letrozole 2.5 mg (n = 12) or letrozole 10 mg (n = 12). Response at three months was measured by change in tumor volume according to WHO criteria (partial response was defined as a reduction in tumor volume > or = 65%). Tumor volumes were assessed clinically, by ultrasound and mammography, and pathologically. All 24 patients were estrogen receptor-positive, were considered 'receptor-rich', and mean age was 77.6 years and 71.6 years in the letrozole 2.5 mg and 10 mg treatment groups, respectively. There were five complete clinical responses and seven partial clinical responses in the patients treated with 2.5 mg letrozole, and nine partial responses and three patients with stable disease in patients treated with 10 mg letrozole. Assessed by ultrasound and mammography, the 12 patients treated with 2.5 mg had one complete response, nine partial responses and two with no change. In the 12 patients treated with 10 mg letrozole, imaging gave eight partial responses and four with no change. One patient treated with the 2.5 mg dose had a complete clinical and pathological response. There was no significant difference between the two doses in effect on tumor volume, and no recordable side effects associated with either dose. Letrozole used in a neoadjuvant setting is highly effective, producing clinically beneficial reductions in tumor volume allowing all patients to have breast conserving surgery, and has an acceptable safety profile.
    Breast Cancer Research and Treatment 04/2001; 66(3):191-9. · 4.47 Impact Factor
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    ABSTRACT: Although clinical response to primary chemotherapy in stage II and III breast cancer is associated with a survival advantage, it is the degree of pathological response in the breast and ipsilateral axilla that best identifies patients with a good long-term outcome. A mathematical model of the initial response of 39 locally advanced tumours to anthracycline-based primary chemotherapy has been previously shown to predict subsequent clinical tumour size. This model allows for the possibility of primary resistant disease, the presence of which should therefore be associated with a worse outcome. This study reports the application of this model to an additional five patients with locally advanced breast cancer, as well as to 63 patients with operable breast cancer, and confirms the biological reality of the model parameters for these 100 breast cancers treated with primary anthracycline-based chemotherapy. The tumours that responded to chemotherapy had higher cell-kill (P < 0.0005), lower resistance (P < 0.0001) and slower tumour regrowth (P < 0.002). Furthermore, ER-negative tumours had higher cell-kill (P < 0.05), as compared with ER-positive tumours. All patients with a pathological complete response had zero resistance according to the model. Furthermore, the long-term implication of chemo-resistant disease was demonstrated by survival analysis of these two groups of patients. At a median follow-up of 3.7 years, there was a statistically significantly worse survival for the 37 patients with locally advanced breast cancer identified by the model to have more than 8% primary resistant tumour (P < 0.003). The specificity of this putative prognostic indicator was confirmed in the 63 patients presenting with operable disease where, at a median follow-up of 7.7 years, those women with a resistant fraction of greater than 8% had a significantly worse survival (P < 0.05). Application of this model to patients treated with neoadjuvant chemotherapy may allow earlier identification of clinically significant resistance and permit intervention with alternative non-cross-resistant therapies such as taxoids.
    British Journal of Cancer 08/2000; 83(1):98-103. · 5.08 Impact Factor
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    ABSTRACT: Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of ïfosfamide at a dose of 9g/m(2) over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M:18F) with a median age of 28 years (range 13-45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and 61 months. Median overall survival for the whole group is 36 months. Haematological toxicity, particularly neutropenia (WHO grade IV), was observed in all cases but improved over the 3 courses of treatment in all patients. Non-haematological toxicity was not a major problem; no significant cardiac, hepatic, renal, pulmonary or neuro toxicity was observed and there were no deaths on treatment. This regime shows promise in patients with difficult Hodgkin's disease and warrants further study.
    Leukemia and Lymphoma 06/2000; 37(5-6):561-70. · 2.61 Impact Factor
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    ABSTRACT: Between October 1993 and September 1994, 33 women with metastatic breast cancer aged between 29 and 74 years with a median age of 58 were entered into a study of oral chemotherapy from three UK centres. Patients by definition had metastatic disease and were fit and well with performance status 0 or 1 in 23 cases, 2 in seven cases and 3 in two cases (one missing). Five patients had received prior adjuvant CMF chemotherapy, nine first line non-anthracycline containing chemotherapy for relapse, eight patients second line non-anthracycline containing chemotherapy and all patients had had hormone therapy either as adjuvant or for relapsed disease. Adjuvant radiotherapy had been given to 17 and palliative radiotherapy to 12 patients. In nine patients there was one site of disease at start of therapy, in 10 two sites, in 11 three sites and in three patients four or more sites. The regimen comprised oral idarubicin 15 mg/m2 on day 1, 10 mg/m2 on days 2 and 3 and oral cyclophosphamide 250 mg/m2 (maximum 400 mg) on days 1, 2 and 3. Treatment was continued until disease progression or toxicity. RESULTS: Overall 25% of 32 evaluable patients responded objectively including one complete response; 50% of patients had stable disease and 25% of patients progression. Among patients who had had no prior chemotherapy the objective response rate was 37.5%; 45% of patients had symptomatic improvement. The most common severe toxicity was granulocytopenia WHO grade 3 or more in 69.7% of patients. Thrombocytopenia grade 3 or 4 was seen in four patients. Six patients had documented infections and all but four patients had alopecia. All patients complained of mild or moderate fatigue. Nausea and vomiting occurred in 75% of patients but only four individuals had grade 3 toxicity. Two patients stopped therapy after myocardial infarction and one after impaired cardiac function was noted. The median time to progression was 2.7 months (1-11.5 months) and median survival time 8.8 months (1-13+ months). CONCLUSION: The combination chemotherapy is active in heavily treated patients with manageable toxicity but there are problems in heavily pre-treated patients. There was good compliance in taking medication and at the doses chosen the drugs appear to be suitable for younger fitter patients.
    Critical Reviews in Oncology/Hematology 02/2000; 33(1):61-6. · 4.64 Impact Factor
  • Leonard RC, Howell A
    Advances in Breast Cancer 01/2000; 2::2-4,.
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    ABSTRACT: Tamoxifen is the most commonly prescribed adjuvant therapy for women with breast cancer. It has agonist activity on the endometrium and is associated with an increased risk of endometrial cancer. The aim of this study was to evaluate whether screening with transvaginal ultrasound (TV USS) with or without hysteroscopy is worthwhile. A total of 487 women with breast cancer, 357 treated with tamoxifen and 130 controls, were screened with TV USS, and endometrial thickness was measured. Women with thickened endometrium underwent outpatient hysteroscopy. Length of time on tamoxifen ranged from 5 to 191 months (mean, 66 months), and endometrial thickness ranged from 1 to 38 mm (mean, 7.3 mm). Women treated with tamoxifen had significantly thicker endometrium than did controls (P <.0001). There was a statistically significant (P <.0001) positive correlation between length of time on tamoxifen and endometrial thickness. One hundred forty-five women had endometrium greater than 5 mm on USS, and 134 underwent successful outpatient hysteroscopy, 61 of whom had atrophic endometrium, resulting in a 46% false-positive scan rate. The remaining women all had benign features to explain the USS findings. TV USS detects a high incidence (41%) of apparent endometrial thickening in women treated with tamoxifen, although 46% had atrophic endometrium on further assessment, and none of the remaining asymptomatic women had significant lesions. Length of time on tamoxifen relates to endometrial thickening as measured by TV USS. TV USS is a poor screening tool because of the high false-positive rate. The low frequency of significant findings suggests that endometrial screening in asymptomatic women is not worthwhile.
    Journal of Clinical Oncology 07/1999; 17(7):2050-4. · 18.04 Impact Factor
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    ABSTRACT: Over a 5-year period, 75 patients with locally advanced breast cancer presenting to the Edinburgh Breast Unit were managed with a policy of infusional primary chemotherapy. For 65 patients, the regimens comprised infusional 5 fluorouracil with anthracycline and/or either cyclophosphamide or cisplatinum (AcF, CAF or ECF) whilst 10 older patients had CMF-inf. The overall activity and tolerability for the regimens was good with a 76% objective response rate including 15% clinical complete responses. Surgery was possible in 64% and pathological complete responses confirmed in 7 (9.3%). Median disease free survival (DFS) is 5.23 years. Factors predicting for DFS or Overall Survival (OS) were assessed in this small group and ER positive patients did better than ER negative although there was surprisingly no negative DFS or OS association with inflammatory disease or advancing age. We found a paradoxical interaction with use of post-chemotherapy tamoxifen which was significantly associated with poorer DFS and OS overall and in the ER negative subgroups.
    The Breast 07/1999; 8(3):110-5. · 2.49 Impact Factor
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    ABSTRACT: Postmenopausal patients with oestrogen receptor-positive locally advanced T4b, N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients), 1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There was no apparent difference in response rate between 2.5 and 10 mg letrozole. Only 17 patients with anastrozole have so far completed the 3-month treatment period. Median clinical, mammographic and ultrasound reductions in tumour volumes for patients treated with letrozole were 81% (95% confidence interval (CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI 52-76) respectively. This compares with a median reduction in tumour volume for tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48). There were seven complete clinical responses (CR), sixteen patients who achieved 50% or greater reduction in tumour volume (PR) and one no change (NC) for letrozole and four CRs, twelve PRs and one progressive disease for anastrozole. Best radiological responses were one CR, twenty PRs and three NCs for letrozole and one CR, fifteen PRs and one NC for anastrozole. This study has shown that the new aromatase inhibitors, letrozole and anastrozole, are highly effective agents in the neoadjuvant setting and they should now be compared with tamoxifen as first-line treatment in a randomised study.
    Endocrine Related Cancer 07/1999; 6(2):227-30. · 5.26 Impact Factor
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    ABSTRACT: This study was designed to evaluate new bone resorption and tumour markers as possible alternatives to serial plain radiographs for the assessment of response to treatment. Thirty-seven patients with newly diagnosed bone metastases from breast cancer, randomized to receive oral pamidronate or placebo tablets in addition to anticancer treatment within the context of a multicentre EORTC trial, who were both assessable for radiographic response in bone and had serum and urine samples collected for more than 1 month were studied. The markers of bone metabolism measured included urinary calcium (uCa), hydroxyproline (hyp), the N-telopeptide cross-links of type I collagen (NTx) and total alkaline phosphatase. The tumour markers measured were CA15-3 and cancer-associated serum antigen (CASA). Before treatment, levels of Ntx, uCa and Hyp were elevated in 41%, 24% and 28% respectively, and CA15-3 and CASA increased in 69% and 50%. For assessment of response and identification of progression, Ntx was the most useful bone marker. All markers behaved similarly in no change (NC) and partial response (PR) patients. There was a significant difference (P < or = 0.05) in Ntx levels (compared to baseline) at 1 and 4 months and in CA15-3/CASA at 4 months between patients with PR or NC and those with progressive disease (PD), and at 4 months between those with time to progression (TP) > 7 and those with TP < or = 7 months. The diagnostic efficiency (DE) for prediction of PD following a > 50% increase in Ntx or CA15-3 was 78% and 62% respectively. An algorithm to predict response to therapy has been developed for future prospective evaluation.
    British Journal of Cancer 04/1999; 80(1-2):221-8. · 5.08 Impact Factor
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    ABSTRACT: 8-Chloroadenosine-3',5'-monophosphate (8-ClcAMP) is a novel antitumour agent currently undergoing phase I clinical trials in several European centres. In this study, its antitumour activity against human tumour xenografts and its dependence on schedule were investigated. When administered by continuous infusion at doses of 100 or 50 mg/kg/day to nude mice bearing human tumour xenografts, 8-ClcAMP inhibited the growth of the HT 29 colorectal, ZR-75-1 breast, HOX 60 and PE04 ovarian and PANC-1 pancreatic carcinoma xenografts. However, these infusion schedules produced hypercalcaemia and severe weight loss. In an attempt to optimise antitumour activity and minimise toxicity, several other schedules were studied. In comparison with continuous administration of 8-ClcAMP at 50 mg/kg/day for 14 days which, although producing complete growth inhibition in the HOX 60 model, was associated with a marked body weight loss, schedules in which the infusion was interrupted (infusion on either days 0-4; 7-11 or days 0-2; 6-8) produced minimal weight loss but also reduced antitumour activity. However, co-administration of salmon calcitonin with continuous infusion of 8-ClcAMP prevented both hypercalcaemia and body weight loss in 3/6 animals while still producing marked inhibition of tumour growth. These data indicate that 8-ClcAMP has broad-spectrum antitumour activity and the major side-effect of hypercalcaemia may at least in part be ameliorated by the use of salmon calcitonin.
    European Journal of Cancer 03/1998; 34(3):384-8. · 5.06 Impact Factor
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    BMJ Clinical Research 10/1997; 315(7111):811-2. · 14.09 Impact Factor

Publication Stats

2k Citations
690.15 Total Impact Points

Institutions

  • 1984–2009
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 2001
    • University of Franche-Comté
      Becoinson, Franche-Comté, France
  • 1990–1993
    • The University of Edinburgh
      • • Division of Health Sciences
      • • Division of Pathology
      Edinburgh, SCT, United Kingdom