Search PubMed⌕ Search

Biomedical subjects

J W Leer

Publications and source records attributed to J W Leer.

At least 19 recordsLinked to original sources
PubMed2004

Guidelines for the infrastructure of training institutes and teaching departments for radiotherapy in Europe.

AIM: To develop guidelines for the infrastructure of training institutes and teaching departments for medical specialist training in radiotherapy within Europe. MATERIAL AND METHODS: Guidelines for teaching departments were developed under consideration of the updated European Core Curriculum for Radiotherapists (Radiation Oncologists) by an expert panel jointly appointed by the European Union of Medical Specialists and the European Society of Therapeutic Radiology and Oncology. The group approached national professional and scientific societies for information on national requirements for teaching departments. Based on this information, a draft document was circulated among the national and professional societies for radiotherapy in Europe for review before a European consensus conference took place in Brussels in December 2002. RESULTS: The guidelines for the infrastructure of training institutes and teaching departments for medical specialist training in radiotherapy within Europe were endorsed by representatives of 35 European nations during the Brussels consensus conference on December 14, 2002. CONCLUSION: The infrastructure guidelines represent an important instrument that can be used by teaching departments for comparison of their situation with that of other departments in Europe as a basis for negotiations with authorities on resources provided for training.

Clinical Competence↗
PubMed2001

Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.

BACKGROUND: Short-term preoperative radiotherapy and total mesorectal excision have each been shown to improve local control of disease in patients with resectable rectal cancer. We conducted a multicenter, randomized trial to determine whether the addition of preoperative radiotherapy increases the benefit of total mesorectal excision. METHODS: We randomly assigned 1861 patients with resectable rectal cancer either to preoperative radiotherapy (5 Gy on each of five days) followed by total mesorectal excision (924 patients) or to total mesorectal excision alone (937 patients). The trial was conducted with the use of standardization and quality-control measures to ensure the consistency of the radiotherapy, surgery, and pathological techniques. RESULTS: Of the 1861 patients randomly assigned to one of the two treatment groups, 1805 were eligible to participate. The overall rate of survival at two years among the eligible patients was 82.0 percent in the group assigned to both radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone (P=0.84). Among the 1748 patients who underwent a macroscopically complete local resection, the rate of local recurrence at two years was 5.3 percent. The rate of local recurrence at two years was 2.4 percent in the radiotherapy-plus-surgery group and 8.2 percent in the surgery-only group (P<0.001). CONCLUSIONS: Short-term preoperative radiotherapy reduces the risk of local recurrence in patients with rectal cancer who undergo a standardized total mesorectal excision.

Adenocarcinoma↗
PubMed2001

Isolated late local recurrences with high mitotic count and early local recurrences following breast-conserving therapy are associated with increased risk on distant metastasis.

PURPOSE: Local recurrence (LR) after breast-conserving therapy (BCT) is associated with an increased risk for the development of distant metastasis. We studied risk factors for distant metastasis risk (DMR) and poor prognosis within a group of patients with LR as first event. PATIENTS AND METHODS: From a cohort of 1481 breast carcinomas treated with BCT in the period 1980-1994, a total of 68 pT1-3 N0-1 patients developed LR as first event. We have studied risk factors for the development of distant metastasis within this group of patients with LR. In addition to clinical factors (age at BCT and LR, mode of detection, location of LR, and treatment of LR), the histology slides of the primary and the recurrent tumor were reviewed. Immunohistochemical staining was performed for the following proteins: bcl-2, cyclin D1, E-cadherin, EGF receptor, ER, PR, Ki-67, c-erbB-2/neu, and p53. Statistical analyses were performed using conditional logistic regression. RESULTS: At a median follow-up after LR of 5.6 years, the 5-year DMR was 53%. In univariate analysis, none of the factors of the primary tumor was found to be associated with DMR after LR. Of the recurrent tumor the following factors were found to be risk factors for high DMR after LR: interval between treatment of the primary tumor and LR at 2 years or less (relative risk, 2.38; 95% confidence interval, 1.22-4.76; p = 0.008) and high mitotic count (relative risk, 2.51; 95% confidence interval, 1.03-6.15; p = 0.04). All patients with noninvasive recurrent tumor were alive at the time of analysis. Patients with an interval of greater than 2 years and a recurrent tumor with high mitotic count were found to have an equally poor prognosis compared to patients with LRs detected after a short interval. CONCLUSION: LR after BCT is associated with higher DMR and poor prognosis. Patients with LR within 2 years after BCT are especially at high risk. Late recurrences with high mitotic count have the same poor prognosis as early recurrences. For these patients, systemic treatment at time of the detection of LR should be considered.

Analysis of Variance↗
PubMed2001

No downstaging after short-term preoperative radiotherapy in rectal cancer patients.

PURPOSE: In retrospective studies, total mesorectal excision (TME) surgery has been demonstrated to result in a reduction in the number of local recurrences of rectal cancer. Reports on improved local control after preoperative, hypofractionated radiotherapy have led to the introduction of a randomized multicenter trial to evaluate the effect of TME surgery with and without preoperative radiotherapy. Treatment with preoperative radiotherapy might have an effect on the pathologic characteristics that determine staging of rectal cancer. We investigated the occurrence of downstaging in rectal cancer patients treated with and without preoperative radiotherapy. PATIENTS AND METHODS: We analyzed the differences in tumor size, number of examined lymph nodes, tumor-node-metastasis stage, and histopathologic features in 1,321 patients entered onto a randomized trial. The trial compared preoperative radiotherapy (5 x 5 Gy) followed by TME surgery with TME surgery alone. Patients who had an interval of more than 10 days between the start of radiotherapy and surgery were excluded from analysis. RESULTS: Differences were observed in tumor size (P <.001) and total number of examined lymph nodes (P <.001). No difference in tumor or node classification was detected. The irradiated group demonstrated more poorly differentiated tumors as well as more mucinous tumors. CONCLUSION: In rectal cancer patients, short-term, preoperative radiotherapy with 5 x 5 Gy does not lead to downstaging if the interval between the start of radiotherapy and surgery does not exceed 10 days.

Adult↗
PubMed2001

Circulating atrial natriuretic peptide plasma levels as a marker for cardiac damage after radiotherapy.

PURPOSE: To investigate whether plasma concentrations of atrial natriuretic peptide (ANP) could be used to identify patients with radiation mediated cardiac dysfunction. MATERIALS AND METHODS: Circulating levels of ANP were measured in patients who have been irradiated on a large part of the heart (50-80%; Hodgkin's disease) or smaller part of the heart (20-30%; primary breast cancer). C-terminal ANP was determined by radioimmunoassay (RIA) using a commercial kit. RESULTS: In this study ANP plasma levels of 121 patients (Hodgkin's disease, 73 patients; breast cancer, 48 patients) and 67 controls were examined. ANP plasma levels of both Hodgkin patients (28.8+/-2.2, P=0.003) and breast cancer patients (20.4+/-2.8 ng/l, P=0.01) were significantly elevated when compared to age-matched controls (13.5+/-1.2 ng/l). Both for the Hodgkin (R=0.42, P=0.05) and breast cancer group (R=0.50, P=0.09) a positive relation between ANP plasma values and age was found. However, no clear relation between ANP plasma levels and time post treatment could be demonstrated. Patients with clinical symptoms of cardiovascular disease (n=25) had significantly higher ANP plasma levels (P<0.001) compared to patients in the same treatment group without evidence of cardiac disease (50.2+/-7.5 vs. 23.3+/-1.3 ng/l, P<0.001, and 38.2+/-12.4 vs. 16.3+/-1.6 ng/l, P<0.001, for Hodgkin's disease and breast cancer, respectively). Eight patients suffered from essential hypertension (n=8), whereas the remaining group of 17 patients showed a variety of cardiac disorders (i.e. myocardial infarction, decreasing ventricular function, and atrial fibrillations). In 11 patients cardiac problems were manifest either before or within a few years after mediastinal therapy. In two patients treated for Hodgkin's disease, and in four patients treated for breast cancer cardiac problems became manifest a long time (>10 years) after radiotherapy. Probably in this group of patients cardiac problems are related to the therapy. CONCLUSIONS: The present study indicates that ANP plasma levels could be used to identify patients with radiation induced cardiac dysfunction.

Adult↗
PubMed2001

Structural changes in the auricles of the rat heart after local ionizing irradiation.

BACKGROUND AND PURPOSE: Irradiation of the heart may lead to late cardiovascular complications and depending on the dose to cardiac-related death. There is increasing evidence that left atrial appendages play an important role in left ventricular filling especially in cardiac disease. The aim of the present study was to investigate the radiation response of the atria of the rat heart (auricles in particular) at morphological, histological and transcriptional level. MATERIAL AND METHODS: Sprague-Dawley rats were irradiated with a single dose locally on the heart (0-22.5 Gy). End-diastolic diameters of left auricles were measured during evaluation of cardiac function. Histopathological evaluations were performed at various time points up to 16 months post irradiation. Changes in mRNA expression of procollagen types I and III and pro-fibrogenic cytokines (TGF-beta1 and IL-1beta) were investigated using competitive PCR. RESULTS: Irradiation leads to a dose-dependent decrease in end-diastolic diameter of the left auricles. This decrease was observed at 4 months post-irradiation, where no gross damage of the ventricle has been reported. Histologically, epicardial fibrosis was found already 1 month post irradiation, and the frequency/severity of the structural changes appeared to be dose-dependent and progressive with time post irradiation. At 9 months, fibrosis was observed in all three layers (epicardium, myocardium and endocardium) of both auricles. On the level of gene expression, increases in procollagen types I and III were observed at 12 and 3 months post irradiation, respectively. Increases in IL-1beta and TGF-beta1, cytokines known to influence collagen deposition at different levels, preceded the upregulation of procollagen mRNA. CONCLUSIONS: Auricles of the rat heart show a marked pathological response to ionizing radiation, characterized by generalized accumulation of collagen (fibrosis) and a reduction of end-diastolic diameter. The reduction of auricular volume and loss of elasticity will negatively contribute to the pump function of the irradiated ventricle.

Animals↗
PubMed2000

Psychological distress two years after diagnosis of breast cancer: frequency and prediction.

The present prospective study aimed at (1) investigating the frequency of high levels of psychological distress in women with early-stage breast cancer almost two years after diagnosis and (2) identifying characteristics associated with long-term distress. One hundred and seventy women participated on two occasions. Two months after surgery, patients completed questionnaires measuring psychosocial variables (e.g., stressful life-events, health complaints, sleep problems, social support, subjective distress, personality factors), demographic and biomedical variables (e.g., TNM status, type of surgery). At the second measurement, subjective distress was assessed for a second time by means of the Impact of Events Scale (IES). Almost two years after diagnosis, 16% of the women reported a high level of psychological distress as measured by the Intrusion scale (IES). Best predictors of a high level of distress were: intrusive thoughts about the disease, trait-anxiety, health complaints and problems with sleeping. No significant association was found between previous life-events, social support or biomedical variables and levels of distress.

Adult↗
PubMed2000

Radiation therapy in localized prostate cancer: long-term results and late toxicity.

This study was performed to determine the long-term results of radiotherapy in localized prostate cancer. The frequency and severity of late gastrointestinal and genitourinary toxicities were also investigated. Between 1980 and 1991, 206 men with localized prostate cancer were treated with radiotherapy alone at our hospital. Biopsy, transurethral resection of the prostate, or both, confirmed the diagnosis. Overall survival, cancer-specific survival, disease-free survival, local recurrence-free survival and metastasis-free survival were determined and compared with age, stage, grade and diagnostic intervention. A change in treatment policy occurred in 1987. The treatment results of the two periods are compared. Late toxicity was registered according to the Radiation Therapy Oncology Group scale. The 8-year overall survival rates were 60%, 44% and 29% for Stages T1, T2 and T3 respectively (P=0.028). The 8-year cancer-specific survival rates were 86%, 66% and 34% for Stages T1, T2 and T3 respectively (P=0.002). Transurethral resection of the prostate had a negative influence on cancer-free and disease-free survivals, owing especially to an increased incidence of metastases. In the bladder and rectum, late toxicity of grade 2 or more occurred in 26 (13%) of the 199 patients who were alive at 6 months after radiotherapy. One of these patients developed late toxicity 5 years after the radiotherapy. Radiation dose and field size had no detectable influence on the development of late toxicity. The difference between overall survival and cancer-specific survival confirms that many of these patients die without any clinical signs of prostate cancer or metastases. This observation puts a question mark over whether a biochemical endpoint alone is of clinical relevance. Although not statistically significant, local recurrence-free, disease-free and cancer-specific free survivals from 1987 onwards improved for larger tumours, which was most likely due to the administration of higher doses of radiation.

Adult↗
PubMed1999

Risk factors for local recurrence after breast-conserving therapy for invasive carcinomas: a case-control study of histological factors and alterations in oncogene expression.

PURPOSE: Many studies have focused on histological risk factors for local recurrence (LR) after breast-conserving therapy (BCT). In addition to histological factors, we studied alterations in the expression of various proteins in relation to LR using a case-control approach. METHODS AND MATERIALS: Ninety-nine LR occurred in a patient cohort of 1,481 tumors treated with BCT. These patients were randomly matched, each with two controls. Matching was performed for age group (< or = 50 and > 50 years), pN stage, and follow-up time. Histology slides were reviewed. Immunohistochemical staining was performed for the following proteins: bcl-2, CD31, cyclin D1, E-cadherin, EGF receptor, ER, PR, Ki-67, c-erbB2/neu, and p53. Statistical analyses were performed using conditional logistic regression. RESULTS: Sixty-six cases and 139 controls with invasive carcinoma remained for analysis. The following variables were significant risk factors for LR: young age (p = 0.006), high nuclear grade (p = 0.04), high mitotic count (p = 0.03), extensive DCIS around the tumor (p = 0.02) but not within the tumor, poorly differentiated type of DCIS (p = 0.03), > 20% ki-67 positive cells (p = 0.006), and PR negativity (p = 0.03). When the analysis was performed for patients < or = and > 50 years, these risk factors were found in the older patients, but not in the younger patients. CONCLUSION: High mitotic count and Ki-67 positivity are risk factors for LR. EDCIS surrounding the invasive tumor is a risk factor for LR, especially when of poorly differentiated type. Age is an important risk factor for LR independent of other risk factors, including alterations in oncogene expression.

Adult↗
PubMed1999

[Locoregional radiotherapy after mastectomy not useful for all Dutch breast cancer patients].

Two recent randomized clinical trials from Denmark and Canada show that postoperative radiotherapy of breast cancer patients in whom the findings revealed a high risk of dying from the disease not only causes improvement of the locoregional tumour control but also prolongs survival. However, this does not establish definitely which patients belong to this 'high risk category'. Results of retrospective studies from Leiden suggest that selective withholding of postoperative radiotherapy in the Netherlands is justified for large groups of breast cancer patients. Both clinically manifest parasternal recurrences and axillary recurrences are rare among these patients. The condition is, however, that the axillary dissection is radical and performed properly.

Adult↗
PubMed1999

Detection and quantitative measurement of transforming growth factor-beta1 (TGF-beta1) gene expression using a semi-nested competitive PCR assay.

A polymerase chain reaction (PCR) technique was optimized for detection and quantification of very low concentrations (down to a few molecules) of transforming growth factor beta1 (TGF-beta1) mRNA. The strategy involved a combination of a competitive PCR assay and a semi-nested PCR. In the present study, the semi-nested PCR technique was tested in several rat organs containing different concentrations of target mRNA. A control fragment for TGF-beta1 was used to correct for differences in amplification of various cDNA samples. TGF-beta1 mRNA levels were also corrected according to the abundance of the "housekeeping" gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in the same samples. The differences of sensitivity among the standard (one-step) and semi-nested (two-step) competitive PCR assays for the detection of TGF-beta1 are discussed. In conclusion, the semi-nested PCR protocol provides greatly enhanced sensitivity over standard PCR analysis. It is a reproducible and very specific method for quantification of only a few molecules of TGF-beta1 mRNA in a background of non-target molecules.

Animals↗
PubMed1999

Changes in circulating atrial natriuretic peptide in relation to the cardiac status of Rhesus monkeys after total-body irradiation.

PURPOSE: In order to determine the presence of cardiac damage associated with total-body irradiation (TBI), both echocardiographic parameters and circulating levels of atrial natriuretic peptide (ANP) were measured in three different age-cohorts of Rhesus monkeys (Macaca mulatta) previously treated with TBI without additional chemotherapy, at post irradiation intervals up to 30 years, at the former TNO/Radiobiological Institute at Rijswijk. MATERIALS AND METHODS: Standard echocardiographic techniques were used to measure cardiac dimensions and left ventricular function in situ. Plasma-ANP concentration was measured by radioimmunoassay (RIA). After necropsy, tissue samples from the heart were taken for histological analysis. RESULTS: Plasma-ANP levels of animals which received TBI were significantly (P = 0.0005) elevated when compared to age-matched controls (66.4 +/- 8.4 vs. 33.1 +/- 5.7 ng/l). Moreover, a positive correlation (P = 0.032) between plasma-ANP values and time post treatment was found in the TBI group. TBI affected cardiac dimensions; however, no significant differences in cardiac functional parameters were observed between the different treatment groups. Necropsy reports demonstrated slight but consistent cardiovascular damage in several animals treated with TBI, in terms of increased incidence of mild epicardial and coronary arterial wall fibrosis, compared to age-matched controls. CONCLUSIONS: The concentration of plasma-ANP proved to be an important parameter for subclinical cardiac damage. In humans, serial determinations of plasma ANP in individual patients might provide relevant information about the cardiac status after TBI.

Animals↗
PubMed1999

Results of ruthenium irradiation of uveal melanomas: the Dutch experience.

BACKGROUND AND PURPOSE: To update our results of the treatment of uveal melanomas using ruthenium applicators in 49 patients treated with graded doses and subsequently in 52 patients with maximal scleral doses of 800 Gy and an effective top dose of at least 160 Gy. MATERIAL AND METHODS: One hundred and one patients were treated with brachytherapy only, in 25 patients it was combined with transpupillary thermotherapy (TTT). RESULTS: A complete remission was found in 62.6% of the patients and in 31.3% a stable disease with an average follow-up of 74.6 months. Above a top dose of 120 Gy only in one of 95 patients continuous tumour growth after treatment was observed. Useful vision could be preserved in 51.5% of the patients. The initial tumour prominence and top dose strongly correlated with treatment outcome. CONCLUSIONS: Ruthenium application for uveal melanomas with the doses we have used is successful, with a substantial number of patients having their eyes preserved, their tumour controlled and their vision retained. Further improvements can be obtained with ruthenium irradiation with lower maximal scleral doses combined with TTT.

Adult↗
PubMed1999

The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study.

PURPOSE: To answer the question whether a single fraction of radiotherapy that is considered more convenient to the patient is as effective as a dose of multiple fractions for palliation of painful bone metastases. PATIENTS: 1171 patients were randomised to receive either 8 Gy x 1 (n = 585) or 4 Gy x 6 (n = 586). The primary tumour was in the breast in 39% of the patients, in the prostate in 23%, in the lung in 25% and in other locations in 13%. Bone metastases were located in the spine (30%), pelvis (36%), femur (10%), ribs (8%), humerus (6%) and other sites (10%). METHOD: Questionnaires were mailed to collect information on pain, analgesics consumption, quality of life and side effects during treatment. The main endpoint was pain measured on a pain scale from 0 (no pain at all) to 10 (worst imaginable pain). Costs per treatment schedule were estimated. RESULTS: On average, patients participated in the study for 4 months. Median survival was 7 months. Response was defined as a decrease of at least two points as compared to the initial pain score. The difference in response between the two treatment groups proved not significant and stayed well within the margin of 10%. Overall, 71% experienced a response at some time during the first year. An analysis of repeated measures confirmed that the two treatment schedules were equivalent in terms of palliation. With regard to pain medication, quality of life and side effects no differences between the two treatment groups were found. The total number of retreatments was 188 (16%). This number was 147 (25%) in the 8 Gy x 1 irradiation group and 41 (7%) in the 4 Gy x 6 group. It was shown that the level of pain was an important reason to retreat. There were also indications that doctors were more willing to retreat patients in the single fraction group because time to retreatment was substantially shorter in this group and the preceding pain score was lower. Unexpectedly, more pathological fractures were observed in the single fraction group, but the absolute percentage was low. In a cost-analysis, the costs of the 4 Gy x 6 and the 8 Gy x 1 treatment schedules were calculated at 2305 and 1734 Euro respectively. Including the costs of retreatment reduced this 25% cost difference to only 8%. The saving of radiotherapy capacity, however, was considered the major economic advantage of the single dose schedule. CONCLUSION: The global analysis of the Dutch study indicates the equality of a single fraction as compared to a 6 fraction treatment in patients with painful bone metastases provided that 4 times more retreatments are accepted in the single dose group. This equality is also shown in long term survivors. A more detailed analysis of the study is in progress.

Adult↗
PubMed1999

Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Prospective randomised trial with standard operative and histopathological techniques. Dutch ColoRectal Cancer Group.

OBJECTIVE: To document local recurrence in primary rectal cancer when standardised techniques of surgery, radiotherapy, and pathology are used, and to investigate whether the local recurrence rate after total mesorectal excision permits the omission of adjuvant short term preoperative radiotherapy. DESIGN: Prospective randomised study. SETTING: Dutch (n = 80), English (n = 1), German (n = 1), Swedish (n = 9), and Swiss (n = 1) hospitals. SUBJECTS: The first 500 randomised Dutch patients with primary rectal cancer. MAIN OUTCOME MEASURES: Local recurrence, survival, operation-related factors, specific pathological tumour characteristics, short and long term morbidity, and quality of life. RESULTS: Between January 1996 and April 1998, 871 Dutch and 94 other patients were randomised. Our feasibility analysis shows that cooperation between and within the participating disciplines goes well. With regard to the surgical part, this can be confirmed by the large number of operations attended by consultant surgeons (58%). The number of abdominoperineal resections appeared to be low (30%), as did the percentage of lateral margins involved (13%). The rate of adverse effects of radiotherapy was acceptable. Apart from a larger operative blood loss and a higher infective complication rate in the irradiated group, no significant differences were found with regard to morbidity and mortality between the randomised groups. CONCLUSIONS: The accrual of our trial is going well and it is feasible; short term preoperative radiotherapy is safe even in combination with TME.

Adult↗
PubMed1998

Local recurrence after breast-conserving therapy for invasive breast cancer: high incidence in young patients and association with poor survival.

PURPOSE: To study risk factors for local recurrence (LR) after breast-conserving therapy (BCT) for invasive breast cancer and, for patients with an LR, the mode of detection, location, treatment, influence of radiation therapy, and impact on survival. METHODS AND MATERIALS: 1360 patients (median age 52 years; range 24-88) with a total of 1393 pT1-2 N0-1 tumors treated with BCT between 1980-1994 were studied (median follow-up 52 months). The adequacy of radiation treatment of the patients developing LR was studied in a quality control study. The impact of LR on overall survival and distant metastasis was studied in a Cox regression model with LR as a time-dependent covariate. RESULTS: A total of 88 LR occurred with a 5- and 10-year LR risk of 8 and 12%. Age was the only significant risk factor. Compared to patients > 65 years old, patients < 45 years old and patients 45-65 years old had a relative risk (RR) of 4.09 and 2.41, respectively, of developing LR. Risk on LR was found to increase gradually with younger age. Radiation therapy was considered adequate and did not play a role in influencing the LR rate. Almost 65% of the LR were true or marginal recurrences. Of all LR, 80% appeared during the first 5 years and were detected with equal frequency by the patient herself, the physician, and annual mammography. LR was a major predictor for distant metastasis (RR: 4.90; 3.15-7.62) and death (RR: 4.29; 2.93-6.28). CONCLUSION: Young age is a major risk factor for LR and there is a significant gradual increase in LR with decreasing age. LR is associated with a higher risk of distant metastasis and death. Whether LR is the cause of or a marker for distant metastasis remains unresolved.

Adult↗
PubMed1998

Additive effect of concomitant multiple low-dose doxorubicin and thoracic irradiation on ex vivo cardiac performance of the rat heart.

The effects of doxorubicin alone or combined with local heart irradiation on ex vivo cardiac performance were studied in Sprague-Dawley rats. Rats were treated with doxorubicin either administered as a single bolus injection or administered weekly during a period of 10 weeks. In "combined" experiments, local heart irradiation with a single dose of 15 Gy was given prior to drug administration. Evaluation of cardiac performance was performed 14 weeks after initiation of treatment. At drug doses that were tolerated by the rat, single injections with doxorubicin (sd-DXR; up to a dose of 5 mg/kg) did not lead to a change in cardiac performance whereas multiple injections with low-dose doxorubicin (mld-DXR; up to a cumulative dose of 20 mg/kg) led to a dose-dependent decrease in cardiac function. Extracardial toxicity as a result of mld-DXR (cumulative dose < or =15 mg/kg) was mild when compared to the toxicities observed after sd-DXR (5.0 and 7.5 mg/kg). When administration of mld-doxorubicin was preceded by 15 Gy, cardiac performance further decreased. The present data indicate that the interaction between doxorubicin and local heart irradiation with a dose of 15 Gy is additive, when the treatments are given concomitantly. Irradiation did not lead to an increase of DXR-mediated extracardial toxicities. The isolated working rat heart preparation offers a reliable method to evaluate the effects of doxorubicin and new anthracycline analogue on the heart.

Animals↗