Prognostic significance of tumor cell proliferation analyzed in fine needle aspirates from primary breast cancer.

The objective of this study was to analyze the role of proliferating fraction (PF) measured with Ki-67/MIB-1 antibody in a large series of preoperative fine-needle aspirate (FNA) biopsies as a prognosticator of disease recurrence. The study comprised 732 patients who all had a conclusive cytological diagnosis of breast cancer. The follow-up time ranged from 1.2 to 10.2 years with a median of 5.7 years. In multivariate analysis Ki-67/MIB-1 value was a strong (p < 0.001) significant, prognosticator of disease recurrence free interval (DRFI) independent of lymph node status, progesterone receptor content, and tumor size. In the subgroup analysis of 430 node-negative patients the distant recurrence-free rate after 5 years was 94.4% in patients with Ki-67/MIB-1 value < 15% compared to 88.7% in patients with Ki-67/MIB-1 value > or = 15% (p = 0.03). Test of the interaction between tumor size and the value of PF revealed a p-value of 0.06. If the patients, in addition, had a tumor size >20 mm the distant recurrence-free rate after 5 years was 93.2% if Ki-67/MIB-1 < 15% compared to 80.7% in patients with Ki-67/MIB-1 value > or = 15%. This difference was statistically significant (p < 0.01). For patients with tumors <20mm Ki-67/MIB-1 value did not add any prognostic information. In the subgroup of 302 node-positive patients the distant recurrence-free rate after 5 years was 86.0% in patients with Ki-67/MIB-1 value < 15% compared to 70.6% in patients with Ki-67/MIB-1 value > or = 15% (p < 0.01). We conclude that PF assessed by Ki-67/MIB-1 antibodies in preoperative FNA biopsies has a significant prognostic value independent of lymph node status, PgR status and tumor size. To our knowledge, this is the first study demonstrating PF, which can contribute prognostic information when analyzed in preoperative smears.

Radiation therapy in the management of brain metastases from breast cancer.

A retrospective analysis of 99 patients treated at Radiumhemmet, Karolinska Hospital 1979-1990 with palliative radiotherapy for brain metastases from breast cancer was performed. A relief of symptoms was obtained in 45% of patients. Median time from diagnosis of breast cancer until CNS metastases was 33 months. Median survival time with CNS metastases after diagnosis was 5 months. Prognostic indicators for survival were studied. Patients operated for a singular brain metastasis and irradiated postoperatively had a mean survival of 21 months while patients with multiple brain metastases and meningeal spread displayed a short median survival. Extracranial disease status influenced prognosis significantly. Radiation dose (CRE) did not correlate with survival.

Long-term cardiac mortality following radiation therapy for Hodgkin's disease: analysis with the relative seriality model.

PURPOSE: (a) To assess the increased risk of death due to ischemic heart disease (IHD) in a group of patients treated for Hodgkin's disease (HD) with radiation therapy (RT) as the primary treatment. (b) To quantify the dose response of IHD using a biophysical model. MATERIALS AND METHODS: Patient material consisted of 157 patients diagnosed for HD between 1972 and 1985 who received RT as the primary treatment at Radiumhemmet, Karolinska Hospital. The general population formed the control group. The RT treatments were reconstructed based on the individual treatment data and simulator films. Individual clinical and dosimetrical data were analyzed with the relative seriality model. The material was also analyzed grouping the material according to dose-volume constraints. RESULTS: Of the 157 patients, 13 (8.3%) died due to IHD. The standardized mortality ratio (SMR) was 5.0 (95% CI, 2.7-8.6). Analysis of dose-volume histograms (DVH) showed an increasing risk with increasing dose to a larger volume fraction. The observed individual clinical complication data could not be modeled unambiguously. The group analysis resulted in the dose-response parameters: D(50)=71 Gy, gamma=0.96 and s=1.0. CONCLUSIONS: A significantly increased risk of death due to IHD following RT for HD was found. The risk was found to increase with higher dose and larger volume fraction irradiated.

Radiation pneumonitis after breast cancer irradiation: analysis of the complication probability using the relative seriality model.

BACKGROUND: Toxicity of the respiratory system is quite common after radiotherapy of thoracic tumors; breast cancer patients represent one of the groups for which there is also a long expected survival. The quantification of lung tissue response to irradiation is important in designing treatments associated with a minimum of complications and maximum tumor control. METHODS: The study population consisted of 68 patients who received irradiation for breast cancer at Stage II. Radiation pneumonitis was retrospectively assessed on the basis of clinical symptoms and radiological findings. For each patient, a measure of the exposure (i.e., the lung dose-volume histogram [DVH]) and a measure of the outcome was available. Based on these data, a maximum likelihood fitting to the relative seriality model was performed. The uncertainties of the model parameters were calculated and their impact on the dose-response curve was studied. The optimum parameter set was then applied to 5 other patient groups treated for breast cancer, and the normal tissue complication probability (NTCP) was calculated. Each group was individuated by the radiotherapy treatment technique used; the dose distribution in the lung was described by a mean DVH and the incidence of radiation pneumonitis in each group was known. Lung radiosensitivity was assumed to be homogeneous through all of the calculations. RESULTS: The relative seriality model could describe the dataset. The volume effect was found to be relevant in the description of radiation pneumonitis. Age was found to be associated with increased risk of radiation pneumonitis. Two distinct dose-response curves were obtained by splitting the group according to age. The impact of the parameter uncertainties on the dose-response curve was quite large. The parameter set determined could be used predictively on 3 of the 5 patient groups. CONCLUSION: The complication data could be modeled with the relative seriality model. However, further independent datasets, classified according to the same endpoint, must be analyzed before introducing NTCP modeling in clinical practice.

Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer.

BACKGROUND AND PURPOSE: Some types of radiation therapy have been associated with an increased risk of cardiac mortality and morbidity in patients with early-stage breast cancer. A relationship has been observed between cardiac radiation dose-volume and the level of excess risk of cardiac mortality. However, relatively few data are available on the morbidity from myocardial infarction associated with adjuvant radiotherapy. PATIENTS AND METHODS: From 1971 to 1976, a total of 960 patients with operable breast cancer were randomly allocated to preoperative radiation therapy, postoperative radiation therapy or to surgery alone. A previous analysis of the cardiac dose-volumes with the treatment techniques used in the trial indicated that the irradiated patients could roughly be divided into three groups. Information on the number of myocardial infarctions was obtained through computerized record linkage with a population-based registry of myocardial infarctions in Stockholm County. Information on cause-specific mortality was obtained from the Swedish Cause-of-Death Registry. The median follow-up was 20 years (range 17-23 years). RESULTS: A total of 58 patients developed an acute myocardial infarction during the period of follow-up. The number of myocardial infarction cases was not significantly different between the three treatment groups. When analyzed according to estimated cardiac radiation dose-volumes, patients in the highest dose-volume subgroup exhibited a hazard of myocardial infarction of 1.3 (95% CI 0.7-2.6) relative to that of the surgical controls, whereas the corresponding relative hazard for the intermediate and low dose-volume subgroups was below unity. Data on death due to cardiovascular disease showed that patients in the high dose-volume group exhibited a hazard of 2.0 (95% CI 1.0-3.9, P = 0.04) relative to that of the surgical controls. Concerning death due to ischemic heart disease, the relative hazard for the same subgroup was 2.5 (95% CI 1.1-5.7, P = 0.03). The difference between the groups was established after 4-5 years. The cumulative incidence curves continued to diverge up to about 10-12 years. No further divergence appeared after 12 years, but the number of events was low. CONCLUSIONS: This analysis confirms and extends previous results from the trial. Cardiac mortality was positively correlated with the cardiac dose-volume. Patients receiving high dose-volumes exhibited an increased mortality of ischemic heart disease, but not of myocardial infarction, which implies another mechanism, e.g. radiation-induced microvascular damage to the heart.

Myocardial infarction among women with early-stage breast cancer treated with conservative surgery and breast irradiation.

PURPOSE: To assess the possible impact of the irradiation on the risk of acute myocardial infarction among breast cancer patients treated with conservative surgery and postoperative radiation therapy. METHODS AND MATERIALS: The incidence of and mortality from acute myocardial infarction was assessed in a group of 684 women with early-stage breast cancer diagnosed during 1976-1987 who had been treated with breast conserving surgery plus postoperative radiation therapy given with tangential photon fields. In 94% of the patients the total dose was between 48-52 Gy given with 2 Gy daily fractions 5 days per week for a total treatment period of about 4 1/2-5 1/2 weeks. In 88% of the patients the target volume included the breast parenchyma alone. In the remaining patients regional nodal areas were also irradiated. A concurrent group of 4,996 breast cancer patients treated with mastectomy without postoperative radiation therapy was used as a reference. RESULTS: After a median follow-up of 9 years (range: 5-16 years) 12 conservatively treated patients (1.8%) had developed an acute myocardial infarction and 5 (0.7%) had died due to this disease. The age-adjusted relative hazard of acute myocardial infarction for the conservative group vs. the mastectomy group was 0.6 (95% C.I.: 0.4-1.2) and for death due to this disease 0.4 (0.2-1.1). The incidence of acute myocardial infarction among the conservatively treated women was similar irrespective of tumor laterality. CONCLUSIONS: There was no indication of an increased risk of acute myocardial infarction with the radiation therapy among the women treated with conservative surgery. However, due to the small number of events the study could not exclude the possibility that cardiac problems may arise in some patients with left-sided cancers who have their heart located anteriorly in the mediastinum. Individual, three-dimensional dose planning represents one method to identify such patients and is basic to technical changes aimed at decreasing the cardiac radiation dose volume.