The impact of loco-regional recurrences on metastatic progression in early-stage breast cancer: a multistate model.

To study whether the effects of prognostic factors associated with the occurrence of distant metastases (DM) at primary diagnosis change after the incidence of loco-regional recurrences (LRR) among women treated for invasive stage I or II breast cancer. The study population consisted of 3,601 women, enrolled in EORTC trials 10801, 10854, or 10902 treated for early-stage breast cancer. Data were analysed in a multivariate, multistate model by using multivariate Cox regression models, including a state-dependent covariate. The presence of a LRR in itself is a significant prognostic risk factor (HR: 3.64; 95%-CI: 2.02-6.5) for the occurrence of DM. Main prognostic risk factors for a DM are young age at diagnosis (< or =40: HR: 1.79; 95%-CI: 1.28-2.51), larger tumour size (HR: 1.58; 95%-CI: 1.35-1.84) and node positivity (HR: 2.00; 95%-CI: 1.74-2.30). Adjuvant chemotherapy is protective for a DM (HR: 0.66; 95%-CI: 0.55-0.80). After the occurrence of a LRR the latter protective effect has disappeared (P = 0.009). The presence of LRR in itself is a significant risk factor for DM. For patients who are at risk of developing LRR, effective local control should be the main target of therapy.

Impact on survival of early detection of isolated breast recurrences after the primary treatment for breast cancer: a meta-analysis.

PURPOSE: The purpose was to establish the impact on survival of early detection of a local recurrence of breast cancer as compared to late detection. DESIGN: A meta-analysis was carried out using Cochrane review manager software (RevMan version 4.2). Studies were included if women were treated for primary breast cancer without evidence of distant metastasis at primary diagnosis and if these concerned routine follow-up strategies focusing on the early detection of curable recurrences. Data regarding the risk for death were derived from each study. Multi level models were used to study heterogeneity by using MLWin. RESULTS: Thirteen studies concerning 2,263 patients were included. Early detection of breast cancer recurrences during follow-up gave a significantly better survival as compared to late detected recurrences (HR: 1.68 (95% CI: 1.48-1.91)). Survival was better when the recurrence was found by mammography instead of physical examination or in patients without symptoms as compared to those with symptoms (HR: 2.44 (95% CI: 1.78-3.35); HR: 1.56 (95% CI: 1.36-1.79), respectively). If all breast cancer recurrences would be detected earlier, that 5-8 deaths (i.e. an absolute reduction in mortality of 17-28%) would be avoided by performing routine follow-up during a 10 year-period for 1,000 breast cancer patients. CONCLUSION: These data support the hypothesis that detection of isolated loco-regional or contra-lateral breast cancer recurrences in patients without symptoms has beneficial impact on survival of breast cancer patients when compared to late symptomatic detection.

Isolated loco-regional recurrence of breast cancer is more common in young patients and following breast conserving therapy: long-term results of European Organisation for Research and Treatment of Cancer studies.

The aim of this study was to evaluate prognostic factors for isolated loco-regional recurrence in patients treated for invasive stage I or II breast cancer. The study population comprised 3602 women who had undergone primary surgery for early stage breast cancer, who were enrolled in European Organisation for Research and Treatment of Cancer (EORTC) trials 10801, 10854, or 10902, by breast conservation (55%) and mastectomy (45%). The median follow-up time varied from 5.3 (range: 0.6-9.5) to 11.9 years (range: 0.6-17.4). Main outcome was the occurrence of isolated loco-regional recurrence. The results of multivariate analysis showed that younger age and breast conservation were risk factors for isolated loco-regional recurrence (breast cancer under 35 years of age versus over 50 years of age: hazard ratio 2.80 (95% CI 1.41-5.60)); breast cancer age 35-50 years versus over 50 years: hazard ratio 1.72 (95% CI 1.17-2.54); breast conservation (hazard ratio: 1.82 (95% CI 1.17-2.86)). After perioperative chemotherapy, less isolated loco-regional recurrences were observed (hazard ratio 0.63 (95% CI 0.44-0.91)). No significant interaction effects were observed. It is concluded that young age and breast conserving therapy are both independent predictors for isolated loco-regional recurrence. As an isolated loco-regional recurrence is a potentially curable condition, women treated with breast conservation or diagnosed with breast cancer at a young age should be monitored closely to detect local recurrence at an early stage.

Effectiveness of routine visits and routine tests in detecting isolated locoregional recurrences after treatment for early-stage invasive breast cancer: a meta-analysis and systematic review.

PURPOSE: To review the effectiveness of routine visits and routine tests in detecting isolated locoregional recurrences in asymptomatic patients after treatment for early-stage invasive breast cancer. METHODS: Systematic review and meta-analysis. The proportion of isolated locoregional recurrences diagnosed during routine visits or routine tests in asymptomatic patients was compared with the proportion of isolated locoregional recurrences in symptomatic patients. RESULTS: Twelve studies that involved a total of 5,045 patients and 378 isolated locoregional recurrences were identified. Pooling data showed an overall estimate of 40% of isolated locoregional recurrences diagnosed during routine visits or routine tests in asymptomatic patients (95% CI, 35 to 45). Of these, 47% (95% CI, 39 to 54) were diagnosed after mastectomy, and 36% (95% CI, 28 to 43) were diagnosed after breast-conserving therapy (relative risk, 1.327; 95% CI, 1.014 to 1.738). Apart from differences in therapy, we have not been able to discern subgroups of patients for whom results were different. CONCLUSION: Approximately 40% of isolated locoregional recurrences are diagnosed during routine visits and routine tests in asymptomatic patients treated for early-stage invasive breast cancer. We could not assess whether these were detected by either physical examination or other tests, nor if the detection of asymptomatic isolated recurrences had any influence on potential for cure or quality of life. As the overall quality of the included studies and the overall incidence of isolated locoregional recurrences are low, this systematic review highlights the need for prospective comparative studies on cost-effective strategies for the follow-up of patients after a diagnosis of breast cancer.

Patient's needs and preferences in routine follow-up after treatment for breast cancer.

The purpose of the study was to analyse the needs of women who participated in a routine follow-up programme after treatment for primary breast cancer. A cross-sectional survey was conducted using a postal questionnaire among women without any sign of relapse during the routine follow-up period. The questionnaire was sent 2-4 years after primary surgical treatment. Most important to patients was information on long-term effects of treatment and prognosis, discussion of prevention of breast cancer and hereditary factors and changes in the untreated breast. Patients preferred additional investigations (such as X-ray and blood tests) to be part of routine follow-up visits. Less satisfaction with interpersonal aspects and higher scores on the Hospital Anxiety and Depression Scale (HADS) scale were related to stronger preferences for additional investigation. Receiving adjuvant hormonal or radiotherapy was related to a preference for a more intensive follow-up schedule. There were no significant differences between patients treated with mastectomy compared to treated with breast-conserving therapy. During routine follow-up after a diagnosis of breast cancer, not all patients needed all types of information. When introducing alternative follow-up schedules, individual patients' information needs and preferences should be identified early and incorporated into the follow-up routine care, to target resources and maximise the likelihood that positive patient outcomes will result.

Impact of locoregional treatment on the early-stage breast cancer patients: a retrospective analysis.

Although adequate locoregional treatment improves local and regional control in early-stage breast cancer, uncertainty still exists about the role of locoregional therapy with respect to survival. To study the impact of surgery and radiotherapy on locoregional control and survival, we combined the data of three European Organisation for Research and Treatment of Cancer (EORTC) Breast Cancer Group trials including early-stage breast cancer patients with long-term follow-up. Risk ratios (RR) were estimated for locoregional recurrence and overall survival using Cox regression models. All analyses were adjusted for tumour size, nodal status, age, adjuvant radiotherapy, adjuvant chemotherapy and trial. The combined data-set consisted of 3648 patients. The median follow-up period was 11 years. 5.9% of the patients who underwent mastectomy and 10.8% of the patients who underwent breast-conserving therapy had a locoregional recurrence (P<0.0001). The risk of death after breast-conserving therapy was similar compared with mastectomy (RR 1.07, P=0.37). Adjuvant radiotherapy after mastectomy was associated with a lower risk for locoregional recurrence (RR 0.43, P<0.001) and death (RR 0.73, P=0.001). Patients with 1-3 positive nodes benefited the most from radiotherapy after mastectomy. Breast-conserving therapy was associated with an impaired locoregional control. However, breast-conserving therapy was not associated with a worse overall survival. Adjuvant radiotherapy in mastectomised patients was associated with both a significantly superior locoregional control and overall survival. The effect of adjuvant radiotherapy was most profound in patients who had 1-3 positive nodes.

Sentinel lymph node biopsy in breast cancer.

The concept of sentinel lymph node (SLN) biopsy in breast cancer patients is simple, attractive and rapidly emerging as a new standard of care. Several aspects of the technique of lymphatic mapping, case selection, pathologic analysis and the finding of micrometastases, and the accuracy of the technique are important subjects of study and debate in the literature and will be discussed in this review. High identification rates can be attained by the use of both radioguided and blue dye lymphatic mapping. Intradermal injection of tracers has reported to be successful, suggesting that dermal and parenchymal lymphatics drain to the same SLN. Extra axillary drainage is only seen after peri- or intratumoural injection. SLN biopsy is most widely used for both palpable and non-palpable T1 and T2 tumours, and limited experience exists for other indications. Accuracy is high only in experienced hands. The impact of failure of the procedure on regional disease control and survival will be assessed in a trial of the NSABP (National Adjuvant Breast and Bowel Project). The influence of a positive SLN biopsy with and without axillary dissection on survival and local control will be studied in trials of the BASO (British Association of Surgical Oncology), ACOSOG (American College of Surgeons Oncology Group) and EORTC (European Organisation for Research and Treatment of Cancer). These phase III trials and related studies on the importance of micrometastases in the SLN will give new insights in the safety of the SLN procedure and in the importance of treatment of regional lymph nodes in relation to local disease control and survival.

Altered expression of p53 and its regulated proteins in phyllodes tumours of the breast.

The histological characteristics of phyllodes tumours of the breast are often not related to their clinical outcome. Additional studies must therefore be performed to investigate the possible relationship of cell biological parameters to the biological behaviour of these tumours. The expression of Ki-67, p53, and its regulated proteins has been studied in 19 primary phyllodes tumours, from patients with known follow-up, using immunohistochemical and molecular biological techniques. Overexpression of the p53 protein was observed in four cases and mutation in two cases. In only one case, the sequence alteration, at codon 273, was associated with overexpression of p53 protein and with strong expression of Ki-67 (30 per cent). This alteration was found in the primary, the recurrent, and the metastatic tumour samples. Moreover, the same p53 gene mutation, Arg273Cys, was detected in all tumour samples. No mutation was found in adjacent normal breast tissue, indicating that this was an acquired mutation. Unexpectedly, strong BAX expression was observed in the primary tumour. The patient died during the follow-up period. It is concluded that p53 gene status and an accumulation of BAX, both involved in the same apoptosis-controlling pathway, may be of prognostic relevance in phyllodes tumours.

The composition of serous fluid after axillary dissection.

OBJECTIVE: To analyse the composition of the serous fluid formed after axillary dissection. DESIGN: Descriptive study. SETTING: University hospital and teaching hospital, The Netherlands. SUBJECTS: 16 patients whose axillas were dissected as part of a modified radical mastectomy for stage I or II breast cancer. MAIN OUTCOME MEASURES: Chemical and cellular composition of axillary drainage fluid on the first, fifth, and tenth postoperative days compared with the same constituents in blood and with reported data on the composition of peripheral lymph. RESULTS AND CONCLUSION: On the first postoperative day the drainage fluid contained blood contents and a high concentration of creatine phosphokinase (CPK). After day one it changed to a peripheral lymph-like fluid but containing different cells, more protein, and no fibrinogen, making coagulation impossible. The reduction in the fluid production must be caused by other wound healing processes, such as formation of scars and connective tissue.

Medical and psychosocial effects of early discharge after surgery for breast cancer: randomised trial.

OBJECTIVE: To assess the medical and psychosocial effects of early hospital discharge after surgery for breast cancer on complication rate, patient satisfaction, and psychosocial outcomes. DESIGN: Randomised trial comparing discharge from hospital 4 days after surgery (with drain in situ) with discharge after drain removal (mean 9 days in hospital). Psychosocial measurements performed before surgery and 1 and 4 months after. SETTING: General hospital and cancer clinic in Rotterdam with a socioeconomically diverse population. SUBJECTS: 125 women with operable breast cancer. MAIN OUTCOME MEASURES: Incidence of complications after surgery for breast cancer, patient satisfaction with treatment, and psychosocial effects of short stay or long stay in hospital. RESULTS: Patient satisfaction with the short stay in hospital was high; only 4% (2/56 at 1 month after surgery and 2/52 at 4 months after surgery) of patients indicated that they would have preferred a longer stay. There were no significant differences in duration of drainage from the axilla between the short stay and long stay groups (median 8 v 9 days respectively, P=0.45) or the incidence of wound complications (10 patients v 9 patients). The median number of seroma aspirations per patient was higher for the long stay group (1 v 3.5, P=0.04). Leakage along the drain occurred more frequently in short stay patients (21 v 10 patients, P=0.04). The two groups did not differ in scores for psychosocial problems (uncertainty, anxiety, loneliness, disturbed sleep, loss of control, threat to self esteem), physical or psychological complaints, or in the coping strategies used. Before surgery, short stay patients scored higher on scales of depression (P=0.03) and after surgery they were more likely to discuss their disease with their families (at 1 month P=0.004, at 4 months P=0.04). CONCLUSIONS: Early discharge from hospital after surgery for breast cancer is safe and is well received by patients. Early discharge seems to enhance the opportunity for social support within the family.

Cost of care in a randomised trial of early hospital discharge after surgery for breast cancer.

The aim of this study was to determine the effect of the reduction of the length of hospital stay after surgery for breast cancer on the rate of care consumption and the cost of care. Patients with operable breast cancer were randomised to a short or long postoperative hospital stay. Data on care consumption were collected for a period of 4 months in diaries administered by patients, and socioeconomic status was evaluated by questionnaires. A cost minimisation analysis using the 'societal' perspective was performed and savings were compared with the savings of hospital charges. The use of professional home care was higher for the short stay group during the first month (7.2 versus 1.3 h, P < 0.0001). The number of out-patient consultations, the intensity of informal home care and patient's expenses did not increase after early discharge. The total cost of care was reduced by US$1320 by introducing the short stay programme (P = 0.0007), but the savings were substantially lower than the savings in hospital charges (US$2680).

Ultrasound-guided aspiration biopsy for detection of nonpalpable axillary node metastases in breast cancer patients: new diagnostic method.

This study was designed to evaluate the accuracy of ultrasonography alone and in combination with fine-needle aspiration biopsy (FNAB) for detection of axillary metastases of nonpalpable lymph nodes in breast cancer patients. Ultrasonography was carried out in 150 axillas of 148 patients (mean age 57 years, range 30-80 years); and in 93 axillas lymph nodes were detected. Nodes were described according to their dimension and echo patterns and were compared with histopathologic results. FNAB was carried out in 81 axillas (122 nodes). The sensitivity of ultrasonography was highest (87%) when size (length >5 mm) was used as criterion for malignancy, but the specificity was rather low (56%). When nodes with a malignant pattern (echo-poor or inhomogeneous) were visualized, specificity was 95%. Ultrasound-guided FNAB had a sensitivity of 80% and a specificity of 100% and detected metastases in 63% of node-positive patients. It is concluded that FNAB is an easy, reliable, inexpensive method for identifying patients with positive nodes. In the case of negative findings, other diagnostic procedures to exclude lymph node metastases, such as sentinel node mapping, could be performed.

Continuity of information for breast cancer patients: the development, use and evaluation of a multidisciplinary care-protocol.

The multidisciplinary nature of much patient-care may lead to gaps in the continuity of information which they receive, as well as to different care-professionals giving them contradictory information. As a counter-measure, a protocol has been developed which integrates medical, nursing, and a variety of extramural events and activities into a comprehensive description of 15 'moments' in the care of breast cancer surgery-patients. Among innovations, the protocol includes information about psychosocial guidance following diagnosis, and about the discharge procedure and contact with fellow-sufferers. The protocol was implemented in Rotterdam in 1994, in two hospitals and in the community; and evaluated formatively on the basis of reactions from 53 patients and 81 care-professionals. Both groups found its form and content to be successful and informative.

A prospective randomized trial of high versus low vacuum drainage after axillary dissection for breast cancer.

BACKGROUND AND METHODS: The influence of negative pressure on fluid production and complication rates after axillary dissection for breast cancer was studied in a prospective randomized trial. Patients were randomized for either a high or a low vacuum drainage system. Drainage volumes and complication rates were recorded. RESULTS: No statistically significant differences were found between the low vacuum group (n = 68) and the high vacuum group (n = 73) in volume (728 ml versus 780 ml) and duration (9.5 days versus 10 days) of seroma production, number of wound complications (5 versus 6), or infections (3 versus 2). There was a significant positive relationship between body mass index and seroma production, independent of the drainage system (P = 0.002). The drainage volume of the separately drained breast wound after mastectomy and lumpectomy was larger for the high vacuum system (55 ml versus 100 ml, P = 0.02). Vacuum loss was more frequent in the high vacuum drain group (11 versus 2, P = 0.01), where as leakage around the drain occurred more often in the low vacuum group (18 versus 6, P = 0.004). CONCLUSION: There are no differences in axillary fluid production or wound complication rates after axillary dissection and subsequent drainage between high and low vacuum drainage systems.

Staging methods for the assessment of dementia: Perspectives.

Most dementias in old age are characterized by a progressive course with interindividual variability in pattern and rate of progression. Developing a system for staging such dementia poses a challenge in capturing this variability in a system that will afford comparisons among individuals and predictions of future change. Several core questions underlie the development of such systems: (1) Is there a definable order in which abilities are lost? (2) Which skills and functions should be considered essential for the staging of dementia and what is their relative weight? (3) Can the different skills be captured within one staging system? (4) How is the whole range of function captured, and are the differences between stages clearly defined? (5) Which populations can be rated with each staging system? The determination of this last question is based on understanding which other medical conditions may interfere with the course of dementia and how prior characteristics, such as education, affect ratings on specific scales for the staging of dementia. Several systems for staging dementia in older adults are described. These include the Clinical Dementia Rating, the Global Deterioration Scale/Brief Cognitive Rating Scale/Functional Assessment Staging System, the Six Clinical Phases of Cognitive Decline, the Hierarchic Dementia Scale, and the Functional Capacity Scale. Some aspects of the utility of these systems are reviewed, and the issues for further research are discussed.

Fc receptor stimulation of phosphatidylinositol 3-kinase in natural killer cells is associated with protein kinase C-independent granule release and cell-mediated cytotoxicity.

Although diverse signaling events are initiated by stimulation of multichain immune recognition receptors on lymphocytes, it remains unclear as to which specific signal transduction pathways are functionally linked to granule exocytosis and cellular cytotoxicity. In the case of natural killer (NK) cells, it has been presumed that the rapid activation of protein kinase C (PKC) enables them to mediate antibody-dependent cellular cytotoxicity (ADCC) and "natural" cytotoxicity toward tumor cells. However, using cloned human NK cells, we determined here that Fc receptor stimulation triggers granule release and ADCC through a PKC-independent pathway. Specifically, pretreatment of NK cells with the selective PKC inhibitor, GF109203X (using concentrations that fully blocked phorbol myristate acetate/ionomycin-induced secretion) had no effect on FcR-initiated granule release or ADCC. In contrast, FcR ligation led to the rapid activation of phosphatidylinositol 3-kinase (PI 3-kinase), and inhibition of this enzyme with the selective inhibitor, wortmannin, blocked FcR-induced granule release and ADCC. Additional experiments showed that, whereas FcR-initiated killing was wortmannin sensitive and GF109203X insensitive, natural cytotoxic activity toward the tumor cell line K562 was wortmannin insensitive and GF109203X sensitive. Taken together, these results suggest that: (a) PI 3-kinase activation induced by FcR ligation is functionally coupled to granule exocytosis and ADCC; and (b) the signaling pathways involved in ADCC vs natural cytotoxicity are distinct.

Cytokine-enhanced NK cell-mediated cytotoxicity. Positive modulatory effects of IL-2 and IL-12 on stimulus-dependent granule exocytosis.

NK cells are a subpopulation of lymphocytes that kill virally infected cells and tumor cells without previous sensitization. Although exposure to distinct cytokines, including IL-2 and IL-12, can enhance these cytotoxic responses, the mechanism of this lymphokine-augmented killing remains unclear. Inasmuch as the cytotoxic event is a multistep process, there are many potential targets for lymphokine regulation. We focused on whether selected lymphokines directly modulate the intracellular signaling pathways critical for NK cell secretory function. In our experimental model, homogeneous, cloned human CD16+/CD3- NK cells were pretreated with either IL-2 or IL-12 and then stimulated with direct pharmacologic activators of the secretory response (e.g., PMA and ionomycin for intact cells or GTP gamma S for streptolysin-O permeabilized cells). Previous exposure of the cells to IL-2 or IL-12 enhanced the stimulus-induced release of granule-derived proteins (hexosaminidase and serine proteases) in a cytokine concentration- and time-dependent fashion. Furthermore, the cytokines increased the efficacies without changing the potencies of the secretagogues used in these studies. These results suggest that IL-2 and IL-12 augment NK cell-mediated cytotoxicity by increasing the maximal level of granule exocytosis evoked by Ca2+ and/or G protein-dependent intracellular signaling pathways.