Follow-up Of Breast Cancer Patients Research Articles

The prognostic value of the soluble urokinase-type plasminogen activator receptor (s-uPAR) in plasma of breast cancer patients with and without metastatic disease

Elevated levels of soluble uPAR (s-uPAR) and other fibrinolytic parameters functionally related to the urokinase-type plasminogen activator system might indicate the presence of cancer cells. In 25 breast cancer patients with metastases s-uPAR was significantly increased compared with 25 patients without metastases and with 25 healthy controls: 420 pg mL-1 vs. 145 pg mL-1 (P = 0.005) and 190 pg mL-1 (P = 0.003). Plasmin-alpha2-antiplasmin (PAP) complexes and d-dimers were significantly increased in breast cancer patients with metastases compared with patients without metastases and with healthy controls. The levels of plasminogen activator inhibitor (PAI)-1 activity, uPA antigen and factor (F)XIIa did not significantly differ between the patient groups and healthy controls. PAP complexes (529 microg L-1 vs. 420 microg L-1; P = 0.03), d-dimers (278.5 ng mL-1 vs. 79.0 ng mL-1; P = 0.005) and FXIIa (1.64 ng mL-1 vs. 1.19 ng mL-1; P = 0.01) were significantly higher in patients with metastases not surviving compared with patients with metastases surviving the 3-year follow-up period. Plasma s-uPAR levels in the patients with metastases did not discriminate between patients surviving and patients not surviving after 3-year follow-up. No significant differences in s-uPAR or any of the other parameters were found in the five patients developing metastases during follow-up. A single value of s-uPAR is of limited value in the follow-up of breast cancer patients with and without metastatic disease and does not predict survival or future metastases.

Health-related quality-of-life measurement in randomized clinical trials in breast cancer--taking stock.

Measurement of health-related quality-of-life (HRQOL) in randomized clinical trials in breast cancer has become common. In this review, we take stock of the contribution that HRQOL measurement in breast cancer clinical trials makes to clinical decision making regarding selection of optimal treatment. A series of MEDLINE searches was conducted to identify all randomized trials in breast cancer that included self-reported HRQOL or psychosocial outcomes. A total of 256 citations were identified that included HRQOL or psychosocial outcomes in breast cancer patients, and 66 of these involved randomized clinical trials of treatment. These 66 reports of breast cancer clinical trials of treatment are discussed in this review. Forty-six of the trials evaluated biomedical interventions, and 20 evaluated psychosocial interventions. Among the biomedical trials, eight trials evaluated HRQOL in primary management of breast cancer, seven trials evaluated HRQOL in adjuvant therapy of breast cancer patients, 20 trials involved metastatic breast cancer, eight trials involved symptom control/supportive care, and three trials evaluated different approaches to investigation or follow-up of breast cancer patients. Among the psychosocial trials, 13 trials evaluated HRQOL in adjuvant therapy of breast cancer patients, and their partners or spouses, six trials involved metastatic breast cancer, and one trial focused on symptom control. We found that the contribution of HRQOL measurement to clinical decision making depended on the clinical setting. In primary management of breast cancer, where medical outcomes of several treatment options are equivalent, HRQOL measurement provided added information for clinical decision making beyond that of traditional medical outcomes. In trials in the adjuvant setting, HRQOL measurement did not influence clinical decision making. In metastatic disease, HRQOL outcomes provided little information beyond that obtained from traditional medical outcomes, including toxicity. In the symptom control/supportive care setting, results of HRQOL questionnaires targeting specific symptoms (e.g., emesis) guided treatment decisions. In psychosocial intervention trials, psychosocial and/or HRQOL measurements often provided the only outcome information; therefore, selection of instruments that captured attributes likely to be altered by the intervention was essential. Until results of ongoing trials in breast cancer are available, caution is recommended in initiating new HRQOL studies unless treatment equivalency is expected, or unless the HRQOL questions target unique or specific issues that can only be addressed through patient self-report, including outcomes of psychosocial interventions.

Follow-up after Primary Treatment for Breast Cancer

Follow-up after primary treatment for breast cancer is a routine practice aiming at early detection and management of local recurrences and/or distant metastases of the disease or of new primaries. Breast self-examination and periodic physical examination, mammography, and pelvic examination are the most important methods in following-up these patients. The, at one time, more popular intensive routine diagnostic evaluation (including head, chest, abdominal, and pelvic computerized tomography and/or magnetic resonance imaging, liver ultrasonography, bone scans, tumor markers, etc.) is not currently considered appropriate and cost-effective. However, flexibility, based on clinical judgement, is required on the part of medical staff involved in the follow-up in order appropriately to adapt the general guidelines and meet the specific needs of the individual patients. Non-specialist or non-physician models of follow-up care have been proposed as interesting and cost-effective alternatives in the follow-up of breast cancer patients.

Evidence to Support a Change in Follow-up Policy for Patients with Breast Cancer: Time to First Relapse and Hazard Rate Analysis

The ideal follow-up for patients with cancer should be sensitive to the likelihood of relapse, for prompt investigation and treatment if indicated, together with the support of patient confidence. The current British Association of Surgical Oncologists guidelines for patients with breast cancer suggest intensive follow-up, including 3-monthly clinic visits during the first 2 years. These recommendations place increasing demands on clinical resources. The combined outcome of screening, early detection, dedicated clinical services that emphasize rapid diagnosis and concomitant improved survival, have resulted in increasing absolute numbers of diagnosed breast cancer patients in follow-up clinics. This article examines the follow-up of breast cancer patients to determine if the convention should be adjusted to obtain more from current resources while maintaining equivalent patient care.The data on all patients with breast cancer attending one general oncology clinic were examined in order to determine the pattern of relapse. Analyses identified: (1) the time to relapse at any site and at specific sites; and (2) the prognostic significance of three factors for subsequent relapse, namely nodal status, menopausal status and T stage at diagnosis.In 416 consecutive patients, the annual rate of relapse of breast cancer was found to increase progressively over the first 4 years. Nodal disease was the most important single variable as a predictor of relapse. The annual hazard rate for relapse for node positive patients in the first year was 5%; this increased to 10% and 14% in years three and four respectively. In contrast, in those patients who were node negative at diagnosis (302/416; 73%), the hazard rate for relapse was 1% in year one, increasing to 5% in years three and four.Intensive early follow-up of breast cancer patients provides no clear clinical gain for the great majority of patients, since early relapse is rare in the first year. The use of clinical funds and staff resources might be optimized to focus clinical follow-up on those patients at risk of recurrence. We suggest that all patients should continue to be monitored and receive psychological care through access to their general practitioner, skilled breast care nurses and specialized counsellors. Any patient at risk, or developing symptoms of relapse, would have immediate clinical access to the oncologist for diagnostic investigations. This strategy would optimize psychological patient care and use the full backup of clinical resources during the prolonged period over which relapse becomes more probable.

Quantification of MUC1 in breast cancer patients: A method comparison study

Objective: To compare the performance of four serum assays for the quantification of MUC1 in breast cancer patients. Study design: A total of 282 serum samples were evaluated with two automated (Boehringer Mannheim Enzymun-Test® CA 15-3 and Chiron ACS™ BR) and two manual assays (Centocor CA 15-3® radioimmunoassay [RIA] and Biomira Truquant® BR RIA™). Sera were obtained from healthy controls ( n=50), patients with benign ( n=25) and malignant breast disease ( n=77) and patients with other malignancies ( n=69). In addition, sera from pregnant women ( n=56) and patients with liver cirrhosis ( n=5) were included. Results: Intraassay coefficients of variation (C.V.s) were highest for the manual Centocor CA 15-3 assay (7.4% for values below 50 kU/l and 8.1% for values above 180 kU/l). Interassay C.V.s were highest for the manual Truquant BR assay (11.7% for the lower concentration values and 18.6% for the higher concentration values). False positive rates ranged between 0% for the Centocor CA 15-3 RIA and 14% for the ACS BR assay (cut-off: 30 kU/l). In monitoring breast cancer patients all four assays show similar patterns, although absolute MUC1 values found may differ up to 50%. Conclusion: For monitoring purposes all assays perform equally well, however, automated assays show lower inter- and intraassay variability, especially in the higher value range. Therefore we recommend the use of the same, automated, assay for quantification of MUC1 during the follow-up of breast cancer patients.

Detection of the first recurrence during intensive follow-up of breast cancer patients.

Breast cancer patients are routinely followed after primary treatment. Many intensive diagnostic methods (tumor markers, chest X-ray, mammography, liver echography, bone scans) are performed periodically. However, it remains to be determined how often attempts should be made to detect the first recurrence of breast cancer by these methods. To evaluate the effect of imaging diagnosis and tumor markers, we analyzed methods of detection of first recurrence sites during intensive follow-up of breast cancer patients. Of 550 female patients who had been surgically treated between July 1992 and December 1996, 65 recurrent cases had been diagnosed as of December 1997. Thirty cases (46%) had been found as a result of symptoms related to the site of recurrence and 14 cases (22%) were detected by physical examination. In the remaining 21 cases (32%), detection was by other methods: in eight cases by imaging diagnosis, in three cases based on abnormal tumor markers and in 10 cases by imaging diagnosis and abnormal tumor markers. Twenty-nine cases (45%) followed every 1-3 months had presented with symptoms at routine or interval appointments. There was a significant difference between first recurrence sites (loco-regional, bone and viscera) and the methods of detection (symptoms, physical examination and other diagnostic methods) (P < 0.0001). However, no statistical difference in overall survival after operation was observed between the 30 cases found as a result of symptoms and the 35 cases detected by physical examination or other diagnostic methods. Taken together with ASCO's surveillance guidelines (J Clin Oncol 1997;15:2149-56), intensive follow-up of breast cancer patients should be limited to high-risk breast cancer patients, especially those who enter randomized clinical trials. A careful history and physical examination are in practice indicated every 3-6 months for 3 years and then every 6 months for the following 2 years.

The effectiveness of the routine clinic visit in the follow-up of breast cancer patients: Analysis of a defined patient cohort

The study aimed to identify the proportion of patients with relapse or a contralateral breast tumour who are diagnosed as a consequence of regular follow-up in a specialist breast clinic after breast conserving surgery and radiotherapy for early breast cancer. A retrospective review was undertaken of 490 consecutive patients entered into a randomized clinical trial of radiotherapy fractionation at a single institution. As part of the trial, patients were reviewed in a multidisciplinary breast clinic 3-monthly for the first 3 years, 6-monthly between 3 and 5 years and annually thereafter, with biennial mammography. For this study, information was retrieved from hospital records to ascertain: (a) whether patients were symptomatic at the time of relapse or contralateral breast tumour; and (b) whether they presented at a scheduled appointment or brought their appointment dates forward. The subsequent management of patients with relapse was reviewed to determine whether or not this may have been influenced favourably by a policy of regular follow-up. Twenty-one (44%) of the 48 patients with locoregional relapse were asymptomatic. Of these, 17 were detected by clinical examination (that is, directly as a result of a routine clinic attendance), while four were detected by routine mammography. Ten of the 17 patients diagnosed by clinical examination had successful surgery for locoregional relapse and all have remained disease free. Five of 17 developed distant metastases within 6 months and two others had skin nodules on the breast excised. Only three of the 67 patients with distant relapses were asymptomatic. Two of the 11 patients with contralateral breast tumours were asymptomatic and were diagnosed on routine mammography. The benefits and cost-effectiveness of less rigid approaches to follow-up of breast cancer patients needs to be evaluated in large prospective randomized trials.

The prognostic significance of increasing marker levels in metastatic breast cancer patients with clinically complete remission, partial remission or stable disease.

TPS, CA 15-3 and CEA were determined in metastatic breast cancer patients during treatment. After six months of follow-up the patients were divided into four groups according to the UICC criteria for treatment response. Forty-six patients with a more favorable prognosis (complete remission, partial remission or stable disease) were followed for an extended period. In 30 of the 46 patients at least one marker had increased at the end of the six-month period by at least 25% (TPS in 54%, CA 15-3 in 20%, CEA in 20%). All these 30 patients subsequently developed progression. The prognostic sensitivity was 83%, 30% and 30%, respectively, for TPS, CA 15-3 and CEA. The combination of TPS and CA 15-3 showed a sensitivity of 96%. The median lead time was about 8 months for TPS and CA 15-3, but less than 50% of the patients showed a lead time for CA 15-3 as compared to TPS. We conclude that TPS and CA 15-3 determinations are helpful for the prediction of progression during the follow-up of breast cancer patients.

Implication of video assisted thoracoscopic surgery in the diagnosis of pulmonary metastasis of breast cancer

PURPOSE: To determine pulmonary metastasis, video assisted thoracoscopic surgery (VATS) was performed on the patients who had undergone breast cancer aurgery. PATIENTS AND METHODS: Nineteen patients with a history of breast cancer underwentVATS, because of subsequent abnormal pulmonary shadows on chest computed tomograms (CT). All patients were suspected to have pulmonary metastasis from breast cancer. RESULTS: The VATS procedure showed 10(52%) patiens to have pulmonary metastasis, but, 9(48%) had primary lung cancers or benign lesions. In the patients of pulmonary metastasis, 7 had nodular lesions (5 had a single nodule and 2 had two nodules with a median diameter of 8.5 mm), and 3 patients had pleural dissemination. The follow-up period of the patients with pulmonary metastasis ranged from 3 to 28 months. Three patients died of brain metastasis and respiratory failure, 3 suffered recurrence and 4 were free from disease after VATS. CONCLUSION: VATS was useful for distinguishing small metastatic lesions from other diseases and a minimally invasive surgical approach in the follow-up of breast cancer patients suspected of pulmonary metastasis.

Clinical evaluation of potential usefulness of CEA, CA 15-3, and MCA in follow-up of breast cancer patients.

The potential usefulness of MCA, CA 15-3 and CEA in monitoring of breast cancer patients was evaluated in 135 female patients with histologically confirmed breast cancer. The patients were classified into two groups as follows: group of patients with no evidence of disease, NED; and group of patients with progressive disease, PD. In total, 2106 measurements of CEA, CA 15-3, and MCA were performed using an enzyme immunoassay. Serum levels of all three markers in the NED group differed significantly from those of patients with PD. The observed differences in the sensitivity and specificity of CEA, CA 15-3, and MCA tests were not significant. The serum concentrations of a particular marker correlated well with the concentrations of the other two markers, except when CEA was correlated with MCA or CA 15-3 in NED group patients. The elevation of tumor markers preceded by some 7 months the clinical evidence of dissemination, and marker levels reflected at a high percentage the response to therapy in PD patients. Therefore, this clinical study confirmed that MCA, CA 15-3 and also CEA are suited to discriminate between disease and disease-free periods, and also validated the usefulness of markers for treatment response monitoring.

The efficacy of surgical treatment of breast cancer

The purpose of the analysis was to resolve the two opposing claims regarding the efficacy of surgical treatment of breast cancer, namely the course of the disease is not affected by surgery because breast cancer is an incurable systemic disease, as shown by a previous analysis, results of randomized breast cancer treatment trials and long-term follow-up of breast cancer patients; and breast cancer can be cured if detected early, as shown by reduced breast cancer mortality observed in results from randomized breast cancer-screening trials using mammograms. Seven randomized breast cancer-screening trials commonly cited as having produced evidence for reduced breast cancer mortality were analysed to identify any flaws in the trial design that would lead to confounding factors that could have affected the results. Flaws were identified in all trials in that the treatment protocols, by requiring that the type and degree of treatment depended on the stage of the tumour at diagnosis, required that up five factors were varied in each trial, confounding the results. Correlations were sought between some of these factors and the breast cancer mortality reduction observed in some screened groups to determine which factors had the main influence on the observed results. No correlation was found between reduced breast cancer mortality and earlier surgical intervention. In fact, the trial with the most earlier surgical intervention had the smallest reduction in mortality; and that with the least earlier surgical intervention had the largest reduction in mortality. This demonstrates that the earlier-diagnosis hypothesis is invalid. Some correlation was established between reduced mortality and reduced use of radiotherapy, suggesting that radiotherapy had a greater influence on mortality than surgery. Analysis of deaths from other causes suggests that there are at least two effects involved: immune suppression caused by radiotherapy, and increased classification of breast cancer deaths as deaths from other causes following ischaemic heart damage caused by radiotherapy. Claims that mammographic screening reduces breast cancer mortality are therefore unproven. The conclusion from the previous analysis, that surgery has not been shown to reduce mortality for any form of cancer, is therefore still valid. Surgery for breast cancer should therefore be considered as a palliative measure and radiotherapy should be avoided as a routine technique.

Recommendations on follow-up of breast cancer patients following primary therapy.

Follow-up of breast cancer patients who have completed their primary therapy has not been standardized. The literature is reviewed and it is proposed that "minimal" follow-up with history and physical examination is the most appropriate procedure. Data show that more expensive imaging studies be carried out only in patients who are symptomatic from their disease, otherwise such an intensive follow-up schedule is not cost effective.

82 P - CAl5.3: A breast cancer marker predicting location of metastases even before treatment

The aim of this study was to asses the ability of the antigenic tumor marker CA15.3 to identify, predict and exclude metastases in bone/viscera both in pretreatment determinations and dwing follow-up of breast cancer patients. Serum values of CA15.3 were measured in a prospective series of 164 patients prior to therapy and every 3 months during a minimum of 2 years-follow-up. In our series, 8 out of 14 (57.2%) and 51 out of 150 (34.0%) of patients with normal and elevated pretreatment values of CAl5.3 progressed (p = 0.085). Whereas 21 out of 51 patients (41.2%) who showed progression of the disease with pretreatment CA15.3 normal values developed bone metastases, 8 out of 8 (100%) patients with previous CA15.3 determinations superior to 40 U/ml and progression had bone metastases p = 0.0180) showing a predilection for this site of relapse in this group of patients. Considering the “follow-up determinations”, 27 patients out of 51 (52.9%) with CA15.3 pretreatment values inferior to 40 U/ml and progression showed CAl5.3 elevations during follow-up, CA15.3 correctly classified 64.4% of patients with progression (70.3% if only bone/viscera metastases are included) (sensitivity) and 94.3% without (specifity). Our results seem to indicate that patients with pretreatment CA15.3 high values are prone to develop bone metastases more frequently than other any other type of progression. There is the possibility that tumor heterogenety plays a role in this question. Cells expressing CAl 5.3 would possibly have more “bone-affinity”.

56. Long-term follow-up of breast cancer patients with micrometastatic tumour cells in bone marrow at primary surgery — prognostic impact in comparison to nodal status

56. Long-term follow-up of breast cancer patients with micrometastatic tumour cells in bone marrow at primary surgery — prognostic impact in comparison to nodal status

Individual reference ranges of CA 15-3, MCA and CEA in recurrence of breast cancer.

The long-term intra-individual variation of the title tumour markers was studied in the group of 33 patients which developed no relapse. The average biological intra-individual CV was 11.2% for CA 15-3 and 14.9% for MCA whereas those of CEA strongly depended on the concentration. The intra-individual standard deviation of CEA was independent of concentration and amounted to 0.23 g/L. Individual reference ranges the analytes were much smaller than the group reference ranges. Individual reference limits were calculated on the basis of the average intra-individual variation. In 21 of the 22 patients who developed recurrence during the follow-up period, individual reference limits of CA 15-3 and/or CEA were exceeded 1 to 31 months (median 10 months) before clinical evidence (diagnostic sensitivity 95%). Group reference limits were exceeded only in 13 patients (diagnostic sensitivity 60%) and occurring later. The diagnostic specificity was 97%. MCA did not provide additional information. The combination of CA 15-3 and CEA is an excellent for detection and exclusion of recurrence in the follow-up of breast cancer patients if decision-making is based on individual reference limits. Improvement of the long-term analytical quality of the tumour marker assays, particularly in the low concentration range is necessary.

A survey in Puglia: The attitudes and opinions of specialists, general physicians and patients on follow-up practice

The follow-up for breast cancer patients is a well established routine practice requiring the organization and coordination of many professional figures and a large expenditure of national health funds. To study the problems in practical clinical management of such a complicated health program in a typical population, a questionnaire survey of the opinions and attitudes of specialists, general practitioners and patients directly involved in clinical follow-up was performed in the Puglia region of Southern Italy. A representative sample of specialists (n = 285), general practitioners (n = 263) and patients (n = 284) involved in the management of follow-up practice for breast cancer in Puglia received different questionnaires to ascertain their behaviour, attitudes, opinions, perception of the disease and the organizational requirements for treatment. A total of 57.4% of questionnaires were returned. The most important results were: (a) about one-third of cases complained of difficulties in follow-up management due to the lack of cooperation and integration of follow-up procedures among specialists; (b) the general practitioners preferred to have a more active role in follow-up; (c) the patients reported that being managed by more than one physician or living far from follow-up facilities resulted in an inferior quality of life.

Evaluation of Autogenous Tissue Breast Reconstruction Using MRI

Recent controversy encountered with silicone breast implants has increased the use of autogenous tissue for breast reconstruction following mastectomy. Surveillance of patients who have undergone autogenous tissue reconstruction is important in the evaluation of recurrent or new cancer. Magnetic resonance imaging (MRI) has proven to be a useful technique in the delineation of soft tissues and provides excellent resolution. Recently, MRI has been reported to be a valuable diagnostic imaging modality for the evaluation of augmented breast implant patients with regard to implant rupture detection, silicone granuloma identification, and silicone gel migration delineation. In this study, various autologous tissue donor sites currently available for breast reconstruction were imaged by MRI. The following donor flaps were included: fleur-de-lis, TRAM, gluteal, and tensor fasciae latae. A total of 10 clinical cases were investigated. The anatomic basis of each flap type is illustrated, and various tissue components of flap tissue (skin, fat, and muscle) are demonstrated on MRI scan. Anatomic knowledge of autogenous tissue types and MRI appearance of the flap-breast-chest-wall interface are critical in the surveillance and follow-up of breast cancer patients.

Breast cancer and clinical utility of CA 15-3 and CEA.

This manuscript summarizes the experiences with CA 15-3 and CEA obtained in 8,000 breast cancer patients. These markers were usually in normal range (CEA < 6 micrograms/L, CA 15-3 < 40 U/L) before surgery and increased only before the development of distant metastases. 80% of all patients with metastases had elevated marker levels several months before or at the time of detection of metastases. Therefore CA 15-3 and CEA determinations should be used as an easy method for screening of metastases during follow-up of breast cancer patients.

Value of routine abdominal and lymph node sonography in the follow-up of breast cancer patients

Objective: The aim of this study was to review usefulness and intervals for abdominal sonography during the follow-up of breast cancer patients. Additionally, we assessed the value of regional lymph node sonography in patients with possible locoregional recurrence. Subjects: Retrospectively, 2657 abdominal ultrasound examinations of 414 patients and 299 sonographic examinations of the regional lymph nodes in 227 patients after surgical treatment for breast cancer were evaluated. Results: Follow-up abdominal sonography revealed metastases in 6.8% of patients, and in 1% of examinations. There was no dependence on the initial T- or N-stage. At sonography of the regional lymph nodes in patients with suspicious palpatory findings metastatic nodes were found in 15.9% of patients, and in 12% of examinations. Conclusion: Risk-adapted follow-up intervals for abdominal sonography cannot be proposed, regular examinations are not recommended. Lymph node sonography is useful and promising in the evaluation of suspicious palpatory findings.

Routine follow-up of breast cancer patients

The outcome of routine follow-up of women treated for breast cancer by mastectomy has been analysed. Over 157 woman-years of follow-up, 315 routine visits were made by 33 women who had been subjected to mastectomy. At these routine clinics two asymptomatic recurrences were diagnosed. Both of these patients died within 2 years of relapse. At 26 routine clinic visits, a diagnosis other than recurrence of breast cancer was made. Routine follow-up of women treated for breast cancer by mastectomy has limited value.