Prognostic factors for lymphedema after primary treatment of breast carcinoma.

BACKGROUND: Lymphedema of the arm is a serious consequence of breast carcinoma treatment. Postmastectomy lymphedema of the upper limb usually is related to certain risk factors such as axillary surgery, radiotherapy, obesity, venous outflow obstruction, delayed wound healing, and infection. The objective of the current study was to identify the risk factors for secondary lymphedema after breast carcinoma treatment. METHODS: A total of 1278 breast carcinoma patients, all of whom were residents of Florence area, Italy at the time of diagnosis and who were operated on by the same surgeon between 1989 and 1997, were included in the current analysis. The circumference of the upper arm was measured and lymphedema was defined as being present when an increase of > 5% of the sum differences between the two arms was found. The observed cumulative probability of lymphedema occurrence was estimated using the Kaplan-Meier method. The Cox proportional hazards models were fitted to assess the relative excess risk of lymphedema and to check for confusing factors. All patients with lymphedema who were living in the Florence area were referred to a specialist for treatment. RESULTS: Two hundred three cases of lymphedema of the ipsilateral arm were found (15.9%). The right arm was affected in 44.5% of the cases and the left arm in 55.5%. The risk of developing late lymphedema was found to be significantly related to a pathologic T2 classification (hazards ratio [HR] = 1.44; 95% confidence interval [95% CI], 1.06-1.94) and postoperative radiotherapy (HR = 1.35; 95%CI, 1.00-1.83). Patients who had > 30 lymph nodes removed were found to have a borderline increased risk of lymphedema (HR = 1.64; 95% CI, 0.99-2.74). Multivariate analysis identified postoperative radiotherapy (HR = 1.38; 95% CI, 1.02-1.86) and the number of lymph nodes removed (HR = 1.29; 95% CI, 1.04-1.59) to be independent predictors of lymphedema. CONCLUSIONS: The results of the current study demonstrated that the risk of lymphedema was correlated with the use of postoperative radiotherapy and the number of lymph nodes removed.

General practitioners and mammographic screening uptake: influence of different modalities of general practitioner participation. Working Group.

AIMS AND BACKGROUND: To compare the impact of different modalities of general practitioner (GP) involvement, including the introduction of target payments, on the attendance rate of organized population-based screening programs for breast cancer in Italy. STUDY DESIGN: The study was conducted between 1994 and 1996 in four Italian cities where mammographic screening programs are active: Caltanissetta (CL), Firenze (FI), Modena (MO) and Torino (TO). The impact on attendance rate of different invitation strategies based on active GP involvement was tested in each center. The additional effect of economic incentives was also assessed. The incentives were proportional to the level of compliance attained by each GP and weighted by the size of his eligible patients' list. RESULTS: In the Firenze project, an invitation signed by the GP and the project co-ordinator attained a statistically significant higher participation (difference: 4.2%, chi2 = 7.42, P = 0.006). In Caltanissetta and Torino there was a significant increase of about 7% in the response rate to the postal reminder in the groups contacted by the GPs. No difference was observed in the Modena project between the two groups. CONCLUSIONS: The main contributions of GP involvement can be: "cleaning up" the invitation lists, especially when computerized archives with the mammographic history of the target population are not available; increasing the women's participation by signing the invitation letter, by counseling and active participation in the invitation phase; co-operating in the reminder phase by recalling women non responders at first invitation. The offer of target payment had a certain impact on the screening uptake, but not easily distinguishable from GP signature of the invitation letter; further studies of appropriate design should be planned. Organizational factors, such as availability of a list of non-responders, might be crucial in order to enhance the effect of the GPs' action.

Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer.

BACKGROUND: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in preclinical studies. We determined the efficacy of fenretinide in preventing a second breast malignancy in women with breast cancer. METHODS: We randomly assigned 2972 women, aged 30-70 years, with surgically removed stage I breast cancer or ductal carcinoma in situ to receive for 5 years either fenretinide orally (200 mg/day) or no treatment. The primary end point was the incidence of contralateral breast cancer or ipsilateral breast cancer 7 years after randomization. Other end points considered post hoc were the same outcomes stratified by menopausal status, incidence of distant metastases, overall mortality, and tumors in other organs. The hazards of breast cancer occurrence were determined by Cox proportional hazards regression analysis. Statistical tests were two-sided. RESULTS: At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P =.642) or ipsilateral breast cancer (P =.177) between the two arms. However, an interaction was detected between fenretinide treatment and menopausal status in both outcomes (P for interaction in both outcomes =.045), with a possible beneficial effect in premenopausal women (contralateral breast cancer: adjusted hazard ratio [HR] = 0.66, and 95% confidence interval [CI] = 0.41-1.07; ipsilateral breast cancer: adjusted HR = 0.65, and 95% CI = 0.46-0. 92) and an opposite effect in postmenopausal women (contralateral breast cancer: adjusted HR = 1.32, and 95% CI = 0.82-2.15; ipsilateral breast cancer: adjusted HR = 1.19, and 95% CI = 0.75-1. 89). There were no statistically significant differences between the two arms in tumors in other organs, incidence of distant metastasis, and all-cause mortality. CONCLUSIONS: Fenretinide treatment of women with breast cancer for 5 years appears to have no statistically significant effect on the incidence of second breast malignancies overall, although a possible benefit was detected in premenopausal women. These studies, particularly the post hoc analyses, are considered exploratory and need to be confirmed.

Early diagnosis, place of diagnosis and persistent differences at 10 years in breast cancer survival. Hospitals and breast clinic cases prognosis.

In the Province of Florence (central Italy), the Center for Cancer Prevention (CSPO) runs a breast clinic for early diagnosis of breast cancer at which women can present as self-referrals or be referred by a general practitioner. About 55% of breast cancers incident in the area were diagnosed at CSPO. This paper evaluates the differences observed in 10-year observed and relative survival between hospitals and breast clinic cases. A population-based data set of 1182 invasive cases diagnosed in the years 1985 and 1986 (Tuscany Cancer Registry) was analyzed. Cox models were used to evaluate the effects of place of diagnosis on observed survival. In comparison to hospital cases, breast clinic cases showed a significantly higher frequency of localized cancer (55% vs 37%) and a better relative survival, persistent at 10 years of follow-up (69% vs 58%). The better survival of breast clinic cases persisted after age adjustment (hospitals cases; RR = 0.71, 95% CI: 0.60-0.84) and after age + diffusion of disease adjustment (RR = 0.79, 95% CI: 0.66-0.93). For regionally diffused cancers, breast clinic cases showed a 10-year survival significantly better than hospital cases. In conclusion, even if some bias (i.e. lead-time and length bias) could affect the comparison, breast clinic cases showed a better survival persistent until 10 years after diagnosis. An earlier stage distribution explained, at least partly, the different prognosis.

Chemoprevention trial of contralateral breast cancer with fenretinide. Rationale, design, methodology, organization, data management, statistics and accrual.

The Fenretinide (4-HPR) Breast Cancer Study is a randomized multicenter clinical trial originally designed and conducted by the investigators of the Istituto Nazionale Tumori of Milan. The study is sponsored by the National Cancer Institute of Bethesda and by the Italian National Research Council. The trial was designed to evaluate the effectiveness of the synthetic retinoid 4-HPR, at a dose of 200 mg per os every day for 5 years, in reducing the incidence of contralateral breast cancer in a population of patients previously operated on for breast cancer. Between 1987 and 1993, the Istituto Nazionale Tumori of Milan and 9 other collaborating Centers enrolled 2,972 women between the ages of 30 and 70 years who had been previously operated on for T1-T2 N- M0 breast cancer. This paper describes the rationale, design, methodology, organization, data management, statistics and accrual of the participating population.

Long-term sequelae of breast cancer surgery.

BACKGROUND: Quality of care is today a major issue in oncology, and much attention is given to research on the outcome of breast cancer care. Too little attention has been devoted in the scientific literature to the consequences of treatment in long-term survivors, and in particular to the possible side effects. The specific aim of this contribution is to present population-based data about the long-term impact of breast cancer care in women who had an incident cancer in 1985/1986. PATIENTS AND METHODS: The cases are 476 breast cancers incident in the City of Florence in 1985-86. Women still living 5 years later were invited to have an interview and a physical examination. Lymphedema, peripheral nerve lesions and damage to the shoulder were assessed. RESULTS: Of the 346 5-year survivors, 238 accepted our invitation: 35.2% of the women reported some early postoperative sequelae, 30.2% had a chronic lymphedema and 18.9% a shoulder deficit. Comparing breast-conserving surgery with radical mastectomy, the risk of chronic lymphedema (OR = 1.62; 95% C1: 0.91-2.88) and other lesions was higher for women who had a radical surgery. Women who had a breast-conserving surgery more often reported an early lymphedema (OR = 1.60; 95% Cl: 0.88-2.88). CONCLUSIONS: The proportion of women who complained of (or manifested at the physical examination) a minor or major disability of the arm in our study was high. The impact of these functional problems in terms of quality of life should also be assessed, but it is our impression that there is need for much greater attention to the issue of long-term survivor sequelae.

Time trends of benign/malignant breast biopsy ratios a multicenter Italian study.

AIMS AND BACKGROUND: Although they have been decreasing over time due to improved specificity of diagnostic assessment, benign biopsies of the breast are still common. Benign biopsies should be regarded as negative events, due to their economical and psychological cost and their possible negative impact on cosmesis and on further diagnostic evaluation. METHODS: Retrospective data on benign/malignant breast biopsies ratio (B/M) were collected in 9 Italian centers for a period of 10-15 years. The time trend of B/M and its association to age or to single centers was evaluated. RESULTS: Overall 31,001 cases were considered. A strong association of B/M to age was evident (average B/M values were 5.0, 1.3, 0.6, and 0.2 for women aged < 40, 40-49, 50-59, and > 59 years). A significant trend of decreasing B/M over time was observed only for one center. Age standardized B/M was significantly different (P < 0.000001) between centers, ranging between 0.34 and 1.69. Multivariate analysis confirmed an independent significant association of age and center to B/M. CONCLUSIONS: Marked differences in B/M are evident between centers, which cannot be explained by the confounding effect of age or by any apparent difference in the diagnostic protocol. The observed differences are likely ascribed to individual variations in diagnostic aggressivity. A progressive increase of the predictive value of calls for surgical biopsy may be achieved over time and centers with a high B/M should make every effort to optimize their performance. Acceptable (< 40 = 5, 40-49 = 1.5, 50-59 = 0.75, > 59 = 0.3) and desirable (2.5, 0.75, 0.35, 0.15) age specific reference standards for B/M are proposed.

Breast cancer screening: characteristics and results of the Italian programmes in the Italian group for planning and evaluating breast cancer screening programmes (GISMa).

In 1990, GISMa (Italian Group for planning and evaluating Mammographic Screening - Gruppo Italiano per la pianificazione e la valutazione dei programmi di Screening Mammografico), a working group of operators (radiographers, radiologists, epidemiologists, clinicians, surgeons) involved in screening programmes ongoing in Italy, was created within the Italian School of Senology. The aim of this study is to illustrate data, presented at the GISMa meeting held in April 1994, concerning the characteristics of each programme and some early indicators of effectiveness. To assess these parameters (concerning compliance level, recall rate, benign/malignant biopsy ratio, detection rate, stage distribution, nodal involvement and number of cancers with a diameter under 1 cm, rate of cancer, etc.), 'acceptable' and 'desirable' standards obtained from Italian and North-European cancer screening experiences have been adopted. Most programmes have shown an acceptable standard for most of the indicators, and many of them have attained desirable levels. In most screening programmes the occurrence of interval cancers has not yet been measured, but all centres have (or are working to set up) a systematic active procedure to collect the data. The results indicate that common guidelines can be adopted, even when working in very heterogeneous contexts, and that it is possible to achieve a very high effectiveness and efficacy level. As regards quality control and cost/benefit issues, the goal of extending centralised, population-based screening programmes to other Italian regions becomes a priority.

Accuracy and reliability of frozen section diagnosis in a series of 672 nonpalpable breast lesions.

Frozen section (FS) diagnosis was routinely performed in a large series of nonpalpable breast lesions from 1977 through 1991. The original FS diagnoses of 672 patients were classified in four categories (1 = benign lesion, 2 = in situ carcinoma, 3 = invasive carcinoma, 4 = deferred diagnosis) and compared with the diagnoses obtained at review of the permanent paraffin sections to estimate the accuracy of FS. A review of the mammographic pattern of the lesion was also performed. Frozen section diagnostic conclusion was deferred to permanent paraffin sections in only 22 cases (3.3%). Benign or malignant (grouping in situ and invasive carcinomas) FS diagnoses were accurate in 623 of 650 cases (95.8%). Overall, the prevalence of malignant lesions was 44.8% with a benign/malignant ratio of 1.2. The diagnosis was modified on the basis of permanent sections in 27 cases (4.2%) with three false positives and 24 false negatives. Sensitivity and specificity of FS diagnoses were 91.7 and 99.2%, respectively. When the comparison between FS and histologic diagnoses was analyzed according to the mammographic pattern, sensitivity among patients with microcalcifications as the only alteration was lower (88.8%) than among patients with opacities (94.9%). On the basis of these results, FS is to be considered a feasible and reliable diagnostic procedure in nonpalpable breast lesions, particularly in cases excised because of a mammographic opacity that is identifiable on gross examination of the surgical specimen.

Independent double reading of screening mammograms.

OBJECTIVE: To evaluate the cost effectiveness of independent double reading of screening mammograms. SETTING: Prospective study of 18,817 women undergoing first or repeat screening in a population based programme in the Florence district. METHODS: Mammograms were independently double read by experienced radiologists. Subjects with mammographic abnormalities reported by at least one reader were recalled for diagnostic assessment. The mean increase in recall rate, cancer detection rate, and screening costs attributable to double reading was calculated. RESULTS: Eleven of 125 cancers were detected by only one reader. The mean increase in cancer detection rate attributable to double reading compared with single reading was 4.6% (95% confidence interval (CI) 1.1 to 8.9). From a total of 748 cases referred for diagnostic assessment, 196 subjects were referred by one reader only. The mean increase in referral rate attributable to double reading compared with single reading was 15.1% (CI 12.3 to 17.8). Double reading caused a marked increase in the cost for each woman screened -8.5% at the first screening and 6.2% at repeat screening and a more limited increase in the cost for each cancer detected -3.5% at the first screening and 2.7% at repeat screening. Cancers detected by only one screener were at an earlier stage than those detected by both screeners (P = 0.6, not significant). CONCLUSIONS: Independent double reading results in only a modest increase in the detection of cancers and therefore may not be cost effective.

Assessment of lesions detected at mammographic screening: performance at first or repeat screening in the Florence programme.

OBJECTIVE: To evaluate the assessment criteria and the results achieved in the detection of breast lesions at mammographic screening. SETTING: Review of cases assessed in the last screening round of Florence city (FC--first screening round: 29,522 subjects) and Florence district (FD --repeat screening round: 13,268 subjects) programmes. METHODS: Referral and biopsy rates, predictive values, and prevalence of cancers detected by screening were determined, as well as the frequency of the diagnostic procedures used at assessment, and their contribution to the final diagnosis according to the mammographic appearance of the suspected lesion. Assessment costs were estimated. RESULTS: Referral rate (FC 4.2%; FD 1.8%), referral positive predictive value (FC 18.7%; FD 28.3%), surgical biopsy rate (FC 0.96%; FD 0.6%), benign/malignant biopsy ratio (FC 0.20; FD 0.13), and prevalence of cancers detected by screening (FC 0.78%; FD 0.5%) were all within the European Community (EC) recommended standards for screening performance. The benign biopsy rate was considerably lower than that of recommended standards. The cost for each subject assessed was 179,000 Italian lire at the first and 116,000 lire at repeat screening. The cost for each subject screened that was attributable to assessment was 7600 lire at the first or 2100 lire at repeat screening. CONCLUSIONS: Limited referral rates and costs were achieved and the proportion of cancers detected by screening was high. The number of referrals was further reduced at repeat screening, and assessment had a limited impact on total screening costs. Detail or magnification mammography, palpation, sonography, and fine needle aspiration cytology all contributed to the final diagnosis and should be immediately available at the assessment clinic. The observed benign biopsy rate was particularly low and suggests that EC recommended standards should be modified.

Non-palpable lesions of the breast detected by mammography--review of 1182 consecutive histologically confirmed cases.

We report on 1182 consecutive histologically confirmed non-palpable breast lesions detected by mammography (infiltrating carcinoma 427, in situ carcinoma 121, benign 634). The proportion of cancer cases varied according to age (< 50 years = 33%; 50-59 years = 46%; > 59 years = 63%), mammographic pattern (regular opacities = 8%, parenchymal distortions = 20%, isolated calcifications = 42%, irregular opacities = 62%, stellate opacities = 73%), and calendar period (1970-1985 = 29%, 1986-1989 = 56%; 1990-1992 = 69%). A sharp decrease of the benign/malignant biopsy ratio was evident after routine fine-needle aspiration cytology (sonography-guided or stereotaxic) was introduced in 1986. The independent significant association of cancer frequency to age, calendar period and mammographic pattern was confirmed by multivariate analysis. A significant trend over time in favour of conservative surgery was also observed for cancer cases (1970-1979 = 6%, 1980-1985 = 41%, 1986-1992 = 83%). Among invasive cancers, node involvement was observed in 11.5% of cases, being associated with tumour size (pT1a = 0%, pT1b = 7%, pT1c = 13%, pT2a = 33%). Five-, ten- and fifteen-year overall survivals of invasive cancers were 98.1, 95.7 and 87.3%, respectively.

Fine-needle aspiration cytology of nonpalpable breast lesions: US versus stereotaxic guidance.

The authors evaluated ultrasound (US)-guided fine-needle aspiration cytology (FNAC) in 270 patients with suspicious findings at mammography. FNAC with a 10-MHz transducer and real-time scanner was performed when a lesion seen mammographically was unequivocally depicted at US. The needle was inserted with variable obliquity to the scanning plane. Stereotaxically guided FNAC was performed when lesions were not visible at US. High suspicion at mammography and positive cytologic reports led to surgical biopsy. Of the 270 lesions, 120 (44.4%) were visible at US. Opacities were the most frequently visualized lesions. Inadequate samplings were most frequently reported for opacities with smooth margins. Differences in accuracy and inadequacy rate between the two modalities were not significant. Cancer was surgically confirmed in 86 of 110 cases. The other 160 lesions were considered benign, and mammographic follow-up in 120 has shown no change. Because FNAC with US guidance was faster and less expensive, it is recommended as the technique of choice in lesions detectable with US.

Radial scars of the breast: review of 38 consecutive mammographic diagnoses.

The authors report 38 consecutive cases of histologically proved breast radial scars (RSs) detected at mammography. In a retrospective review of mammograms in 30 matched cases of nonpalpable RS and nonpalpable scirrhous cancer, the characteristic mammographic features of RS were confirmed: (a) the absence of a central opacity, often substituted by a radiolucent area; (b) the presence of multiple elongated thin spicules radiating from the center of the lesion; (c) the infrequency of any palpable finding, even for superficial lesions of relatively large size. Microcalcifications with aspecific structure were found in the lesions on mammograms of 14 of the 38 cases and in 24 of the histologic specimens. The typical mammographic features of RS were not specific to RS, being present in a minority of cancer cases. For two blinded readers, sensitivity was 86.7% and 76.7% and specificity was 78% and 80%, respectively. Although some specific mammographic features may suggest the presence of RS, the final differential diagnosis from scirrhous cancer should be based on histologic evidence, and surgical biopsy should be advised for any stellate lesion detected at mammography.

First results of a mammographic screening program in two municipalities of Massa-Carrara Province (Italy).

AIMS AND BACKGROUND: A mammographic screening for breast cancer was started in 1989 in two municipalities of Massa-Carrara province. This paper describes the results of the first two years and evaluates the quality of the program via early indicators. METHODS: We calculated the attendance rate at first screening, the proportion of women recalled for further examinations (recall rate), the ratio between benign lesions and carcinomas detected by screening, the staging of the screen detected cancers and the ratio between detection rate and expected incidence (P/I ratio). RESULTS: Out of 14826 invited women 10407 (70.2%) attended the first screening; 266 (2.6%) of them were referred for further investigations but only 63 (0.6%) required surgical biopsy. A histological confirmed malignancy was found in 39 women corresponding to a detection rate of 3.7/1000. According to pTNM classification 89.1% of all cancers were either Tis or in stage T1; and in two third of the cases there was no nodes involvement. CONCLUSION: The results achieved so far, evaluated via early indicators, show a good start of the program.

Histological pattern of benign breast disease as a risk factor for invasive breast cancer.

Morphological criteria for histologic diagnosis of both typical and atypical breast epithelial hyperplasias have recently been thoroughly reviewed. Typical epithelial hyperplasia ranges from mild to florid and is characterized by a lack of cytologic atypia. Atypical hyperplasia (AH) is a borderline epithelial lesion between typical hyperplasia and carcinoma in situ. AH represents the most important histopathologic predictor of future breast cancer (BC) according to a case-control study we have recently carried out in a cohort of women previously treated for histologically confirmed benign breast disease (BBD). The use of histologically defined categories in order to predict BC risk depends on the utilization of strict and uniform diagnostic criteria that are currently far from being defined and widely accepted as shown in studies of inter-observer variability among pathologists. Further studies are needed to evaluate inter-observer reproducibility and to assess BC risk among women with different BBD types.

What healthy women think, feel and do about cancer, prevention and breast cancer screening in Italy.

In preparation for a major campaign to encourage participation in a breast screening programme for all women between 50-70 years old in Florence, Italy, an in-depth study of 200 women's attitudes and practices regarding cancer and its prevention was undertaken. 72% participated in semistructured interviews, and inclination to participate was analysed in terms of Yes (39%), Uncertain (36%), and No (20%) (5% were unspecified). Age (P = 0.03), area of birth (P = 0.01), education level of husband (P = 0.04) and prior Pap smear (P = 0.00) or mammography (P = 0.00) were among the variables statistically associated with inclination to participate. While the women shared more or less common images of cancer, concern for health, and belief in the importance of God and destiny, those less inclined to participate felt less personally vulnerable, had less faith in medicine's ability to cure or prevent cancer, were more distant from the medical system and culture in general and regarded information about health or illness more as unnecessary or dangerous than beneficial. Understanding and consideration of both "popular" and "medical" cultures need to be encouraged.