Utility of prognostic genomic tests in breast cancer practice: The IMPAKT 2012 Working Group Consensus Statement.

BACKGROUND: We critically evaluated the available evidence on genomic tests in breast cancer to define their prognostic ability and likelihood to determine treatment benefit. DESIGN: Independent evaluation of six genomic tests [Oncotype Dx™, MammaPrint(®), Genomic Grade Index, PAM50 (ROR-S), Breast Cancer Index, and EndoPredict] was carried out by a panel of experts in three parameters: analytical validity, clinical validity, and clinical utility based on the principles of the EGAPP criteria. PANEL STATEMENTS: The majority of the working group members found the available evidence on the analytical and clinical validity of Oncotype Dx™ and MammaPrint(®) to be convincing. None of the genomic tests demonstrated robust evidence of clinical utility: it was not clear from the current evidence that modifying treatment decisions based on the results of a given genomic test could result in improving clinical outcome. CONCLUSIONS: The IMPAKT 2012 Working Group proposed the following recommendations: (i) a need to develop models that integrate clinicopathologic factors along with genomic tests; (ii) demonstration of clinical utility should be made in the context of a prospective randomized trial; and (iii) the creation of registries for patients who are subjected to genomic testing in the daily practice.

Supportive care organisation in France: an in depth study by the French speaking association for supportive care in cancer (AFSOS).

BACKGROUND: Supportive care in cancer (SCC) was further enhanced in the Second National Cancer Act decreed in December 2009. The aim of our study was to assess current SCC efficacy. PATIENTS AND METHODS: The French speaking association for supportive care in cancer (AFSOS) conducted an observational study to evaluate practices, organisations and information given to patients. A specific 32 point questionnaire was sent to 1621 French physicians (MDs) caring for cancer patients. RESULTS: Three different organisations were evaluated: the individual MDs, the transversal team and its particular structure specialised in global patient care specifically developed at comprehensive cancer centres - CCC. During their disease, 68% of patients received SCC, which was more available during the palliative period (90%) than at the diagnosis (44%). Our results found that 71% of cancer departments had a specific interdisciplinary cross-team to provide SCC, particularly in CCC (62%; p=0.01) while 37% had specific inpatient units. A specific organisation dedicated to home care was greater in CCC than in public or private centres (69%, 45%, 20% respectively; p=0.01). Adverse event information was performed more by an oncologist than other specialists (p=0.01). CONCLUSION: Our results suggest that the specific SCC organisation could be a useful management tool to improve supportive care for cancer patients.

Radiotherapy for invasive breast cancer: guidelines for clinical practice from the French expert review board of Nice/Saint-Paul de Vence.

PURPOSE: While new strategies for the treatment of invasive breast cancer (BC) are emerging, radiotherapy (RT) modalities are still under debate. The French expert review board of Nice-Saint-Paul de Vence was asked firstly to conduct a qualitative evidence-based systematic review and then to establish clinical practice guidelines for the use of post operative RT in invasive BC. METHODS AND MATERIALS: A search to identify eligible studies was undertaken using the Medline® database. All phase III randomized trials and systematic reviews evaluating the role and modalities of RT in invasive BC were included, together with some noncontrolled studies if no randomized trials were identified. The quality and clinical relevance of the studies were evaluated to determine the level of evidence. RESULTS: The maximum delay between surgery and RT should ≤8 weeks when chemotherapy (CT) is not indicated. This should not exceed 24 weeks when adjuvant CT is administered. Whole breast RT delivering 50 Gy in 25 fractions followed by a boost of 10-16 Gy remains the standard of care after conservative surgery (CS). In the elderly population, for certain cases presenting comorbidities associated with a limited life expectancy, RT indication (even hypofractioned) and boost delivery may be unnecessary in the light of an unfavourable risk/benefit ratio. RT technique and indications should not vary in case of neoadjuvant CT followed by CS. After total mastectomy, RT should be indicated in N+ and in N- patients with high risk of local recurrence. The experts recommend to initiate tamoxifen at the end of RT, while aromatase inhibitors could be administered either concomitantly or sequentially with RT. There is no consistent data to delay (or suspend) trastuzumab administration during RT. As for all patients, in case of concurrent RT-trastuzumab administration, reduction of cardiac tissues exposure is highly recommended. After breast reconstruction, RT should be delivered as after standard CS without boost. CONCLUSION: Due to significant variations in practice in the treatment of patients with BC, our group aimed to provide guidelines for clinical practice. The systematic review of the literature formed the basis of our evidence-based recommendations; however expert agreements were necessary on those subjects that are still under debate. Our group will update these guidelines every 4 years, taking in consideration new advances in technology, new drugs administration, biologic tools and innovative therapeutic options.

[Screening digital mammography: one year result for the Alpes-Maritimes region]. / Numérique en dépistage organisé: bilan à 1 an dans les Alpes-Maritimes.

PURPOSE: After one year of experience with screening digital mammography, the results of this technique (n=9640) are compared to screen-film mammography (n=240 376) with double reading. METHODS: Evaluation for each technique of the rate of call-back, positive results before and after work-up by the first reader and distribution based on the BI-RADS classification by the ACR, rate of complementary US, detected abnormalities (microcalcifications) and detected cancers. RESULTS: The rate of positive mammograms was significantly higher for the digital technique (17.3% versus 15.1%) because of the first reader (16.3% versus 13.9%) whereas it was significantly lower after complementary work-up (3% versus 3.7%). The rate of BI-RADS 0 was significantly higher with digital imaging irrespective of patient age. The rate of US was higher for type 1 and 2 breasts at digital imaging (46% versus 36%, p<0.0001) while the reverse was true for denser breasts (49% versus 54%; p:0.0005). More microcalcifications were detected on digital imaging (24.4% versus 21.8%) without impact on the rate of DCIS and invasive carcinomas. The rate of cancers detected with both technique were identical. CONCLUSION: The increased number of positive results at first reading and increased number of US for digital mammography may relate to a learning curve and difficulties in comparing with prior examinations. These results should continuously be monitored and compared to national averages.

[Breast cancer chemoprevention. Rational, trials results and future]. / Chémoprévention du cancer du sein. Justificatifs, résultats des essais et perspectives.

Breast cancer (BC) is the first female cancer in France, accounting for 49,240 new cases in 2004. Approximately 80% of those tumors have positive hormone receptors (HR). Tamoxifen was used in four chemoprevention randomized trials, as well as another SERM (Selective Estrogen Receptor Modulation), raloxifen. This review analyses the updated results of these trials. All trials have shown that the risk of developing HR positive BC was reduced by tamoxifen or raloxifen, but without impact on HR negative BC and overall survival. Moreover, several unfavorable side effects (thrombo-embolic accidents and uterine cancers) have been observed. A new assessment of BC risk factors seems necessary, including not only family history and some histopathological abnormalities (e.g. atypical hyperplasia), but also new elements such as high bone and breast density and thoracic irradiation at young age (Hodgkin's disease). Indeed, tamoxifen efficacy seems optimal in very "high-risk" women. Therefore, the creation of a new and most comprehensive "risk model" is necessary as well as a tailored SERM use (maybe with other compounds), in order to optimize results and reduce potential side effects.

[Edifice program: analysis of screening exam practices for cancer in France]. / Le programme Edifice : analyse des pratiques de dépistage du cancer en France.

INTRODUCTION: The practices of screening and the parameters influencing these practices are not well known in France. The objectives of the Edifice study were to analyze a large cohort of patients and doctors in order to further characterize these parameters. PATIENTS AND METHODS: The study was performed by the Institute TNS Healthcare-SOFRES, and included 2 parallel studies: 1) on 1 609 healthy persons representative of the global French population and aged 40 to 75 years (N = 1 509), with an over representation of patients aged 50 to 74 years living in the 22 pilot French departments pilots; 2) on 600 generalist practitioners. Data were collected and analyzed by the expert panel... RESULTS: Ninety-three, 25, 36 and 6% of the patients in the general population declared to have performed at least one a screening exam for breast, colon, prostate, and lung carcinoma respectively. Seventy, 20, 60 and 4% of GP declare to propose systematically to a 40-75-year-old patient a screening test for breast, colon, prostate, or lung cancer. For breast cancer screening the adhesion of the GP is independent of the date of implementation of a general screening in their own regions, while for colorectal screening, 34 and 20% of the patients living in the pilot versus other departments were screened. Overall, prostate cancer screening is recommended by the GP panel for 77.1% of patients aged 50 to 75 years. CONCLUSIONS: This study shows a good adhesion of screening procedures for GP and patients, shows that screening is improved by general screening policy in colorectal cancer, but that prostate cancer screening practices exceed what is recommended according to evidence based medicine.

Prognostic factors in 1,038 women with metastatic breast cancer.

BACKGROUND: Treatment of metastatic breast cancer (MBC) remains palliative. Patients with MBC represent a heterogeneous group whose prognosis and outcome may be dependent on host factors. The purpose of the present study was dual: first, to draw up a list of factors easily available in everyday clinical practice requiring no sophisticated or costly methods and second, to provide results from a large cohort of women who underwent diagnostic and treatment at a single institution. PATIENTS AND METHODS: From 1975 to 2005, a total of 1,038 women with MBC during their follow-up were included in this retrospective analysis. Patients were subsequently assigned to five groups according to the period of metastatic diagnosis. RESULTS: It is shown that age at initial diagnosis, hormonal receptor status and site of metastasis are the most relevant prognostic factors for predicting survival from the time of metastastic occurrence. It is also shown that a metastasis-free interval is an easily and immediately available multifactorial prognostic index reflecting the multiparametric variability of the disease. CONCLUSION: These fundamental observations may assist physicians in evaluating the survival potential of patients and in directing them toward the appropriate therapeutic decision.

Breast cancer screening in France: results of the EDIFICE survey.

BACKGROUND: The EDIFICE survey aimed to investigate the compliance of the general population to the screening tests available in France for the 4 most common cancers: breast, colorectal, prostate and lung. Implementation of breast cancer screening has been generalized in France since 2003: women aged between 50 and 74 years are systematically invited to perform a mammography every second year. Results pertaining to breast cancer are reported hereafter. METHODS: This nationwide observational survey was carried out in France from 18 January to 2 February 2005 among representative samples of 773 women aged between 40 and 75 years and 600 general practitioners (GPs). Information collected included socio-demographic characteristics, attitude towards cancer screening and actual experience of cancer screening, as well as GPs' practice regarding screening. The precision of the results is +/- 4.3% for a 95% confidence interval. RESULTS: Among the 507 participating women aged between 50 and 74 years, 92.5% (469/507) had undergone at least one mammography: 54.6% (256/469) underwent this test on their own initiative and 44.6% (209/469) of women performed it in the framework of a systematic screening plan. Most women participating in the systematic screening (89.0% i.e. 186/209) had a mammography within the last dating from less than 2 years versus 73.8% (189/256) of those who performed it outside the screening program (Chi(2) test; p<0.01). Interestingly, 422 women (61.9% i.e. 422/682 women aged between 40-75 years with at least one mammography) had performed a mammography before the recommended age for screening. There was a significant correlation (p = 0.009) between the existence of a first mammography before 50 years of age and subsequent screening on women's own initiative (54.6% of 469 screened women). Main reasons for not performing the screening test every second year (77 women aged between 50-74 years) included: feeling unconcerned and/or unmotivated (p = 0.0001), no cancer anxiety (p = 0.020) and no recommendation by the GP (p = 0.015); Of the 600 participating GPs, 68.6% (412/600) systematically recommended a mammography to their patients. GPs' perceptions of the reasons for women's avoidance of the screening test were unwillingness to be aware of mammography results (44.4% - 266/600) and the belief that mammography was painful (52.5% - 315/600). CONCLUSION: The main result of the EDIFICE survey is the high rate of women's attendance at mammography screening. The EDIFICE survey pointed out that systematic and organized screening played a major role in the regularity of screening tests for breast cancer every second year. GPs and gynaecologist are key actors in heightening public awareness.

Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study.

BACKGROUND: Trastuzumab (T) combined with chemotherapy has been recently shown to improve outcome in HER2-positive breast cancer (BC). The aim of this study was to evaluate the toxic effects of concurrent radiation therapy (RT) and T administration in the adjuvant setting. PATIENTS AND METHODS: Data of 146 patients with stages II-III HER2-positive BC were recorded. Median age was 46 years. In all, 32 (23%) and 114 (77%) patients received a weekly and a 3-week T schedule, respectively. A median dose of 50 Gy was delivered after surgery. Internal mammary chain (IMC) was irradiated in 103 (71%) patients. RESULTS: Grade >2 dermatitis and esophagitis were noted in 51% and 12%, respectively. According to the Common Toxicity Criteria v3.0 scale and HERA (HERceptin Adjuvant) trial criteria, respectively, 10% and 6% of the patients had a grade >/=2 of left ventricular ejection fraction (LVEF) decrease after RT. Multivariate analyses revealed two independent prognostic factors: weekly T administration (for LVEF decrease) and menopausal status (for dermatitis). Higher level of T cumulative dose (>1600 mg) was only borderline of statistical significance for acute esophagitis toxicity. CONCLUSION: We showed that weekly concurrent T and RT are feasible in daily clinical practice with, however, a decrease of LVEF. Cardiac volume sparing and patient selections for IMC irradiation are highly recommended. Longer follow-up is warranted to evaluate late toxic effects.

Epirubicin-vinorelbine vs FEC100 for node-positive, early breast cancer: French Adjuvant Study Group 09 trial.

The aim of the study was to compare our reference adjuvant chemotherapy, FEC100 (fluorouracil 500 mg m(-2), epirubicin 100 mg m(-2) and cyclophosphamide 500 mg m(-2), six cycles every 21 days), to an epirubicin-vinorelbine (Epi-Vnr) combination for early, poor-prognosis breast cancer patients. Patients (482) were randomised to receive FEC100, or Epi-Vnr (epirubicin 50 mg m(-2) day 1 and vinorelbine 25 mg m(-2), days 1 and 8, six cycles every 21 days). The 7-year disease-free survival rates were 59.4 and 58.8%, respectively (P=0.47). The relative dose intensity of planned epirubicin doses was 89.1% with FEC100 and 88.9% with Epi-Vnr. There were significantly more grades 3-4 neutropenia (P=0.009) with Epi-Vnr, and significantly more nausea-vomiting (P<0.0001), stomatitis (P=0.0007) and alopecia (P<0.0001) with FEC100. No cases of congestive heart failure were reported, whereas four decreases in left ventricular ejection fraction occurred after FEC100 and five after Epi-Vnr. One case of acute myeloblastic leukaemia was registered in the FEC100 arm. After 7 years of follow-up, there was no difference between treatment arms. Epi-Vnr regimen provided a good efficacy in such poor-prognosis breast cancer patients, and could be an alternative to FEC100, taking into account respective safety profiles of both regimens.

Ultrasound-guided percutaneous radiofrequency ablation in elderly breast cancer patients: preliminary institutional experience.

Breast cancer is a major source of morbidity and mortality in the elderly population and the number of patients will increase by 30% in future decades. Surgery and endocrine therapy could be considered as the standard treatment in elderly breast cancer patients, but anaesthesia for surgery requires a specific approach taking into account physiological and psychological alterations secondary to ageing. In cases with major alterations of performance status, percutaneous radiofrequency ablation (RFA) could be substituted for the surgical treatment. The aim of the current study is to evaluate the efficacy and feasibility of this technique. Five tumours in four consecutive patients (aged 79-82 years) contraindicated for surgery with symptomatic cT1-2N0M0, positive oestrogen receptor status, low grade were treated by percutaneous radiofrequency-lump ablation under local analgesia, using percutaneous ultrasound guidance. Thermal lesions were produced with RF power 30 W, at a frequency of 500 kHz. Ultrasound-guided percutaneous biopsy of the RF treated breast was performed during the follow-up. We report a successful RFA lump ablation experience in the treatment of four tumours (4/5). One local recurrence occurred within 4 months after RFA. The other biopsies taken during the follow up showed all fat necrosis within the oil cyst and no malignant cells. One abscess occurred at 9 months within the treated area. After a mean follow up of 29.4 months, all the patients are still alive without any other signs of recurrence or metastases. Ultrasound-guided percutaneous RFA is safe and feasible in the management of breast cancer in elderly patients. Nevertheless, further large comparative studies are needed in order to validate such a minimally invasive procedure in current practice.

Phase II study of bleomycin, vindesine, mitomycin C and cisplatin (BEMP) in recurrent or disseminated squamous cell carcinoma of the uterine cervix.

OBJECTIVE: We carried out a phase II trial with BEMP [bleomycin, vindesine (Eldisine(R)), mitomycin C and cisplatin] in patients with recurrent and/or metastatic squamous cell carcinoma of the uterine cervix with the specific aim to assess whether BEMP was of particular interest when certain disease sites were involved. PATIENTS AND METHODS: Eligible patients received four cycles of E 3 mg/m(2), day 1 + 8; P 50 mg/m(2), day 1; B 15 mg/day (continuous infusion), day 2-4 and M 8 mg/m(2), day 5 (on alternate cycles), every 3 weeks during an induction phase. Thereafter, those without progression continued with MEP every 4 weeks in a maintenance phase. MEP consisted of E 3 mg/m(2), day 1 + 8, M 6 mg/m(2) (on alternate cycles) and P 50 mg/m(2), both on day 1. All drugs were given i.v. Both response evaluation and toxicity grading were assessed according to World Health Organization criteria. RESULTS: Of the 161 eligible patients, 143 were assessable for survival, 148 for toxicity and 131 for response. Overall response rate was 45% [complete (CR) 14.5%, partial response (PR) 30.5%]. Most responsive disease sites were lung, lymph nodes and skin metastases (>60% response, CR rate >25%). Median duration of response was 7.6 months. Survival was significantly better in patients with only distant metastases: 12.9 months versus 8.6 months in those with other disease sites involved (P = 0.002). In a multivariate analysis, patients with a good performance status yielded a better prognosis (P = 0.0017), as did the patients with only metastatic disease compared with those who had pelvic disease also or solely (P = 0.045). There were two toxic deaths and 21% of patients stopped treatment because of excessive toxicity. CONCLUSIONS: Patients with a good performance status and only distant metastases seem optimal candidates to receive the BEMP regimen. This benefit should be balanced against the expected serious toxic effects.

Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: results of French Adjuvant Study Group 02 and 07 trials.

BACKGROUND: The purpose was to compare disease-free survival (DFS) between epirubicin-based chemoendocrine therapy and tamoxifen alone in one to three node-positive (N1-3), estrogen-receptor-positive (ER+), postmenopausal early breast cancer (EBC) patients. PATIENTS AND METHODS: We analyzed, retrospectively, 457 patients randomized in FASG 02 and 07 trials who received: tamoxifen alone (30 mg/day, 3 years); or FEC50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2, cyclophosphamide 500 mg/m2, six cycles every 21 days) plus tamoxifen started concurrently. Radiotherapy was delivered after the third cycle in FASG 02 trial, and after the sixth in FASG 07 trial. RESULTS: The 9-year DFS rates were 72% with tamoxifen and 84% with FEC50-tamoxifen (P = 0.008). The multivariate analysis showed that pathological tumor size >2 cm was an independent prognostic factor (P = 0.002), and treatment effects remained significantly in favor of chemoendocrine therapy (P = 0.0008). The 9-year overall survival rates were 78% and 86%, respectively (P = 0.11). In the multivariate model, there was a trend in favor of chemoendocrine therapy (P = 0.07). CONCLUSION: The addition of FEC50 adjuvant chemotherapy to tamoxifen significantly improves long-term DFS in N1-3, ER+ and postmenopausal women. Chemoendocrine therapy seems to be more effective than tamoxifen in terms of long-term survival.

Different clinical impact of estradiol receptor determination according to the analytical method: A study on 1940 breast cancer patients over a period of 16 consecutive years.

The knowledge of estrogen receptor (ER) status is important in the management of breast cancer patients. More precisely, analytical methods for ER determination have changed over the last two decades from ligand binding assay (LBA) dextran-coated charcoal (DCC) to enzyme immuno-assay (EIA) and more recently immunohistochemistry (IHC). We examined the respective clinical impact of ER determination according to these 3 methods over the period 1983-1999 within a group of 1940 patients, all operated and followed in the single institution Centre Antoine Lacassagne. Validated cut off values were 10 and 15 fmol/mg protein for both LBA-DCC and EIA, respectively and 10% of stained cells for IHC. During the years it was noted that the initial size of the tumor decreased and that the proportion of positive axillary nodes and negative ER tumors was different according to the ER method. ER negativity was 20, 13 and 10% in LBA-DCC, EIA, IHC, respectively. ER was a strong predictor of overall survival in the whole population (Mantel-Cox, p < 0.00001); however when stratifying the analysis on ER method groups, ER was still a prognostic indicator in the EIA, LBA-DCC group but not in the IHC group (the follow-up was too short). It is important to keep these data in mind when conducting large retrospective studies evaluating prognostic markers in breast cancer patients.

Long-term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group results.

BACKGROUND: The aim of the study was to evaluate and compare incidence and risk factors of left ventricular dysfunction (LVD) in early breast cancer patients receiving (E+) or not (E-) epirubicin-based adjuvant chemotherapy. PATIENTS AND METHODS: Among eight FASG trials, 3577 assessable patients were analyzed retrospectively: 2553 received epirubicin, 662 received hormonotherapy alone and 362 had no systemic treatment. Chemotherapy was FEC regimen in 86% of cases (fluorouracil, epirubicin, cyclophosphamide). Epirubicin cumulative dose was < 300 mg/m2 in 1040 patients, 300-600 in 1155, > or = 600 in 279, followed by radiotherapy in 96% of cases. RESULTS: Twenty delayed LVD occurred: two in E- patients and 18 in E+ patients. In E+ patients, 14 patients normalized their cardiac function or did not require further investigations, one patient was stabilized with specific treatment, two patients worsened their functions and one died of congestive heart failure. The 7-year risk of LVD was 1.36% (95% CI 0.85-1.87) in E+ patients and 0.21% (95%CI: 0.00-0.52) in E- patients (P = 0.004). Two significant risk factors were identified: age > or = 65 years and body mass index > 27 kg/m2. CONCLUSION: After a long-term follow-up, epirubicin-related LVD risk was acceptable (1.36%) with one toxic death (0.04%). In 78% of cases, LVD were transient or well controlled.

Radiological and surgical placement of port devices: a 4-year institutional analysis of procedure performance, quality of life and cost in breast cancer patients.

PURPOSE: The present study is designed to evaluate and compare percutaneous radiologic arm port (R) and surgical subclavian port (S) devices in two homogeneous sets of breast cancer patients in terms of safety, efficacy, quality of life (QoL) and cost analysis. MATERIAL AND METHODS: This study involved a retrospective review of a prospective databank including 200 consecutive port device implantation attempted procedures performed over a 4-year period, in two similar groups of 100 breast cancer women who underwent either the surgical cephalic vein cutdown approach or the percutaneous basilic vein catheterization for intravenous adjuvant chemotherapy. Parameters analyzed included technical success, procedure duration, complications, QoL and cost evaluation for both techniques. RESULTS: The success rate for port implantation was higher for R than for S placement (96% versus 91%). Mean implant duration time was 5.6 and 7.6 months for R and S, respectively. The overall complication rate was 10 and 16% for R and S, respectively. Mean implant duration time, without any complication or death, was 6.4 and 7.8 months for R and S, respectively. Six and seven percent for R and S, respectively, had to be removed prematurely. Both techniques exhibited very good QoL. Direct costs were respectively euro 230.8 and 219.1 for R and S, respectively. CONCLUSION: The significant advantages of R over S include higher success rate, higher cosmetic results despite a 15% relative overcost for R placement. Both are indicated for breast cancer chemotherapy treatment, nevertheless R placement is mandatory in anxious patients who fear surgery, in case of previous cervico-thoracic irradiation or upper extremity venous thrombosis, or in patients at risk of respiratory insufficiency.

Secondary leukemia after epirubicin-based adjuvant chemotherapy in operable breast cancer patients: 16 years experience of the French Adjuvant Study Group.

BACKGROUND: The purpose of this study was to evaluate incidence and risk factors of secondary leukemia after adjuvant epirubicin-based chemotherapy in breast cancer patients. PATIENTS AND METHODS: Among eight French Adjuvant Study Group trials, 3653 patients were assessable: 2603 received epirubicin; 682 received hormonotherapy; and 368 had no systemic treatment. Chemotherapy was FEC regimen in 85% of cases (fluorouracil 500 mg/m2, epirubicin 50, 75 or 100 mg/m2, cyclophosphamide 500 mg/m2, three or six cycles). Epirubicin cumulative dose was <300 mg/m2 in 1045 patients; 300-600 mg/m2 in 1187; and > or =600 mg/m2 in 286, followed by radiotherapy in 96% of cases. The median follow-up was 104 months. RESULTS: Eight cases of leukemia occurred in epirubicin-exposed patients and one in non-exposed patients. After 9 years, the risk of developing a leukemia was 0.34% (95% confidence interval 0.11-0.57) in epirubicin-exposed patients. In patients receiving chemotherapy, leukemia subtypes were: AML2 (two), AML3 (one), AML4 (three) and ALL (two). None of the classically recognized risk factors was significantly correlated with the occurrence of a leukemia. CONCLUSION: Irrespective of the dose, the incidence of secondary leukemia after adjuvant epirubicin-based chemotherapy was low. After a long follow-up, the benefit/risk ratio for early breast cancer patients remained in favor of epirubicin-based adjuvant chemotherapy: eight cases (0.31%) occurred, and in some of them, treatment causality could be debatable.

Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy.

PURPOSE: The aim of this multicenter trial was to evaluate the role of ovarian suppression in patients with early breast cancer previously treated with local surgery and adjuvant chemotherapy. PATIENTS AND METHODS: Nine hundred and twenty-six premenopausal patients with completely resected breast cancer and either axillary node involvement or histological grade 2 or 3 tumors were randomized after surgery to adjuvant chemotherapy alone (control arm) or adjuvant chemotherapy plus ovarian suppression (ovarian suppression arm). Ovarian suppression was obtained by either radiation-induced ovarian ablation or triptorelin for 3 years. The analyses were performed with Cox models stratified by center. RESULTS: Median follow-up was 9.5 years. Mean age was 43 years. Ninety per cent of patients had histologically proven positive axillary nodes, 63% positive hormonal receptors and 77% had received an anthracycline-based chemotherapy regimen. Ovarian suppression was by radiation-induced ovarian ablation (45% of patients) or with triptorelin (48%). At the time of randomization, all patients had regular menses or their follicle-stimulating hormone and estradiol levels indicated a premenopausal status. The 10-year disease-free survival rates were 49% [95% confidence interval (CI) 44% to 54%] in both arms (P = 0.51). The 10-year overall survival rates were 66% (95% CI 61% to 70%) for the ovarian suppression arm and 68% (95% CI 63% to 73%) for the control arm (P = 0.19). There were no variations in the treatment effect according to age, hormonal receptor status or ovarian suppression modality. However, in patients <40 years of age and with estrogen receptor-positive tumors, ovarian suppression significantly decreased the risk of recurrence (P = 0.01). CONCLUSIONS: The results of this trial, after at least 10 years of follow-up, do not favor the use of ovarian suppression after adjuvant chemotherapy. The potential beneficial effect in younger women with hormono-dependent tumors should be further assessed.

Efficacy and safety of single agent capecitabine in pretreated metastatic breast cancer patients from the French compassionate use program.

BACKGROUND: A retrospective source review identifying predictive factors and assessing safety and efficacy in pretreated metastatic breast cancer (MBC) patients treated with capecitabine in a French compassionate-use program. PATIENTS AND METHODS: 197 patients received capecitabine at an initial total dose 0.25-3.0 g/m2/day, twice daily for 14 consecutive days, every 3 weeks. RESULTS: Median patient age was 56 years (range, 31-88), 19% had performance status (PS) 3-4. Prior palliative and adjuvant treatment was reported in 96 and 61% of patients respectively. Best overall response rate (ORR) was 15% (95% confidence interval [CI], 11-21%) and 49% had benefit (CR, PR or SD). Median time to progression (TTP) and overall survival were 4.8 and 14.7 months, respectively. Median TTP in responders was 8.9 months (95%CI 6.1-11.7). Grade 3/4 neutropenia and grade 3 thrombocytopenia occurred in 8 and 3% of patients respectively. Hand-foot syndrome (grade 3/4 in 16% of patients), diarrhea, stomatitis and asthenia were prevalent. Multivariate analysis showed ORR was significantly influenced by PS > or = 2 (p = 0.004), time from metastases diagnosis to capecitabine treatment (p = 0.015) and presence of liver metastases at inclusion (p = 0.047). Abnormal liver function tests at baseline were associated with severe thrombocytopenia and anemia. Four treatment-related deaths occurred. CONCLUSION: Capecitabine is active in heavily pretreated MBC patients and has a favorable toxicity profile with the added advantage of being an oral drug administered in an outpatient setting.