Prospective evaluation of serum anti-Müllerian hormone dynamics in 250 women of reproductive age treated with chemotherapy for breast cancer.

AIM: Women of reproductive age with breast cancer generally receive gonadotoxic chemotherapy. Fertility issues are of great concern for them. However, little is known on ovarian damage during chemotherapy and its evolution during long-term follow-up. The aim of this study was to provide a detailed description of serum anti-Müllerian hormone (AMH) evolution during chemotherapy and 24-month follow-up. METHODS: This prospective cohort study was conducted in 250 patients, aged 18-39 years, diagnosed with breast cancer and treated with adjuvant/neoadjuvant chemotherapy. Each patient underwent blood AMH measurement at each chemotherapy cycle, and at 6, 12 and 24 months after chemotherapy. Menses occurrence was also recorded. RESULTS: Mean basal AMH level was 4.19 ± 4.84 ng/mL, and was negatively correlated with age. Serum AMH level rapidly decreased in all patients after each chemotherapy cycle to undetectable levels in most of them, and slowly increased in 45% of the patients during the 24-month follow-up. AMH decrease was significantly associated with age and basal AMH level, but not with cyclophosphamide dose and tamoxifen use. The prevalence of chemotherapy-related amenorrhoea was 92.4% at the end of chemotherapy; women with amenorrhoea being significantly older and having lower basal AMH than women who resumed menses. CONCLUSIONS: Our study confirms rapid and deep ovarian reserve alteration in young women receiving chemotherapy for breast cancer, and shows moderate AMH recovery in some patients. Although AMH cannot alone predict fertility potential, these new data emphasise the need for post-treatment ovarian insufficiency follow-up, strongly support the use of fertility preservation strategies and may provide new tools for improved counselling.

[Hormonal treatment in breast cancer]. / Hormonothérapie du cancer du sein.

The discovery of breast cancer carcinoma sensitivity to estradiol (E) suppression is the starting point of hormonal treatment. Hormonal receptors (ER and PR) are the pathway of the action of estradiol on breast tumor cells. The detection of at least one of these two receptors is needed to classify a tumor as hormone sensitive. The hormonal treatment of breast cancer attempts to suppress the stimulating action of E on tumor cells. This can be done by decreasing E synthesis--ovarian suppression (OS) or aromatase inhibitors (AIs)--or by compelling with E on receptors--tamoxifen (TAM). In advanced breast cancer, hormonal treatment gives good response with few side effects. In young patient, the treatment is based on TAM. It could be associated with OS. In post-menopausal women, AIs are more potent than TAM. They are used in the first line treatment and TAM as a second line. Fulvestrant is not superior TAM or AIs. In the adjuvant setting, hormonal treatment gives a significant reduction of recurrence and death. In young patient, the treatment is based on TAM. It could be associated with OS. In post-menopausal patients, adjuvant treatment must include an AIs for at least one part of the treatment. A survey of bone density is necessary.

Celecoxib and exemestane versus placebo and exemestane in postmenopausal metastatic breast cancer patients: a double-blind phase III GINECO study.

The aim of this study was to evaluate antitumor effects of cyclooxygenase-2 inhibitors in breast carcinoma and their ability to act synergistically with aromatase inhibitors (AIs). Postmenopausal metastatic breast cancer patients without previous adjuvant AI treatment received exemestane 25 mg/days plus either celecoxib 400 mg twice daily or placebo. The primary endpoint was progression-free survival (PFS). This trial was prematurely terminated (N = 157 of 342 planned) after cardiovascular toxicity was reported in other celecoxib trials. Although no PFS difference was observed between the two arms (9.8 months for both, P = 0.72), a trend favoring celecoxib was observed in 60 tamoxifen-resistant patients (9.6 vs. 5.1 months; P = 0.14) and in 126 patients treated >or=3 months before study termination (12.2 vs. 9.8 months; P = 0.09). No severe adverse events were reported. Cyclooxygenase-2 inhibitors seemingly contribute to reverse endocrine resistance in breast cancer patients, although further study is necessary to allow development of a new therapeutic strategy.

Pegase 03: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem cell transplantation in first-line treatment of metastatic breast cancer.

Pegase 03 is a multicenter prospective randomized phase III trial evaluating the impact of first-line high-dose chemotherapy (HDC) with stem cell support on overall survival (OS), disease-free survival (DFS) and response rate in 308 patients with histologically proven metastatic breast cancer responding to induction therapy. Eligible patients received four induction cycles with FEC 100 (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2)). Patients with objective response (N=179) were randomized to one cycle of HDC (cyclophosphamide 6000 mg/m(2) and thiotepa 800 mg/m(2) (CHUT)) and stem cell support (N=88), or no further treatment (N=91). All patients were observed until disease progression or death. One toxic death occurred after CHUT. Other toxicities were manageable. The response rate at 3 months was higher in the intensification arm: 82.7% (25.3% complete response (CR)) versus 59.2% (14.1% CR) (P=0.0002). Median follow-up was 48 months. Median DFS was 11 and 6.6 months in the intensification and the observation arms, respectively (P=0.0001). There was no survival difference: 33.6 versus 27.3% OS at 3 years (P=0.8) and 22.9 versus 22.3 months median time to relapse in the intensification and observation arms, respectively. In this randomized trial, HDC with CHUT improved DFS but not OS, corroborating findings from earlier trials.

Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial.

BACKGROUND: Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. METHODS: 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. RESULTS: After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded. CONCLUSIONS: Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

Phase II trial of pegylated liposomal doxorubicin-cyclophosphamide combination as first-line chemotherapy in older metastatic breast cancer patients.

OBJECTIVE: To evaluate the efficacy and toxicity of pegylated liposomal doxorubicin (PLD; Caelyx)-cyclophosphamide combination in older metastatic breast cancer patients. METHODS: A multicenter phase II trial was conducted. Inclusion criteria were age 65-75 years, ECOG 0-1 and left ventricular ejection fraction > or =50%. First-line chemotherapy was given to metastatic breast cancer patients resistant to hormonal therapy. The treatment schedule was PLD 40 mg/m(2) and cyclophosphamide 500 mg/m(2) on day 1 every 4 weeks. Efficacy was the primary endpoint, while response duration and tolerance were the secondary endpoints. RESULTS: Thirty-five patients (median age 71.3 years) were enrolled. No treatment-related death, no congestive heart failure or decrease in left ventricular ejection fraction and no febrile neutropenia were reported. TOXICITY: grade 3 dyspnea was found in 1 patient, neutropenia in 11 patients (7 grade 3, 4 grade 4), grade 3 mucositis in 4 patients, grade 3 hand-foot syndrome in 1 patient and a generalized rash in 1 patient. An objective response (complete and partial response) was achieved in 10 (28.6%) patients and disease control in 24 (69%) with a progression-free survival of 8.8 months and a median overall survival of 20.3 months. CONCLUSION: The PLD-cyclophosphamide combination is moderately active and safe in elderly metastatic breast cancer patients, but cannot be recommended routinely due to myelotoxicity and mucositis hazards.

Clinical impact of fluorine-18 fluorodeoxyglucose positron emission tomography in cancer patients. A comparative study between dedicated camera and dual-head coincidence gamma camera.

AIM: Positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) can be performed using a dedicated PET scanner (PET-I) or a dual-head coincidence gamma camera (CGC-I). The aim of this study was to comparatively assess the impact of PET-I and CGC-I on clinical management in cancer patients. METHODS: From November 2000 to November 2002, PET-I and CGC-I were performed at an interval of 2 days in 151 patients with colorectal cancer (n=40), breast cancer (n=28), thyroid cancer (n=23), lung tumors (n=22), germ cell tumors (n=14), unknown primary cancer (n=7) and other cancers (n=17). PET-I and CGC-I were interpreted independently with knowledge of conventional imaging (CI). In June 2003, theoretical management, e.g. treatment modality/ies and treatment intent (curative or palliative), after CI, PET-I and CGC-I were stated during multidisciplinary sessions and were a posteriori considered as appropriate or inappropriate using pathological and follow-up data. RESULTS: The theoretical management proposed after PET-I and after CGC-I was similar in 112/151 (74%; 95% CI: 66-81%) patients. In 125 assessable patients, theoretical management after PET-I was appropriate in 86% (95% CI: 79-92%), significantly higher (P=0.0033) than after CGC-I (70%; 95% CI: 62-78%). Both proportions were also higher than after CI (46%; 95% CI: 37-56%), (P<0.0001). A similar trend for higher proportions of appropriate management after PET-I than after CGC-I was observed for each tumor localization. CONCLUSIONS: The clinical impact of PET-I is superior to that of CGC-I in a large series of cancer patients. Although CGC-I could be considered as an acceptable alternative, PET-I remains the standard and should preferably equip nuclear medicine departments.

Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study.

The combination of intravenous (i.v.) vinorelbine and epirubicin is highly active in the treatment of metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated a regimen alternating i.v. and oral vinorelbine in combination with epirubicin as first-line chemotherapy of patients with MBC. In all, 49 patients with MBC received, as first-line treatment, a combination regimen consisting of i.v. vinorelbine 25 mg m(-2) plus epirubicin 90 mg m(-2) given on day 1, and oral vinorelbine 60 mg m(-2) on day 8 (or day 15 if neutrophils <1500 mm(-3)) every 3 weeks, in an open-label, multicentre phase II study. Treatment was to be repeated for a maximum of six cycles. The study population had a median age of 55 years, half of the patients had received prior adjuvant chemotherapy and 86% presented a visceral involvement. In all, 25 responses were documented and validated by an independent panel review, yielding response rates of 51% (95% CI: 36-66) in the 49 enrolled patients and 54.5% (95% CI: 39-70) in the 44 evaluable patients. Median durations of progression-free survival and survival were 8 and 20 months, respectively. Neutropenia was the main dose-limiting toxicity, but complications were uncommon, four patients having experienced febrile neutropenia and six having developed neutropenic infection. Other frequently reported adverse events included stomatitis, nausea and vomiting, which were rarely severe. No toxic death was reported. Among patients who received six cycles, global score of quality of life remained stable. This regimen alternating oral and i.v. vinorelbine in combination with epirubicin is effective and safe. Oral vinorelbine on day 8 offers greater convenience to the patient, and decreases the need for i.v. injection and reduces time spent in hospital. Therefore, oral vinorelbine is a convenient alternative to the i.v. form in combination regimens commonly used to treat MBC.

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.

Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer.

The purpose of the study was to evaluate the efficacy and safety of docetaxel plus epirubicin (ET) and of 5-fluorouracil plus epirubicin and cyclophosphamide (FEC) as first-line chemotherapy for metastatic breast cancer. A total of 142 patients (intent-to-treat (ITT)) with at least one measurable lesion were randomised to receive docetaxel 75 mg m(-2) plus epirubicin 75 mg m(-2) or 5-fluorouracil 500 mg m(-2) plus epirubicin 75 mg m(-2) and cyclophosphamide 500 mg m(-2) intravenously once every 3 weeks for up to eight cycles. Prophylactic granulocyte-colony-stimulating factor was only permitted after the first cycle, if required. Per-protocol analysis (n=132) gave an overall response rate for ET of 63.1% (95% confidence interval (CI), 50-78%) and for FEC 34.3% (95% CI, 23-47%) after a median seven and six cycles, respectively. Intent-to-treat population (n=142) gave an overall response rate for ET of 59% (95% CI, 47-70%) and for FEC 32% (95% CI, 21-43%) after a median seven and six cycles, respectively. The median response duration for ET was 8.6 months (95% CI, 7.2-9.6 months) and for FEC 7.8 months (95% CI, 6.5-10.4 months). The median time to progression (ITT) for ET was 7.8 months (95% CI, 5.8-9.6 months) and for FEC 5.9 months (95% CI, 4.6-7.8 months). After a median follow-up of 23.8 months, median survival (ITT) for ET and FEC were 34 and 28 months, respectively. Nonhaematologic grade 3-4 toxicities were infrequent in both arms. Haematologic toxicity was more common with ET and febrile neutropenia was reported in 13 patients (18.6%) in the ET group. Two deaths in the ET group were possibly related to study treatment. In conclusion, both ET and FEC were associated with acceptable toxicity. ET is a highly active first-line therapy for metastatic breast cancer.

Immunohistochemical study of cell cycle regulatory proteins in intraductal breast carcinomas--a preliminary study.

The aim of this study was to assess the levels of cell cycle regulatory proteins p21waf1 (p21), p53, Cyclin A, Cyclin D1 and Ki-67 to see whether they correlated with recurrence-free survival (RFS). From 1982 to 1996, 50 patients aged less than 51 years underwent lumpectomy followed by radiotherapy for a pure ductal carcinoma in situ (DCIS). For each case, the following immunohistochemical stains were carried out: Ki-67, Cyclin A, Cyclin D1, p53 and p21waf1 (p21). The percentage of positive nuclei was assessed. Multiple combinations of these factors were performed; in particular, we called the sum of Ki-67 and Cyclin A a global proliferation factor (GPF). Correlations with classical clinicopathological data were assessed. After a multivariate analysis, only GPF, Van Nuys Prognostic Index (VNPI) grade and mitotic index were independent predictive factors of recurrence in the whole population. In the population with close surgical margins, when the GPF level was less than the 25th percentile or more than the 75th percentile recurrence was low. In this preliminary study, GPF seems to be of interest to help in the decision process in the post-surgical management of the patient.

Phase II multicentre study of docetaxel plus 5-fluorouracil in patients with anthracycline-pretreated metastatic breast cancer.

The purpose of the study was to determine the efficacy and safety of docetaxel plus continuous infusion of 5-fluorouracil (5-FU) in patients with metastatic breast cancer previously treated with anthracyclines. A total of 41 patients with histologically proven metastatic breast cancer and performance status 0-2, who had received at least one anthracycline-containing regimen, received docetaxel 85 mg m(-2) followed by continuous infusion of 5-FU 750 mg m(-2) day(-1) for 5 days every 3 weeks for up to eight cycles. All patients received corticosteroid premedication, but there was no prophylactic colony-stimulating factor support. The most frequent metastatic sites were the liver (61%), bone (29%), and lung (29%). All 41 patients were assessable for toxicity and 30 were eligible and assessable for efficacy. The objective response rate was 70.0% (95% CI: 53.6-86.4%) for the per protocol group and 53.7% (95% CI: 38.4-68.9%) for the intent-to-treat (ITT) population. For the ITT population, median duration of response was 8.4 months (95% CI: 6.7-12.2 months), median time to progression was 6.7 months (95% CI 5.5-8.6 months), and median survival was 17 months (95% CI: 12.3-not recorded months). Grade 3/4 neutropenia occurred in 54% of patients, with febrile neutropenia in 24% of patients and 5% of cycles, but infections were rare. Stomatitis was frequent, grade 3 in 24% of patients and grade 4 in one patient (2%), but manageable. Diarrhoea was rare, grade 3 in 7% of patients and 1% of cycles. Other grade 3/4 nonhaematological toxicities were infrequent. In conclusion, this docetaxel/5-FU regimen is highly active and well tolerated in patients with anthracycline-pretreated metastatic breast cancer. The efficacy is particularly promising, as one-third of patients were either second-line and/or anthracycline-resistant/refractory.

Phase II study of oral vinorelbine in first-line advanced breast cancer chemotherapy.

PURPOSE: A phase II trial was performed to evaluate the efficacy, tolerance, and pharmacokinetic profiles of oral vinorelbine (Navelbine). Oral Navelbine (NVB; Pierre Fabre Médicament, Boulogne, France) was given as first-line chemotherapy for locally advanced or metastatic breast carcinoma (ABC). PATIENTS AND METHODS: Sixty-four patients were entered to receive oral NVB on a weekly basis for a total of 8 weeks unless progression or toxicity occurred. Oral NVB was given at 60 mg/m(2) weekly for the first three administrations and was increased to 80 mg/m(2) for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Patients with objective response or stable disease continued treatment up to a total of 12 weeks or more. RESULTS: Fifty-eight evaluable patients were included in our study. Four patients (6.9%) had complete responses, and 14 (24.1%) had partial responses, for an overall response rate of 31% (95% CI, 19% to 43%). Median progression-free survival was 17.4 weeks. Median overall survival is not yet reached. There were no treatment-related deaths. The main toxicity was neutropenia: grade 4 in 17.2% of the patients, and 1.8% of administrations and associated clinical serious events in 4 patients (6.2%). Grade 3 and 4 nausea and/or vomiting were noted in 3.1% and 4.6% of the patients, respectively. Only one patient developed grade 3 neuroconstipation. An analysis of Quality of Life Questionnaire C30 forms revealed no significant alteration between baseline and weeks 8 and 16 in global quality of life. CONCLUSION: Oral NVB at this schedule is an effective and well-tolerated agent in the treatment of ABC and offers a promising alternative to the intravenous route. Combination studies are ongoing.

Patterns of failure in a randomized trial of adjuvant chemotherapy in postmenopausal patients with early breast cancer treated with tamoxifen.

BACKGROUND: We studied the effect of adjuvant anthracycline-based chemotherapy in postmenopausal patients with resected early breast cancer treated with adjuvant tamoxifen. PATIENTS AND METHODS: The trial included 835 patients with either axillary lymph node involvement, or tumors with histological grade II or III. They were randomized after local surgery to receive either tamoxifen (TAM group) or tamoxifen plus chemotherapy (TAM-CT group) consisting of six courses of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), or 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC). Radiotherapy was given after completion of adjuvant chemotherapy in the TAM-CT group and after surgery in the TAM group. RESULTS: The 5-year disease-free survival (DFS) rates were 73% in the TAM group and 79% in the TAM-CT group (log-rank test, P = 0.06). The 5-year overall survival rates were 82% and 87%, respectively (P = 0.06). The 5-year distant metastasis rates were 22% and 16% (P = 0.02), and the 5-year local recurrence rates were 6% and 4%, respectively (P = 0.23). There were no significant differences for contralateral breast cancer or other new primary malignancies. Chemotherapy tended to be more effective for patients who had tumors without estrogen receptors (trend test, P = 0.05). CONCLUSIONS: Anthracycline-based chemotherapy administered to postmenopausal patients receiving adjuvant tamoxifen gave a borderline significant benefit on overall and DFS, mainly by a reduction in distant metastases. Delaying radiotherapy after six courses of chemotherapy did not affect local control after up to 10 years of follow-up.

Improved survival after one course of perioperative chemotherapy in early breast cancer patients. long-term results from the European Organization for Research and Treatment of Cancer (EORTC) Trial 10854.

The aim of this study was to examine whether one course of perioperative polychemotherapy yields better results in terms of survival, progression-free survival (PFS) and locoregional control than surgery alone in early stage breast cancer. From 1986 to 1991, 2795 patients with stage I/II breast cancer were randomised to receive either one perioperative course of an anthracycline-containing chemotherapeutic regimen within 36 h after surgery or surgery alone. Patients were followed-up for overall survival, PFS and locoregional recurrence. The median follow-up period at time of the analysis was 11 years. PFS and locoregional control were significantly better (P=0.025 and P=0.004, respectively) in the perioperative chemotherapy arm. Node-negative patients seemed to benefit most from the perioperative FAC. Patients who received perioperative chemotherapy and locoregional therapy alone had significantly better overall survival rates than patients who received locoregional therapy alone (P=0.004). Patients who received additional systemic therapy did not seem to benefit from one course of perioperative chemotherapy (P=0.65). One course of perioperative polychemotherapy does improve PFS and locoregional control in early stage breast cancers. This effect is still present after 11 years of follow-up.

Epirubicin--docetaxel combination in first-line chemotherapy for patients with metastatic breast cancer: final results of a dose-finding and efficacy study.

The aim of the study was to define a regular and tolerable dose of the epirubicin-docetaxel combination in first-line chemotherapy of patients with metastatic breast cancer. Sixty-five women with measurable and/or evaluable disease were treated with epirubicin escalated from 60 to 110 mg/m(2) according to 5 dose levels, in combination with a fixed dose of 75 mg/m(2) docetaxel, every 21 days for 6 cycles, without preventive use of hematopoietic growth factors or antibiotics. Forty-three women received adjuvant chemotherapy, consisting of anthracyline- or anthracenedione-based regimens in 39 cases (60%). Twenty-seven women were treated in the phase I study (3 at epirubicin 60 mg/m(2), and 6 at each subsequent dose level). Dose-limiting toxicity consisted of grade III asthenia and febrile neutropenia (epirubicin 75 mg/m(2)), grade IV thrombopenia and grade III asthenia (epirubicin 90 mg/m(2)), grade IV stomatitis and grade III diarrhea (epirubicin 100 mg/m(2)), and grade III diarrhea (epirubicin 110 mg/m(2)). In the phase II study, an additional 38 women were treated at epirubicin 90 mg/m(2) and epirubicin 100 mg/m(2). During the 349 cycles delivered, grade IV neutropenia occurred in 90%; febrile neutropenia requiring hospitalization occurred in 62 (17.8%) and lasted more than 3 days in 12 (3.4%). Nonhematologic toxicity was acceptable. Three left ventricular ejection fraction depressions occurred and normalized during follow-up. The overall response rate in the 62 evaluable women was 69.4% (range: 58--81%), with a median duration of 7.8 months. After 26 months of follow-up, the median time to progression was 9.1 months and median overall survival was 22.7 months. On the basis of efficacy and toxicity, the recommended dose of the combination is epirubicin 100 mg/m(2) plus docetaxel 75 mg/m(2).

[Evaluation of predictive factors, particularly the Van Nuys index, of local recurrence in ductal carcinoma in situ of the breast: study of 166 cases with conservative treatment and review of the literature]. / In process citation.

Ductal carcinoma in situ (DCIS), a non metastazing lesion of the breast is more frequently observed due to the improvement of mammography and widespread use of screening. The most important risk of this disease is local recurrence. In about half of cases, it occurs as an infiltrating carcinoma. In a series of 166 DCIS treated by lumpectomy plus radiotherapy, we have studied clinico-pathological factors for the prognosis of local recurrences and particularly the Van Nuys Index criteria (nuclear grade, necrosis, size, margin width). After median follow up of 75 months, 21 recurrences were observed with 10 corresponding to an infiltrating carcinoma and one of them died. The size of DCIS evaluated on pathological documents (histological slides and shames), the Van Nuys Prognostic Index (VNPI) and the mitotic index were the main prognostic factors of local recurrence. We discuss these results and confront them to a review of the literature focalised on the delicate problem of the decision of conservative treatment. A multidisciplinary approach (Breast : Surgeon, Radiologist, Pathologist and Radiotherapist), a standardisation of pathological criteria (size, margin width) and the continuation of randomised trials are necessary to fine the best attitude of conservative therapy.

Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer.

This comparative phase III trial of mitoxantrone+vinorelbine (MV) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin (FAC/FEC) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy, while resulting in an improved tolerance in relation to alopecia and nausea/vomiting. This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC.

Intensification of adjuvant chemotherapy: 5-year results of a randomized trial comparing conventional doxorubicin and cyclophosphamide with high-dose mitoxantrone and cyclophosphamide with filgrastim in operable breast cancer with 10 or more involved axillary nodes.

PURPOSE: To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes. PATIENTS AND METHODS: Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m(2) plus cyclophosphamide 600 mg/m(2), with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates. RESULTS: There were no significant differences in DFS (P =.44), DDFS (P =.67), or OS (P =.99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P =.01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P <.001). CONCLUSION: This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m(2) with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.

Oral vinorelbine: feasibility and safety profile.

BACKGROUND: Patient preference as well as concerns and difficulties with intravenous access and pharmaco-economic issues have driven the development of oral vinorelbine. PATIENTS AND METHODS: Four phase II studies were conducted in chemotherapy-naive non-small-cell lung cancer (NSCLC) and as first-line chemotherapy of advanced breast cancer (ABC). As recommended in the phase I dose-finding study, the first step used a weekly dose of 80 mg/m2. This regimen was associated with an excessive rate of early deaths (10%) due to complicated neutropenia and led to discontinuation of the first two studies. In a second step, the dose of 60 mg/m2/week was given for the first three courses and subsequently increased to 80 mg/m2/week, in the absence of severe neutropenia. RESULTS: One hundred and thirty eight patients (76 with NSCLC and 62 with ABC) received this regimen, of whom only five were unable to undergo dose escalation. The incidence of febrile neutropenia and neutropenic sepsis were low (2.9 and 3.6%, respectively). Although severe events were uncommon, nausea/vomiting and diarrhoea were frequent and primary prophylaxis with antiemetics should be recommended. CONCLUSIONS: Overall, the safety profile of oral vinorelbine at 60 mg/m2/week for the first three courses with escalation to 80 mg/m2 is qualitatively comparable to that of i.v. vinorelbine at standard doses. Similarly to i.v. chemotherapy, close haematological monitoring is necessary.