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M J Piccart

Publications and source records attributed to M J Piccart.

At least 19 recordsLinked to original sources
PubMed2006

[Towards an individualization of systemic treatment of breast tumors].

Clinical trials of adjuvant treatment of breast cancers have been limited for a long time to overall comparisons of heterogeneous populations. A new generation of clinical trials should be implemented, with especially the selection of the patients as a function of the molecular characteristics of their tumour. Unquestionable biological data must be taken into account to raise relevant questions, such as the role of topoisomerase II in the response to anthracyclines or the role of p53 in the response to taxanes. Microarrays technology, which allows the establishment of expression profiles of the whole genome, are very powerful tools which have allowed to reclassify breast tumours and to obtain "molecular signatures" characteristic for the risk of metastatic recurrence. A large randomised prospective study has been recently initiated with the aim of comparing the prognostic value of this signature to that of classical histopathologic criteria. In the next future, it will be possible to consider an individualisation of the prescription of cancer chemotherapies on molecular validated bases.

Biomarkers, Tumor↗
PubMed2005

Adjuvant chemotherapy in 2005: standards and beyond.

The 2003 St. Gallen consensus panel divided the many available adjuvant chemotherapy (CT) regimens into those with "standard efficacy" (ACx4, CMFx6) and those with "superior efficacy" (FA(E)Cx6, CA(E)Fx6, A(E)-->CMF, TACx6, ACx4--> paclitaxel (P)x4 or docetaxel (D)x4) but also greater complexity, toxicity and cost. This paper will summarize the latest information on long-term side effects of the "superior" regimens and 5-year benefits reported in taxane trials, including those of a "new" sequential regimen, FECx3--> docetaxelx3. Rapidly expanding evidence of marked heterogeneity in the magnitude of CT benefits according to the tumour oestrogen receptor (ER) status, a claim made for many years by IBCSG investigators, will be reviewed; it will lead to the conclusion that a revolution needs to take place in the way oncologists think about the CT added value and design adjuvant clinical trials. The conclusions proposed to the 2005 St. Gallen consensus panel are that: adequately dosed anthracycline-based CT regimens remain an acceptable standard for many women; a lower threshold for using taxanes in sequence or combination with anthracyclines (A) is justified in the presence of an ER-negative or low-ER tumour status, other aggressive biologic features (such as HER-2 overexpression), fear about A-induced cardiotoxicity; no recommendation can yet be made as far as the optimal taxane-A regimen, the best taxane or the best taxane schedule.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Long-term survival in pituitary metastasis from breast cancer.

We report the interesting case of a patient who is a long-term survivor of breast cancer with metastasis to the pituitary gland. This patient was treated with surgery and radiotherapy in 1995 and during her second relapse, which occurred in 2004, chemotherapy was given. This treatment resulted in a partial response.

Breast Neoplasms↗
PubMed2005

Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now?

In the last few decades, proliferative markers have been broadly evaluated as prognostic and predictive factors for early stage breast cancer patients. Several papers evaluating one or more markers have been published, often with contradictory results. As a consequence, there is still uncertainty about the role of these proliferative markers. The present paper critically reviews the current knowledge about the following markers: thymidine labeling index, S phase fraction/flow cytometry, Ki 67, thymidine kinase (TK), cyclins E, cyclin D, the cyclin inhibitors p27 and p21, and topoisomerase IIalpha. For each marker, the prognostic and predictive role was separately analyzed. Only papers published in English in peer-reviewed journals before June 2004 that include at least 100 evaluable patients were selected. In addition, the prognostic and predictive role of the proliferative markers had to be assessed through multivariate analyses. One hundred and thirty-two papers fulfilled these criteria and 159 516 patients were analyzed. Unfortunately, several methodological problems in the research to date prevent us from including any one of these proliferative markers among the standard prognostic and predictive factors. Early incorporation of translational research and new technologies with clinical trials are needed to prospectively validate biological markers and allow their use in clinical practice.

Biomarkers, Tumor↗
PubMed2004

HER-2/neu as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel.

PURPOSE: To evaluate the predictive value of HER-2 in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin (A) or with single-agent docetaxel (T). EXPERIMENTAL DESIGN: Patients from this study participated in a phase III clinical trial in which doxorubicin or docetaxel was administered for advanced disease. HER-2 was evaluated by IHC. In all positive cases, FISH was used to confirm the HER-2 positive status. The different cohorts of patients identified by HER-2 were examined to assess a possible relationship between HER-2 status and treatment effect. RESULTS: Tumor samples were available for 176 of the 326 patients entered in the clinical trial (54%). HER-2 positivity was observed in 20% of the study population. A statistically significant interaction was found between response rates to the study drugs and HER-2 status, with HER-2 positive patients deriving the highest benefit from the use of T (odds ratio for HER-2 positive patients treated with T = 3.12 (95% CI 1.11-8.80), p = 0.03). The interaction between HER-2 and response rates to A and T was also confirmed by a multivariate analysis. No statistically significant interaction was found between HER-2 and drugs efficacy evaluated in terms of time to progression and overall survival, although in the HER-2 negative cohort A was at least as effective as T in term of overall survival. CONCLUSIONS: These results suggest that in HER-2 positive breast cancer patients docetaxel might be more active than doxorubicin, while in HER-2 negative patients doxorubicin might be at least as effective as docetaxel. Although the present results cannot have an impact on current practice, they allow us to formulate the hypothesis that HER-2 positive breast cancer is a heterogeneous disease with regard to sensitivity to anthracyclines and taxanes, and that this might be dependent upon other molecular markers including the p-53 and topoisomerase II alpha genes. This hypothesis is currently being tested prospectively in two different 'bench to bed-side' clinical trials.

Adolescent↗
PubMed2004

Adjuvant chemotherapy in elderly patients with breast cancer: a survey of the Breast International Group (BIG).

BACKGROUND: To collect oncologists' experience and opinion on adjuvant chemotherapy in elderly breast cancer patients. MATERIALS AND METHODS: A questionnaire was circulated among the members of the Breast International Group. RESULTS: A total of 277 oncologists from 28 countries participated in the survey. Seventy years is the age cut-off commonly used to define a patient as elderly. Biological age and the biological characteristics of the tumor are the most frequently used criteria to propose adjuvant chemotherapy to an elderly patient. Combination therapy with cyclophosphamide, methotrexate and fluorouracil on days 1 and 8 is the most frequently prescribed regimen. Great interest exists in oral chemotherapy. CONCLUSION: There is interest among those who responded to the survey to validate a comprehensive geriatric assessment for use as a predictive instrument of toxicity and/or activity of anticancer therapy and to evaluate the role of a treatment option that is potentially less toxic and possibly as effective as polychemotherapy.

Aged↗
PubMed2004

Prolonged schedule of temozolomide (Temodal) plus liposomal doxorubicin (Caelyx) in advanced solid cancers.

Temozolomide (Temodal) is an oral imidazotetrazine. Increased temozolomide exposure and subsequent depletion of O-alkylguanine alkyltransferase may improve the activity of temozolomide. The rationale for investigating temozolomide plus Caelyx is based on their antitumor activity, their formulation and no significant overlapping toxicities. We conducted a study of a prolonged schedule of temozolomide (orally on days 1-7 and 15-21) plus Caelyx (day 1) every 28 days. Twenty-one patients (melanoma n=10, sarcoma n=7 and other n=4) were assigned to four dose levels (DL; temozolomide+Caelyx, mg/m): DL1: 100+30 (n=3 patients), DL2: 100+40 (n=6 patients), DL3: 125+40 (n=6 patients) and DL4: 150+40 (n=6 patients). Dose-limiting toxicities were noted after 2 or more cycles in one patient at DL3 (stomatitis) and one patient at DL4 (grade 4 ANC >/=7 days). Treatment delays and/or dose reductions (due to hematological toxicity) were necessary in five of six patients receiving DL4 compared with one of six patients at DL3, and one patient at DL1 and 2. Thus, the recommended dose was temozolomide 125 mg/m (daily for 7 days every other week) plus Caelyx 40 mg/m (day 1 every 4 weeks). Other toxicities were mild. Antitumor activity was observed in eight patients, including one complete response (melanoma), three partial responses (one melanoma, two sarcomas) and four patients with stable disease (three melanomas, one Ewing), with a duration lasting from 14 to 135+weeks. Two melanoma patients showed tumor stabilization in non-irradiated cerebral lesions. This schedule of temozolomide allowed higher dose intensity (1750 mg/m in 4 weeks) compared to the standard 5-day regimen (1000 mg/m in the same amount of time).

Adult↗
PubMed2004

Correlation between complete response to anthracycline-based chemotherapy and topoisomerase II-alpha gene amplification and protein overexpression in locally advanced/metastatic breast cancer.

UNLABELLED: Anthracycline-based regimens are among the most active but also with greater risk of both acute and long-term side effects, namely cardiotoxicity. Predictive markers of response to anthracyclines are therefore essential. Topoisomerase-IIalpha (topo-II) is the target of anthracyclines and preliminary data suggest its promising role as a predictive marker of sensitivity to these drugs. After screening a population of about 350 patients with locally advanced or metastatic breast cancer, two subgroups were selected for the present analysis: a study group (31 patients), composed of 14 complete responders (CR-a) and 17 true non-responders (PD-a) to anthracycline-based CT, and a control group (28 patients), composed of 7 CR (CR-t) and 21 true non-responders (PD-t) to taxane-based CT. True non-responders were defined as progressive disease (PD) within the first three cycles of CT. Archival tumor samples of these patients were collected, biological markers evaluated and their status correlated with response to therapy. HER-2 and topo-II gene status were evaluated by FISH (Vysis multi-color probe-positivity cut-off: >/=2 ratio for HER-2 and >/=1.5 for topo-II), topo-II protein was evaluated by IHC (positivity cut-off >10%). All cases in which HER-2 gene was non-amplified did not show topo-II gene aberrations. No association was found between HER-2 gene amplification and response to anthracyclines (5/14 (36%) CR and 5/17 (29%) PD to anthracycline-based CT were HER-2+). The topo-II gene was amplified in 3/14 (21%) CR but only in 1/17 (6%) PD to anthracyclines. Amplification of the topo-II gene was seen in 1/7 (14%) CR and in 3/21 (14%) PD to a taxane-based CT. Topo-II protein was overexpressed in 6/11 (55%) CR and in 2/17 (12%) PD to anthracyclines, while in the control group, overexpression was seen in 5/7 (71%) CR and 8/20 (40%) PD. IN CONCLUSION: i) HER-2 gene amplification did not seem to be correlated with response to anthracyclines. ii) Both topo-II gene amplification and protein overexpression seem to correlate with response to anthracyclines, although other factors, such as p53 and cell proliferation, are most likely to be involved. iii) The role of combined evaluation of several relevant markers and of potential 'molecular signatures' are currently being evaluated in prospective randomized clinical trials.

Adult↗
PubMed2003

Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study.

PURPOSE: To compare the efficacy of a standard anthracycline-based regimen to a dose-intensified anthracycline regimen in locally advanced breast cancer. PATIENTS AND METHODS: Locally advanced breast cancer patients were randomly assigned onto a study comparing cyclophosphamide (C; 75 mg/m(2) orally days 1 to 14), epirubicin (E; 60 mg/m(2) intravenously [IV] days 1, 8), and fluorouracil (F; 500 mg/m(2) IV days 1, 8) six cycles every 28 days versus E (120 mg/m(2) IV day 1), C (830 mg/m(2) IV day 1), and granulocyte colony-stimulating factor (filgrastim; 5 micro g/kg/d subcutaneously days 2 to 13) six cycles every 14 days. The study was designed to detect a 15% improvement; that is, from 50% to 65% in median progression-free survival (PFS) in favor of the dose-intensified regimen. RESULTS: A total of 448 patients were enrolled over a period of 3 years. The median dose intensity delivered for C and E reached, respectively, 85% and 87% of that planned in the CEF arm and 96% and 95% of that planned in the EC arm. The dose-intensified arm was slightly more emetogenic and generated more grade 3 to 4 anemia but less febrile neutropenia episodes. After a median follow-up of 5.5 years, 277 events have been reported. The median PFS was 34 and 33.7 months for CEF and EC, respectively (P =.68), and the 5-year survival rate was 53% and 51% for CEF and EC, respectively (P =.94). CONCLUSION: Dose-intensified EC does not provide a measurable therapeutic benefit over CEF as neoadjuvant chemotherapy for unselected locally advanced breast cancer patients.

Adolescent↗
PubMed2003

An EORTC-ECSG phase I study of LU 79553 administered every 21 or 42 days in patients with solid tumours.

A single-agent dose-escalating phase I and pharmacokinetic study on the naphthalamide agent, LU 79553, was performed to determine its safety profile, maximum tolerated dose (MTD) and recommended dose for phase II studies. LU 79553 was given intravenously (i.v.) every 3 weeks to patients with advanced solid cancers (an extended cohort of patients also received the drug every 6 weeks). 59 patients were enrolled into the study (50 patients in the 3-weekly schedule and 9 patients in the 6-weekly schedule). Dose levels studied ranged from 10 mg/m(2) to 160 mg/m(2). Neuro-muscular toxicity was identified as the dose-limiting toxicity (DLT). This muscular toxicity was observed after administrating total doses of 160-450 mg/m(2) (median 330 mg/m(2)). Non-DLTs consisted of diarrhoea, nausea and vomiting, fatigue and local venous phlebitis. The major haematological toxicities observed were anaemia and neutropenia (and were mainly observed at the two highest dose levels). The proposed dose for phase II studies using the 3-weekly regimen is 100 mg/m(2)/course (60 min infusion in 500 ml normal saline), but a close clinical follow-up of the patients for neuromuscular toxicity is mandatory. Prolongation of the treatment interval to 6 weeks, based upon the long half-life of the drug in the plasma and tissue, observed during this study, seemed not to be feasible in this heavily pretreated group of patients.

Adult↗
PubMed2003

Use and abuse of taxanes in the management of metastatic breast cancer.

Taxanes are currently introduced early in the treatment of patients with metastatic breast cancer (MBC), both as single agents and in combination with anthracyclines. Two different patient populations exist: those with no or minimal prior anthracycline exposure and those who have failed previous anthracyclines. The data generated through phase III trials in first-line MBC therapy will be reviewed and their interpretation for routine clinical practice (use versus abuse) will be discussed. Ways of improving taxane-based treatment tailoring both in the pre- and postgenomic eras will be addressed.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Clinical outcome of breast cancer patients with liver metastases alone in the anthracycline-taxane era: a retrospective analysis of two prospective, randomised metastatic breast cancer trials.

Liver metastases have long been known to indicate an unfavourable disease course in breast cancer (BC). However, a small subset of patients with liver metastases alone who were treated with pre-taxane chemotherapy regimens was reported to have longer survival compared with patients with liver and metastases at other sites. In the present study, we examined the clinical outcome of breast cancer patients with liver metastases alone in the context of two phase III European Organisation for Research and Treatment of Cancer (EORTC) trials which compared the efficacy of doxorubicin (A) versus paclitaxel (T) (trial 10923) and of AC (cyclophosphamide) versus AT (trial 10961), given as first-line chemotherapy in metastatic BC patients. The median follow-up for the patients with liver metastases was 90.5 months in trial 10923 and 56.6 months in trial 10961. Patients with liver metastases alone comprised 18% of all patients with liver metastases, in both the 10923 and 10961 trials. The median survival of patients with liver metastases alone and liver plus other sites of metastases were 22.7 and 14.2 months (log rank test, P=0.002) in trial 10923 and 27.1 and 16.8 months (log rank test, P=0.19) in trial 10961. The median TTP (time to progression) for patients with liver metastases alone was also longer compared with the liver plus other sites of metastases group in both trials: 10.2 versus 8.8 months (log rank test, P=0.02) in trial 10923 and 8.3 versus 6.7 months (log rank test, P=0.37) in trial 10961. Most patients with liver metastases alone have progression of their disease in their liver again (96 and 60% of patients in trials 10923 and 10961, respectively). Given the high prevalence of breast cancer, improved detection of liver metastases, encouraging survival achieved with currently available cytotoxic agents and the fact that a significant portion of patients with liver metastases alone have progression of their tumour in the liver again, a more aggressive multimodality treatment approach through prospective clinical trials seems worth exploring in this specific subset of women.

Antineoplastic Agents↗
PubMed2003

New data on chemotherapy in the adjuvant setting.

In the last few months, there have been three sets of new, provocative data that might have important implications for the daily prescription of adjuvant chemotherapy (CT) in the future. (1) Urokinase-type plasminogen activator (UPA) and type 1 plasminogen activator inhibitor (PAI-1), two molecular markers of invasion already known for their powerful prognostic value in node-negative breast cancer, seem to predict for enhanced benefit from adjuvant CT, while the benefit from adjuvant endocrine therapy seems independent of them. The predictive value of these markers, however, remains suboptimal and an important limitation lies in their evaluation through a cytosolic assay, which is compromised for small tumours (<1cm). (2) Breast cancer 'gene expression profiles' have been identified through DNA-microarray technology and seem to be better predictors of clinical outcome in young women (less than 55 years old) with stage I or II breast cancer, when compared to the currently used clinical-pathological criteria. Remarkably, these molecular data suggest that the prognostic profile of breast cancer does not depend on lymph node status and that it is possible to identify a group of node-positive breast cancer patients with an unexpectedly good prognosis. Prospective and independent confirmation is needed, but these data are fascinating and carry the hope that CT decision-making in breast cancer will be greatly facilitated in the future. (3) The recently reported CALGB 9741 (or INT 69741) trial shakes our belief that 'one cycle of CT every 3 weeks' is the adequate adjuvant treatment for node-positive breast cancer. Launched in 1999, it aimed to test two novel concepts based on mathematical models of tumour cell growth kinetics. Concept 1 implies that dose-densification of CT, i.e., delivering drugs at reduced intervals, will maximize the chances of eradicating the tumour; and concept 2 extends the first one to encompass situations of heterogeneous drug sensitivity through the use of sequential dose-dense, non-cross-resistant single agents or regimens. The 3-year results of this trial strongly support concept 1; a longer follow-up and a confirmation study are desirable before recommending changes in routine patient care.

Biomarkers, Tumor↗
PubMed2003

The best use of chemotherapy in the adjuvant setting.

Currently, based on the results of large randomized clinical trials and the conclusions of the Oxford meta-analysis (EBCTCG. Lancet 1998; 352: 930; Peto R. Fifth Main Meeting of the Early Breast Cancer Trialist's Collaborative Group, Oxford, UK, September 2000) and following internationally accepted treatment guidelines (National Institutes of Health Consensus Development Panel. J Natl Cancer Inst 2001; 93(13): 979; Goldhirsch et al. J Clin Oncol 2001; 19: 3817), the vast majority of primary breast cancer patients is offered adjuvant medical therapy. Regarding adjuvant chemotherapy (CT), the two most important and challenging tasks of the medical oncologist today are (1) to identify who needs CT and (2) to select the CT regimen that will work best for the individual patient, while at the same time minimizing the risk of severe or permanent toxicities. The second question will be the focus of this paper.

Anthracyclines↗
PubMed2003

The pipeline of new anticancer agents for breast cancer treatment in 2003.

In recent years, strategy in cancer therapy in general, and breast cancer in particular, has been the use of maximum tolerated doses of toxic non-specific agents as well as the investigation of a range of new agents that specifically target tumor-related molecules, in a variety of biological pathways. The trial of chemotherapy (CT) versus chemotherapy+trastuzumab (Herceptin) in HER-2-overexpressing metastatic breast cancer (MBC) was one of the first to use a biological agent in combination with chemotherapy with success and, together with some trials of taxanes in anthracycline-resistance patients one of the few to demonstrate an overall survival (OS) advantage in MBC. Five main molecular pathways are of particular interest in terms of new drug development in breast cancer: the estrogen receptor (ER) pathway, the tyrosine kinase signal transduction pathway, the cell cycle regulation pathway, the apoptosis pathway and the angiogenesis pathway. This review will focus on new agents, cytotoxic, hormonal and molecular-targeted, which are in advanced clinical stages of development for the treatment of MBC.

Antineoplastic Agents↗
PubMed2003

A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy.

BACKGROUND: We evaluated the efficacy of a single fixed 6 mg dose of pegfilgrastim (a pegylated version of filgrastim) per cycle of chemotherapy, compared with daily administration of filgrastim, in the provision of neutrophil support. PATIENTS AND METHODS: Patients (n = 157) were randomized to receive either a single 6 mg subcutaneous (s.c.) injection of pegfilgrastim or daily 5 mg/kg s.c. injections of filgrastim, after doxorubicin and docetaxel chemotherapy (60 mg/m(2) and 75 mg/m(2), respectively). Duration of grade 4 neutropenia, depth of neutrophil nadir, incidence of febrile neutropenia, time to neutrophil recovery and safety information were recorded. RESULTS: A single 6 mg injection of pegfilgrastim was as effective as daily injections of filgrastim for all efficacy measures for all cycles. The mean duration of grade 4 neutropenia in cycle 1 was 1.8 and 1.6 days for the pegfilgrastim and filgrastim groups, respectively. Results for all efficacy end points in cycles 2-4 were consistent with the results from cycle 1. A trend towards a lower incidence of febrile neutropenia was noted across all cycles with pegfilgrastim compared with filgrastim (13% versus 20%, respectively). A single fixed dose of pegfilgrastim was as safe and well tolerated as standard daily filgrastim. CONCLUSIONS: A single fixed dose of pegfilgrastim administered once per cycle of chemotherapy was comparable to multiple daily injections of filgrastim in safely providing neutrophil support during myelosuppressive chemotherapy. Pegfilgrastim may have utility in other clinical settings of neutropenia.

Adult↗
PubMed2003

Second malignancies following adjuvant chemotherapy: 6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment of node-positive breast cancer patients.

BACKGROUND: Alkylating agents and topoisomerase-II inhibitors have been associated with the occurrence of secondary leukemias and myelodysplastic syndromes in breast cancer patients treated with adjuvant chemotherapy. Conversely, data on the occurrence of second solid malignancies in this setting are scarce. PATIENTS AND METHODS: This study retrospectively evaluates the occurrence of second hematological and solid malignancies in the context of a prospective multicenter phase III trial comparing epirubicin-cyclophosphamide at intermediate doses (EC), or at full doses (HEC), with classical cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in 777 patients with early breast cancer. RESULTS: At a median follow-up of 73 months, the following 8-year actuarial rates of second solid primaries were observed: CMF 5.5% [95% confidence interval (CI) 1.5% to 9.5%], EC 4.1% (95% CI 0.1% to 8.1%), and HEC 7.2% (95% CI 3.2% to 11.2%) (P = 0.79 by log rank test). Three secondary acute myeloid leukemias (AML) were reported, all in the HEC arm (incidence = 1.2%, 95% CI 0.0% to 2.5%), which by a three arm comparison allows us to conclude that HEC is statistically different (borderline significance) from CMF and EC (P = 0.05). CONCLUSIONS: HEC, as delivered in this trial, cannot be recommended in clinical practice because of the lack of superiority over classic CMF and because of the increased risk of AML observed in this arm. Prolongation of conventional anthracycline-based treatment beyond the current standard of four to six cycles is not recommended in clinical practice.

Adult↗