Publications by authors named "Jean-Paul Guastalla"

49 Publications

Does a homeopathic medicine reduce hot flushes induced by adjuvant endocrine therapy in localized breast cancer patients? A multicenter randomized placebo-controlled phase III trial.

Support Care Cancer 2019 May 7;27(5):1879-1889. Epub 2018 Sep 7.

Department of Medical Oncology, Centre Léon Bérard, 28 rue Laennec, 69373, Lyon Cedex 08, France.

Purpose: Endocrine therapy (ET) used to reduce the risk of recurrence in hormone receptor-expressing disease (75% of breast cancers) is associated with worsening of climacteric symptoms with a negative impact on quality of life (QoL). Homeopathy might allow a better management of hot flushes (HF).

Methods: In this multicenter randomized double-blind placebo-controlled phase III study ( ClinicalTrials.gov NCT01246427), we enrolled ≥ 18 years old women with histologically proven non metastatic localized breast cancer, with Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≤ 1, treated for at least 1 month with adjuvant ET, and complaining about moderate to severe HF. Patients should not be scheduled for chemotherapy or radiotherapy, and had no associated pathology known to induce HF. After a 2- to 4-week placebo administration, we randomly assigned (1:1) patients with HFS ≥ 10 using an interactive web-based centralized platform to BRN-01 homeopathic medicine complex (Actheane®) in arm A or Placebo (Arm P). Randomization was stratified by adjuvant ET (taxoxifen/aromatase inhibitor) and recruiting site. HF scores (HFS) were calculated as the mean of HF frequencies before randomization, at 4, and at 8 weeks post-randomization (pre-, 4w,- and 8w-) weighted by a 4-level intensity scale. Primary endpoint was assessed at 4-week post-randomization, as the variation between pre- and 4w-HFS. Secondary endpoints included HFS variation between pre- and 8w-HFS, compliance and tolerance assessed 8 weeks after randomization, and QoL and satisfaction assessed at 4- and 8-week post-randomization.

Results: Two hundred ninety-nine patients were included, and 138 (46.2%) randomized (A, 65; P, 73). Median 4w-HFS absolute variation (A, - 2.9; P, - 2.5 points, p = 0.756) and relative decrease (A, - 17%; P, - 15%, p = 0.629) were not statistically different. However, 4w-HFS decreased for 46 (75%) in A vs 48 (68%) patients in P arm. 4w-QoL was stable or improved for respectively 43 (72%) vs 51 (74%) patients (p = 0.470).

Conclusions: The efficacy endpoint was not reached, and BRN-01 administration was not demonstrated as an efficient treatment to alleviate HF symptoms due to adjuvant ET in breast cancer patients. However, the study drug administration led to decreased HFS with a positive impact on QoL. Without any recommended treatment to treat or alleviate the HF-related disabling symptoms, Actheane® could be a promising option, providing an interesting support for better adherence to ET, thereby reducing the risk of recurrence with a good tolerance profile.
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http://dx.doi.org/10.1007/s00520-018-4449-xDOI Listing
May 2019

Motivations of patients seeking supportive care for cancer from physicians prescribing homeopathic or conventional medicines: results of an observational cross-sectional study.

Homeopathy 2016 Nov 24;105(4):289-298. Epub 2016 Oct 24.

Laboratoires Boiron, Messimy, France.

Background & Aims: The motivations of patients who consult a homeopathic (GP-Ho) or conventional (GP-CM) general practitioner for supportive care during cancer treatment have not been widely studied. We investigated the reasons why cancer patients consult a GP-Ho versus a GP-CM for supportive care and the GPs' motivations for their prescriptions.

Methods: This observational survey was carried out in France between October 2008 and October 2011. GPs across France were randomly selected and asked to recruit four cancer patients each. At inclusion, the sociodemographic and clinical (including psychological) characteristics and medical history of the patients were recorded by the GPs and the patients noted their quality of life (QoL) and anxiety/depression using the Quality of Life Questionnaire-C30 (QLQ-C30) and Hospital Anxiety and Depression Scale (HADS) self-questionnaires. The main motivations of the patients regarding the type of GP consultation and the main reasons for the GPs' prescriptions were recorded.

Results: Six hundred and forty four patients were included in the analysis: 399 consulted a GP-CM (n = 112) and 245 a GP-Ho (n = 73). Patients consulting a GP-Ho were more often female [OR = 1.93; 95%CI: 1.11-3.35; p = 0.02], employed in a professional capacity [OR = 6.57; 95%CI: 1.96-21.99; p = 0.002], have a shorter time since cancer diagnosis [OR = 2.19; 95%CI: 1.24-3.87; p = 0.007], have received targeted anticancer therapy [OR = 3.70; 95%CI: 1.67-8.18; p = 0.001] and have a high QLQ-C30 score for constipation [OR = 1.01; 95%CI: 1.00-1.02; p = 0.001]. Patients mainly consulted a GP-Ho to receive overall care (73.5% vs. 64.9%; p = 0.024) and medicines to prevent anticancer treatment-related side-effects (63.7% vs. 41.4%; p < 0.0001). In contrast, patients consulted a GP-CM to receive psychological care (50.1% vs. 40.8%; p = 0.021) and more information regarding the oncologists' strategic decisions (p < 0.0001). There was a significantly greater prescription of psychotropic drugs by GP-CM (53.7% vs. 22.4%, p < 0.0001).

Conclusions: Patients consulting a GP-Ho or GP-CM had different motivations for seeking supportive care. There was a significantly greater prescription of psychotropic drugs by GP-CM.
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http://dx.doi.org/10.1016/j.homp.2016.09.001DOI Listing
November 2016

Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: A phase 2 randomized study.

Breast 2015 Jun 5;24(3):182-90. Epub 2015 Mar 5.

UCLA School of Medicine, Los Angeles, CA, USA. Electronic address:

Introduction: This phase 2 randomized study evaluated trebananib (AMG 386), a peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction of angiopoietin-1 and -2 with Tie2, in combination with paclitaxel with or without bevacizumab in previously untreated patients with HER2-negative locally recurrent/metastatic breast cancer.

Methods: Patients received paclitaxel 90 mg/m(2) once weekly (3-weeks-on/1-week-off) and were randomly assigned 1:1:1:1 to also receive blinded bevacizumab 10 mg/kg once every 2 weeks plus either trebananib 10 mg/kg once weekly (Arm A) or 3 mg/kg once weekly (Arm B), or placebo (Arm C); or open-label trebananib 10 mg/kg once a week (Arm D). Progression-free survival was the primary endpoint.

Results: In total, 228 patients were randomized. Median estimated progression-free survival for Arms A, B, C, and D was 11.3, 9.2, 12.2, and 10 months, respectively. Hazard ratios (95% CI) for Arms A, B, and D versus Arm C were 0.98 (0.61-1.59), 1.12 (0.70-1.80), and 1.28 (0.79-2.09), respectively. The objective response rate was 71% in Arm A, 51% in Arm B, 60% in Arm C, and 46% in Arm D. The incidence of grade 3/4/5 adverse events was 71/9/4%, 61/14/5%, 62/16/3%, and 52/4/7% in Arms A/B/C/D. In Arm D, median progression-free survival was 12.8 and 7.4 months for those with high and low trebananib exposure (AUCss ≥ 8.4 versus < 8.4 mg·h/mL), respectively.

Conclusions: There was no apparent prolongation of estimated progression-free survival with the addition of trebananib to paclitaxel and bevacizumab at the doses tested. Toxicity was manageable. Exposure-response analyses support evaluation of combinations incorporating trebananib at doses > 10 mg/kg in this setting.

Trial Registration: ClinicalTrials.gov, NCT00511459.
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http://dx.doi.org/10.1016/j.breast.2014.11.003DOI Listing
June 2015

Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial.

Lancet Oncol 2013 Jan 12;14(1):72-80. Epub 2012 Dec 12.

Cross Cancer Institute, Edmonton, AB, Canada.

Background: We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety.

Methods: BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov, number NCT00688740.

Findings: Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and 55% (51-59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68-0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72-79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 0·74, 0·61-0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC.

Interpretation: Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation.

Funding: Sanofi.
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http://dx.doi.org/10.1016/S1470-2045(12)70525-9DOI Listing
January 2013

Can treatment with Cocculine improve the control of chemotherapy-induced emesis in early breast cancer patients? A randomized, multi-centered, double-blind, placebo-controlled Phase III trial.

BMC Cancer 2012 Dec 17;12:603. Epub 2012 Dec 17.

Centre Léon Bérard, 28 rue Laennec, Lyon Cedex 08, 69373, France.

Background: Chemotherapy induced nausea and vomiting (CINV) remains a major problem that seriously impairs the quality of life (QoL) in cancer patients receiving chemotherapy regimens. Complementary medicines, including homeopathy, are used by many patients with cancer, usually alongside with conventional treatment. A randomized, placebo-controlled Phase III study was conducted to evaluate the efficacy of a complex homeopathic medicine, Cocculine, in the control of CINV in non-metastatic breast cancer patients treated by standard chemotherapy regimens.

Methods: Chemotherapy-naïve patients with non-metastatic breast cancer scheduled to receive 6 cycles of chemotherapy including at least three initial cycles of FAC 50, FEC 100 or TAC were randomized to receive standard anti-emetic treatment plus either a complex homeopathic remedy (Cocculine, registered in France for treatment of nausea and travel sickness) or the matching placebo (NCT00409071 clinicaltrials.gov). The primary endpoint was nausea score measured after the 1st chemotherapy course using the FLIE questionnaire (Functional Living Index for Emesis) with 5-day recall. Secondary endpoints were: vomiting measured by the FLIE score, nausea and vomiting measured by patient self-evaluation (EVA) and investigator recording (NCI-CTC AE V3.0) and treatment compliance.

Results: From September 2005 to January 2008, 431 patients were randomized: 214 to Cocculine (C) and 217 to placebo (P). Patient characteristics were well-balanced between the 2 arms. Overall, compliance to study treatments was excellent and similar between the 2 arms. A total of 205 patients (50.9%; 103 patients in the placebo and 102 in the homeopathy arms) had nausea FLIE scores > 6 indicative of no impact of nausea on quality of life during the 1st chemotherapy course. There was no difference between the 2 arms when primary endpoint analysis was performed by chemotherapy stratum; or in the subgroup of patients with susceptibility to nausea and vomiting before inclusion. In addition, nausea, vomiting and global emesis FLIE scores were not statistically different at any time between the two study arms. The frequencies of severe (Grade ≥ 2) nausea and vomiting were low in our study (nausea: P: 17.6% vs C: 15.7%, p=0.62; vomiting: P: 10.8% vs C: 12.0%, p=0.72 during the first course).

Conclusion: This double-blinded, placebo-controlled, randomised Phase III study showed that adding a complex homeopathic medicine (Cocculine) to standard anti-emetic prophylaxis does not improve the control of CINV in early breast cancer patients.
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http://dx.doi.org/10.1186/1471-2407-12-603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582626PMC
December 2012

Mechanisms of resistance to endocrine therapies for breast cancer.

Horm Mol Biol Clin Investig 2012 Apr;9(2):165-71

Abstract Breast cancer is the most frequently diagnosed cancer in women and 70% of the cases are hormone-dependent. The presence of ERα is one of the most important prognostic factors predictive of response to endocrine therapy in human breast cancers. Resistance to endocrine therapies has become a major public health concern and it appears essential to understand the mechanisms underlying this phenomenon. This review provides insights into the molecular mechanisms associated with resistance to endocrine therapies and presents the different strategies currently developed in pre-clinical models to overcome this resistance.
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http://dx.doi.org/10.1515/hmbci-2011-0001DOI Listing
April 2012

Multidisciplinarity and medical decision, impact for patients with cancer: sociological assessment of two tumour committees' organization.

Bull Cancer 2012 Apr;99(4):E34-42

Centre Leon-Bérard, Lyon, France.

Purpose: Medical practices in oncology are expected to be multidisciplinary, yet few articles studied how this may be concretely applied. In the present study, we evaluated the organization of two multidisciplinary committees, one for breast cancer and one for sarcoma, in a French Comprehensive Cancer Centre.

Methods: Both tumours were specifically chosen so as to emphasise substantial differences in relation with incidence, histological subtypes, management strategy, and scientific evidence. Between 2003 and 2004, 404 decision processes were observed, 210 for sarcoma (26 meetings) and 194 for breast cancer (10 meetings). The number of physicians who took part in the discussions and their medical specialties were systematically noted as well as the number of contradictory discussions, medical specialties represented in these contradictory discussions and the topics of contradiction. The last measured data was whether the final committee's decision was in conformity with the referent preferences or not. All these measures were related to the referent's medical speciality and working place, to the stage of the disease and to the disease management stage.

Results: Committees' specificities concerned their organization, referent's medical specialties, the number of participants in discussions and their medical specialties. Discussions in the sarcoma committee tended to be more multidisciplinary, involving more specialties. Initial strategy proposal for one patient was modified during the discussions for 86 patients out of 210 (41%) and for 62 out of 194 (32%) respectively for sarcoma and breast cancer. However, there was no significant difference in the rate of contradictory discussions between breast cancer and sarcoma committees (32% versus 41% respectively; P = 0.08). The rates of contradictory discussions were similar for localized cancers, local relapse and metastasis disease (37%, 41% and 34% respectively; P = 0.86).

Conclusions: The present study reports more than 30% of changes concerning strategy for patient with cancer due to multidisciplinary discussions. This indicates that, providing tumour committees are adapted to the pathologies' characteristics, they can promote a collective and multidisciplinary approach to oncology.
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http://dx.doi.org/10.1684/bdc.2012.1559DOI Listing
April 2012

[Cervix cancer and corpus cancer of the uterus].

Rev Prat 2011 Dec;61(10):1435-42

Centre Léon-Bérard, 69008 Lyon, France.

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December 2011

[Thrombosis and breast cancer: incidence, risk factors, physiopathology and treatment].

Bull Cancer 2012 Feb;99(2):199-210

Hôpital européen Georges-Pompidou, département d'oncologie médicale, 20, rue Leblanc, 75908 Paris Cedex 15, France.

Breast cancer is associated with a low rate of thromboembolic events (TEE) when compared to other cancers, without influence of the histological type on incidence. Risk factors include the stage of cancer, and the patients' profile and management: hospitalization, surgery and presence of a central catheter but also some cytotoxic chemotherapy, tamoxifen, and some anti-angiogenic targeted therapies. The pathophysiology of TEE includes a cross-stimulation phenomenon, involving tumor cells with procoagulant activity, and factors of hemostasis, coagulation and fibrinolysis. Circulating cellular microparticles bearing tissue factor play a major role, as well as thrombogenic platelet interactions with tumor cells via P-selectin. The occurrence of TEE in a cancer patient significantly increases the risk of death. Prevention is framed by recommendations in surgical patients. Curative treatment is based on the use of low molecular weight heparin for at least six months.
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http://dx.doi.org/10.1684/bdc.2011.1533DOI Listing
February 2012

[Adjuvant treatments in breast cancer: interest of completion of axillary dissection in case of micrometastases or isolated tumor cells in sentinel lymph node].

Bull Cancer 2012 Apr;99(4):463-9

Centre Léon-Bérard, 28, Lyon, France.

Prognostic signification of micrometastases ou isolated tumor cells (ITC) has not yet been clearly precised. Management of the axilla in case of micrometastases or ITC depends on the local pratices: no surgical completion or axillary lymph node dissection (ALND). Axillary lymph node status is the most important prognostic factor in patients with breast cancer; morbidity of ALND is now well known whereas its therapeutic benefit has not been demonstrated. This study is based on a retrospective database of 1375 patients who underwent sentinel node (SN) biopsy for breast cancer. In case of micrometastase or ITC in SN with completion axillary dissection, we examined if non-sentinel lymph node status has changed the indications of adjuvant treatments (chimiotherapy or radiotherapy). The results of our study show that non-sentinel lymph node status modify systemic therapy for a very few patients (less than 4% concerning chimiotherapy and less than 15% concerning radiotherapy).
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http://dx.doi.org/10.1684/bdc.2011.1527DOI Listing
April 2012

First-line endocrine therapy alone could be a reasonable treatment option for hormone-positive, HER2-positive metastatic breast cancer.

Bull Cancer 2012 Feb;99(2):E18-25

Centre Léon-Bérard, Department of Medical Oncology, 28, rue Laennec, 69008 Lyon, France.

Purpose: The treatment strategy for hormone receptor-positive (ER+) HER2-positive (HER2+) metastatic breast cancer has been modified since several randomized trials have proven the effectiveness of anti-HER2 targeted therapy. Previously validated clinical practice guidelines recommending the use of endocrine therapy alone in first line might be changed.

Methods: This study focused on the outcomes of women with ER+ HER2+ metastatic breast cancer receiving first-line endocrine therapy alone at the Léon-Bérard Centre, Lyon, France.

Results: Of 290 patients with ER+ HER2+ tumors, 32 (11%) met the criteria for inclusion. The median age was 54 years (29-79 years). Eighteen patients (56%) had only bone and/or soft tissue metastases. Most patients (n = 21; 65%) had only one metastatic site. Fifteen (47%) had histological grade III disease. The median progression free survival (PFS) was 8.2 months (95% CI: 0.1-16.3) and the median overall survival (OS) was 48 months (95% CI: 22.9-72.9). The overall response rate was 25% (95% CI: 11-49%), including one patient with complete response and seven with partial responses. Ten patients (31%) had stable disease. After failure of endocrine therapy, all patients received trastuzumab. The median PFS after first-line chemotherapy was 8.4 months (95% CI: 5.1-11.8). We identified a group of 10 patients with good prognostic factor (tumor grade < 3 tumors and no visceral metastases), for whom median PFS was 15.5 months (95% CI: 7-23).

Conclusions: Our result suggests that first-line endocrine therapy is a viable therapeutic option for a selected population of metastatic breast cancer patients with HER2-positive tumors. Genomic and transcriptomic signature could help to identify tumors that remain dependant of estrogen-signaling pathway.
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http://dx.doi.org/10.1684/bdc.2011.1537DOI Listing
February 2012

[Antihormonal therapy in breast cancer and mTOR inhibitors].

Bull Cancer 2011 Dec;98(12):1431-7

Centre Léon-Bérard, oncologie médicale, Lyon, France.

Hormonal dependence of breast cancer has been known for a long time, yet about half of breast cancers with estrogen receptor will not respond to antihormonal therapy. Now, we know that this resistance may be related to a dysfunction of the estrogen pathway, or that of growth factors and particularly the pathway of cell activation PI3K/Akt/mTOR. Prevention of these different mechanisms of resistance could involve combination therapies such as anti-estrogens (SERMs, aromatase inhibitors) with inhibitors of the activity of growth factors that are particularly temsirolimus and everolimus for the activation pathway cell PI3K/Akt/mTOR.
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http://dx.doi.org/10.1684/bdc.2011.1496DOI Listing
December 2011

Bevacizumab plus microtubule targeting agents in heavily pre-treated ovarian cancer patients: a retrospective study.

Bull Cancer 2011 Oct;98(9):80-9

CHU Hautepierre, Department of Oncology & Hematology, Strasbourg, France.

OBJECTIVES. As vascular endothelial growth factor (VEGF) is expressed in ovarian cancer, we assessed the efficacy and safety of bevacizumab (a monoclonal antibody targeting VEGF) plus microtubule targeting agents for heavily pre-treated ovarian carcinoma patients. METHODS. We retrospectively reviewed 43 patients with recurrent epithelial ovarian carcinoma. Combined treatment included bevacizumab with paclitaxel in 32 (74%), docetaxel in 10 (23%), and vinorelbine in one (2.3%) patients, respectively. RESULTS. The median number of combined treatment was six cycles (range 1-29). On RECIST criteria, the objective response rate (ORR) was 40% (16% CR and 24% PR). Clinical benefit (complete response [CR] plus partial response [PR] and stable disease [SD] lasting ≥ 3 months) was 74% (CI95%: 46.7-77%). Median duration of treatment and overall survival were 3.9 months (range 0.2-14.4 months) and 20.1 months (CI95%: 13.8-20.1) respectively. No toxic death was reported. Grade 3-4 toxicity occurred in 30% of patients. Gastrointestinal perforations and fistula occurred in 3 (7%) and 6 (14%) patients, respectively. CONCLUSION. Although being active in terms of ORR, bevacizumab plus microtubule targeting agents - mainly taxanes - leads to a high rate of gastro-intestinal perforations and fistula in heavily pre-treated ovarian carcinoma patients.
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http://dx.doi.org/10.1684/bdc.2011.1436DOI Listing
October 2011

Final results of ERASME-4: a randomized trial of first-line docetaxel plus either capecitabine or epirubicin for metastatic breast cancer.

Oncology 2011 6;80(3-4):262-8. Epub 2011 Jul 6.

Département de Cancérologie Médicale et Unité INSERM U590Centre Léon Bérard, 28 rue LaënnecFR–69373 Lyon Cedex 08, France.

Objective: To assess the efficacy of capecitabine plus docetaxel (XT) versus epirubicin plus docetaxel (ET) as first-line therapy for metastatic breast cancer (MBC).

Patients And Methods: Patients with no prior chemotherapy for MBC were randomized to 3-weekly cycles of either XT (capecitabine 1,000 mg/m(2) twice daily, days 1-14; docetaxel 75 mg/m(2), day 1) or ET (epirubicin 75 mg/m(2), day 1; docetaxel 75 mg/m(2), day 1). The primary endpoint was non-progression rate 6 months after randomization. The planned sample size was 106 patients based on a randomized, phase II selection design.

Results: Between April 2004 and January 2007, 68 patients were randomized, giving 82% power to select the best regimen according to a 6-month non-progression rate. Slow accrual led to premature study termination. Baseline characteristics were generally well balanced between arms. The 6-month non-progression rates were 75.8% with XT versus 65.7% with ET (p = 0.36). After 42 months' median follow-up, median progression-free survival was 12.4 versus 6.8 months, respectively (p = 0.040). The safety profiles were consistent with previous experience.

Conclusion: Further larger studies are warranted to validate these results. Despite more grade 3 hand-foot syndrome, first-line XT may be a valid alternative to ET, potentially improving efficacy.
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http://dx.doi.org/10.1159/000329066DOI Listing
September 2011

New developments in treatment of ovarian carcinoma: focus on trabectedin.

Cancer Manag Res 2010 Oct 1;2:233-42. Epub 2010 Oct 1.

Département de médecine.

Trabectedin is a new marine-derived compound that binds the DNA minor groove and interacts with proteins of the DNA repair machinery. Trabectedin has shown promising single-agent activity in pretreated patients with soft tissue sarcoma, and ovarian and breast cancer, and combination with various other chemotherapeutic drugs seems feasible. Toxicities are mainly hematologic and hepatic, with Grade 3-4 neutropenia and thrombocytopenia observed in approximately 50% and 20% of patients, respectively, and Grade 3-4 elevation of liver enzymes observed in 35%-50% of patients treated with trabectedin. The recently reported results of a large Phase III trial comparing pegylated liposomal doxorubicin (PLD) alone with a combination of PLD and trabectedin in patients with recurrent ovarian cancer showed improved progression-free survival with the combination of trabectedin and PLD, albeit at the price of increased toxicity. Current research focuses on the identification of predictive factors for patients treated with trabectedin, as well as the development of other combinations.
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http://dx.doi.org/10.2147/CMR.S9459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004573PMC
October 2010

Chemotherapy for metastatic breast cancer. Comparison of clinical practice and cost of drugs in two cohorts of patients: 1994-1998 and 2003-2006.

Breast Cancer Res Treat 2011 Jul 24;128(1):187-95. Epub 2010 Dec 24.

Department of Pharmacy, Centre Léon Bérard, Lyon, 69008, France.

Although new chemotherapeutic drugs for metastatic breast cancer (MBC) have been approved over the past decade, it is unclear whether this has changed the overall outcome of patients. This study assessed the clinical and economic impacts of these drugs. We retrospectively studied MBC patients receiving chemotherapy in our institution over two time periods, 1994-1998 and 2003-2006. Patient characteristics and outcomes, and treatment characteristics and costs (€, 2008) were compared. Three hundred and one patients were identified, 149 patients in the first cohort and 152 in second one. The median number of lines of chemotherapy was similar in the two cohorts (three lines). The median costs of chemotherapy per patient nearly doubled over time, from 6,272 € in the 1994-1998 cohort to 13,035 € in the 2003-2006 cohort (P < 0.001). No survival difference was observed between the two groups, with a 3-year survival rate estimated to 41% in the 1994-1998 cohort and 44% in the 2003-2006 cohort (P = 0.52). In multivariate analysis, prognostic factors associated with longer overall survival were single metastatic site (HR 0.48; P < 10⁻³), bone metastases (HR = 0.67; P = 0.007) and positive hormone receptors (HR 0.56; P = 0.0002). New chemotherapeutic agents induced a significant cost increase over time. The limited size and heterogeneity of our cohort do not allow any conclusion concerning their impact on survival.
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http://dx.doi.org/10.1007/s10549-010-1311-3DOI Listing
July 2011

Efficacy of trastuzumab in routine clinical practice and after progression for metastatic breast cancer patients: the observational Hermine study.

Oncologist 2010 29;15(8):799-809. Epub 2010 Jul 29.

Institut Paoli-Calmettes, Oncologie Médicale, 232 Boulevard de St Marguerite, 13273 Marseille Cedex 9, France.

Background: The Hermine study observed the use of trastuzumab for metastatic breast cancer (MBC) in routine practice, including patients who received trastuzumab treatment beyond progression (TBP).

Patients And Methods: The study observed 623 patients for > or = 2 years. Treatment was given according to oncologists' normal clinical practices. Endpoints included duration of treatment, efficacy, and cardiac safety. The TBP subanalysis compared overall survival (OS) in 177 patients who received first-line trastuzumab and either continued trastuzumab for > or = 30 days following progression or stopped at or before progression.

Results: The median treatment duration was 13.3 months. In the first-, second-, and third-line or beyond treatment groups, the median time to progression (TTP) were 10.3 months, 9.0 months, and 6.3 months, and the median OS times were 30.3 months, 27.1 months, and 23.2 months, respectively. Heart failure was observed in 2.6% of patients, although no cardiac-associated deaths occurred. In the TBP subanalysis, the median OS duration from treatment initiation and time of disease progression were longer in patients who continued receiving trastuzumab TBP (>27.8 months and 21.3 months, respectively) than in those who stopped (16.8 months and 4.6 months, respectively). However, the groups were not completely comparable, because patients who continued trastuzumab TBP had better prognoses at treatment initiation. The median TTP was longer in patients who continued trastuzumab TBP (10.2 months) than in those who stopped (7.1 months).

Conclusion: The Hermine findings confirm that the pivotal trials of first-line trastuzumab treatment in MBC patients are applicable in clinical practice. The subanalysis suggests that trastuzumab TBP offers a survival benefit to MBC patients treated with first-line trastuzumab.
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http://dx.doi.org/10.1634/theoncologist.2009-0029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228018PMC
December 2010

Body weight change in women receiving adjuvant chemotherapy for breast cancer: a French prospective study.

Clin Nutr 2010 Apr 26;29(2):187-91. Epub 2009 Aug 26.

Université de Lyon - Centre Léon Bérard, Department of Medical Oncology, 28 rue Laennec, 69008 Lyon, France.

Background & Aims: Adjuvant chemotherapy has frequently been associated with weight gain after breast cancer diagnosis. We aimed to prospectively evaluate body weight variations in French patients with early breast cancer.

Methods: This prospective observational study included 272 breast cancer patients who were candidates for adjuvant chemotherapy. Weight and body mass index were measured at baseline visit, then at 9 and 15 months from baseline (6 and 12-month post-chemotherapy). At baseline visit, information on the benefits of weight gain prevention and healthy diet was given by a dietician. Univariate logistic regression was performed to test the association between weight gain and potential predictive factors.

Results: Thirty percent of patients gained weight during the year before diagnosis, 26% were overweight and 15% were obese. At one year, the mean weight change was +1.5kg (SD=4.1) and +2.3% (SD=6.0); 60% of the cohort had gained weight, with a median increase of 3.9kg (SD=3.0) and 5.9% (SD=4.4). Reported weight gain during the year before diagnosis appears to be the only factor associated with the absence of post-chemotherapy weight gain (OR=0.54, 95% CI [0.31-0.95], p=0.034).

Conclusion: Body weight increased in the post-chemotherapy period in French breast cancer survivors, even when given dietary recommendations. Appropriate weight management interventions with nutritional follow-up and physical activity programs are needed.
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http://dx.doi.org/10.1016/j.clnu.2009.08.003DOI Listing
April 2010

Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas.

Cancer Res 2009 Jul 23;69(13):5383-91. Epub 2009 Jun 23.

Université de Lyon-Centre Léon Bérard, Department of Medical Oncology and EA SIS 4128, Lyon, France.

Lymphopenia is frequent in advanced cancers and predicts the toxicity of chemotherapy. Its effect on relapse and survival is uncertain. Its prognostic value for survival was analyzed in three databases of previously reported prospective multicenter studies: (a) FEC chemotherapy in metastatic breast carcinoma; (b) CYVADIC in advanced soft tissue sarcoma (European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group 62791); and (c) prospective, consecutive phase III studies of aggressive diffuse large-cell non-Hodgkin's lymphomas conducted at Centre Léon Bérard between 1987 and 1993. Univariate and multivariate analyses of prognostic factors for survival were performed. The incidence of lymphopenia of <1,000/microL before treatment was constant among the series: 25%, 24%, and 27%, respectively. Lymphopenia was significantly more frequent (P < 0.05) in metastatic breast cancer patients with performance status (PS) of >1, non-Hodgkin's lymphoma patients with international prognostic index (IPI) of > 0, and advanced soft tissue sarcoma and metastatic breast cancer patients with bone metastases. Inunivariate analysis, lymphopenia of <1,000/microL significantly correlated to overall survival in patients with metastatic breast cancer (median, 10 versus 14 mo; P < 0.0001), advanced soft tissue sarcoma (median, 5 versus 10 months; P < 0.01), and non-Hodgkin lymphoma (median, 11 versus 94 months; P < 0.0001). In multivariate analysis (Cox model), lymphopenia was an independent prognostic factor for overall survival in metastatic breast cancer [RR (relative risk), 1.8; 95% CI (confidence interval), 1.3-2.4] along with liver metastases and PS; in advanced soft tissue sarcoma (RR, 1.46; 95% CI, 1.0-2.1) along with liver metastases, lung metastases, and PS; and in non-Hodgkin's lymphoma (RR, 1.48; 95% CI, 1.03-2.1) along with IPI. Our findings show that lymphopenia is an independent prognostic factor for overall and progression-free survival in several cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-3845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775079PMC
July 2009

Bevacizumab and paclitaxel for breast cancer patients with central nervous system metastases: a case series.

Clin Breast Cancer 2009 May;9(2):118-21

Department of Medical Oncology, Centre Leon Berard, Laennec, France.

Central nervous system (CNS) metastases are a major concern in patients with stage IV breast cancer. Recent studies have shown the efficacy of anti-vascular endothelial growth factor drugs on brain tumors, in particular glioblastoma, but none has explored their efficacy and tolerance in breast cancer patients with CNS metastases. We report 4 cases of patients with CNS metastases treated with bevacizumab and paclitaxel. All but 1 had previous whole-brain radiation therapy, performance status 0-2, and radiographic evidence of progressive CNS metastases. Patients received paclitaxel 80 mg/m2 on days 1, 8, and 15, and bevacizumab 10 mg/kg on days 1 and 15. Response was evaluated according to the World Health Organization criteria. Three patients had brain metastases, and 1 had meningeal lesions. Only 1 patient was chemotherapy-naive. Significant antitumor activity was observed, with 1 complete response and 3 partial responses in the CNS metastases. With a mean follow-up of 9 months, duration of response was 11, 10, 8, and 6 months. No patient had extra-CNS progression. This observed antitumor activity suggests efficiency of the combination of bevacizumab and paclitaxel and warrants further evaluation of this combination as an alternative option for the treatment of multiple CNS metastases in breast cancer.
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http://dx.doi.org/10.3816/CBC.2009.n.021DOI Listing
May 2009

Methotrexate for 2000 FIGO low-risk gestational trophoblastic neoplasia patients: efficacy and toxicity.

Am J Obstet Gynecol 2009 Jun 23;200(6):643.e1-6. Epub 2009 Apr 23.

Université de Lyon, F-69622, Lyon, France.

Objective: We sought to review efficacy and toxicity of an 8-day methotrexate (MTX) regimen in the treatment of patients with low-risk gestational trophoblastic neoplasia (GTN) from the French Trophoblastic Disease Reference Center.

Study Design: Between 1999 and 2006, 142 low-risk GTNs were diagnosed according to International Federation of Gynecology and Obstetrics (FIGO) criteria for GTN and to the FIGO scoring system. We report their characteristics, remission/resistance/recurrence rates, and treatment toxicity.

Results: The 8-day MTX regimen achieved a 77.5% remission rate. All patients but 1 (99.9%) achieved remission and remained disease free until the time of analysis. Severe (grade 3 or 4) blood/bone marrow toxicity and metabolic/laboratory toxicity was noted in 4.2% of cases, of which 2 (1.4%) were grade 4.

Conclusion: For patients with GTN diagnosed according to FIGO criteria and considered low risk according to the FIGO scoring system, an 8-day MTX regimen is an adequate treatment associating a high rate of remission to a low rate of toxicity.
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http://dx.doi.org/10.1016/j.ajog.2009.03.011DOI Listing
June 2009

A comparative study of exemestane versus anastrozole in patients with postmenopausal breast cancer with visceral metastases.

Clin Breast Cancer 2009 Feb;9(1):39-44

Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: Patients developing visceral breast cancer metastases generally receive chemotherapy rather than endocrine therapy. Recent aromatase inhibitor studies have reported activity in such patients; therefore, this study formally evaluated anastrozole and exemestane in postmenopausal patients in this setting.

Patients And Methods: Postmenopausal women with advanced breast cancer and > or = 1 visceral (liver or lung) lesion were randomized to anastrozole (1 mg/day orally) or exemestane (25 mg/day orally) for > or = 8 weeks. The primary endpoint was objective response in visceral lesions based on modified Response Evaluation Criteria in Solid Tumors. Secondary endpoints included clinical benefit (objective response plus stable disease > or = 180 days), overall survival, and adverse events.

Results: A total of 130 patients were enrolled, and 128 patients (64 anastrozole, 64 exemestane) were included in the intent-to-treat analysis. Accrual delays caused study closure before the target enrollment (N = 200) was reached, limiting the statistical power of the study. Objective response in visceral sites was approximately 15% in both groups. Clinical benefit in visceral sites was 32% of the patients treated with anastrozole and 38% of the patients treated with exemestane. Median survival was 33.3 months and 30.5 months in the anastrozole and exemestane groups, respectively. Toxicities were similar to those previously reported; however, treatment-related adverse events were more frequent with anastrozole (41%) than with exemestane (31%). Both treatments were generally well tolerated in patients with postmenopausal breast cancer with visceral metastases.

Conclusion: Efficacy was similar in both treatment groups for all endpoints. Aromatase inhibitors can be considered as a treatment option in postmenopausal patients with hormone receptor-positive visceral breast cancer metastases.
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http://dx.doi.org/10.3816/CBC.2009.n.007DOI Listing
February 2009

A phase 2 trial of whole-brain radiotherapy combined with intravenous chemotherapy in patients with brain metastases from breast cancer.

Cancer 2008 Nov;113(9):2532-8

Multidisciplinary Medical Oncology Day Unit, Edouard Herriot Hospital, Lyon, France.

Background: A study was conducted to determine the efficacy, tolerability, and safety of concurrent cisplatin and vinorelbine chemotherapy and radiotherapy in patients with previously untreated brain metastases from breast cancer.

Methods: Twenty-five patients with untreated brain metastases from breast cancer were treated with cisplatin (at a dose of 20 mg/m(2)/day, Days 1-5) and vinorelbine (6-mg/m(2) bolus on Day 1 and 6 mg/m(2)/day continuous infusion on Days 1-5) chemotherapy combined with concurrent 30-gray fractionated external-beam radiotherapy. Chemotherapy was given at 3-week intervals for a total of 4 cycles. Primary endpoint was the rate of radiologic response of brain metastases.

Results: Complete response in the brain was observed in 3 patients, and partial response was noted in 16 patients, yielding a 76% response rate in the brain. The overall systemic response rate was 44%. Progression-free and overall survival were 3.7 months and 6.5 months, respectively. Overall toxicity was acceptable; nonhematologic grade 3-4 events were noted in 5 (20%) patients, and there were no toxic deaths.

Conclusions: Concurrent chemoradiation with cisplatin and vinorelbine for brain metastases from breast cancer appears to be active and well tolerated.
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http://dx.doi.org/10.1002/cncr.23858DOI Listing
November 2008

[Adjuvant therapies: the example of breast cancer].

Rev Prat 2008 Apr;58(8):817-9

Centre Léon-Bérard, 69008 Lyon.

Adjuvant chemotherapy, initiated following surgery, aims at controlling "microscopic" metastatic disease before its progression to a "clinical" recurrence. Its efficiency in localized breast cancer was officially demonstrated in 1992 in the Early Breast Cancer Trialists' Collaborative Group meta-analysis. This analysis helped clarify the benefits of therapeutic interventions according to progression stage, age and tumour biological features, especially in the presence of hormone receptors. Later on, new trials further defined the benefits of modern therapies, and especially trastuzumab in patients overexpressing HER2. The assessment of the theoretical benefits of adjuvant therapies takes into account the risk of individual recurrence and the potential decrease of the latter following a given therapeutic intervention--this decrease depending on tumor biological features. Deciding whether an adjuvant therapy should be initiated is difficult since benefits (observed in the long term) are often moderate while toxicities (immediately observed) are significant. The development of national and regional therapeutic guidelines markedly diminished the arbitrary aspect of the decision. Developing tools which could help implying the patient in this therapeutic decision is a priority.
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April 2008

HER2 status in ovarian carcinomas: a multicenter GINECO study of 320 patients.

PLoS One 2007 Nov 7;2(11):e1138. Epub 2007 Nov 7.

JE2492, Université Paris-Sud, IFR69, Villejuif, France.

Background: Despite a typically good response to first-line combination chemotherapy, the prognosis for patients with advanced ovarian cancer remains poor because of acquired chemoresistance. The use of targeted therapies such as trastuzumab may potentially improve outcomes for patients with ovarian cancer. HER2 overexpression/amplification has been reported in ovarian cancer, but the exact percentage of HER2-positive tumors varies widely in the literature. In this study, HER2 gene status was evaluated in a large, multicentric series of 320 patients with advanced ovarian cancer, including 243 patients enrolled in a multicenter prospective clinical trial of paclitaxel/carboplatin-based chemotherapy.

Methodology/principal Findings: The HER2 status of primary tumors and metastases was evaluated by both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis of paraffin-embedded tissue on conventional slides. The prognostic impact of HER2 expression was analyzed. HER2 gene was overexpressed and amplified in 6.6% of analyzed tumors. Despite frequent intratumoral heterogeneity, no statistically significant difference was detected between primary tumors and corresponding metastases.

Conclusions/significance: Our results show that the decision algorithm usually used in breast cancer (IHC as a screening test, with equivocal results confirmed by FISH) is appropriate in ovarian cancer. In contrast to previous series, HER2-positive status did not influence outcome in the present study, possibly due to the fact that patients in our study received paclitaxel/carboplatin-based chemotherapy. This raises the question of whether HER2 status and paclitaxel sensitively are linked.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001138PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042515PMC
November 2007

[Are antiangiogenic antibodies universal for solid tumor?].

Bull Cancer 2007 Jul;94 Spec No:S191-6

Centre Léon-Bérard, 28, rue Laennec, 69008 Lyon.

After over 30 years of theorizing, the use of angiogenesis inhibitors as anticancer therapy has finally moved from the realm of research to reality. Normal adult vasculature is generally quiescent in nature, with endothelial cells dividing approximately every 10 years. In contrast, the growth of tumours requires constant vascular growth and remodelling in order for solid tumours to grow beyond 1-2 mm3 in size. Vascular endothelial growth factor (VEGF) and its receptors are key regulators of the process of angiogenesis, which make them attractive therapeutic targets. A multitude of VEGF-targeted inhibitory agents are currently being investigated for the treatment of cancer. This review article focuses on recent developments in the use of angiogenesis inhibitors for the treatment of breast, lung, and colorectal cancers.
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July 2007

A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study.

Breast Cancer Res Treat 2008 May 5;109(2):343-50. Epub 2007 Jul 5.

Medical Oncology, Hopital Edouard Herriot, Université de Lyon et Hospices Civils de Lyon, Lyon, France.

Purpose: In first-line metastatic breast cancer, both paclitaxel (P)-doxorubicin (A) and docetaxel (D)-doxorubicin (A) combinations have shown superiority over treatments without taxane. The aim of this study was to compare the two combinations.

Patients And Methods: Chemotherapy-naive (except for adjuvant therapy) metastatic breast cancer patients were randomly assigned to intravenous AD (arm D) or AP (arm P) every 3 weeks for a maximum of four cycles, then four cycles of single agent docetaxel (arm D) or paclitaxel (arm P). Primary endpoint was overall quality of life (QoL) measured by EORTC QLQ-C30 after four courses of doxorubicin-taxane combination. Secondary endpoints were toxicity, overall survival (OS), progression-free survival (PFS), and QoL sub-scores.

Results: Between March 2000 and April 2004, 210 patients were randomized: 103 to arm P and 107 to arm D. Patient characteristics were well balanced between arms. After four courses, QoL score differences between groups or compared to baseline scores were not significant. Response rate was 39.6% for AD and 41.8% for AP. After a median follow-up of 50.2 months, median PFS and median OS were 8.7 and 21.4 months in arm D and 8.0 and 27.3 months in arm P (p = 0.977 and 0.081, respectively). Hematological toxicity was significantly more frequent in arm D than in arm P (p < 10(-6)), as well as grades 3-4 asthenia (p = 0.03). Neuropathy occurred more frequently in arm P (p = 0.03).

Conclusion: In this study, paclitaxel or docetaxel combined with doxorubicin were not significantly different in terms of QoL scores and efficacy, but had different toxicity profiles.
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http://dx.doi.org/10.1007/s10549-007-9651-3DOI Listing
May 2008

First epidemiological data from the French Trophoblastic Disease Reference Center.

Am J Obstet Gynecol 2007 Feb;196(2):172.e1-5

Hospices Civils de Lyon, Hôtel-Dieu, Centre de Référence des Maladies Trophoblastiques, Lyon, France.

Objective: The objective of the study was to describe women registered at the new French Trophoblastic Disease Reference Center and particularly the rates of gestational trophoblastic neoplasia (GTN) after molar pregnancies.

Study Design: Epidemiological data from a prospective cohort of women registered between November 1999 and November 2004 were analyzed.

Results: Four hundred forty-eight women were registered. The referent pathologist reclassified 32% and 5% of assumed partial mole (PM) and complete mole (CM), respectively. GTN developed in 30 of 212 patients with singleton CM (14%) and in 5 of 108 with singleton PM (5%). Among 131 patients with GTN (35 women followed up after registration for a mole and 96 registered for a GTN), 115 (88%) were low-risk and 16 (12%) were high-risk patients according to 2000 International Federation of Gynecology and Obstetrics (FIGO) scoring system.

Conclusion: Creation of trophoblastic disease reference centers is desirable to improve treatment of patients. Our results will have to be compared with future publications based on the new 2000 FIGO oncology committee recommendations.
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http://dx.doi.org/10.1016/j.ajog.2006.10.867DOI Listing
February 2007

A phase II study of an oxaliplatin/vinorelbine/5-fluorouracil combination in patients with anthracycline-pretreated and taxane-pretreated metastatic breast cancer.

Anticancer Drugs 2006 Oct;17(9):1067-73

Centre François Baclesse, Caen, France.

The aim of this phase II study was to evaluate safety and efficacy of an oxaliplatin/vinorelbine/5-fluorouracil (FON) combination in anthracycline and taxane-pretreated metastatic breast cancer patients. The following treatment was given: on day 1 of a 21-day cycle, oxaliplatin 130 mg/m (2-h intravenous infusion); on days 1 and 5, vinorelbine [dose level (DL) 1: 17.5 mg/m; DL2: 22 mg/m]; on days 1-5, continuous infusion 5-fluorouracil (DL1: 600 mg/m/day; DL2: 750 mg/m/day). Forty-seven patients were treated (DL1: 43; DL2: 4). Median age was 54 years; 68% had liver metastases, 53% were taxane refractory/resistant and 38% were anthracycline refractory/resistant. Patients received a median of six treatment cycles. Of 46 eligible patients, 16 had partial response; the overall response rate was 34.8% (95% confidence interval 21.3-50.3%), 11 had stable disease lasting more than 4 months. Median follow-up was 13.0 months, median time to progression 5.7 months and estimated overall survival 18.8 months. DL2 was too toxic with three patients having grade 3-4 toxicity, including one death. At DL1, 26 patients (60%) experienced grade 3-4 neutropenia (six febrile neutropenia) and eight had grade 3 oxaliplatin-specific peripheral neuropathy after a median of 646.4 mg/m oxaliplatin (range 124-1619 mg/m). Oxaliplatin (130 mg/m, day 1)/vinorelbine (17.5 mg/m, days 1,5)/5-fluorouracil (600 mg/m/day, days 1-5) demonstrate encouraging activity and a manageable safety profile in anthracycline- and taxane-pretreated metastatic breast cancer patients.
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http://dx.doi.org/10.1097/01.cad.0000231475.77159.aaDOI Listing
October 2006

Phase I study of pegylated liposomal doxorubicin in combination with ifosfamide in pretreated ovarian cancer patients.

Am J Clin Oncol 2006 Aug;29(4):399-404

Medical Oncology Unit, CHU de Poitiers, Poitiers, France.

Objectives: To determine the dose limiting toxicity, the maximum tolerated dose and the recommended dose of pegylated liposomal doxorubicin (PLD) in association with a fixed dose of ifosfamide (IFO) to patients with recurrent, advanced ovarian cancer (AOC).

Methods: Patients with progressing platinum-sensitive or resistant disease were included in 5 dose levels consisting of PLD (25 mg/m2 to 45 mg/m2, day 1) combined with a fixed IFO dose administered as a continuous infusion (1700 mg/m2/d, day 1 to 3) to define the MTD on the basis of acute toxicity during the first 2 cycles, then confirm the MTD, by the evaluation of delayed toxicity (hand-foot syndrome).

Results: Forty-eight patients were treated. The MTD was determined in the first 29 patients to be dose level V (45 mg/m2), with 2 cases of febrile neutropenia. The recommended dose (level IV) combines 40 mg/m2 PLD on day 1 and 1700 mg/m2/d IFO day 1 to day 3. The principal toxicity was hematotoxicity (grade 3-4 neutropenia 61.8% of patients, grade 3/4 thrombcytopenia 7.2%, and grade 3/4 anemia 21.8%). Nonhematological toxicity essentially consisted of grade 3/4 nausea and vomiting (14%). Nineteen additional patients were included in levels III (11 patients) and IV (8 patients), to evaluate late-onset toxicity. No hand-foot syndrome was observed in the 48 treated patients, confirming the identification of dose level IV as recommended dose.

Conclusion: This study regimen presents an acceptable tolerance. The preliminary assessment of efficacy merits confirmation in a phase II study.
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http://dx.doi.org/10.1097/01.coc.0000224542.80581.46DOI Listing
August 2006