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P Pautier,
A Floquet,
L Gladieff,
E Bompas,
I Ray-Coquard,
S Piperno-Neumann,
F Selle,
C Guillemet,
B Weber,
R Largillier, [......],
A Reynaud-Bougnoux,
C Delcambre,
N Isambert, P Kerbrat,
G Netter-Pinon,
N Pinto,
P Duvillard,
C Haie-Meder,
C Lhommé,
A Rey
[show abstract]
[hide abstract]
ABSTRACT: Background
There is no proven benefit of adjuvant treatment of uterine sarcoma (US). SARCGYN phase III study compared adjuvant polychemotherapy followed by pelvic radiotherapy (RT) (arm A) versus RT alone (arm B) conducted to detect an increase ≥ 20% of 3-year PFS.Methods
Patients with FIGO stage ≤ III US, physiological age ≤ 65 years; chemotherapy: four cycles of doxorubicin 50 mg/m² d1, ifosfamide 3 g/m²/day d1-2, cisplatin 75 mg/m² d3, (API) + G-CSF q 3 weeks. Study was stopped because of lack of recruitment.ResultsEighty-one patients were included: 39 in arm A and 42 in arm B; 52 stage I, 16 stage II, 13 stage III; 53 leiomyosarcomas, 9 undifferenciated sarcomas, 19 carcinosarcomas. Gr 3-4 toxicity during API (/37 patients): thrombopenia (76%), febrile neutropenia (22%) with two toxic deaths; renal gr 3 (1 patient). After a median follow-up of 4.3 years, 41/81 patients recurred, 15 in arm A, 26 in arm B. The 3 years DFS is 55% in arm A, 41% in arm B (P = 0.048). The 3-year overall survival (OS) is 81% in arm A and 69% in arm B (P = 0.41).ConclusionAPI adjuvant CT statistically increases the 3 year-DFS of patients with US.
Annals of Oncology 11/2012; · 6.43 Impact Factor
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F. Grudé,
M. Campone,
A. Lortholary,
R. Delva,
P. Soulie, P. Kerbrat,
G. Ganem,
H. Bourgeois,
S. Van Hulst,
E. Vuillemin,
A.-C. Hardy-Bessard,
M.-J. Goudier,
H. Simon,
B. Lucas,
F. Priou,
C. Riché,
E. Gamelin
[show abstract]
[hide abstract]
ABSTRACT: L’Observatoire des médicaments et des innovations thérapeutiques (OMIT) Bretagne et Pays de la Loire a été créé en 2003 par
lesAgences régionales de l’hospitalisation (ARH) respectives. Il est spécialisé en cancérologie, assure le suivi qualitatif
de médicaments en continu et fédère les établissements publics et privés des deux régions sur des objectifs communs. Les prescriptions
de trastuzumab (Herceptin®) ont fait l’objet d’une analyse dans tous les établissements recensés par l’OMIT. Suite aux résultats
positifs des essais HERA, NSABP B31 et NCCTG N9831 présentés en séance plénière au Congrès de l’ASCO (American Society of
Clinical Oncology) en mai 2005, et publiés depuis, les praticiens du comité de pilotage OMIT ont décidé de colliger toutes
les données des patientes traitées dans ces situations afin de connaître les schémas thérapeutiques employés, l’incidence
des dysfonctionnements cardiaques en pratique courante ainsi que leurs facteurs de risque.
The “Observatoire des Médicaments et Innovations Thérapeutiques OMIT” directed by ARH Bretagne et Pays de la Loire, has been
created in 2002. He’s specialized in oncology, monitoring a few drugs every year and brings together public and private hospitals
of both two regions on commun objectives. The prescriptions of trastuzumab (Herceptin®) were the object of an analysis in
all the establishments listed by OMIT in 2003/2004. Further to the positive results of the trials HERA, NSABP B31 and NCCTG
N9831 presented in plenary session to the Congress of the ASCO (Americal Society of Clinical Oncology) in May 2005, and published
since, the medical oncologists and the pharmacists of the scientific steering Committee decided to bring together all the
data of the patients treated in these situations to know the therapeutic plans used, the incidence of cardiac dysfunction
in practice current and their risk factors.
Mots clésTrastuzumab-Cancer-Toxicité cardiaque
KeywordsTrastuzumab-Cancer-Cardiac toxicity
Oncologie 04/2012; 12(5):362-368. · 0.17 Impact Factor
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P. Morice,
F. Planchamp,
E. Daraï,
E. Leblanc,
J. -P. Lefranc,
D. Querleu,
H. Crouet,
J. Dauplat,
E. Fondrinier, P. Kerbrat,
M. Le Taillandier,
J. Levêque,
P. Rauch,
F. Selle,
R. Villet
[show abstract]
[hide abstract]
ABSTRACT: ContexteLa mise à jour de ces recommandations a été élaborée par la Fédération nationale des centres de lutte contre le cancer (FNCLCC)
en partenariat avec les secteurs public, privé et l’Institut national du cancer.
ObjectifActualiser les recommandations du chapitre «Traitement chirurgical» issu du rapport intégral validé en 1999.
MéthodsL’actualisation des Standards, Options: Recommandations (SOR) repose sur une revue et une analyse critique des données scientifiques
disponsibles et sur le jugement argumenté des experts au sein d’un groupe de travail représentatif des modes et lieux d’exercice
et des disciplines concernées par la prise en charge des patients atteints de cancer.
RésultatsCet article présente les recommandations SOR 2007 relatives au traitement chirurgical des stades précoces et des stades avancés,
établies à l’issue du processus d’actualisation.
ContextThe French federation of comprehensive cancer centres (FNCLCC) initiated the update of these recommendations in collaboration
with the French national cancer institute and with specialists from French public universities, general hospitals and private
clinics.
ObjectivesTo update the recommendations of the “surgical treatment” chapter in the complete report validated in 1999.
MethodsThe guideline updating process is based on a systematic literature review and critical appraisal by a multidisciplinary group
of experts, with feedback from specialists in cancer care delivery. The Standards, Options: Recommendations are thus based
on the best available evidence and expert agreement.
ResultsThis article presents the 2007 updated recommendations concerning the surgical treatment of early-stage and advanced-stage
epithelial ovarian cancers.
Oncologie 04/2012; 10(4):283-288. · 0.17 Impact Factor
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A Morvan,
B de Korvin,
C Bouriel,
A Carsin,
P Tas,
C Bendavid,
P F Dupré, P Kerbrat,
H Mesbah,
P Poree,
J Levêque
[show abstract]
[hide abstract]
ABSTRACT: This study aims to evaluate the sensibility and specificity of MRI in the detection and size measuring of residual breast cancer in patients treated with neoadjuvant chemotherapy before surgery.
This is a retrospective study of 32 women, who underwent breast MRI before and after neoadjuvant treatment. MRI has been confronted to surgical pathology results.
The sensibility of MRI to assess pathologic Complete Response (no invasive residual tumor) was excellent (100%) but the specificity was low (55,5%). There was no false negative case and four false positive cases (Two ductal carcinomas in situ and two scars-like fibrosis). When MRI outcomes were compared with the presence or absence of invasive or in situ residual carcinoma, only one false negative case was noticed (one "in situ" residual tumor). The correlation between tumor size measured by MRI and histopathology was low (r=0,32). Underestimations of tumor size were due to non-continuous tumor regression or invasive lobular carcinoma or association of invasive carcinoma and intra ductal breast cancer. Over estimations of tumor size were due to chemotherapy-induced changes.
MRI is a sensitive but poorly specific method to assess the pathological complete response after neoadjuvant chemotherapy. Estimation of tumor size and detection of isolated residual in situ carcinoma are fare. Therefore, surgical intervention remains necessary whatever the MRI outcomes.
Journal de Radiologie 06/2010; 91(6):693-9. · 0.42 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Breast cancer (BC) is the first female cancer in France, accounting for 49,240 new cases in 2004. Approximately 80% of those tumors have positive hormone receptors (HR). Tamoxifen was used in four chemoprevention randomized trials, as well as another SERM (Selective Estrogen Receptor Modulation), raloxifen. This review analyses the updated results of these trials. All trials have shown that the risk of developing HR positive BC was reduced by tamoxifen or raloxifen, but without impact on HR negative BC and overall survival. Moreover, several unfavorable side effects (thrombo-embolic accidents and uterine cancers) have been observed. A new assessment of BC risk factors seems necessary, including not only family history and some histopathological abnormalities (e.g. atypical hyperplasia), but also new elements such as high bone and breast density and thoracic irradiation at young age (Hodgkin's disease). Indeed, tamoxifen efficacy seems optimal in very "high-risk" women. Therefore, the creation of a new and most comprehensive "risk model" is necessary as well as a tailored SERM use (maybe with other compounds), in order to optimize results and reduce potential side effects.
Bulletin du cancer 06/2009; 96(5):519-30. · 0.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Ovarian yolk sac tumor (YST) is a very rare malignancy arising in young women. Chemotherapy has dramatically improved the prognosis. Current treatment consists of surgery followed by bleomycin, etoposide, and cisplatin (BEP) chemotherapy. However, given the rarity of this tumor, ovarian YST-specific survival and outcome after such treatment are not precisely known.
This report concerns prospectively recorded cases that were either treated at Institut Gustave Roussy (Villejuif, France) or referred there for advice about therapy. From 1990 to 2006, 52 patients underwent surgery followed by BEP chemotherapy. Data on patient characteristics, treatment, survival, and fertility outcome were analyzed to assess treatment efficacy and gonadal toxicity after achieving a complete remission.
Thirty-five patients had stage I/II tumors while 17 patients presented with stage III/IV disease. With a median follow-up of 68 months, the overall 5-year survival and disease-free survival rates were 94% and 90%, respectively. Forty-one women underwent fertility-sparing surgery. Pregnancy was achieved in 12 of 16 (75%) women who attempted conception. Overall, 19 pregnancies have been recorded.
BEP chemotherapy following fertility-sparing surgery is a very effective treatment of ovarian YSTs. Most of the patients who attempt conception after complete remission will have children.
Annals of Oncology 05/2008; 19(8):1435-41. · 6.43 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The aim of this study is to determine feasibility and efficacy of the combination regimen oxaliplatin and paclitaxel in patients with cisplatin (CDDP)-refractory germ-cell tumors (GCT).
Patients with either a cisplatin absolute-refractory GCT defined as progressive disease (PD) during or within 1 month of CDDP administration or with a poor prognosis relapse, defined as PD between the second and the sixth month after CDDP administration, were treated with a combination of oxaliplatin (130 mg/m(2)) and paclitaxel (175 mg/m(2)) administered every 21 days. Primary end point was efficacy.
Twenty-seven patients were included. Patients were pretreated with a median of two lines of cisplatin-based chemotherapy (range 1-5). Sixteen patients were absolute refractory. Five patients had relapsed after high-dose chemotherapy plus stem-cell support. There were no complete responses but there was one marker-positive partial response and nine disease stabilization (34, 6%). After a median follow-up of 65 months, two patients are disease-free survivors. Main toxicity was leucocytopenia grade 3/4 in 30% of the patients.
Combination chemotherapy with oxaliplatin and paclitaxel is feasible with acceptable toxicity and may be effective if combined with additional treatment in patients with CDDP-refractory GCT.
Annals of Oncology 05/2008; 19(8):1465-9. · 6.43 Impact Factor
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P Pautier,
V Ribrag,
P Duvillard,
A Rey,
I Elghissassi,
I Sillet-Bach, P Kerbrat,
F Mayer,
A Lesoin,
B Brun,
H Crouet,
J C Barats,
P Morice,
C Lhommé
[show abstract]
[hide abstract]
ABSTRACT: The evaluation of first-line intensive combination therapy in small cell carcinoma of the ovary (SCCO).
Debulking surgery; four to six cycles of chemotherapy with cisplatin (P) 80 mg/m(2) day 1, adriamycin (A) 40 mg/m(2) day 1, vepeside (V) 75 mg/m(2)/day days 1-3, cyclophosphamide (EP) 300 mg/m(2)/day days 1-3, every 3 weeks and granulocyte colony-stimulating factor with, in case of a complete remission, high-dose chemotherapy with carboplatin, vepeside, cyclophosphamide and stem-cell support.
Twenty-seven patients (median age 25 years); International Federation of Gynecology and Obstetrics stage: five I, four IIC, 17 IIIC-IV and one unknown. Twenty patients underwent complete surgery. Eight patients progressed under chemotherapy. Among 18 patients in complete response (CR), 10 received high-dose chemotherapy (CT) (three stem-cell collection failures, two protocol violations, two disease progression and one refusal). The main grade 3-4 toxic effects were hematologic. There were eight relapses among the 18 CR, four of which were pelvic alone. Among the 27 patients, 13 died and 10 patients are in CR1, three in CR2. The median follow-up is 37 months (8-166) and the median duration of the 18 CR is 30 months (5-111). Overall survival at 1 and 3 years is 58% [confidence interval (CI) 40% to 75%] and 49% (CI 30% to 67%).
Initial dose-intensive therapy achieves interesting overall survival in SCCO.
Annals of Oncology 01/2008; 18(12):1985-9. · 6.43 Impact Factor
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J-C Eymard,
F Priou,
A Zannetti,
A Ravaud,
D Lepillé, P Kerbrat,
P Gomez,
B Paule,
D Genet,
P Hérait,
E Ecstein-Fraïssé,
F Joly
[show abstract]
[hide abstract]
ABSTRACT: Docetaxel (Taxotere)-based regimens are the new standard therapy in advanced hormone-refractory prostate cancer (HRPC). A synergistic activity has been shown with docetaxel in combination with estramustine in vitro; however, the benefit of this combination remains controversial in clinical practice. We assessed the activity and safety of docetaxel alone and docetaxel-estramustine in HRPC.
Patients (n = 92) with metastatic HRPC and rising prostate-specific antigen (PSA) while receiving androgen suppression were randomized to 3-weekly treatment with either docetaxel 75 mg/m(2), day 1 (D), or docetaxel 70 mg/m(2), day 2, plus oral estramustine 280 mg twice daily, days 1-5 (DE).
Ninety-one patients were treated (DE 47, D 44). A PSA response occurred in 68% (primary endpoint met) and 30% of patients, respectively. Median PSA response duration was 6.0 months in both groups. Median time to progression was 5.7 and 2.9 months, and median survival was 19.3 and 17.8 months in the DE and D arms, respectively. Hematologic and non-hematologic toxic effects were mild and similar in both arms. One patient in each group withdrew due to toxicity. Quality of life was similar in both groups.
Combining estramustine with docetaxel in this schedule is an active and well-tolerated treatment option in HRPC.
Annals of Oncology 07/2007; 18(6):1064-70. · 6.43 Impact Factor
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S Culine, P Kerbrat,
A Kramar,
C Théodore,
C Chevreau,
L Geoffrois,
N B Bui,
J Pény,
A Caty,
R Delva,
P Biron,
K Fizazi,
J Bouzy,
J P Droz
[show abstract]
[hide abstract]
ABSTRACT: High cure rates are expected in good-risk metastatic nonseminomatous germ-cell tumor (NSGCT) patients with bleomycin, etoposide and cisplatin.
Patients received either three cycles of BE500P or four cycles of E500P every 3 weeks. Disease was defined according to the Institut Gustave Roussy prognostic model. Patients were retrospectively assigned into the International Germ Cell Cancer Collaborative Group (IGCCCG) classification. A sample size of 250 patients was necessary for an expected favorable response rate (primary end point) of 90% and not more than a 10% difference between the two arms.
Among 257 assessable patients, 124 and 122 patients achieved a favorable response in the 3BE500P and 4E500P arms, respectively (P = 0.34). Median follow-up was 53 months. The 4-year event-free survival rates were 91% and 86%, respectively (P = 0.135). The 4-year overall survival rates were not significantly different [five deaths versus 12 deaths, respectively (P = 0.096)]. Similar nonsignificant trends were observed in good IGCCCG prognosis patients.
Both regimens produced similar results in terms of favorable response rates. As the trial was underpowered for survival analyses, conclusive data would require a larger randomized trial. Unless such a study is done, 3BE500P is the treatment of choice for metastatic NSGCT patients.
Annals of Oncology 06/2007; 18(5):917-24. · 6.43 Impact Factor
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P Kerbrat,
H Roché,
J Bonneterre,
C Veyret,
A Lortholary,
A Monnier,
P Fumoleau,
P Fargeot,
M Namer,
P Chollet,
M-J Goudier,
B Audhuy,
H Simon,
P Montcuquet,
J-C Eymard,
S Walter,
P Clavère,
J-P Guastalla
[show abstract]
[hide abstract]
ABSTRACT: The aim of the study was to compare our reference adjuvant chemotherapy, FEC100 (fluorouracil 500 mg m(-2), epirubicin 100 mg m(-2) and cyclophosphamide 500 mg m(-2), six cycles every 21 days), to an epirubicin-vinorelbine (Epi-Vnr) combination for early, poor-prognosis breast cancer patients. Patients (482) were randomised to receive FEC100, or Epi-Vnr (epirubicin 50 mg m(-2) day 1 and vinorelbine 25 mg m(-2), days 1 and 8, six cycles every 21 days). The 7-year disease-free survival rates were 59.4 and 58.8%, respectively (P=0.47). The relative dose intensity of planned epirubicin doses was 89.1% with FEC100 and 88.9% with Epi-Vnr. There were significantly more grades 3-4 neutropenia (P=0.009) with Epi-Vnr, and significantly more nausea-vomiting (P<0.0001), stomatitis (P=0.0007) and alopecia (P<0.0001) with FEC100. No cases of congestive heart failure were reported, whereas four decreases in left ventricular ejection fraction occurred after FEC100 and five after Epi-Vnr. One case of acute myeloblastic leukaemia was registered in the FEC100 arm. After 7 years of follow-up, there was no difference between treatment arms. Epi-Vnr regimen provided a good efficacy in such poor-prognosis breast cancer patients, and could be an alternative to FEC100, taking into account respective safety profiles of both regimens.
British Journal of Cancer 06/2007; 96(11):1633-8. · 5.04 Impact Factor
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H Hoarau, P Kerbrat,
A Lesoin,
C Lhommé,
E Luporsi,
T Philip,
D Querleu,
P Saltel,
L Thomas,
P Vennin,
M Véron,
J-J Voigt
Gynécologie Obstétrique & Fertilité 01/2007; 34(12):1195-204. · 0.52 Impact Factor
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H Roché, P Kerbrat,
J Bonneterre,
P Fargeot,
P Fumoleau,
A Monnier,
P Clavère,
M-J Goudier,
P Chollet,
J-P Guastalla,
D Serin
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study was to determine optimal adjuvant therapy between complete hormonal blockade in premenopausal patients with hormone receptor positive breast cancer and one to three positive nodes.
We randomised 333 patients to receive either LHRH agonist (triptorelin 3.75 mg i.m., monthly) plus tamoxifen 30 mg/day for 3 years (TAM-LHRHa, n=164), or fluorouracil 500 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days for six cycles, without any hormonal treatment (FEC50, n=169).
The 7-year disease-free survival (DFS) was 76% with TAM-LHRHa, and 72% with FEC50 (P=0.13). The 7-year overall survival (OS) was 91% and 88%, respectively (P=0.20). The multivariate analysis confirmed that both treatments were not different for DFS and OS (P=0.83 and P=0.41, respectively). Amenorrhoea occurred in 64% of patients treated with FEC50; it was temporary in 58% of cases after hormonotherapy and in 31% after chemotherapy.
In intermediate-risk breast cancer, complete hormonal blockade and chemotherapy provided similar outcomes. Hormonal treatment is an alternative to chemotherapy in hormone-sensitive patients, considering the preference of patients in terms of quality of life.
Annals of Oncology 09/2006; 17(8):1221-7. · 6.43 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The purpose was to compare disease-free survival (DFS) between epirubicin-based chemoendocrine therapy and tamoxifen alone in one to three node-positive (N1-3), estrogen-receptor-positive (ER+), postmenopausal early breast cancer (EBC) patients.
We analyzed, retrospectively, 457 patients randomized in FASG 02 and 07 trials who received: tamoxifen alone (30 mg/day, 3 years); or FEC50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2, cyclophosphamide 500 mg/m2, six cycles every 21 days) plus tamoxifen started concurrently. Radiotherapy was delivered after the third cycle in FASG 02 trial, and after the sixth in FASG 07 trial.
The 9-year DFS rates were 72% with tamoxifen and 84% with FEC50-tamoxifen (P = 0.008). The multivariate analysis showed that pathological tumor size >2 cm was an independent prognostic factor (P = 0.002), and treatment effects remained significantly in favor of chemoendocrine therapy (P = 0.0008). The 9-year overall survival rates were 78% and 86%, respectively (P = 0.11). In the multivariate model, there was a trend in favor of chemoendocrine therapy (P = 0.07).
The addition of FEC50 adjuvant chemotherapy to tamoxifen significantly improves long-term DFS in N1-3, ER+ and postmenopausal women. Chemoendocrine therapy seems to be more effective than tamoxifen in terms of long-term survival.
Annals of Oncology 02/2006; 17(1):65-73. · 6.43 Impact Factor
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P Fumoleau,
H Roché, P Kerbrat,
J Bonneterre,
P Romestaing,
P Fargeot,
M Namer,
A Monnier,
P Montcuquet,
M-J Goudier,
E Luporsi
[show abstract]
[hide abstract]
ABSTRACT: The aim of the study was to evaluate and compare incidence and risk factors of left ventricular dysfunction (LVD) in early breast cancer patients receiving (E+) or not (E-) epirubicin-based adjuvant chemotherapy.
Among eight FASG trials, 3577 assessable patients were analyzed retrospectively: 2553 received epirubicin, 662 received hormonotherapy alone and 362 had no systemic treatment. Chemotherapy was FEC regimen in 86% of cases (fluorouracil, epirubicin, cyclophosphamide). Epirubicin cumulative dose was < 300 mg/m2 in 1040 patients, 300-600 in 1155, > or = 600 in 279, followed by radiotherapy in 96% of cases.
Twenty delayed LVD occurred: two in E- patients and 18 in E+ patients. In E+ patients, 14 patients normalized their cardiac function or did not require further investigations, one patient was stabilized with specific treatment, two patients worsened their functions and one died of congestive heart failure. The 7-year risk of LVD was 1.36% (95% CI 0.85-1.87) in E+ patients and 0.21% (95%CI: 0.00-0.52) in E- patients (P = 0.004). Two significant risk factors were identified: age > or = 65 years and body mass index > 27 kg/m2.
After a long-term follow-up, epirubicin-related LVD risk was acceptable (1.36%) with one toxic death (0.04%). In 78% of cases, LVD were transient or well controlled.
Annals of Oncology 02/2006; 17(1):85-92. · 6.43 Impact Factor
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M Campone,
H Roché, P Kerbrat,
J Bonneterre,
P Romestaing,
P Fargeot,
M Namer,
A Monnier,
P Montcuquet,
M-J Goudier,
P Fumoleau
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study was to evaluate incidence and risk factors of secondary leukemia after adjuvant epirubicin-based chemotherapy in breast cancer patients.
Among eight French Adjuvant Study Group trials, 3653 patients were assessable: 2603 received epirubicin; 682 received hormonotherapy; and 368 had no systemic treatment. Chemotherapy was FEC regimen in 85% of cases (fluorouracil 500 mg/m2, epirubicin 50, 75 or 100 mg/m2, cyclophosphamide 500 mg/m2, three or six cycles). Epirubicin cumulative dose was <300 mg/m2 in 1045 patients; 300-600 mg/m2 in 1187; and > or =600 mg/m2 in 286, followed by radiotherapy in 96% of cases. The median follow-up was 104 months.
Eight cases of leukemia occurred in epirubicin-exposed patients and one in non-exposed patients. After 9 years, the risk of developing a leukemia was 0.34% (95% confidence interval 0.11-0.57) in epirubicin-exposed patients. In patients receiving chemotherapy, leukemia subtypes were: AML2 (two), AML3 (one), AML4 (three) and ALL (two). None of the classically recognized risk factors was significantly correlated with the occurrence of a leukemia.
Irrespective of the dose, the incidence of secondary leukemia after adjuvant epirubicin-based chemotherapy was low. After a long follow-up, the benefit/risk ratio for early breast cancer patients remained in favor of epirubicin-based adjuvant chemotherapy: eight cases (0.31%) occurred, and in some of them, treatment causality could be debatable.
Annals of Oncology 08/2005; 16(8):1343-51. · 6.43 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: To develop a population pharmacokinetic model of vinorelbine administered by short intravenous infusion in metastatic breast cancer patients.
Vinorelbine was administered as infusions of 5-10 min at 15, 20 or 25 mg/m(2) to 30 patients. Blood samples were collected over 18 h. Plasma concentrations of vinorelbine were determined by HPLC. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modeling method.
Vinorelbine concentration-time profiles were best described by a three-compartment open model. Plasma clearance (CL) was high and positively related to lean body weight (LBW) and body surface area (BSA) or to a combination of height and body weight (BW). Elevated serum alkaline phosphatases had a negative effect on CL. Typical population estimates of CL and central distribution volume (V(1)) were 74.2 l/h and 7.8 l, respectively. The interindividual population coefficients of variation for CL and V(1) were 17.0% and 32.0%, respectively. The stability and predictive performance of the final population pharmacokinetic model were assessed using 200 bootstrap samples of the original data.
This study identified combined effects of BSA and serum alkaline phosphatases on clearance. These results partly support the conventional dose adjustment of vinorelbine based on BSA, but suggest dose modification in cases of extreme values of serum alkaline phosphatases.
Cancer Chemotherapy and Pharmacology 04/2004; 53(3):233-8. · 2.83 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The pharmacokinetics of ftorafur, 5-fluorouracil (5FU) and uracil were investigated in order to built a population pharmacokinetic model for the anticancer drug UFT, administered with leucovorin and vinorelbine.
A total of 31 patients with metastatic breast cancer were treated with escalating oral doses of UFT (300 to 500 mg per day) plus leucovorin (90 mg per day) in combination with intravenous vinorelbine (15 to 25 mg/m(2)). Concentration-time data were obtained on days 1, 8, 15 and 21 of cycle 1.
Of the 31 patients treated, 30 were available for the pharmacokinetic analysis. Ftorafur, 5FU and uracil appeared rapidly in plasma and showed large interpatient variations. Ftorafur concentrations were higher than those of 5FU and uracil. AUC significantly increased between day 1, and days 8, 15 and 21. Ftorafur C(max) and AUC values were proportional to UFT dose, whereas C(max) and AUC values of 5FU and uracil were not linearly related to UFT dose. The pharmacokinetics of ftorafur were ascribed to a two-compartment open model in which 5FU was produced from the central compartment. The absorption and exponential distribution rate constants were assumed equal. The effect of uracil on 5FU elimination was straightforward, since no reasonable curve-fitting could be obtained for 5FU data when this covariate was not taken into account. The uracil concentration inducing a 50% reduction in 5FU elimination was 2.67 micro mol.l(-1). This result confirms the important role played by uracil as a competitive inhibitor of 5FU catabolism.
A pharmacokinetic model for ftorafur and 5FU was developed and should be useful to further study drug interactions and establish dosing guidelines.
Cancer Chemotherapy and Pharmacology 09/2003; 52(2):99-107. · 2.83 Impact Factor
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M S Aapro,
F H van Wijk,
G Bolis,
B Chevallier,
M E L van der Burg,
A Poveda,
C F de Oliveira,
S Tumolo,
V Scotto di Palumbo,
M Piccart, [......],
A Goupil,
P G Harper,
C Madronal,
M Namer,
G Scarfone,
J E G M Stoot,
I Teodorovic,
C Coens,
I Vergote,
J B Vermorken
[show abstract]
[hide abstract]
ABSTRACT: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination.
Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks.
A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024).
In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.
Annals of Oncology 04/2003; 14(3):441-8. · 6.43 Impact Factor
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ABSTRACT: LU 103793 is a synthetic analogue of Dolastatin 15 that inhibits tubulin polymerisation. The aim of this study was to evaluate the efficacy and tolerability of LU 103793 in patients with metastatic breast cancer who had been previously treated with two lines of chemotherapy for advanced disease. Patients received LU 103793 at a dose of 2.5 mg/m(2)/day over 5 min for 5 consecutive days every 3 weeks. Thirty-four patients were enrolled and 23 patients were eligible for the evaluation of efficacy. Eleven patients experienced grade 4 neutropenia. Other related grade 3/4 adverse events included asthenia (three patients), stomatitis (1), myalgia (1) and increase of serum bilirubin (2). The main toxicity was hypertension occurring in seven out of 34 patients. There were no objective responses, 7 patients had stable disease. These results do not support the further evaluation of LU 103793 in metastatic breast cancer patients using this dose and schedule.
European Journal of Cancer 03/2003; 39(3):317-20. · 5.54 Impact Factor
