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1.
Ann Hematol ; 103(6): 2013-2020, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-38421404

RÉSUMÉ

Venetoclax is active in both frontline and relapsed/refractory settings for the treatment of chronic lymphocytic leukemia (CLL). Although the prevalence and severity of tumor lysis syndrome (TLS) are well characterized in clinical trials, laboratory and clinical TLS remain relatively unexplored in real-world clinical practice.In this prospective, real-world observational study, we aimed to determine the incidence and outcomes of TLS in patients with CLL receiving venetoclax outside a clinical trial. The study (VeRVe) was conducted in centers in Austria, Germany, and Switzerland.Two hundred and thirty-nine patients were treated according to local label with at least one dose of venetoclax. Patient demographics, baseline characteristics, and blood chemistry at baseline were documented, and descriptive statistical analyses were conducted.Seventy eight patients (33%) were treated with venetoclax monotherapy, 101 (42%) with venetoclax in combination with rituximab and 60 (25%) with venetoclax in combination with obinutuzumab. In all cases, the TLS risk mitigation strategy adhered to the ramp-up protocol. Median age was 73 years and 66% of patients were male. The majority of patients (75%) had relapsed/refractory CLL, 63/192 (32.8%) patients tested had a del(17p) and 93/134 (69.4%) patients tested had unmutated immunoglobulin heavy chain variable region gene (IGHV). Clinical TLS occurred in 5 patients (2.1%) and laboratory TLS occurred in 15 patients (6.3%). Ten patients received specific treatment, of which 6 were hospitalized. There were no deaths due to a TLS event and venetoclax was well-tolerated. Of the 5 clinical TLS events reported, none were fatal or resulted in renal failure (NCT03342144, registered on Nov 10, 2017).


Sujet(s)
Composés hétérocycliques bicycliques , Leucémie chronique lymphocytaire à cellules B , Sulfonamides , Syndrome de lyse tumorale , Humains , Syndrome de lyse tumorale/étiologie , Leucémie chronique lymphocytaire à cellules B/traitement médicamenteux , Sujet âgé , Sulfonamides/usage thérapeutique , Sulfonamides/effets indésirables , Sulfonamides/administration et posologie , Mâle , Femelle , Composés hétérocycliques bicycliques/usage thérapeutique , Composés hétérocycliques bicycliques/effets indésirables , Composés hétérocycliques bicycliques/administration et posologie , Sujet âgé de 80 ans ou plus , Études prospectives , Incidence , Adulte d'âge moyen , Anticorps monoclonaux humanisés/usage thérapeutique , Anticorps monoclonaux humanisés/effets indésirables , Anticorps monoclonaux humanisés/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Allemagne/épidémiologie , Rituximab/administration et posologie , Rituximab/effets indésirables , Rituximab/usage thérapeutique , Autriche/épidémiologie , Antinéoplasiques/effets indésirables , Antinéoplasiques/usage thérapeutique
2.
Int J Cancer ; 153(6): 1227-1240, 2023 09 15.
Article de Anglais | MEDLINE | ID: mdl-37260368

RÉSUMÉ

The prospective, multicenter, noninterventional TACTIC study assessed effectiveness and safety of trifluridine/tipiracil (FTD/TPI) in patients with metastatic colorectal cancer (mCRC) in a real-world setting in Germany, thus evaluating the external validity of the findings from the pivotal RECOURSE trial. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, and quality of life (QoL). Subgroups comprised patients with good (<3 metastatic sites at inclusion, ≥18 months from diagnosis of first metastasis to inclusion) or poor (remaining patients) prognostic characteristics (GPC/PPC). GPC without liver metastases was considered best prognostic characteristics (BPC). In total, 307 eligible patients (pretreated or not suitable for other available therapies) were treated with FTD/TPI. Overall, median [95%-CI] OS was 7.4 months [6.4-8.6], median PFS was 2.9 months [2.8-3.3]. In BPC (n = 65) and GPC (n = 176) compared to PPC (n = 124) subgroup, median OS (13.3 [9.1-17.6] vs 8.9 [7.6-9.8] vs 5.1 [4.4-7.0] months) and median PFS (4.0 [3.3-5.3] vs 3.4 [3.0-3.7] vs 2.6 [2.4-2.8] months) were longer. Patient-reported QoL, assessed by validated questionnaires (EQ-5D-5L, PRO-CTCAE), was stable throughout FTD/TPI treatment. Predominant FTD/TPI-related adverse events of grades 3 or 4 were neutropenia (13.0%), leukopenia (7.5%), and anemia (5.2%). Altogether, palliative FTD/TPI therapy in patients with pretreated mCRC was associated with prolonged survival, delayed progression, maintained health-related QoL, and manageable toxicity. Low metastatic burden and indolent disease were favorable prognostic factors for survival. TACTIC confirms the effectiveness and safety of FTD/TPI, highlighting its value in routine clinical practice.


Sujet(s)
Tumeurs du côlon , Tumeurs colorectales , Démence frontotemporale , Tumeurs du rectum , Humains , Qualité de vie , Uracile/effets indésirables , Tumeurs colorectales/anatomopathologie , Études prospectives , Trifluorothymidine/effets indésirables , Démence frontotemporale/induit chimiquement , Démence frontotemporale/traitement médicamenteux , Pyrrolidines/effets indésirables , Tumeurs du côlon/traitement médicamenteux , Tumeurs du rectum/traitement médicamenteux , Association médicamenteuse , Protocoles de polychimiothérapie antinéoplasique/effets indésirables
3.
J Clin Oncol ; 41(25): 4143-4153, 2023 09 01.
Article de Anglais | MEDLINE | ID: mdl-37352476

RÉSUMÉ

PURPOSE: BRAFV600E mutation is associated with a poor outcome in metastatic colorectal cancer (mCRC). This clinical trial investigated the efficacy of triplet chemotherapy (fluorouracil, folinic acid, oxaliplatin, and irinotecan) combined with either cetuximab or bevacizumab in patients with previously untreated BRAFV600E-mutant mCRC. PATIENTS AND METHODS: In this controlled, randomized, open-label phase II trial, 109 patients were randomly assigned, 107 of whom were included into the full analysis set (FAS). Patients were randomly assigned in a 2:1 ratio to receive either FOLFOXIRI plus cetuximab in the experimental arm (n = 72) or FOLFOXIRI plus bevacizumab in the control arm (n = 35). The primary end point was objective response rate (ORR) according to RECIST 1.1., evaluated in patients treated according to protocol (ATP population). Progression-free survival (PFS), overall survival (OS), toxicity, and feasibility were analyzed as secondary end points. RESULTS: Eighteen patients discontinued study treatment before the first tumor assessment, thus resulting in the ATP population of 89 patients. In these patients, ORR was 51% (30/59) in the cetuximab-based experimental arm and 67% (20/30) in the bevacizumab-based control arm (odds ratio, 1.93; 80% CI, 1.06 to 3.52; P = .92 [one-sided]). In the full analysis set, median PFS was significantly inferior in the experimental arm (6.7 months v 10.7 months; hazard ratio [HR], 1.89; P = .006). Median OS analyzed at an event rate of 64.5% showed a trend toward shorter survival in cetuximab-treated patients (12.9 months v 17.1 months; HR, 1.4; P = .20). CONCLUSION: To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAFV600E-mutant mCRC. FOLFOXIRI plus cetuximab does not induce a higher ORR when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAFV600E-mutant mCRC. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAFV600E-mutant mCRC.


Sujet(s)
Tumeurs du côlon , Tumeurs colorectales , Tumeurs du rectum , Humains , Bévacizumab , Cétuximab , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/génétique , Tumeurs colorectales/anatomopathologie , Protéines proto-oncogènes B-raf/génétique , Études prospectives , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Camptothécine , Fluorouracil , Leucovorine , Tumeurs du côlon/traitement médicamenteux , Tumeurs du rectum/traitement médicamenteux , Adénosine triphosphate/usage thérapeutique
4.
NPJ Breast Cancer ; 8(1): 106, 2022 Sep 19.
Article de Anglais | MEDLINE | ID: mdl-36117201

RÉSUMÉ

Following chemotherapy and human epidermal growth factor 2 (HER2)-targeted neoadjuvant therapy for HER2-positive early breast cancer, residual invasive breast cancer at surgery may be HER2-negative on retesting in some patients. We evaluated outcomes with T-DM1 and trastuzumab in patients randomized in the phase III KATHERINE trial based on HER2-positive central testing of the pre-treatment core biopsy with HER2-negative central testing on their corresponding surgical specimen after neoadjuvant treatment. In the 70/845 (8.3%) patients with HER2-negative residual disease on retesting at surgery, there were 11 IDFS events in the 42 trastuzumab-treated patients (26.2%) and none in the 28 T-DM1-treated patients, suggesting that T-DM1 should not be withheld in this patient population.

5.
Eur J Cancer ; 173: 194-203, 2022 09.
Article de Anglais | MEDLINE | ID: mdl-35940054

RÉSUMÉ

BACKGROUND: The randomised open-label phase III XELAVIRI trial failed to demonstrate non-inferiority of the sequential application of fluoropyrimidine plus bevacizumab followed by additional irinotecan at first progression (Arm A) versus initial combination of all agents (Arm B) for untreated metastatic colorectal cancer in the initial analysis of time-to-failure-of-strategy (TFS, 90% confidence boundary of 0.8). Here, we evaluate efficacy in the full analysis set (FAS), the per-protocol set, in addition to age-related and molecular subgroups. METHODS: Median TFS, overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method and log-rank test. Cox regression models assessed hazard ratios (HRs) and confidence intervals (CIs) (TFS: 90%; OS, PFS: 95%). RESULTS: Of 421 patients, 390 (92.6%), 391 (92.9%) and 357 (84.8%) events for TFS, OS and PFS were observed in the FAS with a median follow-up of 54.2 months (Arm A) versus 52.9 months (Arm B). Non-inferiority of sequential treatment for TFS was missed in the FAS (HR 0.93; 90% CI, 0.79-1.10; P = 0.482) and not shown in the per-protocol set (HR 0.93; 90% CI, 0.75-1.13, P = 0.433). Formal non-inferiority for TFS was observed for patients older than 70 years (HR 1.06; 90% CI, 0.80-1.41; P = 0.670) and patients with RAS mutant tumours (HR 1.12; 90% CI, 0.87-1.43; P = 0.465). In RAS/BRAF wild-type tumours, combination treatment was significantly superior to sequential therapy in all end-points. CONCLUSIONS: In the overall population, XELAVIRI just missed to demonstrate the non-inferiority of sequential compared to combination therapy for TFS. However, the non-inferiority of sequential treatment was observed in elderly patients and RAS mutant tumours. TRIAL REGISTRATION: Trial registration ID (clinicaltrials.gov) NCT01249638.


Sujet(s)
Tumeurs du côlon , Tumeurs colorectales , Tumeurs du rectum , Sujet âgé , Antimétabolites , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Bévacizumab , Camptothécine , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/génétique , Fluorouracil , Humains , Irinotécan , Leucovorine , Essais contrôlés randomisés comme sujet
6.
Eur J Cancer ; 157: 71-80, 2021 11.
Article de Anglais | MEDLINE | ID: mdl-34507244

RÉSUMÉ

BACKGROUND: The XELAVIRI trial compared sequential (fluoropyrimidine and bevacizumab; irinotecan (Iri) at progression) versus initial combination therapy (fluoropyrimidine, bevacizumab, Iri) of treatment-naïve metastatic colorectal cancer (mCRC). In the confirmatory analysis, the primary end-point (non-inferiority of sequential therapy regarding time to failure of strategy, TFS) was not met. Nevertheless, significant differences regarding treatment efficacy were observed according to RAS status. Here, we evaluate the consensus molecular subtypes (CMS) as additional biomarkers for sequential versus combination therapy. MATERIAL AND METHODS: Gene expression was measured using NanoString after mRNA extraction from formalin-fixed paraffin-embedded tumour specimens. CMS were predicted using multinomial regression and correlated with updated data for TFS, overall (OS) and progression-free survival. RESULTS: CMS were predicted in 337 of 421 (80.0%) patients (CMS1: 18.4%; CMS2: 51.6%; CMS3: 2.7%; CMS4: 27.3%). CMS2 together with RAS/BRAF wild-type status was identified as potential predictive marker of benefit from initial combination therapy for OS (HR 0.56, 95% CI 0.33-0.96, p = 0.036) and progression-free survival (HR 0.28, 95% CI 0.29-0.79, p = 0.004) and also trending in TFS (HR 0.63, 90% CI 0.41-0.95, p = 0.066). In patients with RAS-mutated mCRC, CMS1 was associated with longer OS after initial combination therapy (HR 0.43, 95% CI 0.20-0.95, p = 0.038). Interaction testing (two-sided) of CMS and RAS/BRAF status in favour of the combination treatment strategy was significant for OS (p = 0.012) CONCLUSIONS: In patients with RAS/BRAF wild-type mCRC, CMS2 may serve as an additional biomarker of benefit from the initial combination therapy, including Iri. TRIAL REGISTRATION: Trial registration ID (clinicaltrials.gov) NCT01249638.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Tumeurs colorectales/traitement médicamenteux , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Bévacizumab/administration et posologie , Tumeurs colorectales/génétique , Tumeurs colorectales/mortalité , Tumeurs colorectales/anatomopathologie , Femelle , Fluorouracil/administration et posologie , Gènes ras , Humains , Irinotécan/administration et posologie , Mâle , Adulte d'âge moyen , Métastase tumorale , Protéines proto-oncogènes B-raf/génétique
7.
Eur J Cancer ; 137: 81-92, 2020 09.
Article de Anglais | MEDLINE | ID: mdl-32750502

RÉSUMÉ

INTRODUCTION: The XELAVIRI study compared application of fluoropyrimidine (FP) and bevacizumab (Bev) followed by sequential escalation to irinotecan (Iri), FP and Bev (arm A) to upfront combination therapy with FP, Iri and Bev (arm B) in patients with metastatic colorectal cancer (mCRC). To elucidate the impact of age on survival, we evaluated efficacy and early mortality in the underlying trial. METHODS: Patients were stratified for age in three cohorts (<65 years, 65-74 years and ≥75 years). Survival end-points were expressed by the Kaplan-Meier method and compared by log-rank testing and Cox regression. Objective response and 60-day mortality were evaluated by chi-square testing. RESULTS: The efficacy analyses suggest more substantial benefit from upfront combination chemotherapy in younger patients with mCRC. Elderly patients (≥75 years) derived limited benefit from upfront combination chemotherapy, particularly in terms of overall survival. Of 421 randomised patients, 13 patients (3.1%) died within 60 days after treatment initiation with the highest prevalence in elderly patients (1.6% < 65 years, 2.8% 65-74 years and 5.2% ≥ 75 years, p = 0.26). The frequency of 60-day mortality was significantly associated with age (with a maximum of 8.7% in patients aged ≥75 years) in patients undergoing upfront combination therapy (p = 0.027) but not in patients receiving sequential treatment (p = 0.63). CONCLUSION: Combination therapy with FP, Iri and Bev does not substantially improve the outcome of patients aged ≥75 years as compared with sequential treatment algorithm. These patients appear to be at a relevant risk for 60-day mortality under Iri-based combination chemotherapy plus Bev.


Sujet(s)
Tumeurs colorectales/épidémiologie , Facteurs âges , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/mortalité , Tumeurs colorectales/anatomopathologie , Femelle , Humains , Mâle , Métastase tumorale , Taux de survie
8.
J Clin Oncol ; 37(1): 22-32, 2019 01 01.
Article de Anglais | MEDLINE | ID: mdl-30388045

RÉSUMÉ

PURPOSE: The XELAVIRI trial investigated the optimal treatment strategy for patients with untreated metastatic colorectal cancer. We tested the noninferiority of initial treatment with a fluoropyrimidine plus bevacizumab, followed by the addition of irinotecan at first progression (arm A) versus upfront use of fluoropyrimidine plus irinotecan plus bevacizumab (arm B) in a 1:1 randomized, controlled phase III trial. METHODS: The primary efficacy end point was time to failure of the strategy (TFS). Given a 90% CI, a power of 70%, and a one-sided α of .05, the margin for noninferiority was set at 0.8. In the case of demonstrated noninferiority of TFS, an analysis of symptomatic toxicities during TFS would define the superior strategy. Secondary end points included the effect of molecular subgroups on efficacy parameters. RESULTS: A total of 421 randomly assigned patients (arm A: n = 212; arm B: n = 209) formed the full analysis set. Median age was 71 and 69 years, respectively. Noninferiority of TFS was not shown (hazard ratio [HR], 0.86; 90% CI, 0.73 to 1.02). In detail, patients with RAS/BRAF wild-type tumors benefitted from combination chemotherapy (HR, 0.61; 90% CI, 0.46 to 0.82; P = .005), whereas patients with RAS mutant tumors (HR, 1.09; 90% CI, 0.81 to 1.46; P = .58) did not (Cox model for interaction of study arm and RAS status: P = .03). Comparable results were obtained for overall survival. CONCLUSION: Noninferiority of sequential escalation therapy compared with initial combination chemotherapy could not be demonstrated for TFS. RAS status may be important to guide therapy as treatment of patients with upfront combination therapy was clearly superior in RAS/BRAF wild-type tumors, whereas sequential escalation chemotherapy seems to provide comparable results in patients with RAS mutant tumors.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Tumeurs colorectales/traitement médicamenteux , Sujet âgé , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Bévacizumab/administration et posologie , Bévacizumab/effets indésirables , Camptothécine/administration et posologie , Camptothécine/effets indésirables , Camptothécine/analogues et dérivés , Désoxycytidine/administration et posologie , Désoxycytidine/effets indésirables , Désoxycytidine/analogues et dérivés , Calendrier d'administration des médicaments , Femelle , Fluorouracil/administration et posologie , Fluorouracil/effets indésirables , Fluorouracil/analogues et dérivés , Acide folique/administration et posologie , Acide folique/effets indésirables , Humains , Irinotécan/administration et posologie , Irinotécan/effets indésirables , Leucovorine/administration et posologie , Leucovorine/effets indésirables , Mâle
9.
J Clin Oncol ; 32(23): 2423-9, 2014 Aug 10.
Article de Anglais | MEDLINE | ID: mdl-24982456

RÉSUMÉ

PURPOSE: To assess the efficacy of a second-line regimen of oxaliplatin and folinic acid-modulated fluorouracil in patients with advanced pancreatic cancer who have experienced progression while receiving gemcitabine monotherapy. PATIENTS AND METHODS: A randomized, open-label, phase III study was conducted in 16 institutions throughout Germany. Recruitment ran from January 2004 until May 2007, and the last follow-up concluded in December 2012. Overall, 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF). Patients were stratified according to the presence of metastases, duration of first-line therapy, and Karnofsky performance status. RESULTS: Median follow-up was 54.1 months, and 160 patients were eligible for the primary analysis. The median overall survival in the OFF group (5.9 months; 95% CI, 4.1 to 7.4) versus the FF group (3.3 months; 95% CI, 2.7 to 4.0) was significantly improved (hazard ratio [HR], 0.66; 95% CI, 0.48 to 0.91; log-rank P = .010). Time to progression with OFF (2.9 months; 95% CI, 2.4 to 3.2) versus FF (2.0 months; 95% CI, 1.6 to 2.3) was significantly extended also (HR, 0.68; 95% CI, 0.50 to 0.94; log-rank P = .019). Rates of adverse events were similar between treatment arms, with the exception of grades 1 to 2 neurotoxicity, which were reported in 29 patients (38.2%) and six patients (7.1%) in the OFF and FF groups, respectively (P < .001). CONCLUSION: Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Tumeurs du pancréas/traitement médicamenteux , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Désoxycytidine/analogues et dérivés , Désoxycytidine/pharmacologie , Évolution de la maladie , Résistance aux médicaments antinéoplasiques , Femelle , Fluorouracil/administration et posologie , Fluorouracil/effets indésirables , Humains , Leucovorine/administration et posologie , Leucovorine/effets indésirables , Mâle , Adulte d'âge moyen , Composés organiques du platine/administration et posologie , Composés organiques du platine/effets indésirables , Oxaliplatine , Tumeurs du pancréas/anatomopathologie , Analyse de survie , Résultat thérapeutique ,
10.
Eur J Cancer ; 47(11): 1676-81, 2011 Jul.
Article de Anglais | MEDLINE | ID: mdl-21565490

RÉSUMÉ

BACKGROUND: Gemcitabine usually given until progressive disease (PD) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer (APC). Currently there is no accepted active regimen for second-line chemotherapy. Previous phase II studies suggest clinical relevant activity of oxaliplatin, folinic acid and 5-FU (OFF). We initiated a phase III multicentre study comparing OFF versus best supportive care (BSC) in patients with APC progressing while on gemcitabine therapy. METHODS: In this open randomized study, patients with CT and/or MRI confirmed progressive disease while on gemcitabine therapy were randomized 1:1 to OFF or BSC. Stratification included duration of first-line therapy (<3, 3 to 6 and >6 months), performance status (KPS 70-80%; 90-100%) and tumour stage (M1/M0). OFF consisted of folinic acid 200mg/m(2) followed by 5-fluorouracil 2g/m(2) (24h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m(2) on days 8 and 22. After a rest of 3 weeks the next cycle was started on d43. A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy. RESULTS: After inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual (lack of acceptance of BSC by patients and physicians. Patient characteristics were well balanced between both study arms. The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea. Median second-line survival was 4.82 [95% Confidence Interval; 4.29-5.35] months for OFF treatment and 2.30 [95% CI; 1.76-2.83] months with BSC alone (0.45 [95% CI: 0.24-0.83], p = 0.008). Median overall survival for the sequence GEM-OFF was 9.09 [95% CI: 6.97-11.21] and 7.90 [95% CI: 4.95-10.84] months for GEM-BSC (0.50 [95% CI: 0.27-0.95], p = 0.031) respectively. INTERPRETATION: Although stopped prematurely, this randomized trial provides at first time evidence for the benefit of second-line chemotherapy as compared to BSC alone for patients with APC. OFF significantly prolonged survival time compared to BSC alone after failure of first-line therapy with gemcitabine.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Désoxycytidine/analogues et dérivés , Fluorouracil/administration et posologie , Leucovorine/administration et posologie , Composés organiques du platine/administration et posologie , Tumeurs du pancréas/traitement médicamenteux , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Désoxycytidine/usage thérapeutique , Évolution de la maladie , Femelle , Allemagne , Humains , Mâle , Adulte d'âge moyen , Métastase tumorale , Oxaliplatine , Résultat thérapeutique ,
11.
Hum Gene Ther ; 14(5): 483-94, 2003 Mar 20.
Article de Anglais | MEDLINE | ID: mdl-12691613

RÉSUMÉ

Therapeutic vaccination with dendritic cells (DC) can lead to tumor regression in animal models and has shown promising results in the first clinical trials of metastatic renal cell carcinoma and malignant melanoma. In vitro data and results of a clinical phase I/II trial using DC tumor fusions in patients with progressive metastatic renal cell carcinoma are presented here. In addition to toxicity and feasibility, complex immune monitoring was a point of interest. DC precursor cells were obtained from the peripheral blood mononuclear cells (PBMCs) of healthy donors and were fused with either allogeneic (8 patients) or autologous (4 patients) renal tumor cells. In total, 12 patients with progressive metastatic renal cell carcinoma were treated with an average of 2.8 x 10(7) tumor cells fused with 1.8 x 10(7) DC each administered on days 0, 28, and 56 intradermally. Fusion efficacy for the tumor cells used was 14.3% +/- 7.8%. Cell viability was 59.8% +/- 6.8% after fusion and irradiation. We observed no adverse effects and no difference in clinical outcome between the allogeneic and the autologous treatment. Eight patients remained in a progressive disease state and four patients in a stable disease state. T-cell immunity was carefully monitored before, during, and after treatment. Delayed-type hypersensitivity (DTH) reaction using tumor cells was positive after treatment in 7 of 12 patients, 2 of whom were found to have stable disease. An increase in the reactivity against recall antigens was seen in most patients. Interestingly, cytotoxicity of peripheral blood lymphocytes (PBLs) against renal cell carcinoma cells increased during treatment as well as the percentage of interferon-gamma-secreting cells. This effect was significantly enhanced within the group that had stable disease. The lack of adverse effects together with positive immunologic signs justifies further investigation of this novel therapeutic approach. Further studies are necessary to test for clinical effectiveness in patients with tumors, especially those with less advanced disease.


Sujet(s)
Vaccins anticancéreux/usage thérapeutique , Néphrocarcinome/thérapie , Cellules dendritiques/immunologie , Tumeurs du rein/thérapie , Adulte , Sujet âgé , Antigènes CD/métabolisme , Vaccins anticancéreux/immunologie , Néphrocarcinome/immunologie , Néphrocarcinome/anatomopathologie , Fusion cellulaire , Cytokines/biosynthèse , Cytokines/sang , Tests de cytotoxicité immunologique , Cellules dendritiques/cytologie , Technique d'immunofluorescence , Humains , Isoantigènes/immunologie , Tumeurs du rein/immunologie , Tumeurs du rein/anatomopathologie , Activation des lymphocytes , Mâle , Microscopie de fluorescence , Adulte d'âge moyen , Métastase tumorale , Lymphocytes T cytotoxiques/immunologie , Résultat thérapeutique , Cellules cancéreuses en culture
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