The Impact of splenic irradiation during chemoradiation for Gastric and Gastroesophageal junctional cancers in the development of acute hematological toxicity

AbstractMethotrexate (MTX) is an antifolate agent used for the treatment of various malignancies and is eliminated by breast cancer resistance protein (BCRP). Because febuxostat (FBX) is known to inhibit BCRP activity, FBX might exacerbate MTX-related adverse effects. In this study, we examined the drug-drug interaction between FBX and MTX in BCRP-expressing membrane vesicles. Moreover, we retrospectively investigated the impact of FBX on MTX-related adverse effects in 38 patients (144 cycles) receiving high-dose MTX therapy (HDMTX). The Food and Drug Administration Adverse Event Reporting System (FAERS) database and human hepatocellular carcinoma cell line HepG2 cells were used to evaluate the effects of FBX on MTX-induced hepatotoxicity. In the membrane vesicle study, FBX significantly inhibited BCRP-mediated transport of MTX. Concomitant FBX significantly increased the incidence of hepatotoxicity, but not of nephrotoxicity and hematological toxicity in patients receiving HDMTX. FAERS database analyses revealed that the reporting odds ratio of FBX for MTX-induced hepatotoxicity was 4.16 (95% CI: 2.89–5.98). Co-incubated FBX significantly decreased the cell viability and increased cytotoxicity in MTX-treated HepG2 cells. These findings suggest that concomitant FBX enhances MTX-induced hepatotoxicity by inhibiting hepatic BCRP. These findings provide important information for the safe management of HDMTX therapy in clinical settings.

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Cytopenia at Diagnosis Impairs Stem Cell Mobilization Among Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.5828.5828 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5828-5828

Author(s):

Selami Kocak Toprak ◽

Atilla Uslu ◽

Erden Atilla ◽

Pervin Topcuoglu ◽

Gunhan Gurman ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Risk Score ◽

Induction Therapy ◽

Peripheral Blood ◽

Stem Cell Mobilization ◽

Categorical Variables ◽

Hematological Toxicity ◽

Cell Mobilization ◽

The Impact

Abstract Introduction: The GIMEMA group has recently developed a risk score predicting mobilization failure (Musto et al, EHA 2014). The risk score included age, cytopenia at diagnosis, induction therapy and their toxicity. In this study we aimed to evaluate the impact of these factors on peripheral blood stem cell (PBSC) mobilization among patients with multiple myeloma (MM). Patients and methods: 125 newly diagnosed patients with MM (M: 76, F: 49) planned for autologous stem cell transplantation; median age 58 years (range, 30-67) were included in the analysis. This retrospective study examined the impact of age (> 60 years), gender of the patients, cytopenia (Hb<10 gr/dL, absolute neutrophil count < 1x109/L, thrombocyte count < 100x109/L) at diagnosis, and severe hematological toxicity during induction therapy, the type of induction and mobilization methods, the presence of neuropathy, comorbid diseases such as diabetes mellitus, hypertension and renal failure (creatinine > 2 mg/dL), and the use of beta blocker drugs. Patients with CD34+ levels of <20/μL in peripheral blood at maximum stimulation were considered to be Poor Mobilizers. The total amount of PBSC <5x106/kg after a single mobilization procedure was defined as sub-optimal collection. Poor mobilization was observed in only two patients (<2x106/kg). Statistics: Comparison of categorical variables was evaluated by chi-square test or Fisher exact test. Nominal variables were compared with non-parametrical test, Mann-Whitney U or Kruskal Wallis test. P value below as 0.05 was accepted as significance. Results: Optimal mobilization with median two apheresis (1-4) sessions for PBSC was obtained in 85.6% of the patients (n=107). Median CD34+ cells in this group were 8.33x106/kg (5-27x106/kg). The presence of cytopenia at diagnosis was the only significantly detrimental factor on mobilization (90% vs 77.1%, p=0.04). When the patients was scored in four groups as having single or combined variables (age, cytopenia at the diagnosis or during induction therapy), we were not able to develop a risk score. Conclusions: In our experience, 14.4% of the myeloma patients showed suboptimal or poor mobilization. Use of bortezomib, age, presence of neurotoxicity or hematological toxicity at mobilization did not significantly impair mobilization. We were able to confirm only cytopenia at diagnosis, from the four factors reported by Musto et al, as a detrimental factor impairing the stem cell mobilization. Disclosures No relevant conflicts of interest to declare.

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BEAM Vs Cyclophosphamide-Based Conditioning Regimen in Aggressive Multiple Sclerosis: A Retrospective Analysis of European Blood and Marrow Transplantation Society

Blood ◽

10.1182/blood-2019-125233 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3313-3313

Author(s):

Riccardo Saccardi ◽

Manuela Badoglio ◽

Joachim Burman ◽

Grzegorz Helbig ◽

Majid A. Kazmi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Retrospective Analysis ◽

Conditioning Regimen ◽

Working Party ◽

High Rate ◽

Hematological Toxicity ◽

Significant Difference ◽

Conditioning Regimens ◽

The Impact ◽

Autologous Hsct

Background Multiple Sclerosis (MS) is a chronic, immuno-mediated disease of Central Nervous System (CNS), mostly affecting young adults and frequently resulting in a progressive, irreversible disability despite the administration of approved Disease Modifying Treatments (DMTs). Autologous HSCT was shown to induce a high rate of sustained, treatment-free remissions in cases of aggressive MS, seldom associated to a partial reversal of disability. Toxicity of Conditioning Regimen is still a major concern. We retrospectively analyzed the outcome of 926 MS patients reported to the EBMT Registry who underwent autologous HSCT following the two most frequent CRs for this indication in the last 20 years. Patients and Methods Patient data were extracted from both the EBMT database and a disease-specific database developed by the EBMT Autoimmune Diseases Working Party (ADWP). Patients were selected for having received either BEAM + ATG (BEAM) or HD-Cyclophosphamide + ATG (CYC) as conditioning regimen. Hematological toxicity was assessed through Neutrophil (PMN) engraftment and 100-days (early) mortality (eTRM). MS forms at HSCT were reported as Relapsing-Remitting (RR), Secondary Progressive (SP), Primary Progressive (PP) and Progressive-Relapsing (PR). The impact of variables related to both patients (age, gender, year of HSCT, EDSS at HSCT) and disease characteristics (MS form, interval diagnosis-HSCT) at HSCT in the two groups were also evaluated. Results The utilization of conditioning regimens along the observed time period (1998-2018) was variable, with an increase of the HSCT activity in general after 2010 (230 vs 697 procedures) and a prevalence of BEAM before 2010 (205 BEAM vs 25 CYC) and of CYC thereafter (205 BEAM vs 492 CYC, p=0.001). Also, RR forms of MS prevailed over Progressive forms after 2010 (p=0.001) which is reflected in the different distribution across the two regimens, with RR significantly more frequently treated with CYC-based regimen (p<0.001). Gender distribution and age at HSCT was similar in the two groups (p=ns), whilst the interval between diagnosis and HSCT was longer in BEAM group than CYC (8.47 years ± 5.9 vs 7.57 ±5.5, mean ± SD, p=0.012). PMN engraftment in BEAM/ATG- and CYC/ATG-treated patients occurred at +11.0 (8-42) and +10.9 (8-95) days, respectively (median and range, p=ns). Overall eTRM was low (1.4%), but slightly higher in BEAM over CYC (8/402, 2% vs 5/517, 1%, p=ns). Discussion Although autologous HSCT is increasingly used as a treatment in highly active MS, toxicity remains a principal concern in the neurological community despite a marked decrease of TRM over time. The intensity of conditioning regimens has varied in the literature, but the best toxicity/efficacy ratio remains unclear. The non-myeloablative regimen CYC-ATG has become the most common conditioning regimen despite a lack of comparative data with more intense regimens. In our large retrospective analysis of the two most frequent conditioning regimens in the EBMT Registry, there was no significant difference in major toxicity indicators despite differences in chronological period and patients characteristics in the two groups. Comparative analysis of neurological efficacy is currently ongoing and will inform the toxicity/efficacy ratio and clinical choice of conditioning regimen in autologous HSCT in MS. Disclosures Mielke: Bellicum: Consultancy, Honoraria, Other: Travel (via institution); Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; IACH: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; DGHO: Other: Travel support; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; EBMT/EHA: Other: Travel support.

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Long term (five-year) survival following radical surgical treatment plus adjuvant chemotherapy (FAM) in advanced gastric cancer: a controlled study

Revista do Hospital das Clínicas ◽

10.1590/s0041-87812000000400004 ◽

2000 ◽

Vol 55 (4) ◽

pp. 129-136 ◽

Cited By ~ 5

Author(s):

Cláudio Bresciani ◽

Joaquim Gama-Rodrigues ◽

Victor Strassmann ◽

Dan L. Waitzberg ◽

Mitsunori Matsuda ◽

...

Keyword(s):

Gastric Cancer ◽

Surgical Treatment ◽

Survival Rate ◽

Tnm Classification ◽

Controlled Study ◽

Hematological Toxicity ◽

Control Group ◽

Significant Difference ◽

The Impact

Several drugs and their associations are being used for adjuvant or complementary chemotherapy with the aim of improving results of gastric cancer treatment. The objective of this study was to verify the impact of these drugs on nutrition and on survival rate after radical treatment of 53 patients with gastric cancer in stage III of the TNM classification. A control group including 28 patients who had only undergone radical resection was compared to a group of 25 patients who underwent the same operative technique followed by adjuvant polychemotherapy with FAM (5-fluorouracil, Adriamycin, and mitomycin C). In this latter group, chemotherapy toxicity in relation to hepatic, renal, cardiologic, neurological, hematologic, gastrointestinal, and dermatological functions was also studied. There was no significant difference on admission between both groups in relation to gender, race, macroscopic tumoral type of tumor according to the Borrmann classification, location of the tumor in the stomach, length of the gastric resection, or response to cutaneous tests on delayed sensitivity. Chemotherapy was started on average, 2.3 months following surgical treatment. Clinical and laboratory follow-up of all patients continued for 5 years. The following conclusions were reached: 1) The nutritional status and incidence of gastrointestinal manifestation were similar in both groups; 2) There was no occurrence of cardiac, renal, neurological, or hepatic toxicity or death due to the chemotherapeutic method per se; 3) Dermatological alterations and hematological toxicity occurred exclusively in patients who underwent polychemotherapy; 4) There was no significant difference between the rate and site of tumoral recurrence, the disease-free interval, or the survival rate of both study groups; 5) Therefore, we concluded, after a 5-year follow-up, chemotherapy with the FAM regimen did not increase the survival rate.

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Safety Profile of Bortezomib Impacts Survival in Light Chain Amyloidosis

Blood ◽

10.1182/blood.v124.21.5664.5664 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5664-5664

Author(s):

Zoé Van de Wyngaert ◽

Greg Vanoutryve ◽

Guillemette Fouquet ◽

Stéphanie Guidez ◽

Charles Herbaux ◽

...

Keyword(s):

Overall Survival ◽

Dose Reduction ◽

Safety Profile ◽

Cardiac Involvement ◽

Hematological Toxicity ◽

Al Amyloidosis ◽

Kidney Involvement ◽

The Impact ◽

To Receive

Abstract Background. Bortezomib has improved overall survival (OS) in light chain (AL) amyloidosis; however, data on its activity in severe cardiac AL are sparse. Furthermore, the impact of the safety profile of Bortezomib on overall survival in severe cardiac AL amyloidosis remains unknown given the fragile population. We sought to outline the activity and safety profile of Bortezomib in severe cardiac AL amyloidosis. Methods. Twenty-seven patients diagnosed with AL amyloidosis and treated with Bortezomib were included, mean age was 63 years (36-85), with a sex ratio of 18/9. Eighteen patients had cardiac involvement, among which all had Mayo-Clinic stage III staging but 3, and 9 had kidney involvement only. Seventy percent of patients received Bortezomib as a 1st-line therapy, once (19%) or twice weekly (81%), given IV at the starting dose of 1.3g/m2 in combination to Dexamethasone. Thirteen (48%) patients also received an alkylating agent. Results. Overall hematological response rate was 75% in patients who received at least 1 cycle of Bortezomib, and 83% and 62.5% in patients with and without cardiac involvement, respectively. Complete response was obtained in 45%, and 42% and 50% in the 2 groups, respectively. 44% patients with cardiac involvement had an organ response. An hematological toxicity occurred in 26% of patients, similarly in the 2 groups, consisting mainly of thrombocytopenia with no need for treatment modification. Non-hematological toxicity (grade ≥2) rate was 62% in patients with cardiac involvement and 38% in patients with kidney involvement (p=ns), consisting mostly of fatigue, peripheral neuropathy, infection and gastro-intestinal adverse effects, and leading to 25% of dose reduction, and 33% of Bortezomib interruption before cycle 4, similarly in both groups. The median follow-up was 41 months from start of Bortezomib. Seven patients died during the first cycle of treatment, all of them but one had severe stage III cardiac involvement with LVEF <40%. Importantly, the patients with cardiac involvement who were treated past the first cycle had an estimated 3-year OS similar to those with kidney involvement only (50 vs. 62%, p=ns). All patients with cardiac AL who completed at least 3 cycles of treatment and survived beyond 3 months remained alive at follow-up date. In univariate analysis for the cohort as a whole, occurrence of non-hematological toxicity grade ≥2 was associated with a lower OS (20% if present vs. 67% when absent; p=0.001), as for the consequence of Bortezomib dose reduction (54% vs. 71%, respectively; p=0.036), and decrease of the total dose received to less than 50% of the initial dose (12% vs. 92% respectively, p=0.009). Bortezomib interruption (36% vs. 78%, respectively; p=0.004), or inability to receive at least 3 cycles of Bortezomib also impacted OS (36% vs. 78%, respectively; p=0,004). The impact on OS appeared even more dramatic in patients with cardiac involvement. In multivariate analysis, independent variables that were associated with poor OS were the number of Bortezomib cycles (inability to receive at least 3 cycles) (OR=34.7; p=0.001), occurrence of a non-hematological toxicity (OR=5.1; p=0.011), and absence of hematological response (OR=3.6; p=0.05). Conclusion. Bortezomib is an effective treatment of AL amyloidosis, and significantly improves the most adverse patients characterized with severe cardiac presentation. However, the safety profile is of particular concern in severe cardiac AL, particularly the non hematological ≥grade 2 incidence rate; patients often characterized with dose reduction or interruption, inability to receive sufficient dose concentration or number of cycles. This study confirms that alteration of the safety profile of Bortezomib may hamper the benefits seen particularly in severe cardiac AL, questioning on the use of weekly and sub-cutaneous Bortezomib for very fragile AL, as optimized in fragile patients with Myeloma. Disclosures No relevant conflicts of interest to declare.

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The Impact of Liposomal Irinotecan on the Treatment of Advanced Pancreatic Adenocarcinoma: Real-World Experience in a Taiwanese Cohort

Scientific Reports ◽

10.1038/s41598-020-64421-6 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Yung-Yeh Su ◽

Nai-Jung Chiang ◽

Hui-Jen Tsai ◽

Chia-Jui Yen ◽

Yan‐Shen Shan ◽

...

Keyword(s):

Real World ◽

Performance Status ◽

University Hospital ◽

Ductal Adenocarcinoma ◽

Hematological Toxicity ◽

Free Base ◽

Gemcitabine Refractory ◽

Liposomal Irinotecan ◽

Ecog Ps ◽

The Impact

AbstractLiposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI + 5-FU/LV) has shown to provide survival benefits for patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) in NAPOLI-1 trial, in which Asian patients experienced more hematological toxicity and subsequent dose modification. A retrospective chart review to investigate the administration pattern, therapeutic efficacy and safety profile of nal-IRI + 5-FU/LV in 44 consecutive patients with gemcitabine-refractory advanced PDAC treated between December 2016 and December 2018 in National Cheng Kung University Hospital, Taiwan. Most of them had metastatic diseases (88.6%), one-line of prior treatment (72.7%), ECOG PS 0-1 (72.7%) and starting dose of nal-IRI at 60 mg/m2 (≈52 mg/m2 irinotecan free-base) in 65.9%. The overall response rate was 9.1%. The median OS was 6.6 months for the entire cohort, and 7.8 and 2.7 months for patients of ECOG PS 0-1 and>2, respectively. The median OS of ECOG PS 0-1 patients with nal-IRI starting doses at 80 mg/m2 (≈70 mg/m2 irinotecan free-base, n = 13) and 60 mg/m2 (n = 19) were 7.5 and 8.4 months, respectively. Thirty-four percent of patients experienced manageable grade 3-4 hematological toxicity. Our results confirm the clinical benefit of nal-IRI + 5-FU/LV for patients of gemcitabine-refractory advanced PDAC with good performance status in a real-world setting.

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High-Risk, Advanced-Stage Hodgkin Lymphoma: The Impact of Combined Escalated BEACOPP and ABVD Treatment in Patients Who Rapidly Achieve Metabolic Complete Remission on Interim FDG-PET/CT Scan

Acta Haematologica ◽

10.1159/000441962 ◽

2015 ◽

Vol 135 (3) ◽

pp. 156-161 ◽

Cited By ~ 8

Author(s):

Meirav Kedmi ◽

Arie Apel ◽

Tima Davidson ◽

Itai Levi ◽

Eldad J. Dann ◽

...

Keyword(s):

High Risk ◽

Complete Remission ◽

Hodgkin Lymphoma ◽

Fdg Pet ◽

Prognostic Score ◽

Hematological Toxicity ◽

Advanced Stage ◽

Pet Ct ◽

Fdg Pet Ct ◽

The Impact

The escalated BEACOPP (escBEACOPP) regimen improves the outcome of patients with advanced-stage Hodgkin lymphoma (HL) but is associated with cumbersome toxicity. We analyzed the survival outcome of high-risk, advanced-stage HL patients treated with response-adapted therapy. escBEACOPP was administered for 2 cycles, and after complete remission (CR) or partial remission (PR) was observed on FDG-PET/CT, treatment was de-escalated to 4 cycles of ABVD. Sixty-nine patients were evaluated, of them 45 participated in the multicenter, phase II prospective study between 2001 and 2007. Sixty patients had an international prognostic score ≥3. At a median follow-up of 5.6 years, 4 patients had died, 2 of them due to advanced HL. After the initial 2 cycles of escBEACOPP, 52 (75%) patients were in CR and 17 (25%) had a PR. Progression-free survival and overall survival (OS) were 79 and 93%, respectively. OS was predicted from the results of early-interim FDG-PET/CT: 98% of the patients in CR and 79% of those with a PR (p = 0.015). Hematological toxicity was more frequent during the first 2 cycles of escBEACOPP than in the ABVD phase. In conclusion, this retrospective analysis indicates that combined escBEACOPP-ABVD therapy is well tolerated and efficacious in HL patients who achieve negative early-interim PET results, while a positive PET result partially identified those with a worse prognosis.

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The Ribvd Regimen (Rituximab IV, Bendamustine IV, Velcade SC, Dexamethasone IV) Offers a High Complete Response Rate In Elderly Patients With Untreated Mantle Cell Lymphoma. Preliminary Results Of The Lysa Trial “Lymphome Du Manteau 2010 SA”

Blood ◽

10.1182/blood.v122.21.370.370 ◽

2013 ◽

Vol 122 (21) ◽

pp. 370-370 ◽

Cited By ~ 4

Author(s):

Remy Gressin ◽

Mary Callanan ◽

Nicolas Daguindau ◽

Adrian Tempescul ◽

Sylvain Carras ◽

...

Keyword(s):

Response Rate ◽

Complete Response ◽

Primary Prophylaxis ◽

High Response Rate ◽

Hematological Toxicity ◽

Molecular Response ◽

Virus Reactivation ◽

Serious Adverse Events ◽

Cutaneous Rash ◽

The Impact

Abstract This prospective phase II trial (Nov 2011- Dec 2012), supported by the LYSA group, aimed to evaluate the impact on PFS of the RiBVD regimen in newly diagnosed, previously untreated, elderly MCL patients (>65 years or not eligible for ASCT) (NCT01457144). Inclusion criteria were: WHO 2008 MCL not previously treated, CD20 positive, ECOG 0-2, AA stage II-IV, no CNS involvement or active HBV/HCV/HIV infection. Patients were scheduled to receive a total of 6 cycles of the RiBVD regimen, if they responded (IWG criteria) after 4 cycles. The regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1 and 2, Dexamethasone 40 mg/m² IV on D2 and bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with acyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Herein we present preliminary analysis of the trial after 4 RiBVD cycles. Results: A total of 76 patients were included, one was excluded because of HBV active disease and 5 had insufficient data reported in the database. To date we analyzed 70 patients. Patients characteristics: sex ratio M/F 49/21, median age 72 years (y) [64-83] (2 patients were 64 y old), AAstage II/III-IV 5/65, ECOG 0-1/2 59/11, MIPI score low/intermediate/high 3/19/48. Response: 61 responded (ORR=87%), with 19 in PR (26%) and 42 in CR/CRu (60%). Four patients died from pneumonia (n=1), cardiac arrest (n=2) and one following Progressive Multifocal Leukoencephalopathy. Three patients have progressed after 3 cycles. Sixty one patients were analysed by PETscan after 4 cycles, 39 (64%) reached a CR (30 were in CR/CRu and 9 in PR) and 22 remained PET positive (11 patients were in CR/CRu, 10 in PR and 1 stable). RiBVD cycles: 271 cycles were administered out of 280 planned (97%). Twenty four (9%) were delayed, 10 for toxicity. All but one planned Bendamustine doses (n=542) were administered with dosing modified 17 times (3%), mostly for hematological toxicity (n=14). Regarding Bortezomib, 79% (1028/1084) of planned doses were administered, it was prematurely stopped (56, 4%) for neurotoxicity (10 instances) or hematological side effects (46). Rituximab was not administered in 4 instances. Hematologic toxicities: Over the 271 cycles administered, neutropenia was reported in 104 cycles [56 grade 3/4 (g3/4) (21%)], 2.5% with fever; thrombopenia in 181 cycles [41 g3/4 (15%)]; anemia in 210 cycles, [6 g3/4 (2%)]. Non-hematologic toxicities:Reported in >10% of the cycles were : allergic reactions (10.3%, g3/4 <1%), fatigue (40%, g3/4 5%), fever without neutropenia (12%, g3/4 none), weight loss (12%, g3/4 0%), cutaneous rash (12%, g3/4 1.5%), gastrointestinal (40%, g3/4 1.5% ; diarrhea 8%, constipation 17% or emesis 15%), elevated transaminases (14%, g3/4 1%), creatinin (13%, g3/4 none), or glucose (18%, g3/4 1%) ; neuropathy (sensitive or pain) (25%, g3/4 4%). Serious adverse events (SAE) additional to the 4 deaths, were 12 infections including 3 pneumonias (no pneumocystosis), one listeriosis and 2 herpes zoster. Four febrile neutropenia and 3 cutaneous hypersensitivity episodes were also reported. Conclusion Despite 4 toxic deaths (6%), toxicity appears acceptable and manageable. In particular, subcutaneous bortezomib shows markedly decreased neurotoxicity compared to the IV form. This interim analysis shows that four cycles of RiBVD are very effective for untreated elderly MCL patients (ORR 87%) with a high response rate (CR/CRu 60%) which has been shown to be predictive of a long duration of response. An update of these results will be presented at the ASH meeting together with the molecular response rates after 4 cycles. Disclosures: Gressin: Pfizer: Consultancy; Mundipharma: Consultancy. Cartron:Roche: Membership on an entity’s Board of Directors or advisory committees.

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The impact of epoetin-alpha on anemia, red blood cell (RBC) transfusions, and survival in breast cancer patients (pts) treated with dose-dense sequential chemotherapy: Mature results of an AGO phase III study (ETC trial)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.569 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 569-569 ◽

Cited By ~ 14

Author(s):

V. Moebus ◽

H. Lueck ◽

C. Thomssen ◽

N. Harbeck ◽

U. Nitz ◽

...

Keyword(s):

Breast Cancer ◽

Disease Free Survival ◽

Phase Iii ◽

Hematological Toxicity ◽

Transfusion Rate ◽

Breast Cancer Patients ◽

Epoetin Alpha ◽

Dose Dense ◽

The Impact

569 Background: Dose-dense chemotherapy has been shown to have a significant advantage in disease-free survival (DFS) and overall survival (OS) in high risk breast cancer pts, but leads to a higher number of RBC transfusions (CALGB C9741, AGO-ETC). Controversial results have been reported regarding the influence of Epoetin-alpha on DFS and OS in cancer pts. Methods: From 12/98 until 4/03, 1,284 pts were recruited into a multi-center phase-III trial. Breast cancer pts with at least 4 involved lymph nodes and below 65 years of age were randomized between a standard regimen (4 × EC followed by 4 × Paclitaxel) and a dose-dense arm consisting of three courses each of epirubicin (150 mg/m2), paclitaxel (225 mg/m2) and cyclophosphamide (2,500 mg/m2) at 2 weeks interval (ETC). A second randomization ± Epoetin-alpha was performed in the ETC arm only (150 IU/kg/sc three times weekly). Results: In 10/06, 1255 (98%) pts were evaluable. 658 pts were randomized in the dose-dense ETC arm, of whom 333 received Epoetin-alpha. Median follow- up is 62 months. Anemia was seen significantly more often in the ETC-arm alone compared to treatment with Epoetin-alpha (p<0.0001). Altogether, 11% of all patients were treated with RBC transfusions. Standard EC->T treatment resulted in 1% RBC transfusions, but 28% in the ETC arm alone vs. 13% in the ETC + Epoetin-alpha-arm (p<0.0001) received RBC transfusions. Despite this significantly higher transfusion rate the median Hb-value dropped from 12,8g/dl at cycle 1 to 10,7g/dl at cycle 9 in the ETC arm alone. In contrast the same value remained stable with Epoetin-alpha (12,4g/dl at cycle 1 and 9 each). At a median follow-up of 62 months, there is no difference between the ETC-arm alone and the ETC + Epoetin-alpha-arm concerning 5-year DFS and OS ((71% vs. 72% (p=0.86) and 83% vs. 81% (p=0.89)). Conclusions: The dose-dense adjuvant ETC-regimen significantly improves DFS and OS but is combined with relevant hematological toxicity. Epoetin-alpha significantly reduces the number of RBC transfusions and prevents anemia. However, the prevention of anemia has no influence on DFS and OS in the adjuvant treatment with dose-dense ETC. [Table: see text]

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The impact of genetic variability on severe toxicity of (neo-) adjuvant chemotherapy in breast cancer patients receiving 5-fluorouracil, epirubicin, and cyclofosfamide (FEC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1020 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1020-1020

Author(s):

Christof Vulsteke ◽

Diether Lambrechts ◽

Anne-Sophie Dieudonné ◽

Sigrid Hatse ◽

Barbara Brouwers ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Variability ◽

Febrile Neutropenia ◽

Adverse Events ◽

Multi Drug Resistance ◽

Hematological Toxicity ◽

Severe Toxicity ◽

Wild Type ◽

Grade 3 ◽

The Impact

1020 Background: We assessed the impact of single nucleotide polymorphisms (SNP) of potential genes of interest in germline DNA on severe adverse events in breast cancer (bc) patients receiving (neo-) adjuvant FEC chemotherapy. Methods: Cases were retrospectively evaluated through electronic chart review for febrile neutropenia (primary endpoint), febrile neutropenia first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events. The panel of genes, genotyped using iPLEX technology on a MALDI-TOF based MassARRAY Compact Analyser (Sequenom Inc., CA, USA), included ABCBI, ABCC1, ABCC2, ABCG2, ALDH3A1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, DPYD, FGFR4, GPX4, GSTA1, GSTP1, MTHFR, NQ01, TYMS, XPD/ERCC2, XRCC1, UGT1A1, UGT1A6 and UGT2B7. These genes are involved in the metabolization of the studied chemotherapeutics. Because of multiple testing the false discovery rate (FDR) was calculated. Results: We identified 1089 patients treated between 2000-2010 with 3-6 cycles of FEC, for whom germline DNA was available.Homozygous (TT, 0.5%) and heterozygous (GT,11%) genotypes for rs4148350 in the Multi Drug Resistance Protein I (ABCC1/MRP1), compared to wild-type (GG, 88.5%), were associated with febrile neutropenia, febrile neutropenia in first cycle, prolonged grade 4 or deep neutropenia and thrombocytopenia (80 vs 25 vs 15.7%, 40 vs 17.6 vs 9.5%, 100 vs 41.7 vs 33.8% and 20 vs 2.8 vs 0.34% respectively; p 0.0006, 0.01, 0.002 and 0.008 FDR 0.03, 0.65, 0.06 and 0.2). Variant genotypes for rs45511401 (GT/TT, 12%) in ABCC1, compared to wild-type (GG, 88%), were associated with febrile neutropenia, febrile neutropenia in first cycle and thrombocytopenia (26.5 vs 15,8%, 17.1 vs 9.7% and 3.4 vs 0.3%, respectively; p 0.007, 0.03 and 0.005, FDR 0.2, 0.75 and 0.2). Conclusions: Genetic variation in the ABCC1 gene was strongly associated with severe hematological toxicity of FEC. Other previously described SNP were not validated. This is the largest bc study in which the impact of genetic variability on the adverse events of FEC chemotherapy was investigated.

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