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A Atmaca,
S-E Al-Batran,
D Werner,
C Pauligk,
T Güner,
A Koepke,
H Bernhard,
T Wenzel,
A-G Banat,
P Brueck,
K Caca,
N Prasnikar,
F Kullmann,
H Günther Derigs,
M Koenigsmann,
G Dingeldein,
T Neuhaus,
E Jäger
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ABSTRACT: Background:This study was designed to compare cisplatin/docetaxel with oxaliplatin/docetaxel in patients with advanced and metastatic non-small lung cancer as a first-line treatment.Methods:Patients were randomly assigned to receive either cisplatin 75 mg m(-2) and docetaxel 75 mg m(-2) every 3 weeks or oxaliplatin 85 mg m(-2) and docetaxel 50 mg m(-2) every 2 weeks. The primary end point was response rate, and secondary end points were toxicity, time to progression and overall survival.Results:A total of 88 patients (median age: 65 (39-86) years; stage IV: 93%) were randomly assigned. Response rate (complete and partial response) was 47% (95% CI: 33-61%) in the cisplatin/docetaxel arm and 28% (95% CI: 17-43%) in the oxaliplatin/docetaxel arm (P=0.118). There was no significant difference in time to progression (6.3 vs 4.9 months, P=0.111) and median overall survival (11.6 vs 7.0 months, P=0.102) with cisplatin/docetaxel vs oxaliplatin/docetaxel, although slight trends favouring cisplatin were seen. Oxaliplatin/docetaxel was associated with significantly less (any grade) renal toxicity (56% vs 11%), any grade fatigue (81% vs 59%), complete alopecia (76% vs 27%), any grade leukopenia (84% vs 61%) and grade 3/4 leukopenia (44% vs 14%) and neutropenia (56% vs 27%).Conclusion:Oxaliplatin/docetaxel has activity in metastatic non-small cell lung cancer, but it seems to be inferior to cisplatin/docetaxel.British Journal of Cancer advance online publication, 17 January 2013; doi:10.1038/bjc.2012.555 www.bjcancer.com.
British Journal of Cancer 01/2013; · 5.04 Impact Factor
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S-E Al-Batran,
C Pauligk,
R Wirtz,
D Werner,
K Steinmetz,
N Homann,
H Schmalenberg,
R-D Hofheinz,
J T Hartmann, A Atmaca,
H-M Altmannsberger,
E Jäger
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ABSTRACT: The prognostic role of matrix metalloproteinase-9 (MMP-9) in metastatic gastric cancer has not been validated.
We carried out a molecular analysis in 222 metastatic gastric cancer patients obtained from clinical trials. We assessed the messenger RNA (mRNA) expression of MMP-9, vascular endothelial growth factor receptor-A, and epidermal growth factor receptor in a training cohort of 130 patients and conducted an independent validation in 92 patients. Automated RNA extraction from paraffin and RT-quantitative PCR was used. Immunohistochemistry for MMP-9 and diverse immune cell infiltrates was conducted.
In the training cohort, only MMP-9 significantly correlated with patient's survival. At the cut-off with the highest predictive value, 19% of patients had MMP-9 expression above this cut-off and these showed a median survival of 3.6 months compared with 10.5 months (P=1.7e(-6)) in patients with lower expression. Corresponding 1- and 2-year survivals were 9% and 44% and 0 and 21%, respectively. The application of this cut-off to the validation cohort revealed similar distributions of overall survival according to MMP-9 expression on uni- (P<0.001) and multivariate analyses (P<0.001). No differences in survival according to MMP-9 below best cut-off were found. MMP-9 protein assessed by immunohistochemistry was not prognostic.
MMP-9 mRNA expression above a certain cut-off level is associated with dismal survival.
Annals of Oncology 11/2011; 23(7):1699-705. · 6.43 Impact Factor
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ABSTRACT: Rituximab plus combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is widely recommended for the treatment of aggressive B-cell lymphomas. However, there is very little information regarding the management of elderly patients.
We initiated a phase II study of first-line treatment with rituximab and bendamustine in elderly patients (≥80 years) with aggressive B-cell lymphomas who were not eligible for R-CHOP or who did not agree to aggressive treatment. The treatment decision on eligibility for R-CHOP was left to discretion of the physicians.
Fourteen patients with a median age of 85 years (range 80-95 years) were included. The age-adjusted international prognostic index was zero in five patients, one in three patients, and two in six patients. Thirteen patients were assessable for response. Seven patients (54%) had a complete response, two (15%) a partial response, and four (31%) progressive disease. The median overall survival was 7.7 months, and the median progression-free survival 7.7 months; however, six patients (43%) were alive without disease at 20-72 months from the start of treatment. Major toxicity was neutropenia (17% grade 3 and 6% grade 4). All other grade 3 and 4 hematotoxicities and non-hematological toxic effects ranged between 2% and 11%
Because of its efficacy and low toxicity, bendamustine in combination with rituximab may be an alternative treatment for aggressive lymphomas in old patients not eligible for R-CHOP. These results, however, need to be confirmed in larger studies.
Annals of Oncology 01/2011; 22(8):1839-44. · 6.43 Impact Factor
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S-E Al-Batran,
J T Hartmann,
R Hofheinz,
N Homann,
V Rethwisch,
S Probst,
J Stoehlmacher,
M R Clemens,
R Mahlberg,
M Fritz,
G Seipelt,
M Sievert,
C Pauligk, A Atmaca,
E Jäger
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ABSTRACT: The combination of docetaxel (Taxotere), cisplatin, and fluorouracil improved efficacy in gastric cancer, but was associated with substantial toxicity. This study was designed to incorporate docetaxel into a tolerable biweekly (once every 2 weeks) oxaliplatin-based chemotherapy regimen.
Patients with measurable, metastatic adenocarcinoma of the stomach or esophagogastric junction and no prior chemotherapy received oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 2600 mg/m(2) as a 24-h infusion in combination with docetaxel 50 mg/m(2) (FLOT) on day 1 every 2 weeks. Prophylactic growth factors were not administered.
Fifty-nine patients were enrolled; 54 received treatment. Patients had a median age of 60 years (range 29-76) and most (93%) of them had metastatic disease. Objective responses were observed in 57.7% of patients with a median time to treatment response of 1.54 months. Median progression-free survival (PFS) and overall survival were 5.2 and 11.1 months, respectively. Twenty-five percent of patients experienced prolonged (>12 months) PFS. Frequent (>10%) grade 3 or 4 toxic effects included neutropenia in 26 (48.1%), leukopenia in 15 (27.8%), diarrhea in 8 (14.8%), and fatigue in 6 (11.1%) patients. Complicated neutropenia was observed in two (3.8%) patients, only.
Biweekly FLOT is active and has a favorable safety profile.
Annals of Oncology 07/2008; 19(11):1882-7. · 6.43 Impact Factor
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A Atmaca,
S-E Al-Batran,
A Maurer,
A Neumann,
T Heinzel,
B Hentsch,
S E Schwarz,
S Hövelmann,
M Göttlicher,
A Knuth,
E Jäger
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ABSTRACT: Altered histone deacetylase (HDAC) activity has been identified in several types of cancer. This study was designed to determine the safety and maximum tolerated dose (MTD) of valproic acid (VPA) as an HDAC inhibitor in cancer patients. Twenty-six pre-treated patients with progressing solid tumours were enrolled in dose-escalating three-patient cohorts, starting at a dose of VPA 30 mg kg(-1) day(-1). VPA was administered as an 1-h infusion daily for 5 consecutive days in a 21-day cycle. Neurocognitive impairment dominated the toxicity profile, with grade 3 or 4 neurological side effects occurring in 8 out of 26 patients. No grade 3 or 4 haematological toxicity was observed. The MTD of infusional VPA was 60 mg kg(-1) day(-1). Biomonitoring of peripheral blood lymphocytes demonstrated the induction of histone hyperacetylation in the majority of patients and downmodulation of HDAC2. Pharmacokinetic studies showed increased mean and maximum serum VPA concentrations >120 and >250 mg l(-1), respectively, in the 90 and 120 mg kg(-1) cohorts, correlating well with the incidence of dose-limiting toxicity (DLT). Neurotoxicity was the main DLT of infusional VPA, doses up to 60 mg kg(-1) day(-1) for 5 consecutive days are well tolerated and show detectable biological activity. Further investigations are warranted to evaluate the effectivity of VPA alone and in combination with other cytotoxic drugs.
British Journal of Cancer 08/2007; 97(2):177-82. · 5.04 Impact Factor
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ABSTRACT: Valproic acid has been demonstrated to mediate cytotoxic effects against tumor cells by acting as a histone-deacetylase inhibitor. However, to date, there are only limited data on the effects of valproic acid in colon cancer. Moreover, information regarding combinations of the drug with chemotherapeutic agents is very limited. The latter is of interest as there is increasing evidence for synergism between so-called "molecular targeting drugs" and chemotherapy. We first demonstrated that valproic acid dose-dependently reduced the viability of adenocarcimona cell lines. After co-incubation with a variety of chemotherapeutic agents, only valproic acid in combination with mitomycin C consistently induced synergistic growth inhibition in all cell lines. To confirm these results in an ex vivo situation, five samples of fresh colon cancer cells were studied. Again, the effect of valproic acid on the viability of the fresh tumor cells was dose dependent. In four of five samples of freshly isolated colon cancer cells, the synergistic effect of valproic acid and mitomycin C on the inhibition of cell growth was confirmed by calculation of the combination index by multiple drug effect analysis. In conclusion, this is the first demonstration that valproic acid as a model substance for histone-deacetylase inhibitors is effective in tumor cells freshly isolated from patients with colon cancer and that the combination of mitomycin C and valproic acid synergistically decreases viability of colon cancer cells.
Journal of chemotherapy (Florence, Italy) 09/2006; 18(4):415-20. · 1.08 Impact Factor
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S-E Al-Batran,
J Bischoff,
G von Minckwitz, A Atmaca,
U Kleeberg,
I Meuthen,
G Morack,
W Lerbs,
D Hecker,
J Sehouli,
A Knuth,
E Jager
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ABSTRACT: This study evaluates the clinical benefit of pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC), previously treated with conventional anthracyclines. Seventy-nine women with MBC previously treated with anthracyclines received PLD 50 mg m(-2) every 4 weeks. All patients were previously treated with chemotherapy and 30% of patients had > or =3 prior chemotherapies for metastatic disease. Patients were considered anthracycline resistant when they had disease progression on anthracycline therapy for MBC or within 6 months of adjuvant therapy. The overall clinical benefit rate (objective response+stable disease > or =24 weeks) was 24% (16.1% in patients with documented anthracycline resistance vs 29% in patients classified as having non-anthracycline-resistant disease). There was no difference with respect to the clinical benefit between patients who received PLD >12 months and those who received PLD < or =12 months since last anthracycline treatment for metastatic disease (clinical benefit 25 vs 24.1%, respectively). Median time to progression and overall survival were 3.6 and 12.3 months, respectively. The median duration of response was 12 months, and the median time to progression in patients with stable disease (any) was 9.5 months. Fourteen patients (17.7%) had a prolonged clinical benefit lasting > or =12 months. In conclusion, PLD was associated with an evident clinical benefit in anthracycline-pretreated patients with MBC.
British Journal of Cancer 07/2006; 94(11):1615-20. · 5.04 Impact Factor
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ABSTRACT: The aim of the study is to investigate whether platelet activity is increased by hyperprolactinemia during pregnancy as reflected by beta-thromboglobulin level. Forty-eight healthy, pregnant, and 30 healthy, non-pregnant women were investigated with respect to platelet count, collagen/ADP and collagen/epinephrine closure times, beta-thromboglobulin and prolactin levels. The comparison of the variables between the two groups was made by Mann-Whitney U test. The correlation analyses were performed by Spearman's rank correlation test. Our results revealed that platelet counts, collagen/ADP and collagen/epinephrine closure times and beta-thromboglobulin showed no statistically significant differences between pregnant and non-pregnant women. We found no significant correlation between prolactin and collagen/ADP closure time (r = 0.175), between prolactin and collagen/epinephrine closure time (r = -0.112) and between prolactin and beta-thromboglobulin (r = 0.220) in pregnant women. Our findings suggest that platelet activity is comparable during pregnant and non-pregnant states and there is no significant effect of prolactin on platelet function in vivo as reflected by beta-thromboglobulin level.
Experimental and Clinical Endocrinology & Diabetes 05/2006; 114(4):188-91. · 1.69 Impact Factor
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ABSTRACT: Pregnancy in acromegaly is a rather rare event since the fertility is reduced in acromegalic women. Besides, metabolic complications of acromegaly are harmful to both mother and fetus. Little is known about the outcome of pregnancy in acromegalic women. Here, we report seven cases of pregnancy out of 48 acromegalic women followed for 16 years. At diagnosis, five patients had macroadenoma, one patient had microadenoma and the size of the tumor was not documented in one patient. In one patient, acromegaly was initially diagnosed during pregnancy at 29 weeks. When she was 33 weeks, she developed pituitary apoplexy and had an emergency transsphenoidal resection of her macroadenoma during which she also had a cesarian section and delivered a healthy baby girl. In the remaining six patients, pregnancy occurred 6 to 64.5 months after the adenoma resection. Three patients received radiotherapy before getting pregnant. In three patients, pregnancy occurred during bromocriptine treatment and the drug was withdrawn. In one patient, pregnancy occurred during chronic octreotide treatment and therapeutic abortion was performed. In another patient, therapeutic abortion was performed because of uncontrolled disease. In the remaining four patients, there were neither worsening of symptoms nor tumor growth. All four patients gave birth to full-term healthy infants. Out of our seven patients, two developed gestational diabetes mellitus which was controlled with diet. None of the patients had coronary artery disease, hypertension or dyslipidemia. These cases show that pregnancy might be uneventful in acromegalic women when the disease is controlled with prior surgery and radiotherapy.
Experimental and Clinical Endocrinology & Diabetes 04/2006; 114(3):135-9. · 1.69 Impact Factor
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ABSTRACT: Octreotide is the first somatostatin analogue to become available for clinical use in the treatment of acromegaly. To our knowledge, there are no reports describing lipoatrophy in patients treated with octreotide. Here, we report three patients who developed lipoatrophy after treatment with subcutaneous octreotide. Three patients (all women; 36, 43, and 50 years of age) with diagnosis of acromegaly due to pituitary macroadenoma who had undergone transsphenoidal surgery and radiotherapy received subcutaneos octreotide because of uncontrolled disease. The dose of octreotide was increased gradually in all patients. Lipoatrophy was noticed around the injection sites after about 6 years, 30 months, and 4 years of subcutaneous octreotide treatment in all patients. Thereafter, subcutaneous octreotide treatment was changed to intramuscular octreotide-LAR injection in all patients. In two of them, lipoatrophy around all injection sites did not regress after about 8 and 12 months of octreotide-LAR treatment, respectively. In the third patient, lipoatrophy around the injection sites regressed after 12 months of octreotide-LAR treatment. These cases highlight a potential for subcutaneous octreotide to induce lipoatrophy. The underlying mechanism is unknown but an immunological mechanism which is seen in lipoatrophy induced by insulin may be involved in the pathogenesis. Besides; simple trauma, personal susceptibility, mistakes in the administration of the drug, a problem in drug pH, or an idiosyncratic reaction of adipocytes to octreotide or additives in the drug may have caused lipoatrophy in our patients. Lipoatrophy in these cases was observed on long-term subcutaneous octreotide administration. Although intramuscular octreotide-LAR has largely replaced subcutaneous octreotide, we suggest close clinical follow-up for lipoatrophy in patients who are still on subcutaneous octreotide.
Experimental and Clinical Endocrinology & Diabetes 07/2005; 113(6):340-3. · 1.69 Impact Factor
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ABSTRACT: Trofosfamide is increasingly used in the treatment of patients with several types of malignancies. However, the optimal dose of trofosfamide for patients with advanced cancer has not been systematically investigated yet. The aim of this study was to define the maximum tolerated dose (MTD) of continuous oral trofosfamide.
16 patients with advanced lung cancer (14 nonsmall cell lung cancer, 2 small cell lung cancer; 10 male, 6 female; median age 64 years (range 46-82); median Karnofsky status 70%; median number of organs involved 3 (range 1-6)) were enrolled. All patients were previously treated with chemotherapy (median 2x, range 1-6) and 8/16 (50%) with radiotherapy. Patients received trofosfamide p.o. administered in 3 doses per day for 3 weeks (1 cycle) using a 3-patient-cohort dose-escalation strategy. Toxicities were graded according to the WHO Criteria.
Patients received a median of 2 cycles of trofosfamide (range 1-4) at 3 dose levels (90, 125, and 175 mg/m2). Grade 3 and 4 neutropenia, anemia, and thrombocytopenia were observed in 20, 13.3, and 6.6%, respectively. Dose-limiting toxicities during the first cycle were grade 3 muscle weakness and anorexia observed in 1/6 patients in cohort 1 (trofosfamide 90 mg/m2), grade 3 neutropenia in 1/6, and encephalopathy in 1/6 patients in cohort 3 (trofosfamide 175 mg/m2). Therefore, the dose level of 125 mg/m2 was defined as the MTD.
Trofosfamide at 125 mg/m2 administered in 3 doses per day was well tolerated. This dose level is recommended for further clinical studies.
Onkologie 01/2005; 27(6):534-8. · 0.87 Impact Factor
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G von Minckwitz,
S Harder,
S Hövelmann,
E Jäger,
S-E Al-Batran,
S G Loibl, A Atmaca,
C Cimpoiasu,
A M Neumann,
A Abera,
A L Knuth,
M Kaufmann,
D Jäger,
A B Maurer,
W S Wels
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ABSTRACT: INTRODUCTION: ScFv(FRP5)-ETA is a recombinant antibody toxin with binding specificity for ErbB2 (HER2). It consists of an N-terminal single-chain antibody fragment (scFv), genetically linked to truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against ErbB2-overexpressing tumor cells was previously demonstrated in vitro and in animal models. Here we report the first systemic application of scFv(FRP5)-ETA in human cancer patients. METHODS: We have performed a phase I dose-finding study, with the objective to assess the maximum tolerated dose and the dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen patients suffering from ErbB2-expressing metastatic breast cancers, prostate cancers, head and neck cancer, non small cell lung cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4, 10, 12.5, and 20 microg/kg scFv(FRP5)-ETA were administered as five daily infusions each for two consecutive weeks. RESULTS: No hematologic, renal, and/or cardiovascular toxicities were noted in any of the patients treated. However, transient elevation of liver enzymes was observed, and considered dose limiting, in one of six patients at the maximum tolerated dose of 12.5 microg/kg, and in two of three patients at 20 microg/kg. Fifteen minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 microg/kg, indicating that predicted therapeutic levels of the recombinant protein can be applied without inducing toxic side effects. Induction of antibodies against scFv(FRP5)-ETA was observed 8 days after initiation of therapy in 13 patients investigated, but only in five of these patients could neutralizing activity be detected. Two patients showed stable disease and in three patients clinical signs of activity in terms of signs and symptoms were observed (all treated at doses > or = 10 microg/kg). Disease progression occurred in 11 of the patients. CONCLUSION: Our results demonstrate that systemic therapy with scFv(FRP5)-ETA can be safely administered up to a maximum tolerated dose of 12.5 microg/kg in patients with ErbB2-expressing tumors, justifying further clinical development.
