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5. NeoFLOT: Multicenter phase II study of perioperative chemotherapy in resectable adenocarcinoma of the gastroesophageal junction or gastric adenocarcinoma—Very good response predominantly in patients with intestinal type tumors

Author

Schulz, Christoph, Kullmann, Frank, Kunzmann, Volker, Fuchs, Martin, Geissler, Michael, Vehling-Kaiser, Ursula, Stauder, Heribert, Wein, Axel, Al-Batran, Salah-Eddin, Kubin, Thomas, Schäfer, Claus, Stintzing, Sebastian, Giessen, Clemens, Modest, Dominik Paul, Ridwelski, Karsten, and Heinemann, Volker

Published
2015
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8. Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: Results from a randomized trial of the GERMAN AIO CRC Study Group

Author

Stintzing, Sebastian, Kapaun, Christine, Laubender, Rüdiger Paul, Jung, Andreas, Neumann, Jens, Modest, Dominik Paul, Giessen, Clemens, Moosmann, Nicolas, Wollenberg, Andreas, Kirchner, Thomas, and Heinemann, Volker

Published
2013
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11. A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: The AIO KRK 0110 Trial/ML22011 Trial

Author

Teschendorf Christian, Sieber Markus, Denzlinger Claudio, Bangerter Markus, Mayerle Julia, Vehling-Kaiser Ursula, Kullmann Frank, Stintzing Sebastian, Hinke Axel, von Weikersthal Ludwig, Giessen Clemens, Freiberg-Richter Jens, Schulz Christoph, Modest Dominik, Moosmann Nicolas, Aubele Philipp, and Heinemann Volker

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Several randomized trials have indicated that combination chemotherapy applied in metastatic colorectal cancer (mCRC) does not significantly improve overall survival when compared to the sequential use of cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present study investigates the question whether this statement holds true also for bevacizumab-based first-line treatment including escalation- and de-escalation strategies. Methods/Design The AIO KRK 0110/ML22011 trial is a two-arm, multicenter, open-label randomized phase III trial comparing the efficacy and safety of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in the first-line treatment of metastatic colorectal cancer. Patients with unresectable metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, will be assigned in a 1:1 ratio to receive either capecitabine 1250 mg/m2 bid for 14d (d1-14) plus bevacizumab 7.5 mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m2 BID for 14d (d1-14), irinotecan 200 mg/m2 (d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B). Patients included into this trial are required to consent to the analysis of tumour tissue and blood for translational investigations. In Arm A, treatment escalation from Cape-Bev to CAPIRI-Bev is recommended in case of progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to Cape-Bev is possible after 6 months of treatment or in case of irinotecan-associated toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The primary endpoint is time to failure of strategy (TFS). Secondary endpoints are overall response rate (ORR), overall survival, progression-free survival, safety and quality of life. Conclusion The AIO KRK 0110 trial is designed for patients with disseminated, but asymptomatic mCRC who are not potential candidates for surgical resection of metastasis. Two bevacizumab-based strategies are compared: one starting as single-agent chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and another starting with combination chemotherapy (CAPIRI-Bev) and allowing de-escalation to Cape-Bev and subsequent re-escalation if necessary. Trial Registration ClinicalTrials.gov Identifier NCT01249638 EudraCT-No.: 2009-013099-38

Published
2011
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12. Prevalence and influence on outcome of Neuregulin- (NRG1), HER2/neu- and HER3- expression in patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based first-line regimens (FUFIRI vs. mIROX) in the FIRE 1-trial.

Author

Stahler, Arndt, primary, Heinemann, Volker, additional, Giessen, Clemens Albrecht, additional, Schalhorn, Andreas, additional, Stintzing, Sebastian, additional, Fischer von Weikersthal, Ludwig, additional, Vehling-Kaiser, Ursula, additional, Stauch, Martina, additional, Quietzsch, Detlef, additional, Neumann, Jens, additional, Kirchner, Thomas, additional, Jung, Andreas, additional, and Modest, Dominik Paul, additional

Published
2015
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13. Effect of KRAS exon 2 mutations on antitumor activity of afatinib and gefitinib

Author

Gamba, Sebastian, primary, Camaj, Peter, additional, Heinemann, Volker, additional, Laubender, Rüdiger P., additional, Wang, Yan, additional, Zhao, Yue, additional, Stintzing, Sebastian, additional, Giessen, Clemens, additional, Boeck, Stefan, additional, Haertl, Christoph, additional, Bruns, Christiane J., additional, and Modest, Dominik P., additional

Published
2015
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14. Influence of adjuvant pretreatment on outcome of FIRE-3 (AIO KRK-0306): A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients.

Author

Stintzing, Sebastian, primary, Modest, Dominik Paul, additional, Fischer von Weikersthal, Ludwig, additional, Decker, Thomas, additional, Kiani, Alexander, additional, Vehling-Kaiser, Ursula, additional, Al-Batran, Salah-Eddin, additional, Heintges, Tobias, additional, Lerchenmuller, Christian A., additional, Kahl, Christoph, additional, Seipelt, Gernot, additional, Kullmann, Frank, additional, Stauch, Martina, additional, Scheithauer, Werner, additional, Held, Swantje, additional, Giessen, Clemens Albrecht, additional, Moehler, Markus Hermann, additional, Jung, Andreas, additional, Kirchner, Thomas, additional, and Heinemann, Volker, additional

Published
2015
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16. Assessing novel prognostic serum biomarkers in advanced pancreatic cancer: the role of CYFRA 21-1, serum amyloid A, haptoglobin, and 25-OH vitamin D3

Author

Haas, Michael, primary, Kern, Christoph, additional, Kruger, Stephan, additional, Michl, Marlies, additional, Modest, Dominik P., additional, Giessen, Clemens, additional, Schulz, Christoph, additional, von Einem, Jobst C., additional, Ormanns, Steffen, additional, Laubender, Rüdiger P., additional, Holdenrieder, Stefan, additional, Heinemann, Volker, additional, and Boeck, Stefan, additional

Published
2014
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19. Gender and tumor location as predictors for efficacy: Influence on endpoints in first-line treatment with FOLFIRI in combination with cetuximab or bevacizumab in the AIO KRK 0306 (FIRE3) trial.

Author

Heinemann, Volker, primary, Modest, Dominik Paul, additional, Fischer von Weikersthal, Ludwig, additional, Decker, Thomas, additional, Kiani, Alexander, additional, Vehling-Kaiser, Ursula, additional, Al-Batran, Salah-Eddin, additional, Heintges, Tobias, additional, Lerchenmuller, Christian A., additional, Kahl, Christoph, additional, Seipelt, Gernot, additional, Kullmann, Frank, additional, Stauch, Martina, additional, Scheithauer, Werner, additional, Held, Swantje, additional, Giessen, Clemens Albrecht, additional, Jung, Andreas, additional, Kirchner, Thomas, additional, and Stintzing, Sebastian, additional

Published
2014
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20. Second-line therapies in patients with KRAS wild-type metastatic colorectal cancer (mCRC) after first-line therapy with FOLFIRI in combination with cetuximab or bevacizumab in the AIO KRK0306 (FIRE 3) trial.

Author

Modest, Dominik Paul, primary, Stintzing, Sebastian, additional, Von Weikersthal, Ludwig Fischer, additional, Decker, Thomas, additional, Kiani, Alexander, additional, Vehling-Kaiser, Ursula, additional, Al-Batran, Salah-Eddin, additional, Heintges, Tobias, additional, Lerchenmuller, Christian A., additional, Kahl, Christoph, additional, Seipelt, Gernot, additional, Kullmann, Frank, additional, Stauch, Martina, additional, Scheithauer, Werner, additional, Held, Swantje, additional, Giessen, Clemens Albrecht, additional, Jung, Andreas, additional, Kirchner, Thomas, additional, and Heinemann, Volker, additional

Published
2014
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21. Influence of mRNA expression of epiregulin (EREG) and of amphiregulin (AREG) and RAS mutationson outcome of patients with metastatic colorectal cancer treated with 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as first-line treatment (FIRE 1-trial).

Author

Stahler, Arndt, primary, Heinemann, Volker, additional, Giessen, Clemens Albrecht, additional, Crispin, Alexander, additional, Schalhorn, Alexander, additional, Stintzing, Sebastian, additional, Fischer von Weikersthal, Ludwig, additional, Vehling-Kaiser, Ursula, additional, Stauch, Martina, additional, Qietzsch, Detlef, additional, Neumann, Jens, additional, Kirchner, Thomas, additional, Jung, Andreas, additional, and Modest, Dominik Paul, additional

Published
2014
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22. Outcome of patients with metastatic colorectal cancer depends on the primary tumor site (midgut vs. hindgut)

Author

Modest, Dominik P., primary, Schulz, Christoph, additional, von Weikersthal, Ludwig F., additional, Quietzsch, Detlef, additional, von Einem, Jobst C., additional, Schalhorn, Andreas, additional, Vehling-Kaiser, Ursula, additional, Laubender, Rüdiger P., additional, Giessen, Clemens, additional, Stintzing, Sebastian, additional, and Heinemann, Volker, additional

Published
2014
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23. Clinical relevance and utility of cetuximab-related changes in magnesium and calcium serum levels

Author

Stintzing, Sebastian, primary, Fischhaber, Doris, additional, Mook, Charlotte, additional, Modest, Dominik P., additional, Giessen, Clemens, additional, Schulz, Christoph, additional, Haas, Michael, additional, Boeck, Stefan, additional, Michl, Marlies, additional, Stemmler, Joachim, additional, Laubender, Rüdiger P., additional, and Heinemann, Volker, additional

Published
2013
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29. Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: An analysis of the German AIO KRK 0104 trial

Author

Modest, Dominik P., primary, Laubender, Ruediger P., additional, Stintzing, Sebastian, additional, Giessen, Clemens, additional, Schulz, Christoph, additional, Haas, Michael, additional, Mansmann, Ulrich, additional, and Heinemann, Volker, additional

Published
2012
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30. Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated metastatic colorectal cancer

Author

Modest, Dominik Paul, primary, Reinacher-Schick, Anke, additional, Stintzing, Sebastian, additional, Giessen, Clemens, additional, Tannapfel, Andrea, additional, Laubender, Ruediger Paul, additional, Brodowicz, Thomas, additional, Knittelfelder, Regina, additional, Vrbanec, Damir, additional, Schmiegel, Wolff, additional, Heinemann, Volker, additional, and Zielinski, Christoph C., additional

Published
2012
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31. Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: Results from a randomized trial of the GERMAN AIO CRC Stu

Author

Stintzing, Sebastian, primary, Kapaun, Christine, additional, Laubender, Rüdiger Paul, additional, Jung, Andreas, additional, Neumann, Jens, additional, Modest, Dominik Paul, additional, Giessen, Clemens, additional, Moosmann, Nicolas, additional, Wollenberg, Andreas, additional, Kirchner, Thomas, additional, and Heinemann, Volker, additional

Published
2012
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34. Ligand expression of the EGFR ligands amphiregulin, epiregulin, and amplification of the EGFR gene to predict for treatment efficacy in KRAS wild-type mCRC patients treated with cetuximab plus CAPIRI and CAPOX: Analysis of the randomized AIO CRC-0104 trial.

Author

Stintzing, Sebastian, primary, Jung, Andreas, additional, Kapaun, Christine, additional, Reiche, Jana, additional, Modest, Dominik Paul, additional, Giessen, Clemens Albrecht, additional, Vehling-Kaiser, Ursula, additional, Stauch, Martina, additional, Hass, Holger, additional, Fischer von Weikersthal, Ludwig, additional, Kirchner, Thomas, additional, and Heinemann, Volker, additional

Published
2012
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35. Sequential first-line treatment for metastatic colorectal cancer with capecitabine, irinotecan, and bevacizumab: Capecitabine plus bevacizumab (Cape-Bev) versus capecitabine, irinotecan plus bevacizumab (CAPIRI-Bev): The AIO KRK 0110/ML22011 randomized, phase III trial.

Author

Giessen, Clemens Albrecht, primary, Modest, Dominik Paul, additional, Stintzing, Sebastian, additional, Fischer von Weikersthal, Ludwig, additional, Vehling-Kaiser, Ursula, additional, Spaeth-Schwalbe, Ernst, additional, Freiberg-Richter, Jens, additional, Mayerle, Julia, additional, Bangerter, Markus, additional, Denzlinger, Claudio, additional, Sieber, Markus, additional, Teschendorf, Christian, additional, Peuser, Bettina, additional, and Heinemann, Volker, additional

Published
2012
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37. Cetuximab-related skin toxicity in metastatic colorectal cancer (mCRC) patients and its correlation with molecular markers: Results from the German AIO CRC 0104 trial.

Author

Stintzing, Sebastian, primary, Kapaun, Christine, additional, Laubender, Ruediger P., additional, Jung, Andreas, additional, Neumann, Jens, additional, Modest, Dominik Paul, additional, Giessen, Clemens Albrecht, additional, Moosmann, Nicolas, additional, Wollenberg, Andreas, additional, Kirchner, Thomas, additional, and Heinemann, Volker, additional

Published
2012
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39. Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D mutated metastatic colorectal cancer (mCRC)? A meta-analysis of 54 cases.

Author

Heinemann, Volker, primary, Reinacher-Schick, Anke, additional, Stintzing, Sebastian, additional, Giessen, Clemens Albrecht, additional, Tannapfel, Andrea, additional, Laubender, Ruediger P., additional, Brodowicz, Thomas, additional, Knittelfelder, Regina, additional, Vrbanec, Damir, additional, Schmiegel, Wolff, additional, Modest, Dominik Paul, additional, and Zielinski, Christoph, additional

Published
2012
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40. Primary effusion lymphoma (PEL) without effusion: a patient case report of a PEL solid variant

Author

Giessen, Clemens, primary, Di Gioia, Dorit, additional, Huber, Bruno, additional, Seppi, Bettina, additional, Graser, Anno, additional, Duerr, Hans Roland, additional, Mayr, Doris, additional, Kirchner, Thomas, additional, Rosenwald, Andreas, additional, Forstpointner, Roswitha, additional, Heinemann, Volker, additional, Bogner, Johannes R, additional, and Ostermann, Helmut, additional

Published
2011
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41. Clinical characterization of patients with metastatic colorectal cancer depending on the KRAS status

Author

Modest, Dominik P., primary, Stintzing, Sebastian, additional, Laubender, Ruediger P., additional, Neumann, Jens, additional, Jung, Andreas, additional, Giessen, Clemens, additional, Haas, Michael, additional, Aubele, Philipp, additional, Schulz, Christoph, additional, Boeck, Stefan, additional, Stemmler, Hans-Joachim, additional, Kirchner, Thomas, additional, and Heinemann, Volker, additional

Published
2011
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42. A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: The AIO KRK 0110 Trial/ML22011 Trial

Author

Giessen, Clemens, primary, von Weikersthal, Ludwig Fischer, additional, Hinke, Axel, additional, Stintzing, Sebastian, additional, Kullmann, Frank, additional, Vehling-Kaiser, Ursula, additional, Mayerle, Julia, additional, Bangerter, Markus, additional, Denzlinger, Claudio, additional, Sieber, Markus, additional, Teschendorf, Christian, additional, Freiberg-Richter, Jens, additional, Schulz, Christoph, additional, Modest, Dominik Paul, additional, Moosmann, Nicolas, additional, Aubele, Philipp, additional, and Heinemann, Volker, additional

Published
2011
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43. Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer

Author

Fischer von Weikersthal, Ludwig, primary, Schalhorn, Andreas, additional, Stauch, Martina, additional, Quietzsch, Detlef, additional, Maubach, Peter A., additional, Lambertz, Helmut, additional, Oruzio, Daniel, additional, Schlag, Rudolf, additional, Weigang-Köhler, Karin, additional, Vehling-Kaiser, Ute, additional, Schulze, Manfred, additional, Truckenbrodt, Juergen, additional, Goebeler, Mariele, additional, Mittermüller, Johann, additional, Bosse, Daniel, additional, Szukics, Borika, additional, Grundeis, Marc, additional, Zwingers, Thomas, additional, Giessen, Clemens, additional, and Heinemann, Volker, additional

Published
2011
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45. Neo FLOT: Multicenter phase II study of perioperative chemotherapy in resectable adenocarcinoma of the gastroesophageal junction or gastric adenocarcinoma-Very good response predominantly in patients with intestinal type tumors.

Author

Schulz, Christoph, Kullmann, Frank, Kunzmann, Volker, Fuchs, Martin, Geissler, Michael, Vehling‐Kaiser, Ursula, Stauder, Heribert, Wein, Axel, Al‐Batran, Salah‐Eddin, Kubin, Thomas, Schäfer, Claus, Stintzing, Sebastian, Giessen, Clemens, Modest, Dominik Paul, Ridwelski, Karsten, and Heinemann, Volker

Abstract

Perioperative treatment is a standard of care in locally advanced gastroesophageal cancer (GEC) (gastric adenocarcinoma and gastroesophageal junction (GEJ) adenocarcinoma). While preoperative treatment can be applied to the majority of patients, postoperative chemotherapy can be given only to a fraction. The NeoFLOT-study therefore investigates the application of prolonged neoadjuvant chemotherapy (NACT). Patients with T3, T4, and/or node-positive adenocarcinoma (GEC) were eligible for this multicenter phase II trial. NACT consisted of 6 cycles of oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, 5-fluorouracil 2600 mg/m2 and docetaxel 50 mg/m2 (FLOT) applied q 2 wks. Application of adjuvant chemotherapy was explicitly not part of the protocol. R0-resection rate was evaluated as a primary endpoint. Of 59 enrolled patients, 50 patients underwent surgery and were assessable for the primary endpoint. R0-resection rate was 86.0% (43/50). Pathologic complete response (pCR) was 20.0% (10/50) and a further 20% (10/50) of patients achieved near complete histological remission (<10% residual tumor). Among these very good responders, 85% (17/20) had intestinal type tumors, 10% (2/20) had diffuse and 5% (1/20) had mixed type tumors. After 3 cycles of NACT, 6.9% (4/58) of patients developed progressive disease. Median disease-free survival was 32.9 months. The 1-year survival-rate was 79.3%. Grade 3-4 toxicities included neutropenia 29.3%, febrile neutropenia 1.7%, diarrhea 12.1% and mucositis 6.9%. This study indicates that intensified NACT with 6 cycles of FLOT is highly effective and tolerable in resectable GEC. Very good response (pCR and <10% residual tumor) was predominantly observed in patients with intestinal type tumors. [ABSTRACT FROM AUTHOR]

Published
2015
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46. Surrogate endpoints in second-line treatment for mCRC: A systematic literature-based analysis from 23 randomised trials.

Author

Giessen, Clemens, Laubender, Ruediger Paul, Ankerst, Donna Pauler, Stintzing, Sebastian, Modest, Dominik Paul, Schulz, Christoph, Mansmann, Ulrich, and Heinemann, Volker

Subjects
*SURVIVAL analysis (Biometry), *CANCER chemotherapy, *COLON tumors, *CONFIDENCE intervals, *STATISTICAL correlation, *META-analysis, *METASTASIS, *SYSTEMATIC reviews, *RANDOMIZED controlled trials, *TREATMENT effectiveness, *DATA analysis software, *DESCRIPTIVE statistics, RECTUM tumors
Abstract

Purpose. To evaluate progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) as potential surrogate endpoints (SEP) for overall survival (OS) in second-line treatment for metastatic colorectal cancer (mCRC). Methods. A systematic literature search of randomised trials of second-line chemotherapy for mCRC reported from January 2000 to July 2013 was performed. Correlation coefficients weighted by number of patients in the treatment arms between median PFS, ORR and DCR with median OS were estimated. Results. Twenty-three trials reflecting 10 800 patients met the inclusion criteria. Median PFS and OS across all trials were 4.5 months and 11.5 months and median ORR and DCR were 11.4% and 65%, respectively. PFS showed moderate correlation with OS [RPFS = 0.73; 95% confidence interval (CI) 0.61-0.82]. In contrast, ORR only weakly correlated with OS (RORR = 0.58; 95% CI 0.38-0.72, n = 22). Despite a small number of studies (n = 10) reporting on DCR, moderate correlation with OS was observed (RDCR = 0.74; 95% CI 0.56-0.86). Conclusion. Based on the available trial-level data, PFS may serve as an appropriate SEP in second-line chemotherapy for mCRC. A small number of studies revealed moderate correlation of DCR with OS that justifies further investigation. [ABSTRACT FROM AUTHOR]

Published
2015
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47. Effect of KRASexon 2 mutations on antitumor activity of afatinib and gefitinib

Author

Gamba, Sebastian, Camaj, Peter, Heinemann, Volker, Laubender, Rüdiger P., Wang, Yan, Zhao, Yue, Stintzing, Sebastian, Giessen, Clemens, Boeck, Stefan, Haertl, Christoph, Bruns, Christiane J., and Modest, Dominik P.

Abstract

The aim of this study was to investigate the impact of different KRASmutations on the inhibitory potential of afatinib and gefitinib in SW48 colorectal cancer cells. The influence of afatinibgefitinib on cell viability and cell cycle was evaluated in isogenic SW48 KRASwild-typemutant cells. Protein levels of phosphorylatedtotal EGFR, HER-2, HER-3, ERK, and AKT were compared between treateduntreated samples using western blotting. The activity of both afatinib and gefitinib was the lowest in KRASG12CG12SG12D and the highest in G13DG12A mutant subtypes. A 50 decrease in cell viability was achieved at concentrations of 3.0–7.7 moll for afatinib and 5.4–19.5 moll for gefitinib. The effect of both drugs on apoptosis appeared to be stronger than their influence on proliferation and was generally less pronounced in mutant cells than in wild-type cells. The average number of apoptotic cells after treatment with afatinib was 2.6 times as high as the corresponding value following treatment with gefitinib (P<0.01). Levels of pEGFR, pHER-2, pERK, and pAKT were reduced more extensively by afatinib than by gefitinib (P<0.001). Some KRASmutations (G12CG12SG12D) appear to weaken the activity of afatinib and gefitinib whereas others seem to increase sensitivity to treatment (G13DG12A) compared with the parental clone (KRASwild-type). In SW48 colorectal cancer cells, afatinib seems to be more potent than gefitinib because of its superior efficacy in inhibiting both EGFR and HER-2, suppressing signaling along both MEKERK and PI3KAKT pathways to a greater extent.

Published
2015
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48. Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: An analysis of the German AIO KRK 0104 trial.

Author

Modest, Dominik P., Laubender, Ruediger P., Stintzing, Sebastian, Giessen, Clemens, Schulz, Christoph, Haas, Michael, Mansmann, Ulrich, and Heinemann, Volker

Subjects
ANTINEOPLASTIC agents, CANCER chemotherapy, COMBINATION drug therapy, CHI-squared test, COLON tumors, CONFIDENCE intervals, FISHER exact test, GENETIC techniques, METASTASIS, GENETIC mutation, HEALTH outcome assessment, RECTUM tumors, RESEARCH funding, SURVIVAL analysis (Biometry), TREATMENT effectiveness, PROPORTIONAL hazards models, DATA analysis software, DESCRIPTIVE statistics, KAPLAN-Meier estimator
Abstract

Purpose. This study investigated the impact of early tumor shrinkage (ETS) on progression-free- (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated within the AIO KRK 0104 trial as first-line therapy. Moreover, correlations of ETS with clinical characteristics and prognostic markers were evaluated. Patients and methods. In total, 121 patients were included into this analysis. Patients were treated with cetuximab combined with either CAPIRI or CAPOX. ETS at six weeks was defined as a relative change of ≥ 20% in the sum of the longest diameters of target lesions compared to baseline. Survival times were compared between patients with ETS ≥ 20% versus no-ETS. Results. ETS ≥ 20% was observed in 59% of all patients with KRAS wild-type tumors. In these patients ETS ≥ 20% was associated with higher overall response rate (82% vs. 19%, p < 0.001). Also, PFS (8.9 vs. 4.7 months, p < 0.001) and OS (31.6 vs. 15.8 months, p = 0.005) were significantly superior in ETS ≥ 20% of patients compared to no-ETS. In patients with KRAS mutant mCRC ETS ≥ 20% neither had an effect on PFS nor OS. Cetuximab-induced skin toxicity correlated with the occurrence of ETS ≥ 20% (p = 0.002). Conclusion. In patients with KRAS wild-type tumors treated with cetuximab plus capecitabine-based chemotherapy ETS ≥ 20% is an important predictor of favorable outcome. [ABSTRACT FROM AUTHOR]

Published
2013
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49. Cetuximab-based or bevacizumab-based first-line treatment in patients with KRASp.G13D-mutated metastatic colorectal cancer

Author

Modest, Dominik Paul, Reinacher-Schick, Anke, Stintzing, Sebastian, Giessen, Clemens, Tannapfel, Andrea, Laubender, Ruediger Paul, Brodowicz, Thomas, Knittelfelder, Regina, Vrbanec, Damir, Schmiegel, Wolff, Heinemann, Volker, and Zielinski, Christoph C.

Abstract

KRASp.G13D mutant metastatic colorectal cancer (mCRC) has been identified as representing a cetuximab-sensitive subtype of KRASmutant mCRC. This analysis aims to answer the question of whether first-line treatment of p.G13D mCRCs should include cetuximab or bevacizumab. Fifty-four patients with p.G13D mutant mCRC were pooled in this analysis. All patients underwent systemic first-line treatment with a fluoropyrimidine and oxaliplatinirinotecan that was combined with either cetuximab or bevacizumab. The analysis of cetuximab-based and bevacizumab-based regimens in mCRC patients with p.G13D-mutated tumours indicated comparable data for the overall response rate (58 vs. 57) and progression-free survival (8.0 vs. 8.7 months; hazard ratio: 0.96, P=0.9). Overall survival (OS) was 20.1 months in patients treated with cetuximab-based first-line therapy compared with 14.9 months in patients receiving bevacizumab-containing regimens (hazard ratio: 0.70, P=0.29). Logistic regressions modelling OS revealed oxaliplatin-based first-line treatment to correlate with a poor outcome (P=0.03). Moreover, a strong trend in favour of capecitabine compared with infusional 5-FU (P=0.06) was observed. Response to treatment correlated with OS in patients receiving cetuximab-based, but not bevacizumab-based regimens. This retrospective pooled analysis suggests comparable efficacy of cetuximab-based and bevacizumab-based first-line therapy in patients with p.G13D mutant mCRC. The combination with capecitabine and irinotecan was associated with a more favourable outcome compared with infusional 5-FU and oxaliplatin.

Published
2012
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50. A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: The AIO KRK 0110 Trial/ML22011 Trial

Author

Teschendorf Christian, Sieber Markus, Denzlinger Claudio, Bangerter Markus, Mayerle Julia, Vehling-Kaiser Ursula, Kullmann Frank, Stintzing Sebastian, Hinke Axel, von Weikersthal Ludwig, Giessen Clemens, Freiberg-Richter Jens, Schulz Christoph, Modest Dominik, Moosmann Nicolas, Aubele Philipp, and Heinemann Volker

Subjects
Male, Cancer Research, Dose-Response Relationship, Drug, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Antibodies, Monoclonal, Humanized, Irinotecan, lcsh:RC254-282, Deoxycytidine, Bevacizumab, Study Protocol, Oncology, Antineoplastic Combined Chemotherapy Protocols, Quality of Life, Genetics, Humans, Camptothecin, Female, Fluorouracil, Neoplasm Metastasis, Colorectal Neoplasms, Capecitabine
Abstract

Background Several randomized trials have indicated that combination chemotherapy applied in metastatic colorectal cancer (mCRC) does not significantly improve overall survival when compared to the sequential use of cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present study investigates the question whether this statement holds true also for bevacizumab-based first-line treatment including escalation- and de-escalation strategies. Methods/Design The AIO KRK 0110/ML22011 trial is a two-arm, multicenter, open-label randomized phase III trial comparing the efficacy and safety of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in the first-line treatment of metastatic colorectal cancer. Patients with unresectable metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, will be assigned in a 1:1 ratio to receive either capecitabine 1250 mg/m2 bid for 14d (d1-14) plus bevacizumab 7.5 mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m2 BID for 14d (d1-14), irinotecan 200 mg/m2 (d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B). Patients included into this trial are required to consent to the analysis of tumour tissue and blood for translational investigations. In Arm A, treatment escalation from Cape-Bev to CAPIRI-Bev is recommended in case of progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to Cape-Bev is possible after 6 months of treatment or in case of irinotecan-associated toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The primary endpoint is time to failure of strategy (TFS). Secondary endpoints are overall response rate (ORR), overall survival, progression-free survival, safety and quality of life. Conclusion The AIO KRK 0110 trial is designed for patients with disseminated, but asymptomatic mCRC who are not potential candidates for surgical resection of metastasis. Two bevacizumab-based strategies are compared: one starting as single-agent chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and another starting with combination chemotherapy (CAPIRI-Bev) and allowing de-escalation to Cape-Bev and subsequent re-escalation if necessary. Trial Registration ClinicalTrials.gov Identifier NCT01249638 EudraCT-No.: 2009-013099-38

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