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Summary of Research Report 2011 Unit for Research in Clinical Oncology Odense University Hospital The Unit for Research in Clinical Oncology (URCO) manages a high number of research protocols including both protocols from the pharmaceutical industry and investigator-initiated protocols. URCO initiated 24 new protocols in 2011, and managed a total of 43 active protocols plus an additional 36 protocols closed for patient inclusion, but with patients in the follow-up phase. Organization of the Unit for Research in Clinical Oncology Board Clinical Research Unit Department of Cancer and Inflammation Research Board (Research Council) Professor, Senior Consultant Jørn Herrstedt MD, DMSci (chair) Professor, Senior Consultant Marianne Ewertz MD, DMSci Professor, Senior Consultant Per Pfeiffer MD, PhD Professor Henrik Ditzel MD, DMSci Head of Department, Senior Consultant Peter Sørensen MD Senior Consultant Jesper Grau Eriksen MD, PhD Senior Consultant Anette Damkier MD, PhD Senior Consultant Olfred Hansen MD, PhD Senior Consultant Jørgen Johansen MD, PhD Senior Consultant Ann Knoop MD, PhD Senior Consultant Steinbjørn Hansen MD, PhD PhD Student Rikke Dahlrot MD Physicist Carsten Brink PhD Head of Research Nurses Rikke Bjørn RN Lene Sigaard RN Ulrich Heide Køhler Data Manager Clinical Research Unit o Leadership Rikke Bjørn (Head of Research Nurses) Jørn Herrstedt (Head of Research) o 12 Research Nurses o 3 Research administrative assistants o 1 Data Manager o Unit for Experimental Medical Cancer Therapy o Unit for Eksperimental Radiotherapy Investigator-initiated research was strengthened in 2011 and comprised approximately 40% of the entire research activity. A total of 20 PhD students were employed in the Department of Oncology with a research project anchored in the Department and with principal supervisors recruited among clinical or associate professors in the Department (see below). Furthermore five post doc projects were active in 2011. PhD projects 2011 Anders Bertelsen (physicist) Volumetric Modulated Arc Therapy (VMAT) - advantages and disadvantages. Supervisor: Marianne Ewertz Jon Kroll Bjerregaard (MD) Prognostic and predictive markers in pancreatic cancer. Supervisor: Per Pfeiffer Tine Bjørn (physicist) Organ motion - 4D imaging and treatment. Supervisor: Carsten Brink Rikke Hedegaard Dahlrot (MD) From stem cell marker profiles to individual treatment of brain tumour patients. Supervisor: Steinbjørn Hansen Karin Brochstedt Dieperink (RN) Rehabilitation of prostate cancer patients with side effects induced by radiotherapy. Supervisor: Olfred Hansen Lise Eckhoff (MD) Acute and long-term side effects in high-risk breast cancer patients induced by adjuvant docetaxel. Supervisor: Ann Knoop Lise Højberg (MD) IL-6 as predicitive and prognostic marker in patients with malignant melanoma. Supervisor: Lars Bastholt Jeanette Dupont Jensen (MD) Biomarkers in breast cancer Supervisor: Marianne Ewertz Trine Lembrecht Jørgensen (MD). Drug use and comorbidity among elderly Danish cancer patients. Siupervisor: Jørn Herrstedt Annette Raskov Kodahl (MD) Significans of circulating mikroRNAs as a marker in women with breast cancer. Supervisor: Ann Knoop Lotte Holm Land (MD) Comorbidity and survival after treatment for early breast cancer. Supervisor: Marianne Ewertz Ebbe Laugaard Lorenzen (physicist) Risk of cardiac side effects after modern radiotherapy in breast cancer patients. Supervisor: Marianne Ewertz Mette Pøhl (MD) Prognostic profiles in Non Small Cell Lung Cancer (NSCLC). Supervisor: Olfred Hansen Christina Ruhlmann (MD) Identification and management of unwanted side-effects induced by combined chemo-radiotherapy with special emphasis on nausea and vomiting. Supervisor: Jørn Herrstedt Tine Schytte (MD) Clinical advantages and disadvantages using modernized radiotherapy planning and therapy. Supervisor: Olfred Hansen Katrine Rahbek Schønnemann (MD) Predictive and prognostic markers in patients with gastric cancer Supervisor: Per Pfeiffer Line Schmidt Tarpgaard (MD) Biological markers in patients with metastatic colorectal cancer Supervisor: Per Pfeiffer Marianne Feen Rønjom (MD). Radiotherapy-induced hypothyroidism in head and neck cancer patients Supervisor: Jørgen Johansen Mie-Ran Yoon (MD) Late side effects after treatment of patients with primary breast cancer Supervisor: Marianne Ewertz Thea Otto Mattsson (MD) Patient Safety in Oncology. Supervisor: Jørn Herrstedt Figures 1 describes the development in the number of PhD students 2007-2011. Fig 1. Number of PhD Students 2007-2011 The number of peer-reviewed publications increased by 30% in 2011 as compared to 2010 and included a number of 59. Figure 2 describes the development in the number of peer-reviewed publications 2004-2011. Fig 2. Number of peer-reviewed publications 2004-2011 Department of Cancer and Inflammation Research The research group performs translational research into breast and lung cancer and malignant melanoma with particular focus on the development of novel molecular biomarkers for optimised and individualised treatment. Biomedical, molecular and immunological aspects of cancer biology using clinical specimens from patients with well-defined medical histories and follow-up are studied. This research encompasses: Endocrine resistance in ER+ breast cancer patients We are working to identify which women will benefit from endocrine therapy using genetic and protein profiling. We also study the mechanisms of endocrine resistance and identify novel drug target and treatment strategies. Tumor-initiating cancer stem cells in breast cancer Cancer stem cells (or more correctly tumour-initiating cells), are resistant to standard therapy. We are attempting – at the genetic and protein levels – to discover how cancer stem cells function and, most importantly, how this function can be abolished. Using single cell cloning, we have established a number of cell lines that have either a tumour-initiating or a more differentiated cell phenotype. Understanding and inhibition of the metastatic process To study the initial steps of the metastatic process we use an vivo models based on inoculation of human cell lines into mice, and perform global molecular analysis and functional evaluation of candidate metastasis-related genes and proteins to identify key molecules in the metastasis process and therapeutic targets. Currently, we are using nextgeneration sequencing and proteomic analyses to evaluate molecular alterations associated with the metastasis process. Elucidating the function of cancer testis-associated proteins Cancer testis-associated proteins (CTAs) are a family of proteins encoded by genes that are normally expressed only in the human germ cells (testis), but are also expressed in various tumours. Little is known about the function of these proteins in normal and malignant tissues. Our preliminary results suggest that several CTA play a role in germ cell differentiation and may be important in the tumorigenicity process. We are working on similar aspects of other types of cancer, such as prognostic and predictive markers in non-small cell lung cancer, with special focus on patients with resistance to EGFR mutant-targeting drugs and CTA expression in melanoma. Publications (peer-reviewed) 2011 Baker M, Nielsen M, Hansen O, Jahn JW, Korreman S, Brink C. Isotoxic dose escalation in the treatment of lung cancer by means of heterogeneous dose distributions in the presence of respiratory motion. Int J Radiat Oncol Biol Phys 2011; 81 (3): 849-55. Bergmann TK, Gréen H, Andersen CB, Mirza MR, Herrstedt J, Hølund B, du Bois Andreas, Damkier P, Vach W, Brøsen K, Peterson C. Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer. Eur J Clin Pharmacol 2011; 67 (7): 693-700. Bergmann TK, Brasch-Andersen C, Gréen H, Mirza MR, Pedersen RS, Nielsen F, Skougaard K, Wihl J, Keldsen N, Damkier P, Friberg LE, Peterson C, Vach W, Karlsson MO, Brøsen K. Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer. Pharmacogenomics J 2011; 11 (2): 113-120. Bertelsen A, Lorenzen EL, Brink C. Validation of a new control system for Elekta accelerators facilitating continuously variable dose rate. Med Phys 2011; 38 (8): 4802-10. Bertelsen A, Schytte Tine,Bentzen SM, Hansen O, Nielsen M, Brink C. Radiation dose response of normal lung assessed by Cone Beam CT - a potential tool for biologically adaptive radiation therapy. Radiother Oncol 2011; 100 (3): 351-5. Bjerregaard JK, Mortensen MB, Jensen HA, Nielsen M, Pfeiffer P. Prognostic Factors for Survival and Resection in Patients with Initial Nonresectable Locally Advanced Pancreatic Cancer Treated with Chemoradiotherapy. Int J Radiat Oncol Biol Phys 2011 Dec 13 [Epub ahead of print]. Bjørndal K, Krogdahl A, Therkildsen MH, Overgaard J, Johansen J, Kristensen CA, Homøe P, Sørensen CH, Andersen E, Bundgaard T, Primdahl H, Lambertsen K, Andersen LJ, Godballe C. Salivary gland carcinoma in Denmark 1990-2005: a national study of incidence, site and histology. Results of the Danish Head and Neck Cancer Group (DAHANCA). Oral Oncol 2011; 47 (7): 677-82. Bjørndal K, Krogdahl A, Therkildsen MH, Overgaard J, Johansen J, Kristensen C, Homøe P, Sørensen CH, Andersen EV, Bundgaard T, Primdahl H, Lambertsen K, Andersen LJ, Godballe C. Salivary gland carcinoma in Denmark 1990-2005: Outcome and prognostic factors Results of the Danish Head and Neck Cancer Group (DAHANCA). Oral Oncol 2011; 48 (2): 179-85. Christensen K, Ohm Kyvik K, Holm NV, Skytthe A. Register-based research on twins. Scandinavian J Public Health 2011; 39 (7 Suppl): 185-90. Christiansen PM, Bjerre KD, Ejlertsen B, Jensen M-B, Rasmussen BB, Lænkholm A-V, Kroman N, Ewertz M, Offersen B, Toftdahl DB, Møller S, Mouridsen HT, Danish Breast Cancer Cooperative Group. Mortality rates among early-stage hormone receptor-positive breast cancer patients: a population-based cohort study in Denmark. J Natl Cancer Inst 2011; 103 (18): 1363-72. Dahlgaard J, Mazin W, Jensen T, Pøhl M, Bshara W, Hansen A, Kanisto E, Hamilton-Dutoit SJ, Hansen O, Hager H, Ditzel HJ, Yendamuri S, Knudsen S. Analytical variables influencing the performance of a miRNA based laboratory assay for prediction of relapse in stage I non-small cell lung cancer (NSCLC). BMC Research Notes 2011; 4: 424. Darby S, McGale P, Correa C, Taylor T, Arriagada R, Clarke M, Cutter D, Davies C, Ewertz M, Godwin J, Gray R, Pierce L, Whelan T, Wang C, Peto. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011; 378 (9804): 1707-16. Davies A, Zeppetella G, Andersen S, Damkier A, Vejlgaard T, Nauck F, Radbruch L, Sjolund K-F, Stenberg M, Buchanan A. Multi-centre European study of breakthrough cancer pain: pain characteristics and patient perceptions of current and potential management strategies. Eur J Pain 2011; 15 (7): 756-63. Dupont Jensen J, Lænkholm A-V, Knoop Ann, Ewertz M, Bandaru R, Weihua L, Hackl W, Barrett J C, Gardner H. PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res 2011; 17 (15): 667-77. Eckhoff L, Nielsen M, Moeller S, Knoop A. TAXTOX - a retrospective study regarding the side effects of docetaxel given as part of the adjuvant treatment to patients with primary breast cancer in Denmark from 2007 to 2009. Acta Oncol 2011; 50 (7): 1075-82. Ewertz M, Jensen M-B, Gunnarsdóttir KÁ, Højris I, Jakobsen EH, Nielsen D, Stenbygaard LE, Tange UB, Cold S. Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol 2011; 29 (1): 25-31. Ewertz M, Jensen AB. Late effects of breast cancer treatment and potentials for rehabilitation. Acta Oncol 2011; 50 (2): 187-93. Frederiksen C, Qvortrup C, Christensen IJ, Glimelius B, Berglund A, Jensen BV, Nielsen SE, Keldsen N, Nielsen HJ, Brünner N, Pfeiffer P. Plasma TIMP-1 levels and treatment outcome in patients treated with XELOX for metastatic colorectal cancer. Ann Oncol 2011; 22 (2): 369-375. Grankvist J, Fisker R, Iyer VV, Fründ T, Simonsen C, Christensen T, Stenbygaard LE, Ewertz M, Larsson EM. MRI and PET/CT of patients with bone metastases from breast carcinoma. Eur J Radiol 2011; 81 (1): e13-18. Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol— EASE. J Clin Oncol 2011; 29 (11): 1495-501. Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, Hansson J, Guida M, Hyams DM, Gómez H, Bastholt L, Chasalow SD, Berman D. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 2011; 9: 204. Hansson J, Aamdal S, Bastholt L, Brandberg Y, Hernberg M, Nilsson B, Stierner U, von der Maase H, Nordic Melanoma Cooperative Group. Two different durations of adjuvant therapy with intermediatedose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial. Lancet Oncol 2011; 12 (2): 144-52. Herrstedt J, Rapoport B, Warr D, Roila F, Bria E, Rittenberg C, Hesketh PJ. Acute emesis: moderately emetogenic chemotherapy. Support Care Cancer 2011; 19 (1): 15-23. Herrstedt J, Walsh D. Introduction: Supportive care and palliative medicine. Semin Oncol 2011; 38 (3): 335-6. Hildebrandt MG, Bartram P, Bak M, Højlund-Carlsen M, Petersen H, Grupe P, Knoop A, HøjlundCarlsen PF. Low risk of recurrence in breast cancer with negative sentinel node. Dan Med Bull (Online) 2011; 58 (4): A4255. Hoff CM, Hansen HS, Overgaard M, Grau C, Johansen J, Bentzen J, Overgaard J. The importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy--results from the randomized DAHANCA 5 study. Radiother Oncol 2011; 98 (1): 28-33. Hoff CM, Lassen P, Eriksen JG, Hansen HS, Specht L, Overgaard M, Grau C, Johansen J, Bentzen J, Andersen L, Evensen JF, Overgaard J. Does transfusion improve the outcome for HNSCC patients treated with radiotherapy? - results from the randomized DAHANCA 5 and 7 trials. Acta Oncol 2011; 50 (7): 1006-14. Jensen JD, Knoop A, Ewertz M, Lænkholm A-V. ER, HER2, and TOP2A expression in primary tumor, synchronous axillary nodes, and asynchronous metastases in breast cancer. Breast Cancer Res Treat 2011 Jun 11 [Epub ahead of print]. Johansen J, Pedersen H, Godballe C. FDG-PET/CT for detection of the unknown primary head and neck tumor. Q J Nucl Med Mol Imaging 2011; 55 (5): 500-508. Jørgensen TL, Herrstedt J, Friis S, Hallas J. Polypharmacy and drug use in elderly Danish cancer patients during 1996 to 2006. J Geriatr Oncol, 2011 Oct 20 [Epub ahead of print]. Jørgensen JT, Møller S, Rasmussen B, Winther OH, Schønau A, Knoop A. High concordance between two companion diagnostics tests: a concordance study between the HercepTest and the HER2 FISH pharmDx kit. Am J Clin Pathol 2011; 136 (1): 145-51. Kirkwood JM, Bastholt L, Robert C, Sosman JA, Larkin J, Hersey P, Middleton MR, Cantarini MV, Zazulina V, Kemsley K, Dummer R. Phase II, Open-Label, Randomized Trial of the MEK 1/2 Inhibitor Selumetinib as Monotherapy versus Temozolomide in Patients with Advanced Melanoma. Clin Cancer Res 2011; 18 (2): 555-567. Kris MG, Tonato M, Bria E, Ballatori E, Espersen B, Herrstedt J, Rittenberg C, Einhorn LH, Grunberg S, Saito M, Morrow G, Hesketh P. Consensus recommendations for the prevention of vomiting and nausea following high-emetic-risk chemotherapy. Support Care Cancer 2011; 19 (1): 25-32. Kroll Bjerregaard J, Fischer BMB, Vilstrup MH, Petersen H, Mortensen MB, Hansen CR, Asmussen J, Pfeiffer P, Høilund-Carlsen PF. Feasibility of FDG-PET/CT imaging during concurrent chemoradiotherapy in patients with locally advanced pancreatic cancer. Acta Oncol 2011; 50 (8): 1250-2. Land LH, Dalton SO, Jensen M-B, Ewertz M. Impact of comorbidity on mortality: a cohort study of 62,591 Danish women diagnosed with early breast cancer, 1990-2008. Breast Cancer Res Treat 2011; 131 (3): 1013-1020. Land LH, Dalton SO, Jørgensen TL, Ewertz M. Comorbidity and survival after early breast cancer. A review. Crit Rev Oncol Hematol 2011; 81 (2): 196-205. Larsen FO, Pfeiffer P, Nielsen D, Skougaard K, Qvortrup C, Vistisen K, Fromm A-L, Jørgensen TL, Bjerregaard JK, Hoegdall E, Jensen BV. Bevacizumab in combination with cetuximab and irinotecan after failure of cetuximab and irinotecan in patients with metastatic colorectal cancer. Acta Oncol 2011; 50 (4): 574-77. Lassen P, Eriksen JG, Krogdahl A, Hamilton M, Ulhøi BP, Overgaard M, Specht L, Andersen E, Johansen J, Grau C, Overgaard J, Andersen LJ. The influence of HPV-associated p16-expression on accelerated fractionaed radiotherapy in head and neck cancer: Evaluation of the randomised DAHANCA 6&7 trial. Radiother Oncol 2011; 100 (1), s. 49-55. McGale P, Darby SC, Hall P, Adolfsson J, Bengtsson N-Ol, Bennet AM, Fornander T, Gigante B, Jensen M-B, Peto R, Rahimi K, Taylor CW, Ewertz M. Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Radiother Oncol 2011; 100 (2): 167-75. Midtgaard J, Stage M, Møller T, Andersen C, Quist M, Rørth MR, Herrstedt J, Vistisen K, Christiansen B, Adamsen L. Exercise may reduce depression but not anxiety in self-referred cancer patients undergoing chemotherapy. Post-hoc analysis of data from the 'Body & Cancer' trial. Acta Oncol 2011; 50 (5): 660-69. Nielsen TB, Wieslander E, Fogliata A, Nielsen M, Hansen O, Brink C. Influence of dose calculation algorithms on the predicted dose distribution and NTCP values for NSCLC patients. Med Phys 2011; 38 (5): 2412-18. Nielsen TB, Hansen VN, Westberg J, Hansen O, Brink C. A dual centre study of setup accuracy for thoracic patients based on Cone-Beam CT data. Radiother Oncol 2011; 102 (2): 281-286. Nielsen KV, Ejlertsen B, Møller S, Jensen M-B, Balslev E, Müller S, Knoop A, Mouridsen HT. Lack of independent prognostic and predictive value of centromere 17 copy number changes in breast cancer patients with known HER2 and TOP2A status. Mol Oncol 2011; 6 (1) 88-97. Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard Lars, Sørensen P, Kamby C, Møller S, Jørgensen CLT, Andersson M. Gemcitabine Plus Docetaxel Versus Docetaxel in Patients With Predominantly Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer: A Randomized, Phase III Study by the Danish Breast Cancer Cooperative Group. J Clin Oncol 2011; 29 (36) 4748-54. Offersen BV, Brodersen HJ, Møller Nielsen M, Overgaard Jens, Overgaard Marie. Should postmastectomy radiotherapy to the chest wall and regional lymph nodes be standard for patients with 1-3 positive lymph nodes. Breast Care 2011; 6: 347-351. Olver I, Molassiotis A, Aapro M, Herrstedt J, Grunberg S, Morrow G. Antiemetic research: future directions. Support Care Cancer 2011; 19 (1): S49-55. Rohrberg KS, Pappot H, Lassen U, Westman Maj, Olesen RK, Pfeiffer P, Ladekarl M, Sørensen M, Christensen IJ, Skov BG. Biomarkers in tissue from patients with upper gastrointestinal cancers treated with erlotinib and bevacizumab. Cancer Biol Ther 2011; 11 (8): 732-39. Roila F, Herrstedt J, Gralla RJ, Tonato M. Prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: guideline update and results of the Perugia consensus conference. Support Care Cancer 2011; 19 (1): S63-65. Roila F, Warr D, Aapro M, Clark-Snow RA, Einhorn L, Gralla RJ, Herrstedt J, Saito M, Tonato M. Delayed emesis: moderately emetogenic chemotherapy (single-day chemotherapy regimens only). Support Care Cancer 2011; 19 (1): S57-62. Ruhlmann CHB, Herrstedt J. Fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting. Expert Rev Anticancer Ther 2011; 12 (2): 139-150. Ruhlmann CH, Herrstedt Jørn. Safety evaluation of aprepitant for the prevention of chemotherapyinduced nausea and vomiting. Expert Opin Drug Saf 2011; 10 (3): 449-62. Schoennemann KR, Bjerregaard JK, Hansen TP, De Stricker K, Gjerstorff MF, Jensen HA, Vestermark LW, Pfeiffer P. Biweekly cetuximab and irinotecan as second-line therapy in patients with gastro-esophageal cancer previously treated with platinum. Gastric Cancer 2011; 14 (3): 219-25. Schønnemann KR, Yilmaz M, Andersen M, Pfeiffer Per. New recommendation of doses in an ongoing phase II study of docetaxel, oxaliplatin and capecitabine as first line therapy in advanced gastrooesophageal cancer. Acta Oncol 2011; 50 (1): 151-2. Skytthe A, Ohm Kyvik K, Holm NV, Christensen K. The Danish Twin Registry. Scand J Public Health Suppl 2011; 39 (7): 75-78. Sørensen J, Sjøgren P. Den kliniske betydning af opioidinduceret hyperalgesi er uafklaret. Ugeskr Laeger 2011; 173 (13): 965-8. Taylor CW, Brønnum DS, Darby SC, Gagliardi G, Hall P, Jensen M-B, McGale P, Nisbet A, Ewertz M. Cardiac dose estimates from Danish and Swedish breast cancer radiotherapy during 1977-2001. Radiother Oncol 2011; 100 (2): 176-83. Vach W, Høilund-Carlsen PF, Gerke O, Weber WA. Generating Evidence for Clinical Benefit of PET/CT in Diagnosing Cancer Patients. J Nucl Med 2011; 52 (2): 77S-85S. Warning K, Hildebrandt MG, Kristensen B, Ewertz M. Utility of 18FDG-PET/CT in breast cancer diagnostics - a systematic review. Dan Med Bull 2011; 58(7): A4289. Wojdacz TK, Thestrup BB, Cold S, Overgaard J, Hansen LL. No difference in the frequency of locusspecific methylation in the peripheral blood DNA of women diagnosed with breast cancer and agematched controls. Future Oncol 2011; 7 (12): 1451-5.