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  • 251. Suzuki, C
    et al.
    Blomqvist, L
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Jacobsson, H
    Byström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy2012In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 23, no 4, p. 948-954Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To determine whether the change in tumor diameters at the first follow-up computed tomography (CT) examination after baseline examination (first change) correlates with outcome in patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy.

    PATIENTS AND METHODS: The first change was analyzed in a multicenter randomized phase III trial (Nordic VI, N = 567) comparing first-line irinotecan with either bolus or infused 5-fluorouracil. Cox proportional hazards multiple regression model and Kaplan-Meier survival analyses after correction for guarantee-time bias were carried out to evaluate correlations between first change, objective response according to RECIST 1.0, progression-free survival (PFS), and overall survival (OS).

    RESULTS: The hazard ratios for PFS and OS decreased along with first change. A decrease between 10% and <30%, albeit RECIST does not regard this as a partial response, was a positive prognostic factor for PFS and OS. Patients who had new lesions or unequivocal progression of nonmeasurable lesions had a worse prognosis than those with only an increase in size of >20%.

    CONCLUSIONS: The change in tumor size at the first follow-up CT is strongly prognostic for PFS and OS in mCRC.

  • 252. Suzuki, Chikako
    et al.
    Blomqvist, Lennart
    Hatschek, Thomas
    Carlsson, Lena
    Einbeigi, Zakaria
    Linderholm, Barbro
    Lindh, Birgitta
    Loman, Niklas
    Malmberg, Martin
    Rotstein, Samuel
    Soderberg, Martin
    Sundqvist, Marie
    Walz, Thomas M.
    Åström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fujii, Hirofumi
    Jacobsson, Hans
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Impact of the first tumor response at eight weeks on overall survival in metastatic breast cancer patients treated with first-line combination chemotherapy2013In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 30, no 1, p. 415-Article in journal (Refereed)
    Abstract [en]

    The aim of this was to determine whether the change of size observed at the first response evaluation after initiation of first-line combination chemotherapy correlates with overall survival (OS) in patients with metastatic breast cancer (MBC). The change in size of tumors derived from measurements according to Response Evaluation Criteria In Solid Tumors (RECIST) at the first evaluation on computed tomography (CT) was obtained from a multicenter, randomized phase III trial ("TEX trial," n = 287) comparing treatment with a combination of epirubicin and paclitaxel alone or with capecitabine (TEX). Cox regression and Kaplan-Meier analyses were performed to evaluate the correlations between the first change in tumor size, response according to RECIST and OS. Data from CT evaluations of 233 patients were available. Appearance of new lesions or progression of non-target lesions (new/non-target) indicated short OS by univariable regression analysis (HR 3.76, 95 % CI 1.90-7.42, p < 0.001). A decrease by >30 % at this early time point was prognostic favorable (HR 0.69, 95 % CI 0.49-0.98, p = 0.04) and not significantly less than the best overall response according to RECIST. After adjustment for previous adjuvant treatment and the treatment given within the frame of the randomized trial, OS was still significantly shorter in patients with new/non-target lesions after a median 8 weeks of treatment (HR 4.41, 95 % CI 2.74-7.11, p < 0.001). Disease progression at the first evaluation correlates with OS in patients with MBC treated with first-line combination chemotherapy. The main reason for early disease progression was the appearance of new lesions or progression of non-target lesions. These patients had poor OS even though more lines of treatment were available. Thus, these factors should be focused on in the response evaluations besides tumor size changes.

  • 253. Sörbye, Halfdan
    et al.
    Glimelius, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Berglund, Ake
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Fokstuen, Tone
    Tveit, Kjell Magne
    Braendengen, Morten
    Ögreid, Dagfinn
    Dahl, Olav
    Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer.2004In: J Clin Oncol, ISSN 0732-183X, Vol. 22, no 1, p. 31-8Article in journal (Refereed)
  • 254. Sørbye, Halfdan
    et al.
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Tveit, Kjell Magne
    Ogreid, Dagfinn
    Wanderås, Eva Hoff
    Wentzel-Larsen, Tore
    Dahl, Olav
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Secondary treatment and predictive factors for second-line chemotherapy after first-line oxaliplatin-based therapy in metastatic colorectal cancer2007In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 46, no 7, p. 982-988Article in journal (Refereed)
    Abstract [en]

    Two consecutive studies have evaluated the efficacy of oxaliplatin combined with the Nordic bolus schedule of 5-fluorouracil and folinic acid as first-line treatment in metastatic non-resectable colorectal cancer. One hundred and twelve patients were followed after end of first-line treatment and any secondary therapy registered. Fifty-three patients (47%) did not receive second-line irinotecan-based chemotherapy. The main reason was too poor performance status (59%). These patients had a median survival of only 1.7 months after progression of first-line therapy. The best predictive factors at start of first-line chemotherapy for receiving later second-line chemotherapy were performance status and alkaline phosphatase level. Fifty-nine patients (53%) received irinotecan-based second-line therapy. Four (7%) patients had a partial response, and 28 (52%) had stable disease. Median progression-free survival after second-line chemotherapy was 4.1 months and median survival 9.5 months. Median survival after first-line chemotherapy and secondary liver surgery was 34 months and five-year disease-free survival 8%. Survival among patients receiving both first- and second-line chemotherapy was 20.8 months, but only 8.9 months in patients not receiving second-line irinotecan-based chemotherapy. Poor performance status or elevated alkaline phosphatase level at start of first-line chemotherapy predicts whether second-line chemotherapy will be given or not.

  • 255. Sørensen, Nanna M
    et al.
    Byström, Per
    Christensen, Ib J
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nielsen, Hans Jørgen
    Brünner, Nils
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    TIMP-1 is significantly associated with objective response and survival in metastatic colorectal cancer patients receiving combination of irinotecan, 5-fluorouracil, and folinic acid2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 14, p. 4117-4122Article in journal (Refereed)
    Abstract [en]

    Purpose: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to protect cells against apoptosis. We raised the hypothesis that elevated tumor tissue levels and thereby plasma levels of TIMP-1 would predict resistance to apoptosis-inducing chemotherapy.

    Experimental Design: Ninety patients with metastatic colorectal cancer were included in the study. Plasma TIMP-1 and serum carcinoembryonic antigen (CEA) were measured in samples obtained before the first cycle of chemotherapy.

    Results: Analysis of best objective response (complete or partial response versus stable or progressive disease) showed that patients with low plasma TIMP-1 had higher probability of obtaining an objective response [odds ratio (OR), 3.5; 95% confidence interval (95% CI), 1.4-8.5, P = 0.007]. CEA treated as a continuous variable was also a statistically significant predictor of no response (OR, 1.3; 95% CI, 1.0-1.7, P = 0.02, area under the curve 0.66) but much less so. Plasma TIMP-1 was the only significant covariate in a multivariable analysis of best objective response (OR, 3.6; 95% CI, 1.4-9.5; P = 0.001). Plasma TIMP-1 scored as a continuous variable on the log scale (loge) was significantly associated with overall survival [OS; hazard ratio (HR), 3.8; 95% CI, 2.4-5.9; P < 0.0001] and with time to progression (TTP; HR, 1.5; 95% CI, 1.0-2.3; P = 0.048). Multivariable analysis showed that plasma TIMP-1 was significant for OS when including routine clinical baseline covariates (HR, 3.5; 95% CI, 2.1-5.8; P < 0.0001). A multivariable analysis including TTP instead of OS showed that only plasma TIMP-1 was retained in the model (HR, 1.5). CEA was not significantly associated with TTP or OS when TIMP-1 was included in the model.

    Conclusion: This study shows that plasma TIMP-1 levels are significantly and independently associated with objective response, TTP, and OS in patients with metastatic colorectal cancer receiving combination chemotherapy.

  • 256.
    Tarpgaard, Line S.
    et al.
    Odense Univ Hosp, Dept Oncol, DK-5000 Odense, Denmark.;Univ Southern Denmark, Inst Clin Res, Odense, Denmark..
    Christensen, Ib J.
    Rigshosp, Finsen Lab, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, DK-1168 Copenhagen, Denmark..
    Hoyer-Hansen, Gunilla
    Rigshosp, Finsen Lab, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, DK-1168 Copenhagen, Denmark..
    Lund, Ida K.
    Rigshosp, Finsen Lab, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, DK-1168 Copenhagen, Denmark..
    Guren, Tormod K.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Ctr Colorectal Canc Res, Oslo, Norway..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway..
    Tveit, Kjell M.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Ctr Colorectal Canc Res, Oslo, Norway..
    Nielsen, Hans Jorgen
    Copenhagen Univ Hosp, Dept Surg Gastroenterol, Hvidovre, Denmark..
    Moreira, Jose M. A.
    Univ Copenhagen, Fac Hlth & Med Sci, Inst Vet Dis Biol, DK-1168 Copenhagen, Denmark..
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, DK-5000 Odense, Denmark.;Univ Southern Denmark, Inst Clin Res, Odense, Denmark..
    Brunner, Nils
    Univ Copenhagen, Fac Hlth & Med Sci, Inst Vet Dis Biol, DK-1168 Copenhagen, Denmark..
    Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 10, p. 2470-2477Article in journal (Refereed)
    Abstract [en]

    Circulating forms of the urokinase plasminogen activator receptor (uPAR) are associated with prognosis in patients with colorectal cancer. Preclinical studies have shown that uPAR can influence the state of phosphorylation and signalling activity of the epidermal growth factor receptor (EGFR) in a ligand-independent manner. The purpose of the study was to evaluate whether plasma soluble intact and cleaved uPAR(I-III) + (II-III) levels could identify a subpopulation of patients with metastatic colorectal cancer (mCRC) where treatment with cetuximab would have a beneficial effect. Plasma samples were available from 453 patients treated in the NORDIC VII study. Patients were randomized between FLOX and FLOX + cetuximab. The levels of uPAR(I-III) 1(II-III) were determined by time-resolved fluorescence immunoassay. We demonstrated that higher baseline plasma uPAR(I-III) 1(II-III) levels were significantly associated with shorter progression-free survival (PFS) (HR51.30, 1.14-1.48, p=0.0001) and overall survival (OS) (HR51.75, 1.52-2.02, p < 0.0001). Multivariate Cox analysis showed that plasma uPAR(I-III) 1(II-III) was an independent biomarker of short OS (HR51.45, 1.20-1.75, p=0.0001). There were no significant interactions between plasma uPAR(I-III) 1(II-III) levels, KRAS mutational status and treatment either PFS (p=0.43) or OS (p=0.095). However, further explorative analyses indicated that patients with low levels of circulating suPAR and a KRAS wild-type tumor have improved effect from treatment with FLOX+cetuximab as compared to patients with KRAS wild-type and high levels of suPAR. These results thus support the preclinical findings and should be further tested in an independent clinical data set.

  • 257. Tarpgaard, Line S.
    et al.
    Guren, Tormod K.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Christensen, Ib J.
    Pfeiffer, Per
    Kure, Elin H.
    Sorbye, Halfdan
    Ikdahl, Tone
    Yilmaz, Mette
    Johansen, Julia S.
    Tveit, Kjell Magne
    Plasma YKL-40 in Patients with Metastatic Colorectal Cancer Treated with First Line Oxaliplatin-Based Regimen with or without Cetuximab: RESULTS from the NORDIC VII Study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e87746-Article in journal (Refereed)
    Abstract [en]

    Background: We aim to test the hypothesis that high plasma YKL-40 is associated with short progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with first-line oxaliplatin and 5-flourouracil with or without cetuximab. Patients and Methods: A total of 566 patients in the NORDIC VII Study were randomized 1:1:1 to arm A (Nordic FLOX), arm B (Nordic FLOX + cetuximab), or arm C (Nordic FLOX + cetuximab for 16 weeks followed by cetuximab alone as maintenance therapy). Pretreatment plasma samples were available from 510 patients. Plasma YKL-40 was determined by ELISA and dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects. Results: Pretreatment plasma YKL-40 was elevated in 204 patients (40%), and median YKL-40 was higher in patients with mCRC than in healthy subjects (age adjusted, P < 0.001). Patients with elevated YKL-40 had shorter PFS than patients with normal YKL-40 (7.5 vs. 8.2 months; hazard ratio (HR) = 1.27 95% confidence interval (CI) 1.05-1.53 P = 0.013) and shorter OS (16.8 vs. 23.9 months; HR = 1.33, 1.04-1.69, P = 0.024). Multivariate Cox analysis demonstrated that elevated pretreatment YKL-40 was an independent biomarker of short OS (HR = 1.12, 1.01-1.25, P = 0.033). The ratio of the updated plasma YKL-40 (i.e. level after 1, 2, 8 weeks of treatment, and at end of treatment compared to the baseline level) was associated with OS (HR = 1.27, 1.06-1.52, P = 0.011). Conclusions: Plasma YKL-40 is an independent prognostic biomarker in patients with mCRC treated with first-line oxaliplatin-based therapy alone or combined with cetuximab.

  • 258.
    Tarpgaard, Line S.
    et al.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.;Univ Southern Denmark, Odense, Denmark..
    Orum-Madsen, Maj Sofie
    Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Christensen, Ib J.
    Rigshosp, Finsen Lab, Copenhagen, Denmark.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Nordgaard, Cathrine
    Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Noer, Julie
    Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Guren, Tormod K.
    Oslo Univ Hosp Oslo, Dept Oncol, Oslo, Norway.;Oslo Univ Hosp Oslo, KG Jebsen Ctr Colorectal Canc Res, Oslo, Norway..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Ikdahl, Tone
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Kure, Elin H.
    Oslo Univ Hosp, Dept Genet, Oslo, Norway..
    Tveit, Kjell M.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Nielsen, Hans J.
    Copenhagen Univ Hosp, Dept Surg Gastroenterol, Hvidovre, Denmark..
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.;Univ Southern Denmark, Odense, Denmark..
    Brunner, Nils
    Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Moreira, Jose M. A.
    Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
    TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells: A potential novel approach to the treatment of metastatic colorectal cancer2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 37, p. 59441-59457Article in journal (Refereed)
    Abstract [en]

    It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor (EGFR) can have efficacy in KRAS wild-type advanced colorectal cancer (CRC) patients. What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit from EGFR inhibitors. Metalloproteinase inhibitor 1 (TIMP-1) is a pleiotropic factor predictive of survival outcome of CRC patients. Levels of TIMP-1 were measured in pre-treatment plasma samples (n = 426) of metastatic CRC patients randomized to Nordic FLOX (5-fluorouracil and oxaliplatin) +/- cetuximab (NORDIC VII study). Multivariate analysis demonstrated a significant interaction between plasma TIMP-1 protein levels, KRAS status and treatment with patients bearing KRAS mutated tumors and high TIMP-1 plasma level (> 3rd quartile) showing a significantly longer overall survival if treated with cetuximab (HR, 0.48; 95% CI, 0.25 to 0.93). To gain mechanistic insights into this association we analyzed a set of five different CRC cell lines. We show here that EGFR signaling induces TIMP-1 expression in CRC cells, and that TIMP-1 promotes a more aggressive behavior, specifically in KRAS mutated cells. The two sets of data, clinical and in vitro, are complementary and support each other, lending strength to our contention that TIMP-1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy.

  • 259.
    ter Veer, Emil
    et al.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands.
    van Rijssen, L. Bengt
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Surg, Amsterdam, Netherlands..
    Besselink, Marc G.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Surg, Amsterdam, Netherlands..
    Mali, Rosa M. A.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands..
    Berlin, Jordan D.
    Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Nashville, TN USA..
    Boeck, Stefan
    Ludwig Maximilians Univ Munchen, Klinikum Grosshadern, Ctr Comprehens Canc, Dept Internal Med 3, Munich, Germany..
    Bonnetain, Franck
    Univ Hosp Besancon, Methodol & Qual Life Oncol Unit, Besancon, France..
    Chau, Ian
    Royal Marsden NHS Fdn Trust, London, England.;Royal Marsden NHS Fdn Trust, Brompton, Surrey, England..
    Conroy, Thierry
    Inst Cancerol Lorraine, Dept Med Oncol, Vandoeuvre Less Nancy, France.;Lorraine Univ, Vandoeuvre Less Nancy, France..
    Van Cutsem, Eric
    Univ Hosp Gasthuisberg Leuven, Dept Gastroenterol & Digest Oncol, Leuven, Belgium.;Katholieke Univ Leuven, Leuven, Belgium..
    Deplanque, Gael
    Hop Riviera Chablais, Dept Oncol, Vevey, Switzerland..
    Friess, Helmut
    Tech Univ Munich, Klinikum Rechts Isar, Dept Surg, Munich, Germany..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Goldstein, David
    Univ New South Wales, Prince Wales Clin Sch, Prince Wales Hosp, Nelune Canc Ctr, Randwick, NSW, Australia..
    Herrmann, Richard
    Univ Hosp Basel, Dept Med Oncol, Basel, Switzerland..
    Labianca, Roberto
    ASST Papa Giovanni XXIII, Ctr Canc, Bergamo, Italy..
    Van Laethem, Jean-Luc
    Univ Libre Bruxelles, Erasme Univ Hosp, Gastrointestinal Canc Unit, Dept Gastroenterol, Brussels, Belgium..
    Macarulla, Teresa
    Vall dHebron Inst Oncol VHIO, Vall dHebron Univ Hosp, Barcelona, Spain..
    van der Meer, Jonathan H. M.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Surg, Amsterdam, Netherlands..
    Neoptolemos, John P.
    Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England..
    Okusaka, Takuji
    Natl Canc Ctr, Dept Hepatobiliary & Pancreat Oncol, Tokyo, Japan..
    O'Reilly, Eileen M.
    Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, Dept Med, Gastrointestinal Oncol Serv,Div Solid Tumor Oncol, New York, NY USA..
    Pelzer, Uwe
    Charite Univ Med Berlin, Dept Hematol Oncol & Tumor Immunol, Berlin, Germany.;Humboldt Univ, Freie Univ Berlin, Berlin, Germany.;Berlin Inst Hlth, Berlin, Germany..
    Philip, Philip A.
    Wayne State Univ, Dept Oncol, Karmanos Canc Ctr, Detroit, MI USA..
    van der Poel, Marcel J.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Surg, Amsterdam, Netherlands..
    Reni, Michele
    IRCCS San Raffaele Sci Inst, Dept Med Oncol, Milan, Italy..
    Scheithauer, Werner
    Med Univ Vienna, Dept Internal Med 1, Vienna, Austria..
    Siveke, Jens T.
    Univ Hosp Essen, West German Canc Canc, Div Solid Tumor, Translat Oncol, Essen, Germany.;German Canc Consortium DKTK, Partner Site Essen, Heidelberg, Germany.;DKFZ, German Canc Res Ctr, Heidelberg, Germany..
    Verslype, Chris
    Univ Hosp Leuven, Dept Digest Oncol, Leuven, Belgium..
    Busch, Olivier R.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Surg, Amsterdam, Netherlands..
    Wilmink, Johanna W.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands..
    van Oijen, Martijn G. H.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands..
    van Laarhoven, Hanneke W. M.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands..
    Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease2018In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 19, no 3, p. E151-E160Article, review/survey (Refereed)
    Abstract [en]

    Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.

  • 260.
    Thalén Lindström, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Development of anxiety, depression and health-related quality of life in oncology patients without initial symptoms according to the Hospital Anxiety and Depression Scale – a comparative study2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 8, p. 1094-1102Article in journal (Refereed)
    Abstract [en]

    Background: Depression and anxiety are associated with decreased health-related quality of life (HRQoL). The knowledge about the development of anxiety, depression and HRQoL in cancer patients without depression or anxiety, that is initially scoring as non-cases (cutoff <8) according to the Hospital Anxiety and Depression Scale (HADS), is sparse. The objectives were: (1) to evaluate changes in anxiety, depression and HRQoL over 6 months in two independent cohorts of oncology patients initially scoring as non-cases by the HADS, (2) to compare stable non-case patients with the general population regarding HRQoL and (3) to explore the outcomes using >4 rather than >7 as cutoff on any of HADS subscales.

    Methods: The study group (SG) included 245 and the validation group (VG), a previous cohort, included 281 non-cases. Patients who were non-cases (HADS <8) at all completed assessments were categorized as stable non-cases (stable-NC); those who were doubtful/clinical cases (HADS >7) in at least one follow-up were categorized as unstable-NC. Questionnaires were completed at baseline, and after 1, 3 and 6 months. Age- and sex-matched EORTC QLQ-C30 data from the general population were used for HRQoL comparisons.

    Results: One hundred ninety-six (80%) SG and 244 (87%) VG patients were stable-NC and 49 (20%) SG and 37 (13%) VG patients were unstable-NC. SG and VG were similar in all outcomes. Anxiety, depression and HRQoL deteriorated over 6 months for unstable-NC (p<.05). HRQoL for stable-NC was comparable to that in the general population. If >4 had been used as cutoff, most unstable-NC (36/49 and 25/37, respectively) would have been identified at baseline.

    Conclusions: Most non-cases are stable-NC with a high stable HRQoL, indicating no need for re-assessment. A minority develop anxiety or depression symptoms and impaired HRQoL; for these a cutoff >4 rather than >7 on HADS subscales may be useful for early detection. 

  • 261.
    Thalén-Lindström, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Identification of distress in oncology patients: a comparison of the Hospital Anxiety and Depression Scale and a thorough clinical assessment2016In: Cancer Nursing, ISSN 0162-220X, E-ISSN 1538-9804, Vol. 39, no 2, p. E31-E39Article in journal (Refereed)
    Abstract [en]

    Background:

    Screening is recommended to identify cancer patients with distress,anxiety, and depression. The ability of current methods to identify distress inoncology patients is of high importance.

    Objective:

    We compared the HospitalAnxiety and Depression Scale (HADS) with a thorough clinical assessment.Furthermore, we explored the agreement of HADS with clinical assessment outcomesas a function of age, sex, and treatment intention.

    Methods:

    One hundredforty-six oncology patients, representing both sexes, different ages (<65/Q65 years),and treatment intention (curative/palliative), completed the HADS before the clinicalassessment. Two study team members (blind to the HADS results) completedclinical assessments of anxiety, depression, and distress analogous to categoriesused in the HADS.

    Results:

    The HADS identified 49 participants and the clinicalassessment 71 participants as having anxiety, depression, or distress. The overall agreement between the HADS and the clinical assessment was moderate. The greatest differences were found to be a function of participant sex and age.Agreement between the methods was better for females than for males in relation to distress and anxiety and better for the older (Q65 years) than younger participants in relation to depression. By treatment intention, agreement was equal for alldomains.

    Conclusion:

    Especially male and young participants appear to have potential problems that the HADS fails to identify.

  • 262.
    Thalén-Lindström, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Anxiety and depression in oncology patients: a longitudinal study of a screening, assessment and psychosocial support intervention2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 1, p. 118-127Article in journal (Refereed)
    Abstract [en]

    Background. Anxiety and depression in cancer patients are associated with poor health-related quality of life (HRQOL). Clinical interventions to detect and support patients with these symptoms need to be developed and evaluated. We investigated the feasibility of screening with the Hospital Anxiety and Depression Scale (HADS) in a clinical oncology setting. In patients with anxiety or depression symptoms (HADS >7) we explored the use of clinical assessment and psychosocial support and described the development of anxiety, depression and HRQOL during a six-month period. Material and methods. Four hundred and ninety-five consecutive patients were screened for anxiety and depression at the time of their first visit at an oncology department (baseline). Half of the patients with HADS >7 on any of the two HADS subscales were referred to clinical assessment and psychosocial support (intervention group, IG) and half received standard care (SCG) using a historical control group design. HADS and EORTC QLQ-C30 were completed at baseline and after one, three and six months. Results. One hundred and seventy-six (36%) of 495 patients had anxiety or depression symptoms at screening, HRQOL at baseline was clearly impaired for them. Thirty-six (43%) of 84 IG patients attended clinical assessment, resulting in subsequent psychosocial support for 20 (24%) of them. In the SCG, only five (5%) patients attended clinical assessment after self referral, two received subsequent psychosocial support. Anxiety and depression decreased and HRQOL increased statistically significantly over time although anxiety was frequent and HRQOL impaired during the entire six month period. There were no differences between the SCG and IG regarding anxiety, depression or HRQOL at any time point. Conclusion. Systematic screening with HADS is feasible for oncology patients in clinical settings; it identifies patients with persistent symptoms and increases referral to clinical assessment and utilisation of psychosocial support.

  • 263.
    Thalén-Lindström, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hellbom, Maria
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Psychosocial oncology and supportive care.
    Validation of the Distress Thermometer in a Swedish population of oncology patients: accuracy of changes during six months2013In: European Journal of Oncology Nursing, ISSN 1462-3889, E-ISSN 1532-2122, Vol. 17, no 5, p. 625-631Article in journal (Refereed)
    Abstract [en]

    Purpose

    To validate the Swedish version of the Distress Thermometer (DT) against the Hospital Anxiety and Depression Scale (HADS) for screening of distress and to explore how well DT measures changes of distress during six months in a population of heterogeneous oncology patients.

    Methods

    The DT was translated into Swedish according to the forward- and back-translation procedure. HADS total score ≥15 was used as gold standard. Consecutive patients were invited to participate at their first visit to the Oncology department. The HADS and the DT were completed at baseline and after 1, 3 and 6 months.

    Results

    462 baseline and 321 six-month assessments were completed. The patients had a variety of cancer diagnoses (n = 42). Most patients (95%) received active treatment. The DT compared favourably with the HADS. The area under the curve was 0.86 (95% CI, 0.82–0.90). DT ≥ 4 showed a sensitivity of 87%, a specificity of 73%, a positive predictive value (PPV) of 52% and a negative predictive value (NPV) of 95% at baseline. The results from the 1, 3 and 6 months assessments were equivalent baseline results. The DT means changed in the same direction as HADS at all points of assessment. Patients with distress reported statistically significantly more problems in all categories on the associated ‘Problem List’ compared to non-distressed patients.

    Conclusion

    The Swedish version of the DT with a score ≥4 is valid for screening of distress in heterogeneous oncology patients. Its ability to measure changes in distress over time is comparable to HADS.

  • 264.
    Thomsen, Maria
    et al.
    Oslo Univ Hosp, Dept Oncol, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Guren, Marianne Gronlie
    Oslo Univ Hosp, Dept Oncol, N-0424 Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway..
    Skovlund, Eva
    NTNU, Dept Publ Hlth & Nursing, Trondheim, Norway.;Norwegian Inst Publ Hlth, Mental & Phys Hlth, Oslo, Norway..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hjermstad, Marianne Jensen
    Oslo Univ Hosp, Dept Oncol, Reg Advisory Unit Palliat Care, Oslo, Norway.;Norwegian Univ Sci & Technol, Fac Med, Dept Canc Res & Mol Med, European Palliat Care Res Ctr, Trondheim, Norway..
    Johansen, Julia S.
    Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Oncol, Herlev, Denmark..
    Kure, Elin
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway..
    Sorbye, Halfdan
    Univ Bergen, Haukeland Univ Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Clin Sci, Bergen, Norway..
    Pfeiffer, Per
    Univ Southern Denmark, Inst Clin Res, Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Christoffersen, Thoralf
    Univ Oslo, Fac Med, Inst Clin Med, Dept Pharmacol, Oslo, Norway..
    Guren, Tormod Kyrre
    Oslo Univ Hosp, Dept Oncol, N-0424 Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway..
    Tveit, Kjell Magne
    Oslo Univ Hosp, Dept Oncol, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway..
    Health-related quality of life in patients with metastatic colorectal cancer, association with systemic inflammatory response and RAS and BRAF mutation status2017In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 81, p. 26-35Article in journal (Refereed)
    Abstract [en]

    Background: The aim of this study was to evaluate the effect of cetuximab on health-related quality of life (HRQoL) in the NORDIC-VII trial on metastatic colorectal cancer (mCRC), and to assess HRQoL in relation to RAS and BRAF mutation status and inflammatory biomarkers. Patient and methods: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, after every fourth cycle of chemotherapy, and at the end of treatment. HRQoL during 12 cycles of chemotherapy was evaluated over time, compared between treatment arms, and assessed for association with tumour mutation status and inflammatory markers. Results: QLQ-C30 was completed by 512 patients (90%) before start of treatment. HRQoL variables were well balanced across treatment arms at baseline, and no statistically significant differences during treatment were seen. Patients with BRAF-mutated tumours reported poorer HRQoL at baseline and subsequent time points than patients with RAS-mutated or RAS/BRAF wild-type tumours. Patients with high serum interleukin-6 (IL-6) or C-reactive protein (CRP) had markedly impaired HRQoL compared to patients with normal levels. There was a statistically significant association between reduction in IL-6 and CRP levels and improvement in HRQoL during treatment from baseline to cycle 4. Conclusion: The addition of cetuximab to chemotherapy did not affect HRQoL in mCRC patients. Patients with BRAF-mutated tumours have both a worse prognosis and a poor HRQoL. The associations between levels of systemic inflammatory markers and reduced HRQoL suggest that the patients might benefit from anti-inflammatory treatment.

  • 265.
    Thomsen, Maria
    et al.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Kersten, Christian
    Southern Hosp Trust, Dept Oncol, Kristiansand, Norway..
    Sorbye, Halfdan
    Univ Bergen, Haukeland Univ Hosp, Dept Oncol, Bergen, Norway..
    Skovlund, Eva
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Trondheim, Norway..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Pfeiffer, Per
    Univ Southern Denmark, Odense Univ Hosp, Inst Clin Res, Dept Oncol, Odense, Denmark..
    Johansen, Julia S.
    Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Oncol, Herlev, Denmark..
    Kure, Elin H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway..
    Ikdahl, Tone
    Akershus Univ Hosp, Nordbyhagen, Norway..
    Tveit, Kjell Magne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway..
    Christoffersen, Thoralf
    Univ Oslo, Fac Med, Inst Clin Med, Dept Pharmacol, Oslo, Norway..
    Guren, Tormod Kyrre
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway..
    Interleukin-6 and C-reactive protein as prognostic biomarkers in metastatic colorectal cancer2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 46, p. 75013-75022Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim was to explore the prognostic significance of IL-6 and markers of systemic inflammatory response (SIR), in particular C-reactive protein (CRP), in metastatic colorectal cancer (mCRC) patients, in the total study population and according to RAS and BRAF mutation status. Results: High levels of pretreatment serum IL-6 or CRP were associated with impaired outcome, in terms of reduced PFS and OS. Patients with low versus high serum IL-6 levels had median OS of 26.0 versus 16.6 months, respectively (P < 0.001). Stratified according to increasing CRP levels, median OS varied from 24.3 months to 12.3 months, (P < 0.001). IL-6 and CRP levels affected overall prognosis also in adjusted analyses. The effect of IL-6 was particularly pronounced in patients with BRAF mutation (interaction P = 0.004). Materials and Methods: IL-6 and CRP were determined in pre-treatment serum samples from 393 patients included in the NORDIC-VII trial, in which patients with mCRC received first line treatment. The effect of serum IL-6 and CRP on progression-free survival (PFS) and overall survival (OS) was estimated. Conclusions: High baseline serum consentrations of IL-6 or CRP were associated with impaired prognosis in mCRC. IL-6 and CRP give independent prognostic information in addition to RAS and BRAF mutation status.

  • 266. Thomsen, Maria
    et al.
    Kersten, Christian
    Sorbye, Halfdan
    Skovlund, Eva
    Ikdahl, Tone
    Johansen, Julia S.
    Pfeiffer, Per
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tveit, Kjell Magne
    Guren, Tormod Kyrre
    C-reactive protein and interleukin-6 as markers of systemic inflammatory response and as prognostic factors for metastatic colorectal cancer. Data from the randomized phase III NORDIC-VII study2015In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 33, no S15, article id 3548Article in journal (Other academic)
  • 267.
    Thomsen, Maria
    et al.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway;Univ Oslo, Inst Clin Med, Fac Med, Oslo, Norway.
    Skovlund, Eva
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, Trondheim, Norway.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway;Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Bolstad, Nils
    Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway.
    Nustad, Kjell Johannes
    Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark;Univ Southern Denmark, Inst Clin Res, Odense, Denmark.
    Kure, Elin H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.
    Johansen, Julia S.
    Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Oncol, Copenhagen, Denmark;Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Med, Copenhagen, Denmark.
    Tveit, Kjell Magne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway;Univ Oslo, Inst Clin Med, Fac Med, Oslo, Norway;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway.
    Christoffersen, Thoralf
    Univ Oslo, Inst Clin Med, Dept Pharmacol, Fac Med, Oslo, Norway.
    Guren, Tormod Kyrre
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway.
    Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer: a BRAF-mutant subset with high CA 19-9 level and poor outcome2018In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 118, no 12, p. 1609-1616Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Mutation status of RAS and BRAF, as well as serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), are biomarkers used in clinical management of patients with gastrointestinal cancers. This study aimed to examine the prognostic role of these biomarkers in a patient population that started first-line chemotherapy for unresectable metastatic colorectal cancer (mCRC) in the NORDIC-VII study.

    METHODS: CEA and CA 19-9 were measured in serum samples from 545 patients obtained before the start of chemotherapy. Four hundred and ninety-four patients had detectable levels of carbohydrate antigen 19-9 (CA 19-9). RAS (exons 2-4) and BRAF (V600E) mutation status were available from 440 patients. Overall survival (OS) was estimated in patient groups defined by serum CEA or CA 19-9 levels using cut-off values of 5 mu g/L and 35 kU/L, respectively, in the total population and in subgroups according to RAS and BRAF mutation status.

    RESULTS: For both CEA and CA 19-9, elevated serum levels were associated with reduced OS in adjusted analyses which included RAS and BRAF mutation status, baseline World Health Organization performance status, and levels of alkaline phosphatase and C-reactive protein. The negative prognostic information provided by an elevated CA 19-9 level was particularly marked in patients with BRAF mutation (hazard ratio = 4.35, interaction P = 0.003, in an adjusted model for OS).

    CONCLUSIONS: High baseline serum concentrations of CEA and CA 19-9 provide independent information of impaired prognosis in mCRC. In patients with BRAF-mutant tumours, elevated serum CA 19-9 may identify a subgroup with highly aggressive disease and could contribute to improving therapeutic decisions.

  • 268.
    Tilly, Nina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Grusell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kimstrand, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Lorin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gajewski, Konrad
    Uppsala University, The Svedberg Laboratory.
    Pettersson, Mikael
    Uppsala University, The Svedberg Laboratory.
    Bäcklund, Andreas
    Uppsala University, The Svedberg Laboratory.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Development and verification of the pulsed scanned proton beam at the The Swedberg Laboratory in Uppsala2007In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 52, no 10, p. 2741-2754Article in journal (Refereed)
    Abstract [en]

    In this paper we present the recent developments made for the scanning system for proton beams at TSL in Uppsala, showing that this system is now fully functional being able to produce conformal intensity modulated scan patterns with sufficient accuracy. A new control and supervising system handling the beam delivery including the control of the synchrocyclotron and the scanning system is developed and described in detail. A complete dosimetry system with transmission ionization chambers and a multi-wire ionization chamber for monitoring of the beam during scanning has been constructed. The details of the dose monitors and the position sensitive multi-wire ionization chamber are presented in this work. Furthermore, we have established procedures for verification measurements to ensure the quality of the beam and also methods for calibration of the beam monitors and relative and absolute dosimetry for complex scanned beams.

  • 269.
    Tilly, Nina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Johansson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Isacsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Medin, Joakim
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Grusell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    The influence of RBE variations in a clinical proton treatment plan for a hypopharynx cancer2005In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 50, no 12, p. 2765-2777Article in journal (Refereed)
    Abstract [en]

    Currently, most clinical range-modulated proton beams are assumed to have a fixed overall relative biological effectiveness (RBE) of 1.1. However, it is well known that the RBE increases with depth in the spread-out Bragg peak (SOBP) and becomes about 10% higher than mid-SOBP RBE at 2 mm from the distal edge (Paganetti 2003 Technol. Cancer Res. Treat. 2 413-26) and can reach values of 1.3-1.4 in vitro at the distal edge (Robertson et al 1975 Cancer 35 1664-77, Courdi et al 1994 Br. J. Radiol. 67 800-4). We present a fast method for applying a variable RBE correction with linear energy transfer (LET) dependent tissue-specific parameters based on the alpharef/betaref ratios suitable for implementation in a treatment planning system. The influence of applying this variable RBE correction on a clinical multiple beam proton dose plan is presented here. The treatment plan is evaluated by RBE weighted dose volume histograms (DVHs) and the calculation of tumour control probability (TCP) and normal tissue complication probability (NTCP) values. The variable RBE correction yields DVHs for the clinical target volumes (CTVs), a primary advanced hypopharynx cancer and subclinical disease in the lymph nodes, that are slightly higher than those achieved by multiplying the absorbed dose with RBE=1.1. Although, more importantly, the RBE weighted DVH for an organ at risk, the spinal cord is considerably increased for the variable RBE. As the spinal cord in this particular case is located 8 mm behind the planning target volume (PTV) and hence receives only low total doses, the NTCP values are zero in spite of the significant increase in the RBE weighted DVHs for the variable RBE. However, high NTCP values for the non-target normal tissue were obtained when applying the variable RBE correction. As RBE variations tend to be smaller for in vivo systems, this study-based on in vitro data since human tissue RBE values are scarce and have large uncertainties-can be interpreted as showing the upper limits of the possible effects of utilizing a variable RBE correction. In conclusion, the results obtained here still indicate a significant difference in introducing a variable RBE compared to applying a generic RBE of 1.1, suggesting it is worth considering such a correction in clinical proton therapy planning, especially when risk organs are located immediately behind the target volume.

  • 270.
    Tiselius, C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Gunnarsson, U
    Smedh, Kennet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Patients with rectal cancer receiving adjuvant chemotherapy have an increased survival: a population-based longitudinal study2013In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, no 1, p. 160-165Article in journal (Refereed)
    Abstract [en]

    Background

    The aim of this study was to investigate whether or not the use of adjuvant chemotherapy in stage III rectal cancer varies between regions and over time, and if this has had an effect on survival rates.

    Patients and methods

    Patients from the Uppsala/Örebro region below 75 years-of-age, operated 1995-2002 and registered in the Swedish Rectal Cancer Register, were monitored between 1995 and September 2008. A multivariate Cox proportional hazard regression model was used for analysis. Overall survival was described using the Kaplan-Meier method.

    Results

    Four hundred and thirty-six patients with stage III rectal cancer were included. Adjuvant chemotherapy was given to 42% of the patients (proportions varying from 13% to 77% among counties), and there were substantial increases over time. The 5-year overall survival was 65.8% [95% confidence interval (CI) 50-84] for patients having adjuvant chemotherapy compared with 45.6% (95% CI 39-52) for patients not treated with chemotherapy. The multivariate hazard ratio for death was 0.65 (95% CI 0.5-0.8) for patients treated with adjuvant chemotherapy.

    Conclusions

    The use of adjuvant chemotherapy for rectal cancer has increased, but varies considerably between hospitals/counties. In this cohort, those having adjuvant chemotherapy had a longer overall survival.

  • 271.
    Torkzad, Michael R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Lindholm, Johan
    Martling, Anna
    Cedermark, Björn
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Blomqvist, Lennart
    MRI after preoperative radiotherapy for rectal cancer; correlation with histopathology and the role of volumetry.2007In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 17, no 6, p. 1566-1573Article in journal (Refereed)
    Abstract [en]

    The objective is to assess if tumor size after radiotherapy in patients with rectal cancer can be assessed by a second magnetic resonance imaging (MRI), after radiotherapy prior to surgery and to correlate changes observed on MRI with findings at histopathology at surgery. Twenty-five patients with MRI before and after radiotherapy were included. Variables studied were changes in tumor size, T-staging and distance to the circumferential resection margin (CRM). RVs was measured as tumor volume at surgery (Vs) divided by tumor volume at the initial MRI (Vi) in percent. RVm was defined as the tumor volume at the second MRI (Vm) divided by Vi in percent. The ypT-stage was the same or more favorable than the initial MRI T-stage in 24 of 25 patients. The second MRI was not more accurately predictive than the initial MRI for ypT-staging or distance to CRM (p > 0.05). Vm correlated significantly to Vs, as did RVs to RVm, although the former was always smaller than the latter. Vm and RVm correlated well with ypT-stage (p < 0.001). Volumetry seems to correlate with ypT-stage after preoperative radiotherapy for resectable rectal cancer. The value of a second MRI after radiotherapy for assessment of distance to CRM and ypT-staging is, however, not apparent.

  • 272.
    Travis, Lois B
    et al.
    National Cancer Institute, USA.
    Gospodarowicz, Mary
    Canada.
    Curtis, Rochelle E
    National Cancer Institute, USA.
    Clarke, E Aileen
    Toronto.
    Andersson, Michael
    Denmark.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Joensuu, Timo
    Finland.
    Lynch, Charles F
    Iowa.
    van Leeuwen, Flora E
    The Netherlands.
    Holowaty, Eric
    Toronto.
    Storm, Hans
    Denmark.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science. Karolinska Institutet.
    Pukkala, Eero
    Finland.
    Stovall, Marilyn
    Houston.
    Fraumeni, Joseph F
    National Cancer Institute, USA.
    Boice, John D
    USA.
    Gilbert, Ethel
    National Cancer Institute, USA.
    Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease2002In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 94, no 3, p. 182-192Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use.

    METHODS: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided.

    RESULTS: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment.

    CONCLUSIONS: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco.

  • 273. Travis, Lois B
    et al.
    Hill, Deirdre A
    Dores, Graça M
    Gospodarowicz, Mary
    van Leeuwen, Flora E
    Holowaty, Eric
    Glimelius, Bengt
    Andersson, Michael
    Wiklund, Tom
    Lynch, Charles F
    Van't Veer, Mars B
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Storm, Hans
    Pukkala, Eero
    Stovall, Marilyn
    Curtis, Rochelle
    Boice, John D
    Gilbert, Ethel
    Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease2003In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 290, no 4, p. 465-475Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Second cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk.

    OBJECTIVE: To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD.

    DESIGN, SETTING, AND SUBJECTS: Matched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998.

    MAIN OUTCOME MEASURES: Relative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents.

    RESULTS: Breast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5; P =.03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P =.003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses.

    CONCLUSIONS: Hormonal stimulation appears important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation. The high radiation-related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness.

  • 274. Tveit, Kjell Magne
    et al.
    Guren, Tormod
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pfeiffer, Per
    Sorbye, Halfdan
    Pyrhonen, Seppo
    Sigurdsson, Fridbjorn
    Kure, Elin
    Ikdahl, Tone
    Skovlund, Eva
    Fokstuen, Tone
    Hansen, Flemming
    Hofsli, Eva
    Birkemeyer, Elke
    Johnsson, Anders
    Starkhammar, Hans
    Yilmaz, Mette Karen
    Keldsen, Nina
    Erdal, Anne Berit
    Dajani, Olav
    Dahl, Olav
    Christoffersen, Thoralf
    Phase III Trial of Cetuximab With Continuous or Intermittent Fluorouracil, Leucovorin, and Oxaliplatin (Nordic FLOX) Versus FLOX Alone in First-Line Treatment of Metastatic Colorectal Cancer: The NORDIC-VII Study2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 15, p. 1755-1762Article in journal (Refereed)
    Abstract [en]

    Purpose: The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated.

    Patients and Methods: Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points.

    Results: Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated.

    Conclusion: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

  • 275.
    Uhlen, Mathias
    et al.
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.;Danish Tech Univ, Ctr Biosustainabil, Copenhagen, Denmark.;Royal Inst Technol, AlbaNova Univ Ctr, KTH, Sch Biotechnol, Stockholm, Sweden..
    Zhang, Cheng
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Lee, Sunjae
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Sjöstedt, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Fagerberg, Linn
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Bidkhori, Gholamreza
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Benfeitas, Rui
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Arif, Muhammad
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Liu, Zhengtao
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Edfors, Fredrik
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Sanli, Kemal
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    von Feilitzen, Kalle
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Oksvold, Per
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Lundberg, Emma
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Hober, Sophia
    Royal Inst Technol, AlbaNova Univ Ctr, KTH, Sch Biotechnol, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Schwenk, Jochen M.
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Brunnström, Hans
    Lund Univ, Skane Univ Hosp, Div Pathol, Lund, Sweden..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Mardinoglu, Adil
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.;Royal Inst Technol, AlbaNova Univ Ctr, KTH, Sch Biotechnol, Stockholm, Sweden.;Chalmers, Dept Biol & Biol Engn, SE-41296 Gothenburg, Sweden..
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    A pathology atlas of the human cancer transcriptome2017In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 357, no 6352, article id eaan2507Article in journal (Refereed)
    Abstract [en]

    Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.

  • 276. Urayama, Kevin Y.
    et al.
    Jarrett, Ruth F.
    Hjalgrim, Henrik
    Diepstra, Arjan
    Kamatani, Yoichiro
    Chabrier, Amelie
    Gaborieau, Valerie
    Boland, Anne
    Nieters, Alexandra
    Becker, Nikolaus
    Foretova, Lenka
    Benavente, Yolanda
    Maynadie, Marc
    Staines, Anthony
    Shield, Lesley
    Lake, Annette
    Montgomery, Dorothy
    Taylor, Malcolm
    Smedby, Karin Ekstrom
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Feenstra, Bjarke
    Nolte, Ilja M.
    Visser, Lydia
    van Imhoff, Gustaaf W.
    Lightfoot, Tracy
    Cocco, Pierluigi
    Kiemeney, Lambertus
    Vermeulen, Sita H.
    Holcatova, Ivana
    Vatten, Lars
    Macfarlane, Gary J.
    Thomson, Peter
    Conway, David I.
    Benhamou, Simone
    Agudo, Antonio
    Healy, Claire M.
    Overvad, Kim
    Tjonneland, Anne
    Melin, Beatrice
    Canzian, Federico
    Khaw, Kay-Tee
    Travis, Ruth C.
    Peeters, Petra H. M.
    Gonzalez, Carlos A.
    Quiros, Jose Ramon
    Sanchez, Maria-Jose
    Maria Huerta, Jose
    Ardanaz, Eva
    Dorronsoro, Miren
    Clavel-Chapelon, Francoise
    Bueno-de-Mesquita, H. Bas
    Riboli, Elio
    Roman, Eve
    Boffetta, Paolo
    de Sanjose, Silvia
    Zelenika, Diana
    Melbye, Mads
    van den Berg, Anke
    Lathrop, Mark
    Brennan, Paul
    McKay, James D.
    Genome-Wide Association Study of Classical Hodgkin Lymphoma and Epstein-Barr Virus Status-Defined Subgroups2012In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 104, no 3, p. 240-253Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification. We conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided. Two novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 x 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 x 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 x 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 x 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 x 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 x 10(-4)) and replication series (P = .03). Overall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.

  • 277. Valentini, V.
    et al.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Frascino, V.
    Quality assurance and quality control for radiotherapy/medical oncology in Europe: Guideline development and implementation2013In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 39, no 9, p. 938-944Article, review/survey (Refereed)
    Abstract [en]

    The past two decades have brought tremendous changes to the practice of radiation oncology and medical oncology. To manage all the complexities related to the new technologies and the new drugs, the radiation and medical oncologists have to enhance their clinical action and professional skill profile. To accomplish this they have to find reliable tools in the quality of their medical practice and in future research activities. Quality assurance (QA) and quality control (QC) for radiation and medical oncologists mean to clarify the different components of the clinical decision, to supervise with proper methodology the required steps needed to accomplish the agreed outcomes and to control them. Quality for radiation and medical oncology means to supervise each clinical and technical component of the whole process to guarantee that all steps together will arrive at the final and best possible outcome. Key components are guidelines, specialization and a multidisciplinary approach. The research of global quality could represent a further complexity, but it is the best tool to give a perspective and a chance to further improvements of our disciplines and to promote better outcome in all cancer patients. 

  • 278. Valentini, Vincenzo
    et al.
    Glimelius, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Minsky, Bruce D
    Van Cutsem, Eric
    Bartelink, Hanry
    Beets-Tan, Regina G H
    Gerard, Jean-Pierre
    Kosmidis, Paris
    Pahlman, Lars
    Department of Surgical Sciences.
    Picciocchi, Aurelio
    Quirke, Phil
    Tepper, Joel
    Tonato, Maurizio
    Van de Velde, Cornelius J
    Cellini, Numa
    Latini, Paolo
    The multidisciplinary rectal cancer treatment: main convergences, controversial aspects and investigational areas which support the need for an European Consensus.2005In: Radiother Oncol, ISSN 0167-8140, Vol. 76, no 3, p. 241-50Article in journal (Refereed)
  • 279. Van Cutsem, E
    et al.
    Cunningham, D
    Maroun, J
    Cervantes, A
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Raltitrexed: current clinical status and future directions2002In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 13, no 4, p. 513-522Article in journal (Refereed)
    Abstract [en]

    Raltitrexed ('Tomudex') monotherapy is a conveniently administered alternative to 5-fluorouracil (5-FU) in the first-line treatment of advanced colorectal cancer (CRC), and has single-agent activity in a variety of advanced solid tumours. Although both raltitrexed and 5-FU are thymidylate synthase inhibitors, raltitrexed has a specific mode of action and a toxicity profile distinct from 5-FU. The mechanism of action of raltitrexed is also completely different from that of oxaliplatin, irinotecan and other drugs with which it has been combined. These properties, together with preclinical data, suggested that combinations of raltitrexed with 5-FU, other chemotherapeutic agents, or radiotherapy could result in improved therapies for a variety of advanced solid tumours, including advanced CRC. This review outlines the appropriate management of patients treated with raltitrexed, whether as monotherapy or in combination, and discusses the preliminary results of combination studies with raltitrexed in a range of tumour types including advanced CRC, malignant mesothelioma, gastric, pancreatic, head and neck, and non-small-cell lung cancers. Of particular interest is the combination of raltitrexed and oxaliplatin, which has shown promising antitumour effects in first-line treatment of advanced CRC and malignant mesothelioma, a disease that is refractory to chemotherapy.

  • 280. Van Cutsem, Eric
    et al.
    Tejpar, Sabine
    Vanbeckevoort, Dirk
    Peeters, Marc
    Humblet, Yves
    Gelderblom, Hans
    Vermorken, Jan B.
    Viret, Frederic
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gallerani, Elisa
    Hendlisz, Alain
    Cats, Annemieke
    Moehler, Markus
    Sagaert, Xavier
    Vlassak, Soetkin
    Schlichting, Michael
    Ciardiello, Fortunato
    Intrapatient Cetuximab Dose Escalation in Metastatic Colorectal Cancer According to the Grade of Early Skin Reactions: The Randomized EVEREST Study2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 23, p. 2861-2868Article in journal (Refereed)
    Abstract [en]

    Purpose Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data.

    Patients and Methods After 21 days of standard-dose cetuximab (400 mg/m(2) initial dose, then 250 mg/m(2) per week) plus irinotecan, patients with <= grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m(2) per week; group B) cetuximab. Patients with >= grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C).

    Results The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m(2) were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions >= grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors.

    Conclusion Cetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.

  • 281. van de Velde, Cornelis J. H.
    et al.
    Aristei, Cynthia
    Boelens, Petra G.
    Beets-Tan, Regina G. H.
    Blomqvist, Lennart
    Borras, Josep M.
    van den Broek, Colette B. M.
    Brown, Gina
    Coebergh, Jan-Willem
    Van Cutsem, Eric
    Espin, Eloy
    Gore-Booth, Jola
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Haustermans, Karin
    Henning, Geoffrey
    Iversen, Lene H.
    van Krieken, J. Han
    Marijnen, Corrie A. M.
    Mroczkowski, Pawel
    Nagtegaal, Iris
    Naredi, Peter
    Ortiz, Hector
    Pahlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Quirke, Philip
    Roedel, Claus
    Roth, Arnaud
    Rutten, Harm J. T.
    Schmoll, Hans J.
    Smith, Jason
    Tanis, Pieter J.
    Taylor, Claire
    Wibe, Arne
    Gambacorta, Maria Antonietta
    Meldolesi, Elisa
    Wiggers, Theo
    Cervantes, Andres
    Valentini, Vincenzo
    EURECCA colorectal: Multidisciplinary Mission statement on better care for patients with colon and rectal cancer in Europe2013In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no 13, p. 2784-2790Article in journal (Refereed)
    Abstract [en]

    Background: Care for patients with colon and rectal cancer has improved in the last twenty years however still considerable variation exists in cancer management and outcome between European countries. Therefore, EURECCA, which is the acronym of European Registration of cancer care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012 the first multidisciplinary consensus conference about colon and rectum was held looking for multidisciplinary consensus. The expert panel consisted of representatives of European scientific organisations involved in cancer care of patients with colon and rectal cancer and representatives of national colorectal registries.

    Methods: The expert panel had delegates of the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy & Oncology (ESTRO), European Society of Pathology (ESP), European Society for Medical Oncology (ESMO), European Society of Radiology (ESR), European Society of Coloproctology (ESCP), European CanCer Organisation (ECCO), European Oncology Nursing Society (EONS) and the European Colorectal Cancer Patient Organisation (EuropaColon), as well as delegates from national registries or audits. Experts commented and voted on the two web-based online voting rounds before the meeting (between 4th and 25th October and between the 20th November and 3rd December 2012) as well as one online round after the meeting (4th-20th March 2013) and were invited to lecture on the subjects during the meeting (13th-15th December 2012). The sentences in the consensus document were available during the meeting and a televoting round during the conference by all participants was performed. All sentences that were voted on are available on the EURECCA website www.canceraudit.eu. The consensus document was divided in sections describing evidence based algorithms of diagnostics, pathology, surgery, medical oncology, radiotherapy, and follow-up where applicable for treatment of colon cancer, rectal cancer and stage IV separately. Consensus was achieved using the Delphi method.

    Results: The total number of the voted sentences was 465. All chapters were voted on by at least 75% of the experts. Of the 465 sentences, 84% achieved large consensus, 6% achieved moderate consensus, and 7% resulted in minimum consensus. Only 3% was disagreed by more than 50% of the members.

    Conclusions: It is feasible to achieve European Consensus on key diagnostic and treatment issues using the Delphi method. This consensus embodies the expertise of professionals from all disciplines involved in the care for patients with colon and rectal cancer. Diagnostic and treatment algorithms were developed to implement the current evidence and to define core treatment guidance for multidisciplinary team management of colon and rectal cancer throughout Europe.

  • 282. van de Velde, Cornelis J. H.
    et al.
    Boelens, Petra G.
    Borras, Josep M.
    Coebergh, Jan-Willem
    Cervantes, Andres
    Blomqvist, Lennart
    Beets-Tan, Regina G. H.
    van den Broek, Colette B. M.
    Brown, Gina
    Van Cutsem, Eric
    Espin, Eloy
    Haustermans, Karin
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Iversen, Lene H.
    van Krieken, J. Han
    Marijnen, Corrie A. M.
    Henning, Geoffrey
    Gore-Booth, Jola
    Meldolesi, Elisa
    Mroczkowski, Pawel
    Nagtegaal, Iris
    Naredi, Peter
    Ortiz, Hector
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Quirke, Philip
    Roedel, Claus
    Roth, Arnaud
    Rutten, Harm
    Schmoll, Hans J.
    Smith, Jason J.
    Tanis, Pieter J.
    Taylor, Claire
    Wibe, Arne
    Wiggers, Theo
    Gambacorta, Maria A.
    Aristei, Cynthia
    Valentini, Vincenzo
    EURECCA colorectal: Multidisciplinary management: European consensus conference colon & rectum2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 1, p. UNSP 1.e1-Article in journal (Refereed)
    Abstract [en]

    Background

    Care for patients with colon and rectal cancer has improved in the last 20 years; however considerable variation still exists in cancer management and outcome between European countries. Large variation is also apparent between national guidelines and patterns of cancer care in Europe. Therefore, EURECCA, which is the acronym of European Registration of Cancer Care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012, the first multidisciplinary consensus conference about cancer of the colon and rectum was held. The expert panel consisted of representatives of European scientific organisations involved in cancer care of patients with colon and rectal cancer and representatives of national colorectal registries.

    Methods

    The expert panel had delegates of the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy & Oncology (ESTRO), European Society of Pathology (ESP), European Society for Medical Oncology (ESMO), European Society of Radiology (ESR), European Society of Coloproctology (ESCP), European CanCer Organisation (ECCO), European Oncology Nursing Society (EONS) and the European Colorectal Cancer Patient Organisation (EuropaColon), as well as delegates from national registries or audits. Consensus was achieved using the Delphi method. For the Delphi process, multidisciplinary experts were invited to comment and vote three web-based online voting rounds and to lecture on the subjects during the meeting (13th-15th December 2012). The sentences in the consensus document were available during the meeting and a televoting round during the conference by all participants was performed. This manuscript covers all sentences of the consensus document with the result of the voting. The consensus document represents sections on diagnostics, pathology, surgery, medical oncology, radiotherapy, and follow-up where applicable for treatment of colon cancer, rectal cancer and metastatic colorectal disease separately. Moreover, evidence based algorithms for diagnostics and treatment were composed which were also submitted to the Delphi process.

    Results

    The total number of the voted sentences was 465. All chapters were voted on by at least 75% of the experts. Of the 465 sentences, 84% achieved large consensus, 6% achieved moderate consensus, and 7% resulted in minimum consensus. Only 3% was disagreed by more than 50% of the members.

    Conclusions

    Multidisciplinary consensus on key diagnostic and treatment issues for colon and rectal cancer management using the Delphi method was successful. This consensus document embodies the expertise of professionals from all disciplines involved in the care for patients with colon and rectal cancer. Diagnostic and treatment algorithms were developed to implement the current evidence and to define core treatment guidance for multidisciplinary team management of colon and rectal cancer throughout Europe.

  • 283.
    van Rijssen, L. B.
    et al.
    AMC, Dept Surg, Amsterdam, Netherlands..
    ter Veer, E.
    AMC, Dept Med Oncol, Amsterdam, Netherlands..
    Besselink, M. G.
    AMC, Dept Surg, Amsterdam, Netherlands..
    Mali, R. M. A.
    AMC, Dept Med Oncol, Amsterdam, Netherlands..
    Berlin, J.
    Vanderbilt Ingram Canc Ctr, Med Oncol, Nashville, TN USA..
    Boeck, S.
    Ludwig Maximilians Univ Munchen, Dept Internal Med 3, Comprehens Canc Ctr, Munich, Germany..
    Bonnetain, F.
    CHRU Besancon Jean Minjoz, Methodol & Qual Life Unit Oncol EA 3181, Besancon, France..
    Conroy, T.
    Inst Cancerol Lorraine, Med Oncol, Vandoeuvre Les Nancy, France..
    Deplanque, G.
    Hop Riviera Chablais, Med Oncol, Vevey, Switzerland..
    Goldstein, D.
    Univ New South Wales, Canc Survivors Ctr, Canc Res Ctr, Sydney, NSW, Australia..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Neoptolemos, J. P.
    Univ Liverpool, Surg Oncol, Liverpool, Merseyside, England..
    Reni, M.
    Ist Sci San Raffaele, Med Oncol, IRCCS, Milan, Italy..
    Scheithauer, W.
    Med Univ Wien, Dept Internal Med, Vienna Gen Hosp AKH, Vienna, Austria..
    van der Meer, J.
    AMC, Dept Surg, Amsterdam, Netherlands..
    Wilmink, J. W.
    AMC, Dept Med Oncol, Amsterdam, Netherlands..
    van der Poel, M. J.
    AMC, Dept Surg, Amsterdam, Netherlands..
    Busch, O. R.
    AMC, Dept Surg, Amsterdam, Netherlands..
    van Oijen, M. G. H.
    AMC, Dept Med Oncol, Amsterdam, Netherlands..
    van Laarhoven, H. W. M.
    AMC, Dept Med Oncol, Amsterdam, Netherlands..
    COnsensus statement on Mandatory Measurements in PAncreatic Cancer Trials for systemic treatment of unresectable disease (COMMPACT)2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no S5, article id 746PArticle in journal (Other academic)
  • 284. Vernerey, Dewi
    et al.
    Hammel, Pascal
    Paget-Bailly, Sophie
    Huguet, Florence
    Van Laethem, Jean Luc
    Goldstein, David
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Artru, Pascal
    Moore, Malcolm J.
    Andre, Thierry
    Mineur, Laurent
    Chibaudel, Benoist
    Louvet, Christophe
    Bonnetain, Franck
    Prognosis model for overall survival in locally advanced unresecable pancreatic carcinoma: An ancillary study of the LAP 07 trial2015In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 33, no 3, article id 235Article in journal (Other academic)
  • 285. Verslype, C.
    et al.
    Van Cutsem, E.
    Dicato, M.
    Cascinu, S.
    Cunningham, D.
    Diaz-Rubio, E.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Haller, D.
    Haustermans, K.
    Heinemann, V.
    Hoff, P.
    Johnston, P. G.
    Kerr, D.
    Labianca, R.
    Louvet, C.
    Minsky, B.
    Moore, M.
    Nordlinger, B.
    Pedrazzoli, S.
    Roth, A.
    Rothenberg, M.
    Rougier, P.
    Schmoll, H-J
    Tabernero, J.
    Tempero, M.
    van de Velde, C.
    Van Laethem, J-L
    Zalcberg, J.
    The management of pancreatic cancer. Current expert opinion and recommendations derived from the 8th World Congress on Gastrointestinal Cancer, Barcelona, 20062007In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 18, no Suppl. 7, p. VII1-VII10Article in journal (Refereed)
    Abstract [en]

    This article summarizes the expert discussion on the management of pancreatic cancer, which took place during the 8th World Congress on Gastrointestinal Cancer in June 2006 in Barcelona. A multidisciplinary approach to a patient with pancreatic cancer is essential, in order to guarantee an optimal staging, surgery, selection of the appropriate (neo-)adjuvant strategy and chemotherapeutic choice management. Moreover, optimal symptomatic management requires a dedicated team of health care professionals. Quality control of surgery and pathology is especially important in this disease with a high locoregional failure rate. There is now solid evidence in favour of chemotherapy in both the adjuvant and palliative setting, and gemcitabine combined with erlotinib, capecitabine or platinum compounds seems to be slightly more active than gemcitabine alone in advanced pancreatic cancer. There is a place for chemoradiotherapy in selected patients with locally advanced disease, while the role in the adjuvant setting remains controversial. Those involved in the care for patients with pancreatic cancer should be encouraged to participate in well-designed clinical trials, in order to increase the evidence-based knowledge and to make further progress.

  • 286. Vijai, Joseph
    et al.
    Wang, Zhaoming
    Berndt, Sonja I.
    Skibola, Christine F.
    Slager, Susan L.
    de Sanjose, Silvia
    Melbye, Mads
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bracci, Paige M.
    Conde, Lucia
    Birmann, Brenda M.
    Wang, Sophia S.
    Brooks-Wilson, Angela R.
    Lan, Qing
    de Bakker, Paul I. W.
    Vermeulen, Roel C. H.
    Portlock, Carol
    Ansell, Stephen M.
    Link, Brian K.
    Riby, Jacques
    North, Kari E.
    Gu, Jian
    Hjalgrim, Henrik
    Cozen, Wendy
    Becker, Nikolaus
    Teras, Lauren R.
    Spinelli, John J.
    Turner, Jenny
    Zhang, Yawei
    Purdue, Mark P.
    Giles, Graham G.
    Kelly, Rachel S.
    Zeleniuch-Jacquotte, Anne
    Ennas, Maria Grazia
    Monnereau, Alain
    Bertrand, Kimberly A.
    Albanes, Demetrius
    Lightfoot, Tracy
    Yeager, Meredith
    Chung, Charles C.
    Burdett, Laurie
    Hutchinson, Amy
    Lawrence, Charles
    Montalvan, Rebecca
    Liang, Liming
    Huang, Jinyan
    Ma, Baoshan
    Villano, Danylo J.
    Maria, Ann
    Corines, Marina
    Thomas, Tinu
    Novak, Anne J.
    Dogan, Ahmet
    Liebow, Mark
    Thompson, Carrie A.
    Witzig, Thomas E.
    Habermann, Thomas M.
    Weiner, George J.
    Smith, Martyn T.
    Holly, Elizabeth A.
    Jackson, Rebecca D.
    Tinker, Lesley F.
    Ye, Yuanqing
    Adami, Hans-Olov
    Smedby, Karin E.
    De Roos, Anneclaire J.
    Hartge, Patricia
    Morton, Lindsay M.
    Severson, Richard K.
    Benavente, Yolanda
    Boffetta, Paolo
    Brennan, Paul
    Foretova, Lenka
    Maynadie, Marc
    Mckay, James
    Staines, Anthony
    Diver, W. Ryan
    Vajdic, Claire M.
    Armstrong, Bruce K.
    Kricker, Anne
    Zheng, Tongzhang
    Holford, Theodore R.
    Severi, Gianluca
    Vineis, Paolo
    Ferri, Giovanni M.
    Ricco, Rosalia
    Miligi, Lucia
    Clavel, Jacqueline
    Giovannucci, Edward
    Kraft, Peter
    Virtamo, Jarmo
    Smith, Alex
    Kane, Eleanor
    Roman, Eve
    Chiu, Brian C. H.
    Fraumeni, Joseph F.
    Wu, Xifeng
    Cerhan, James R.
    Offit, Kenneth
    Chanock, Stephen J.
    Rothman, Nathaniel
    Nieters, Alexandra
    A genome-wide association study of marginal zone lymphoma shows association to the HLA region2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id UNSP 5751Article in journal (Refereed)
    Abstract [en]

    Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P - 3.95 x 10(-15)) and HLA-B (rs2922994, P - 2.43 x 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.

  • 287.
    Walters, Sarah
    et al.
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Benitez-Majano, Sara
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Muller, Patrick
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Coleman, Michel P.
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Allemani, Claudia
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Butler, John
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England.;Royal Marsden Hosp, Dept Gynaecol Oncol, London SW3 6JJ, England..
    Peake, Mick
    Univ Hosp Leicester, Glenfield Hosp, Leicester LE3 9QP, Leics, England..
    Guren, Marianne Gronlie
    Oslo Univ Hosp, Dept Oncol, N-0424 Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, NO-0424 Oslo, Norway..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bergstrom, Stefan
    Gavle Cent Hosp, Dept Oncol, SE-80187 Gavle, Sweden..
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Rachet, Bernard
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Is England closing the international gap in cancer survival?2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 113, no 5, p. 848-860Article in journal (Refereed)
    Abstract [en]

    Background: We provide an up-to-date international comparison of cancer survival, assessing whether England is 'closing the gap' compared with other high-income countries. Methods: Net survival was estimated using national, population-based, cancer registrations for 1.9 million patients diagnosed with a cancer of the stomach, colon, rectum, lung, breast (women) or ovary in England during 1995-2012. Trends during 1995-2009 were compared with estimates for Australia, Canada, Denmark, Norway and Sweden. Clinicians were interviewed to help interpret trends. Results: Survival from all cancers remained lower in England than in Australia, Canada, Norway and Sweden by 2005-2009. For some cancers, survival improved more in England than in other countries between 1995-1999 and 2005-2009; for example, 1-year survival from stomach, rectal, lung, breast and ovarian cancers improved more than in Australia and Canada. There has been acceleration in lung cancer survival improvement in England recently, with average annual improvement in 1-year survival rising to 2% during 2010-2012. Survival improved more in Denmark than in England for rectal and lung cancers between 1995-1999 and 2005-2009. Conclusions: Survival has increased in England since the mid-1990s in the context of strategic reform in cancer control, however, survival remains lower than in comparable developed countries and continued investment is needed to close the international survival gap.

  • 288.
    Wang, Sophia S.
    et al.
    City Hope Natl Med Ctr, 1500 East Duarte Rd, Duarte, CA 91010 USA;Beckman Res Inst, Dept Populat Sci, Duarte, CA USA.
    Carrington, Mary
    Ragon Inst MGH MIT & Harvard, Cambridge, MA USA;Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD USA.
    Berndt, Sonja I.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Slager, Susan L.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA.
    Bracci, Paige M.
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.
    Voutsinas, Jenna
    City Hope Natl Med Ctr, 1500 East Duarte Rd, Duarte, CA 91010 USA;Beckman Res Inst, Dept Populat Sci, Duarte, CA USA.
    Cerhan, James R.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA.
    Smedby, Karin E.
    Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden;Karolinska Inst, Clin Epidemiol Unit, Dept Med Solna, Stockholm, Sweden.
    Hjalgrim, Henrik
    Rigshosp, Dept Hematol, Copenhagen, Denmark;Statens Serum Inst, Div Hlth Surveillance & Res, Dept Epidemiol Res, Copenhagen, Denmark.
    Vijai, Joseph
    Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA.
    Morton, Lindsay M.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Vermeulen, Roel
    Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands;Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Paltiel, Ora
    Hadassah Hebrew Univ Med Ctr, Braun Sch Publ Hlth & Community Med, Jerusalem, Israel.
    Vajdic, Claire M.
    Univ New South Wales, Ctr Big Data Res Hlth, Sydney, NSW, Australia.
    Linet, Martha S.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Nieters, Alexandra
    Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Baden Wurttembe, Germany.
    de Sanjose, Silvia
    CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain;IDIBELL, Inst Catala Oncol, Canc Epidemiol Res Programme, Unit Infect & Canc, Barcelona 08908, Spain.
    Cozen, Wendy
    Univ Southern Calif, Dept Pathol, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA;Univ Southern Calif, Dept Prevent Med, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA.
    Brown, Elizabeth E.
    Univ Alabama Birmingham, Sch Med, Dept Pathol, Birmingham, AL USA;Univ Alabama Birmingham, UAB Comprehens Canc Ctr, Birmingham, AL USA.
    Turner, Jennifer
    Douglass Hanly Moir Pathol, Dept Histopathol, Sydney, NSW, Australia;Macquarie Univ, Fac Med & Hlth Sci, Sydney, NSW, Australia.
    Spinelli, John J.
    Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada;British Columbia Canc Agcy, Canc Control Res, Vancouver, BC, Canada.
    Zheng, Tongzhang
    Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA.
    Birmann, Brenda M.
    Harvard Med Sch, Boston, MA USA;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.
    Flowers, Christopher R.
    Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA USA.
    Becker, Nikolaus
    German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Baden Wurttembe, Germany.
    Holly, Elizabeth A.
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.
    Kane, Eleanor
    Univ York, Dept Hlth Sci, York, N Yorkshire, England.
    Weisenburger, Dennis
    City Hope Natl Med Ctr, Dept Pathol, Duarte, CA USA.
    Maynadie, Marc
    Univ Burgundy, INSERM, UMR1231, Registry Hematol Malignancies Cote Or, Dijon, France;Dijon Univ Hosp, Dijon, France.
    Cocco, Pierluigi
    Univ Cagliari, Dept Publ Hlth Clin & Mol Med, Cagliari, Italy.
    Albanes, Demetrius
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Weinstein, Stephanie J.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Teras, Lauren R.
    Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA.
    Diver, W. Ryan
    Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA.
    Lax, Stephanie J.
    Univ York, Dept Hlth Sci, York, N Yorkshire, England.
    Travis, Ruth C.
    Univ Oxford, Canc Epidemiol Unit, Oxford, England.
    Kaaks, Rudolph
    German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Baden Wurttembe, Germany.
    Riboli, Elio
    Imperial Coll London, Sch Publ Hlth, London, England.
    Benavente, Yolanda
    CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain;IDIBELL, Inst Catala Oncol, Canc Epidemiol Res Programme, Unit Infect & Canc, Barcelona 08908, Spain.
    Brennan, Paul
    Int Agcy Res Canc, Lyon, France.
    McKay, James
    CHU Henri Mondor, Dept Immunol, Creteil, France.
    Delfau-Larue, Marie-Helene
    CHU Henri Mondor, INSERM, U955, Creteil, France;CHU Henri Mondor, Dept Immunol, Creteil, France.
    Link, Brian K.
    Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA.
    Magnani, Corrado
    Univ Piemonte Orientale, Unit Med Stat & Epidemiol, Dept Translat Med, Novara, Italy;Univ Piemonte Orientale, Ctr Oncol Prevent CPO Piemonte, Novara, Italy.
    Ennas, Maria Grazia
    Univ Cagliari, Dept Biomed Sci, Cagliari, Italy.
    Latte, Giancarlo
    S Francesco Hosp, Div Hematol, Nuoro, Italy.
    Feldman, Andrew L.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA.
    Doo, Nicole Wong
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
    Giles, Graham G.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia;Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
    Southey, Melissa C.
    Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia.
    Milne, Roger L.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia;Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
    Offit, Kenneth
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Musinsky, Jacob
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Arslan, Alan A.
    NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA;NYU, Dept Environm Med, Sch Med, 550 1St Ave, New York, NY 10016 USA;NYU, Langone Med Ctr, Perlmutter Canc Ctr, New York, NY USA.
    Purdue, Mark P.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Adami, Hans-Olov
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Melbye, Mads
    Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA;Statens Serum Inst, Div Hlth Surveillance & Res, Dept Epidemiol Res, Copenhagen, Denmark.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Conde, Lucia
    UCL, UCL Canc Inst, Bill Lyons Informat Ctr, London, England.
    Camp, Nicola J.
    Univ Utah, Sch Med, Dept Internal Med, Huntsman Canc Inst, Salt Lake City, UT USA.
    Glenn, Martha
    Univ Utah, Sch Med, Dept Internal Med, Huntsman Canc Inst, Salt Lake City, UT USA.
    Curtin, Karen
    Univ Utah, Sch Med, Dept Internal Med, Huntsman Canc Inst, Salt Lake City, UT USA.
    Clavel, Jacqueline
    Univ Paris 05, Paris, France;Ctr Res Epidemiol & Stat Sorbonne Paris Cite CRES, Epidemiol Childhood & Adolescent Canc Grp, INSERM, Paris, France.
    Monnereau, Alain
    Univ Paris 05, Paris, France;Univ Bordeaux, Inst Bergonie, Registre Hemopathies Malignes Gironde, Inserm,Team EPICENE,UMR 1219, Bordeaux, France.
    Cox, David G.
    Ctr Leon Berard, INSERM, UMR1052, Canc Res Ctr Lyon, Lyon, France. Ctr Leon Berard, Dept Hematol, Lyon, France;Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
    Ghesquieres, Herve
    CNRS, UMR 5239, Lab Biol Mol Cellule, Pierre Benite, France;Univ Paris 05, Paris, France.
    Salles, Gilles
    CNRS, UMR 5239, Lab Biol Mol Cellule, Pierre Benite, France;Univ Claude Bernard Lyon, Lyon, France;Ctr Hosp Lyon Sud, Hosp Civils Lyon, Dept Hematol, Lyon, France.
    Bofetta, Paulo
    Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA.
    Foretova, Lenka
    MF MU, Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic.
    Staines, Anthony
    Dublin City Univ, Sch Nursing & Human Sci, Dublin, Ireland.
    Davis, Scott
    Univ Washington, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA;Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA.
    Severson, Richard K.
    Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA.
    Lan, Qing
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Brooks-Wilson, Angela
    BC Canc Agcy, Genome Sci Ctr, Vancouver, BC, Canada;Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada.
    Smith, Martyn T.
    Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA.
    Roman, Eve
    Univ York, Dept Hlth Sci, York, N Yorkshire, England.
    Kricker, Anne
    Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW, Australia.
    Zhang, Yawei
    Yale Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT USA;Yale Sch Med, Dept Surg, New Haven, CT USA.
    Kraft, Peter
    Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA;Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Rothman, Nathaniel
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Hartge, Patricia
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Skibola, Christine F.
    Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA USA.
    HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 14, p. 4086-4096Article in journal (Refereed)
    Abstract [en]

    A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma.

  • 289. Wettergren, Lena
    et al.
    Lindberg, Mathilde Hedlund
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Kettis, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ring, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Comparison of two instruments for measurement of quality of life in clinical practice - a qualitative study2014In: BMC Medical Research Methodology, ISSN 1471-2288, E-ISSN 1471-2288, Vol. 14, p. 115-Article in journal (Refereed)
    Abstract [en]

    Background: The study aimed to investigate the meaning patients assign to two measures of quality of life: the Schedule for Evaluation of Individual Quality of Life Direct Weighting (SEIQoL-DW) and the SEIQoL-DW Disease Related (DR) version, in a clinical oncology setting. Even though the use of quality of life assessments has increased during the past decades, uncertainty regarding how to choose the most suitable measure remains. SEIQoL-DW versions assesses the individual's perception of his or her present quality of life by allowing the individual to nominate the domains to be evaluated followed by a weighting procedure resulting in qualitative (domains) as well as quantitative outcomes (index score). Methods: The study applied a cross-sectional design with a qualitative approach and collected data from a purposeful sample of 40 patients with gastrointestinal cancer. Patients were asked to complete two measures, SEIQoL-DW and the SEIQoL-DR, to assess quality of life. This included nomination of the areas in life considered most important and rating of these areas; after completion patients participated in cognitive interviews around their selections of areas. Interviews were audiotaped and transcribed verbatim which was followed by analysis using a phenomenographic approach. Results: The analyses of nominated areas of the two measures resulted in 11 domains reflecting what patients perceived had greatest impact on their quality of life. Analysis of the cognitive interviews resulted in 16 thematic categories explaining the nominated domains. How patients reflected around their quality of life appeared to differ by version (DW vs. DR). The DW version more often related to positive aspects in life while the DR version more often related to negative changes in life due to having cancer. Conclusions: The two SEIQoL versions tap into different concepts; health-related quality of life, addressing losses and problems related to having cancer and, quality of life, more associated with aspects perceived as positive in life. The SEIQoL-DR and the SEIQoL-DW are recommended in clinical practice to take both negative and positive aspects into account and acting on the problems of greatest importance to the patient.

  • 290.
    Whither, Stine Braendegaard
    et al.
    Odense Univ Hosp, Dept Oncol, DK-5000 Odense C, Denmark;Odense Univ Hosp, Acad Geriatr Canc Res AgeCare, Odense, Denmark;Univ Southern Denmark, Dept Clin Res, Odense, Denmark.
    Liposits, Gabor
    Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Skuladottir, Haifa
    Reg Hosp West Jutland, Dept Oncol, Herning, Denmark.
    Hofsli, Eva
    Trondheim Reg & Univ Hosp, Dept Oncol, Trondheim, Norway.
    Shah, Carl-Henrik
    Karolinska Univ Hosp, Theme Canc, Stockholm, Sweden.
    Poulsen, Laurids Östergaard
    Aalborg Univ Hosp, Dept Oncol, Aalborg, Denmark.
    Ryg, Jesper
    Odense Univ Hosp, Dept Geriatr Med, Odense, Denmark;Odense Univ Hosp, Acad Geriatr Canc Res AgeCare, Odense, Denmark;Univ Southern Denmark, Dept Clin Res, Odense, Denmark.
    Osterlund, Pia
    Tampere Univ, Tampere Univ Hosp, Dept Oncol, Tampere, Finland;Univ Helsinki, Dept Oncol, Helsinki Univ Hosp, Helsinki, Finland.
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Qvortrup, Camilla
    Odense Univ Hosp, Dept Oncol, DK-5000 Odense C, Denmark;Odense Univ Hosp, Acad Geriatr Canc Res AgeCare, Odense, Denmark.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, DK-5000 Odense C, Denmark;Odense Univ Hosp, Acad Geriatr Canc Res AgeCare, Odense, Denmark;Odense Univ Hosp, Odense Patient Data Explorat Network, OPEN, Odense, Denmark;Univ Southern Denmark, Dept Clin Res, Odense, Denmark.
    Reduced-dose combination chemotherapy (S-1 plus oxaliplatin) versus full- dose monotherapy (S-1) in older vulnerable patients with metastatic colorectal cancer (NORDIC9): a randomised, open-label phase 2 trial2019In: The Lancet Gastroenterology & Hepatology, ISSN 2468-1253, Vol. 4, no 5, p. 376-388Article in journal (Refereed)
    Abstract [en]

    Background: Older or vulnerable patients with metastatic colorectal cancer are seldom included in randomised trials.The multicentre NORDIC9 trial evaluated reduced-dose combination chemotherapy compared with full-dose monotherapy in older, vulnerable patients.

    Methods: This randomised, open-label phase 2 trial was done in 23 Nordic oncology clinics and included patients aged 70 years or older with previously untreated metastatic colorectal cancer who were not candidates for full-dose combination chemotherapy. Patients were block randomised (1: 1) using a web-based tool to full-dose S-1 (30 mg/m(2) orally twice daily on days 1-14 every 3 weeks) followed by second-line treatment at progression with irinotecan (250 mg/m(2) intravenously on day 1 every 3 weeks or 180 mg/m(2) intravenously on day 1 every 2 weeks) or reduceddose combination chemotherapy with S-1 (20 mg/m(2) orally twice daily on days 1-14) and oxaliplatin (100 mg/m(2) intravenously on day 1 every 3 weeks) followed by second-line treatment at progression with S-1 (20 mg/m(2) orally twice daily on days 1-14) and irinotecan (180 mg/m(2) intravenously on day 1 every 3 weeks). Use of bevacizumab (7.5 mg/kg intravenously on day 1 of each cycle) was optional. Treatment allocation was not masked and randomisation was stratified for institution and bevacizumab. The primary outcome was progression-free survival. Survival analyses were by intention to treat and safety analyses were done on the treated population. This trial is registered with EudraCT, number 2014-000394-39, and is closed to new participants.

    Findings: From March 9, 2015, to Oct 11, 2017, 160 patients with a median age of 78 years (IQR 76-81) were randomly assigned to full-dose monotherapy (n=83) or reduced-dose combination chemotherapy (n=77). At data cutoff (Sept 1, 2018; median follow-up 23.8 months [IQR 18.8-30.9]), 81 (98%) patients in the full-dose monotherapy group and 71 (92%) patients in the reduced-dose combination group had progressed or died. Median progression-free survival was significantly longer with reduced-dose combination chemotherapy (6.2 months [95% CI 5.3-8.3]) than with full-dose monotherapy (5.3 months [4.1-6.8]; hazard ratio [HR] 0.72 [95% CI 0.52-0.99]; p=0.047). Toxicity was evaluated in 157 patients who received treatment. Significantly more patients in the full-dose monotherapy group (51 [62%] of 82 patients) experienced at least one grade 3-4 adverse event than in the reduced-dose combination group (32 [43%] of 75 patients; p=0.014). Grade 3-4 diarrhoea (12 [15%] vs two [3%]; p=0.018), fatigue (ten [12%] vs three [4%]; p=0.083), and dehydration (five [6%] vs none; p=0.060) were more frequent in the full-dose monotherapy group than in the reduced-dose combination group. Treatment-related deaths occurred in three patients during firstline treatment and three patients during second-line treatment (two in the full-dose monotherapy group vs one in the reduced-dose combination group in both cases).

    Interpretation: Reduced-dose combination chemotherapy with S-1 and oxaliplatin for older, vulnerable patients with metastatic colorectal cancer was more effective and resulted in less toxicity than full-dose monotherapy with S-1. Reduced-dose combination chemotherapy could be a preferred treatment for this population.

  • 291.
    Winterling, Jeanette
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    The importance of expectations on the recovery period after cancer treatment2008In: Psycho-Oncology, ISSN 1057-9249, E-ISSN 1099-1611, Vol. 17, no 2, p. 190-198Article in journal (Refereed)
    Abstract [en]

    The purpose was to study expectations concerning recovery-related changes in life, e.g. beliefs regarding future adjustment back to 'normal' life after curative cancer treatment, whether these expectations were met and their importance for both patients' and their spouses' quality of life and psychological distress. Sixty-two patients and 42 spouses took part in the study. Data on recovery-related expectations, measured using a study-specific questionnaire (RRE), on quality of life using EORTC-QLQ C-30 and on psychological distress using HADS, were collected directly after completion of treatment, four and 16 months later. Optimism was measured using LOT at the last follow-up. The results demonstrate that patients generally had higher recovery-related expectations than did their spouses, and their expectations were also fulfilled to a lesser degree at both follow-ups. However, the expectations, or whether these were met, were generally not associated with their quality of life or psychological distress. The few associations that were made indicated that fulfilled expectations meant higher quality of life and/or less distress. The participants' optimism was associated with both their quality of life and psychological distress. It is concluded that optimism influenced the participants' quality of life and psychological distress to a higher degree than did their recovery-related expectations.

  • 292.
    Winterling, Jeanette
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Wasteson, Elisabet
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Glimelius, Bengt
    Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Sjödén, Per-Olow
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Nordin, Karin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Substantial changes in life: perceptions in patients with newly diagnosed advanced cancer and their spouses.2004In: Cancer Nurs, ISSN 0162-220X, Vol. 27, no 5, p. 381-8Article in journal (Refereed)
  • 293.
    Winther, S. B.
    et al.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Osterlund, P.
    Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland..
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Qvortrup, C.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Sorbye, H.
    Haukeland Univ Sykehus, Dept Oncol, Bergen, Norway..
    Pfeiffer, P.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    NORDIC9: A randomized phase II trial exploring treatment of older patients with metastatic colorectal cancer (mCRC) by comparing full dose monotherapy (S-1 followed by irinotecan) with reduced combination regimen (S-1/oxaliplatin followed by S-1/irinotecan)2016In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27, no suppl. 6, article id 601TiPArticle in journal (Refereed)
  • 294.
    Winther, Stine Braendegaard
    et al.
    Odense Univ Hosp, Dept Oncol, Sdr Blvd 29, DK-5000 Odense C, Denmark..
    Österlund, Pia
    Univ Helsinki, Cent Hosp, Dept Oncol, Stenbackinkatu 9,POB 100, FI-00029 Helsinki, Finland.;Univ Helsinki, Clinicum, Haartmaninkatu 8,3th Floor,POB 63, Helsinki 00014, Finland..
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Qvortrup, Camilla
    Odense Univ Hosp, Dept Oncol, Sdr Blvd 29, DK-5000 Odense C, Denmark..
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Postboks 1400, N-5021 Bergen, Norway.;Haukeland Hosp, Dept Clin Sci, Postboks 1400, N-5021 Bergen, Norway..
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Sdr Blvd 29, DK-5000 Odense C, Denmark..
    Randomized study comparing full dose monotherapy (S-1 followed by irinotecan) and reduced dose combination therapy (S-1/oxaliplatin followed by S-1/irinotecan) as initial therapy for older patients with metastatic colorectal cancer: NORDIC 92017In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, article id 548Article in journal (Refereed)
    Abstract [en]

    Background: Metastatic colorectal cancer (mCRC) is a disease of older age, but there is a relative lack of knowledge about effects of chemotherapy in older patients as they are under-represented in clinical trials. Little data can guide whether the strategy in older mCRC patients should be a sequential full-dose monotherapy chemotherapy approach or a dose-reduced combination chemotherapy approach. The oral 5FU prodrug S-1 seems to have less side effects than capecitabine and should be an optimal drug for older patients, but few data are available. Improved geriatric assessments are needed to select which older patients should receive therapy.

    Methods: The NORDIC 9 trial is a Nordic multicenter randomized phase II study comparing full dose monotherapy (S-1 30 mg/m(2) twice daily days 1-14 every 3 weeks, followed by second line irinotecan 250-350 mg/m(2) iv day 1 every 3 weeks or 180-250 mg/m(2) iv day 1 every 2 weeks) with reduced dose combination therapy (S-1 20 mg/m(2) days 1-14 + oxaliplatin 100 mg/m(2) iv day 1 every 3 weeks, followed by second line S-1 20 mg/m(2) days 1-14 + irinotecan 180 mg/m(2) day 1 every 3 week) for older patients (>= 70 years) with mCRC who are not candidates for full-dose standard combination therapy. Additional bevacizumab (7.5 mg/kg) is optional in first-line. Blood samples and tumor tissue will be collected to investigate predictive markers. Geriatric screening tools (G-8, VES-13, Timed-Up-and- Go and Handgrip strength), Charlson Comorbidty Index and quality of life (EORTC QLQ-C30) will be evaluated as predictors of efficacy and toxicity. The target sample size is 150 patients. The primary endpoint is progression-free survival and secondary endpoints are time-to-failure of strategy, overall survival, response rate, toxicity, and correlations between biomarkers, pre-treatment characteristics and geriatric assessments.

    Discussion: The study will add knowledge on how to treat older mCRC patients who are not candidates for standard combination therapy. Furthermore it may provide understanding of efficacy and tolerability of chemotherapy in older cancer patients and thus offer a better chance for tailored treatment strategies in these patients.

  • 295. Worrillow, Lisa
    et al.
    Smith, Alex
    Scott, Kathryn
    Andersson, Michael
    Ashcroft, John
    Dores, Graca
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Holowaty, Eric
    Jackson, Graham
    Jones, Gail L
    Lynch, Charles
    Morgan, Gareth
    Pukkala, Eero
    Scott, Daniel
    Storm, Hans
    Taylor, Penny
    Vyberg, Mogens
    Willett, Eleanor
    Travis, Lois
    Allan, James
    Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma2008In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 45, no 3, p. 142-146Article in journal (Refereed)
    Abstract [en]

    Background and objective: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position-93, rs1800734) modifies the risk of cancer after methylating chemotherapy. Methods: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. Results: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. Conclusions: These data support the hypothesis that the common polymorphism at position - 93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.

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