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  • 101.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Cavalli-Björkman, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Does shared decision making exist in oncologic practice?2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 2, p. 125-128Article in journal (Other academic)
  • 102. Glimelius, Bengt
    et al.
    Dahl, Olav
    Cedermark, Björn
    Jakobsen, Anders
    Bentzen, Sören M
    Starkhammar, Hans
    Grönberg, Henrik
    Hultborn, Ragnar
    Albertsson, Maria
    Pahlman, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Tveit, Kjell-Magne
    Adjuvant chemotherapy in colorectal cancer: A joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group.2005In: Acta Oncol, ISSN 0284-186X, Vol. 44, no 8, p. 904-12Article in journal (Refereed)
  • 103.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hohenberger, Werner Max
    Univ Klinikums Erlangen, Chirurg Klin, Erlangen, Germany..
    Matzel, Klaus E.
    Univ Klinikums Erlangen, Chirurg Klin, Erlangen, Germany..
    Sugihara, Kenichi
    Tokyo Med & Dent Univ, Tokyo, Japan..
    Quirke, Philip
    St James Univ Hosp, Leeds, W Yorkshire, England..
    Further Evaluating the Benefit of Adjuvant Chemotherapy for Colon Cancer Reply2016In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 30, p. 3713-+Article in journal (Refereed)
  • 104.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansen, Christoffer
    Muren, Ludvig Paul
    Nilbert, Mef
    Acta Oncologica and a new generation of scientists in oncology2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 7, p. 849-851Article in journal (Other academic)
  • 105.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kowalski, Jan
    JK Biostat, Stockholm, Sweden.
    Nasstrom, Jacques
    PledPharma AB, Stockholm, Sweden.
    The PLIANT trial gives trustworthy data2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 6, p. 864-866Article in journal (Other academic)
  • 106.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Manojlovic, Nebojsa
    Mil Med Acad Serbia, Clin Gastroenterol & Hepatol, Belgrade.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense.
    Mosidze, Baadur
    Univ Clin, LTD High Technol Med Ctr, Tbilisi.
    Kurteva, Galina
    SHATO EAD, Clin Chemotherapy, Sofia.
    Karlberg, Mia
    Karolinska Inst, Dept Pathol & Oncol, Stockholm.
    Mahalingam, Devalingam
    Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio.
    Buhl Jensen, Peter
    Buhl Oncol, Copenhagen.; PledPharma AB, Stockholm.
    Kowalski, Jan
    JK Biostat, Stockholm.
    Bengtson, Marie
    PledPharma AB, Stockholm.
    Nittve, Malin
    PledPharma AB, Stockholm.
    Nässtrom, Jacques
    PledPharma AB, Stockholm.
    Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx®): a placebo-controlled randomised phase II study (PLIANT)2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 3, p. 393-402Article in journal (Refereed)
    Abstract [en]

    Purpose: Oxaliplatin causes disabling acute and chronic peripheral neuropathy. We explored the preventive effects of calmangafodipir, mimicking the mitochondrial enzyme manganese superoxide dismutase, thereby protecting cells from oxidative stress, in a placebo-controlled, double-blinded randomised phase II study (ClinicalTrials.gov.NCT01619423) in patients with metastatic colorectal cancer (mCRC).

    Patient and methods: mCRC patients treated with modified FOLFOX-6 (folinic acid 200 mg/m2, 5-fluorouracil bolus 400 mg/m2, oxaliplatin 85 mg/m2 and 5-fluorouracil 2400 mg/m2 continuous infusion for 46 h) every fortnight for 8 cycles in first or second line were eligible. Calmangafodipir was given in a phase I dose-finding and in a phase II placebo-controlled study, as a 5-min infusion 10 min prior to oxaliplatin. Neurotoxicity was evaluated by the physician using the Oxaliplatin Sanofi Specific Scale and by the patient using the cold allodynia test and the Leonard scale.

    Results: Eleven patients were included in phase I without any detectable toxicity to calmangafodipir. In the phase II study, 173 patients were randomised to placebo (n = 60), calmangafodipir 2 µmol/kg (n = 57) and calmangafodipir 5 µmol/kg (n = 45, initially 10 µmol/kg, n = 11). Calmangafodipir-treated patients (all three doses pooled) had less physician graded neurotoxicity (odds ratio (90% confidence interval one-sided upper level) 0.62(1.15), p = .16), significantly less problems with cold allodynia (mean 1.6 versus 2.3, p < .05) and significantly fewer sensory symptoms in the Leonard scale (cycle 1–8 mean 1.9 versus 3.0, p < .05 and during follow-up after 3 and 6 months, mean 3.5 versus 7.3, p < .01). Response rate, progression-free and overall survival did not differ among groups.

    Conclusions: Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes.

  • 107.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Martling, A.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    What conclusions can be drawn from the Stockholm III rectal cancer trial in the era of watch and wait?2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 9, p. 1139-1142Article in journal (Other academic)
  • 108.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Melin, Beatrice
    Umeå Univ, Dept Radiat Sci, Umeå.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Beskow, Anna H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Björ, Ove
    Umeå Univ, Dept Radiat Sci, Umeå.
    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.
    Hansson, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Henriksson, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hultdin, Magnus
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Jonsson, Håkan
    Umeå Univ, Dept Radiat Sci, Umeå.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljuslinder, Ingrid
    Umeå Univ, Dept Radiat Sci, Umeå.
    Mindus, Stephanie
    Akad Sjukhuset, Lung & Allergy Clin, Uppsala.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Riklund, Katrine
    Umeå Univ, Dept Radiat Sci, Umeå.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sandin, Fredrik
    Uppsala Univ Hosp, RCC Uppsala Örebro, Uppsala.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Solna.
    Stenling, Roger
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Thellenberg Karlsson, Camilla
    Umeå Univ, Dept Radiat Sci, Umeå.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergh, Anders
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Palmqvist, Richard
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

    Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

    Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

    Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 109.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Montelius, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Proton beam therapy - do we need the randomised trials and can we do them?2007In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 83, no 2, p. 105-109Article in journal (Refereed)
  • 110.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Myklebust, Tor Åge
    Canc Registry Norway, Dept Registrat, Oslo, Norway..
    Lundqvist, Kristina
    Umea Univ, Dept Radiat Sci, Oncol, S-90187 Umea, Sweden..
    Wibe, Arne
    Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Trondheim, Norway..
    Guren, Marianne G.
    Oslo Univ Hosp, Dept Oncol, N-0450 Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, N-0450 Oslo, Norway..
    Two countries - Two treatment strategies for rectal cancer2016In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 121, no 3, p. 357-363Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Trials in rectal cancer have shown that radiotherapy (RT) decreases local recurrence rates, whereas the effects on survival are uncertain. Swedish and Norwegian oncologists have had different treatment recommendations. The aim was to evaluate local recurrence rates and survival in the two countries. Patients and methods: Between 1995 and 2012 rectal cancer patients registered in Sweden and Norway were analyzed, presenting population-based "real world" data. Results: Totally 29,029 Swedish and 15,456 Norwegian patients were analyzed. Resection for cure was performed in two-thirds of the patients. RT was given to 49% of Swedish patients, mainly short-course RT and to 26% of Norwegian patients, predominantly chemoradiotherapy (CRT). In Sweden, the proportion irradiated was stable whereas in Norway, an increase from 10% to 40% was seen. Local 5-year recurrence rates were initially higher in Norway (12%) than in Sweden (8%), whereas they were equally low (4%) during the latter time. No survival differences were seen, however, survival improved with time in both countries. Conclusions: Two entirely different approaches to preoperative therapy resulted in similar survival with initially higher local recurrence rates in Norway, but similarly low rates in later years. This raises questions about optimal RT rates and regimens.

  • 111.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lessons learned from the maturation of a cancer drug: oxaliplatin in colorectal cancer2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 4, p. 395-397Article in journal (Refereed)
  • 112.
    Glimelius, Bengt
    et al.
    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.
    Do we make progress in elderly patients with metastatic colorectal cancer?2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 11, p. 1422-1426Article in journal (Other academic)
  • 113.
    Glimelius, Bengt
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Steineck, Gunnar
    Low evidence of radiation therapy in prostate cancer--a plea for intensified scientific activity.2004In: Acta Oncol, ISSN 0284-186X, Vol. 43, no 4, p. 311-5Article in journal (Other scientific)
  • 114.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Tiret, E.
    Cervantes, A.
    Arnold, D.
    Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up2013In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, no Suppl. 6, p. 81-88Article in journal (Refereed)
  • 115.
    Goey, Kaitlyn K. H.
    et al.
    Univ Med Ctr Utrecht, Dept Med Oncol, Utrecht, Netherlands.
    Mahmoud, Remi
    Univ Med Ctr Utrecht, Dept Med Oncol, Utrecht, Netherlands.
    Sørbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway; Haukeland Hosp, Dept Clin Sci, Bergen, Norway.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Köhne, Claus-Henning
    Klinikum Oldenburg, Univ Clin Internal Med Oncol & Hematol, Oldenburg, Germany.
    Sargent, Daniel J.
    Mayo Clin, Ctr Canc, Div Biomed Stat & Informat, Rochester, MN USA.
    Punt, Cornelis J. A.
    Univ Amsterdam, Acad Med Ctr, Dept Med Oncol, Amsterdam, Netherlands.
    van Oijen, Martijn G. H.
    Univ Amsterdam, Acad Med Ctr, Dept Med Oncol, Amsterdam, Netherlands.
    Koopman, Miriam
    Univ Med Ctr Utrecht, Dept Med Oncol, Utrecht, Netherlands.
    Reporting of patient characteristics and stratification factors in phase 3 trials investigating first-line systemic treatment of metastatic colorectal cancer: A systematic review2018In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 96, p. 115-124Article, review/survey (Refereed)
    Abstract [en]

    Background: Patient characteristics and stratification factors are important factors influencing trial outcomes. Uniform reporting on these parameters would facilitate cross-study comparisons and extrapolation of trial results to clinical practice. In 2007, standardisation on patient characteristics reporting and stratification in metastatic colorectal cancer (mCRC) trials was proposed. We investigated the reporting of prognostic factors and implementation of this proposal in mCRC trials published from 2005 to 2016.

    Methods: We searched PubMed and Embase (January 2005 – June 2016) for first-line phase 3 mCRC trials. Patient characteristics reporting and use of stratification factors were extracted and analysed for adherence to the proposal from 2007.

    Results: Sixty-seven trials (35,315 patients) were identified, reporting 48 different patient characteristics (median: 9 [range: 5–18] per study). Age, gender, performance status (PS), primary tumour site and adjuvant chemotherapy were frequently reported (87%–100%), in contrast to laboratory values, such as alkaline phosphatase, lactate dehydrogenase and white blood cell count (10%–25%). We identified 29 different stratification factors (median: 3 [range: 1–9] per study). The most common strata were PS and treatment centre (>60%). A median of 8/12 (range: 4–11) of the proposed parameters was reported. Although the percentage of studies reporting each factor slightly increased over time, there was no significant correlation between publication year and adherence to the proposal from 2007.

    Conclusions: We observed persistent heterogeneity in the reporting of patient characteristics and use of stratification factors in first-line mCRC trials. The proposal from 2007 has not led to increased uniformity of patient characteristics reporting and use of stratification over time. There is an urgent need to address this issue to improve the interpretation of trial results.

  • 116.
    Goey, Kaitlyn K. H.
    et al.
    Univ Utrecht, Univ Med Ctr Utrecht, Dept Med Oncol, Utrecht, Netherlands.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway;Haukeland Hosp, Dept Clin Sci, Bergen, Norway.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden.
    Adams, Richard A.
    Ctr Trials Res Canc Grp, Cardiff, S Glam, Wales.
    Andre, Thierry
    UMPC Paris 06, Sorbonne Univ, Hop St Antoine, Dept Med Oncol, Paris, France.
    Arnold, Dirk
    Asklepios Klin Altona, Asklepios Tumorzentrum Hamburg, Hamburg, Germany.
    Berlin, Jordan D.
    Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA.
    Bodoky, György
    St Laszlo Hosp, Dept Med Oncol, Budapest, Hungary.
    de Gramont, Aimery
    Inst Hosp Franco Britannique, Dept Med Oncol, Paris, France.
    Diaz-Rubio, Eduardo
    Univ Complutense, Hosp Clin San Carlos, Dept Med Oncol, CIBERONC, Madrid, Spain.
    Eng, Cathy
    MD Anderson Canc Ctr, Dept Med Oncol, Houston, TX USA.
    Falcone, Alfredo
    Univ Pisa, Dept Med Oncol, Pisa, Italy.
    Grothey, Axel
    Mayo Clin, Div Med Oncol, Rochester, MN USA.
    Heineman, Volker
    Univ Clin Munich, Comprehens Canc Ctr, Med Dept 3, Munich, Germany.
    Hochster, Howard S.
    Rutgers Canc Inst New Jersey, New Brunswick, NJ USA.
    Kaplan, Richard S.
    UCL, MRC, Clin Trials Unit, London, England.
    Kopetz, Scott
    MD Anderson Canc Ctr, Dept Med Oncol, Houston, TX USA.
    Labianca, Roberto
    Osped Giovanni 23, Canc Ctr, Bergamo, Italy.
    Lieu, Christopher H.
    Univ Colorado, Div Med Oncol, Denver, CO 80202 USA.
    Meropol, Neal J.
    Flatiron Hlth, New York, NY USA;Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA.
    Price, Timothy J.
    Queen Elizabeth Hosp, Dept Med Oncol, Woodville, SA, Australia.
    Schilsky, Richard L.
    Amer Soc Clin Oncol, Alexandria, VA USA.
    Schmoll, Hans-Joachim
    Martin Luther Univ Halle Wittenberg, Univ Clin Halle, Div Clin Oncol Res, Halle, Germany.
    Shacham-Shmueli, Einat
    Sheba Med Ctr, Canc Ctr, Tel Hashomer, Israel.
    Shi, Qian
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA.
    Sobrero, Alberto F.
    Policlin San Martino IRCCS, Genoa, Italy.
    Souglakos, John
    Univ Gen Hosp Heraklion, Dept Med Oncol, Iraklion, Greece.
    van Cutsem, Eric
    Univ Hosp Gasthuisberg Leuven, Dept Digest Oncol, Leuven, Belgium;Katholieke Univ Leuven, Leuven, Belgium.
    Zalcberg, John
    Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia.
    van Oijen, Martijn G. H.
    Univ Amsterdam, Acad Med Ctr, Dept Med Oncol, Amsterdam, Netherlands.
    Punt, Cornelis J. A.
    Univ Amsterdam, Acad Med Ctr, Dept Med Oncol, Amsterdam, Netherlands.
    Koopman, Miriam
    Univ Utrecht, Univ Med Ctr Utrecht, Dept Med Oncol, Utrecht, Netherlands.
    Consensus statement on essential patient characteristics in systemic treatment trials for metastatic colorectal cancer: Supported by the ARCAD Group2018In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 100, p. 35-45Article in journal (Refereed)
    Abstract [en]

    Background: Patient characteristics and stratification factors are key features influencing trial outcomes. However, there is substantial heterogeneity in reporting of patient characteristics and use of stratification factors in phase 3 trials investigating systemic treatment of metastatic colorectal cancer (mCRC). We aimed to develop a minimum set of essential baseline characteristics and stratification factors to include in such trials. Methods: We performed a modified, two-round Delphi survey among international experts with wide experience in the conduct and methodology of phase 3 trials of systemic treatment of mCRC. Results: Thirty mCRC experts from 15 different countries completed both consensus rounds. A total of 14 patient characteristics were included in the recommended set: age, performance status, primary tumour location, primary tumour resection, prior chemotherapy, number of metastatic sites, liver-only disease, liver involvement, surgical resection of metastases, synchronous versus metachronous metastases, (K)RAS and BRAF mutation status, microsatellite instability/mismatch repair status and number of prior treatment lines. A total of five patient characteristics were considered the most relevant stratification factors: RAS/BRAF mutation status, performance status, primary tumour sidedness and liver-only disease. Conclusions: This survey provides a minimum set of essential baseline patient characteristics and stratification factors to include in phase 3 trials of systemic treatment of mCRC. Inclusion of these patient characteristics and strata in study protocols and final study reports will improve interpretation of trial results and facilitate cross-study comparisons.

  • 117. Golla, Sandeep
    et al.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Kero, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Harms, H.
    Glimelius, Bengt
    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.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Quantitative accuracy of parametric myocardial and tumour blood flow images based on HYPR-LR-filtered dynamic [O-15]water PET2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, no S2, p. S184-S184Article in journal (Other academic)
  • 118. Greenhalf, William
    et al.
    Ghaneh, Paula
    Neoptolemos, John P.
    Palmer, Daniel H.
    Cox, Trevor F.
    Lamb, Richard F.
    Garner, Elizabeth
    Campbell, Fiona
    Mackey, John R.
    Costello, Eithne
    Moore, Malcolm J.
    Valle, Juan W.
    McDonald, Alexander C.
    Carter, Ross
    Tebbutt, Niall C.
    Goldstein, David
    Shannon, Jennifer
    Dervenis, Christos
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Deakin, Mark
    Charnley, Richard M.
    Lacaine, Francois
    Scarfe, Andrew G.
    Middleton, Mark R.
    Anthoney, Alan
    Halloran, Christopher M.
    Mayerle, Julia
    Olah, Attila
    Jackson, Richard
    Rawcliffe, Charlotte L.
    Scarpa, Aldo
    Bassi, Claudio
    Buechler, Markus W.
    Pancreatic Cancer hENT1 Expression and Survival From Gemcitabine in Patients From the ESPAC-3 Trial2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 1, p. djt347-Article in journal (Refereed)
    Abstract [en]

    Background Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection. Methods Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided. Results Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (chi(2)(1)=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (chi(2)(1)=9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (chi(2)(1) = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (chi(2)(1) = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald chi(2)(1) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald chi(2)(1) = 1.22; P = .27) patients. Conclusions Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

  • 119. Gubanski, M.
    et al.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lind, P. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Quality of life in patients with advanced gastric cancer sequentially treated with docetaxel and irinotecan with 5-fluorouracil and folinic acid (leucovin)2014In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 31, no 4, p. 906-Article in journal (Refereed)
    Abstract [en]

    With a median overall survival of only 9-13 months in patients with advanced gastric cancer (GC), the quality of life (QoL) during the palliative treatment remains a key issue. Furthermore, when combinations of two or three drugs are used, the impact on QoL should be carefully evaluated. This was studied within the GATAC trial in patients sequentially treated with docetaxel and irinoteca n with 5-fluorouracil and leucovorin (5-Fu/ Lv). Patients with previously untreated advanced GC were randomly assigned to start with docetaxel 45 mg/m(2) (arm T) or irinotecan 180 mg/m(2) (arm C) with bolus and 44 h infusion of 5-Fu/Lv (D1, q2 weeks). After four courses, there was a prescheduled crossover to the alternative regimen for four additional courses. QoL was measured with the EORTC QLQ-C30 questionnaire at the start of the treatment, at crossover and after completing treatment with both regimens. Eighty-one patients were randomized, and 78 patients started treatment. A total of 191 completed QoL questionnaires were collected. There were no statistically significant differences in QoL scores between the two treatment groups and no changes in mean scores during the 16 weeks of treatment. During the last 8 weeks of treatment, a significantly larger portion of patients with radiological response reported sustained or better QoL scores than those with no radiological response (82 vs. 50 %, p = 0.007). Chemotherapy in advanced GC did not affect QoL average scores. Patients with non-responding tumours reported more often a decline in the global QoL score. The concept of the pre-scheduled switch of chemotherapy regimens prior to progression should be further studied in this disease, as it appears effective, tolerable and not to negatively affect QoL.

  • 120.
    Guren, M.
    et al.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway; KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway.
    Myklebust, T. A.
    Canc Registry Norway, Dept Registrat, Oslo, Norway.
    Lundqvist, K.
    Reg Canc Ctr North, Umeå, Sweden.
    Wibe, A.
    St Olavs Hosp, Dept Surg, 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.
    Two countries - two treatment strategies for rectal cancer2017In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 72, no Supplement: 1, p. S49-S49Article in journal (Other academic)
  • 121.
    Guren, Tormod Kyrre
    et al.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway..
    Thomsen, Maria
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway..
    Kure, Elin H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway..
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, 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..
    Osterlund, Pia
    Tampere Univ Hosp, Dept Oncol, Tampere, Finland..
    Sigurdsson, Fridbjorn
    Landspitali, Dept Oncol, Reykjavik, Iceland..
    Lothe, Inger Marie Bowitz
    Oslo Univ Hosp, Dept Pathol, Oslo, Norway..
    Dalsgaard, Astrid Marie
    Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway..
    Skovlund, Eva
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, Trondheim, Norway..
    Christoffersen, Thoralf
    Univ Oslo, Fac Med, Inst Clin Med, Dept Pharmacol, Oslo, Norway..
    Tveit, Kjell Magne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway.;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway..
    Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 116, no 10, p. 1271-1278Article in journal (Refereed)
    Abstract [en]

    Background: The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis.

    Methods: A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations.

    Results: Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy.

    Conclusions: Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.

  • 122. Gyldenkerne, Niels
    et al.
    Glimelius, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Frödin, Jan Erik
    Kjaer, Mogens
    Pfeiffer, Per
    Hansen, Flemming
    Keldsen, Nina
    Sandberg, Erik
    Jakobsen, Anders
    A phase II study of UFT and Leucovorin in combination with mitomycin C in patients with metastatic colorectal cancer.2004In: Acta Oncol, ISSN 0284-186X, Vol. 43, no 3, p. 276-9Article in journal (Other scientific)
  • 123. Hagness, M.
    et al.
    Guren, T.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pfeiffer, P.
    Line, P.
    Solheim, J.
    Tveitt, K.
    Dueland, S.
    Foss, A.
    Liver Transplantation or Chemotherapy for Non-Resectable Colorectal Liver Metastases?2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, p. 166-166Article in journal (Other academic)
  • 124. Hagness, M.
    et al.
    Guren, T.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pfeiffer, P.
    Line, P.
    Solheim, J.
    Tveitt, K.
    Dueland, S.
    Foss, A.
    Liver Transplantation or Chemotherapy for Non-Resectable Colorectal Liver Metastases?2014In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 98, p. 166-166Article in journal (Other academic)
  • 125.
    Hamfjord, J.
    et al.
    Oslo Univ Hosp, Oslo, Norway.
    Guren, T.
    Oslo Univ Hosp, Oslo, Norway.
    Dajani, O.
    Oslo Univ Hosp, 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, H.
    Univ Bergen, Haukeland Univ Hosp, Bergen, Norway.
    Pfeiffer, P.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.
    Christoffersen, T.
    Univ Oslo, Oslo, Norway.
    Lingjaerde, O.
    Univ Oslo, Oslo, Norway.
    Tveit, K.
    Oslo Univ Hosp, Oslo, Norway.
    Kure, E.
    Oslo Univ Hosp, Oslo, Norway.
    Pallisgaard, N.
    Zealand Hosp, Roskilde, Denmark;Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark.
    Spindler, K.
    Total circulating cell-free DNA (cfDNA) as a prognostic biomarker in metastatic colorectal cancer prior to first-line oxaliplatin-based chemotherapy2018In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 29, no suppl 5, article id O - 026Article in journal (Other academic)
  • 126.
    Hamfjord, J.
    et al.
    Oslo Univ Hosp, Dept Oncol, N-0407 Oslo, Norway;Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.
    Guren, T. K.
    Oslo Univ Hosp, Dept Oncol, N-0407 Oslo, Norway;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway.
    Dajani, O.
    Oslo Univ Hosp, Dept Oncol, N-0407 Oslo, Norway.
    Johansen, J. S.
    Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Oncol, Herlev, 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, H.
    Haukeland Hosp, Dept Oncol, Bergen, Norway;Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Pfeiffe, P.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark;Univ Southern Denmark, Inst Clin Res, Odense, Denmark.
    Lingjaerde, O. C.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway;Univ Oslo, Dept Comp Sci, Oslo, Norway.
    Tveit, K. M.
    Oslo Univ Hosp, Dept Oncol, N-0407 Oslo, Norway;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway.
    Kure, E. H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway;Univ South Eastern Norway, Fac Technol Nat Sci & Maritime Sci, Bo In Telemark, Norway.
    Pallisgaard, N.
    Zealand Univ Hosp, Dept Pathol, Roskilde, Denmark.
    Spindler, K-LG.
    Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy2019In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 30, no 7, p. 1088-1095Article in journal (Refereed)
    Abstract [en]

    Background Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. Patients and methods This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). Results cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050-1645000) for B2M and 5959 alleles/ml (555-854167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6months for levels above ULN and 25.9months for levels below ULN (hazard ratio = 1.83, 95% confidence interval 1.51-2.21, P<0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) = 62.7, P<0.001). Conclusion cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response. Trial registration ClinicalTrials.gov, NCT00145314.

  • 127.
    Hammarström, Klara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Imam, Israa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Korsavidou Hult, Nafsika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ekström, Joakim
    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.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Determining the use of preoperative (chemo)radiotherapy in primary rectal cancer according to national and international guidelines2019In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 136, p. 106-112Article in journal (Refereed)
    Abstract [en]

    Background: Pre-operative radiotherapy (RT) or chemoradiotherapy (CRT) is frequently used prior to rectal cancer surgery to improve local control and survival. The treatment is administered according to guidelines, but these recommendations vary significantly between countries. Based on the stage distribution and risk factors of rectal cancers as determined by magnetic resonance imaging (MRI) in an unselected Swedish population, the use of RT/CRT according to 15 selected guidelines is described. Materials and methods: Selected guidelines from different countries and regions were applied to a wellcharacterized unselected population-based material of 686 primary non-metastatic rectal cancers staged by MRI. The fraction of patients assigned to surgery alone or surgery following pre-treatment with (C) RT was determined according to the respective guideline. RT/CRT administered to rectal cancer patients for other reasons, for example, for organ preservation or palliation, was not considered. Results: The fraction of patients with a clear recommendation for pre-treatment with (C) RT varied between 38% and 77% according to the different guidelines. In most guidelines, CRT was recommended to all patients who were not operated directly, and, in others, short-course RT was also recommended to patients with intermediate risk tumours. If only non-resectable or difficult to resect tumours were recommended pre-treatment, as stated in many Japanese publications, 9% would receive CRT followed by a delay to surgery. Conclusions: According to most guidelines, well over 50% of primary non-metastatic rectal cancer patients from a general population, in which screening for colorectal cancer is not practised, are recommended treatment with pre-operative/neo-adjuvant therapy. (C) 2019 Elsevier B. V. All rights reserved. Radiotherapy and Oncology

  • 128.
    Hammarström, Klara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mezheyeuski, Artur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Korsavidou Hult, Nafsika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sjöblom, Tobias
    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.
    Stage distribution utilizing magnetic resonance imaging in an unselected population of primary rectal cancers2018In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 44, no 12, p. 1858-1864Article in journal (Refereed)
    Abstract [en]

    Background: Pre-operative radiotherapy (RT) or chemo-radiotherapy (CRT) are sometimes recommended prior to rectal cancer surgery, but guideline recommendations vary. The aim was to describe stage distribution and other important characteristics required for the treatment decision of patients with primary rectal cancers utilizing magnetic resonance imaging (MRI) in an unselected population. Patients and methods: All 796 histopathologically verified rectal adenocarcinomas diagnosed 2010-2015 in two counties in Sweden (population 630,000 in 2015) were identified. Staging with pelvic MRI unless contraindications were present, treatment and pathology followed Swedish guidelines.

    Patients and methods: All 796 histopathologically verified rectal adenocarcinomas diagnosed 2010-2015 in two counties in Sweden (population 630,000 in 2015) were identified. Staging with pelvic MRI unless contraindications were present, treatment and pathology followed Swedish guidelines.

    Results: Twenty-three % of cases (n = 186) had distant metastases at diagnosis, demonstrating more advanced tumor and nodal stages when compared with non-metastatic patients (p < 0.001), and they more often displayed MRI-identified mucinous features and extramural vascular invasion (EMVI) than non-metastatic tumors (p < 0.001 for both). In non-metastatic patients, 8% displayed clinical stage T1 (cT1), 21% cT2, and 53% cT3; one-third of the latter threatened or involved the mesorectal fascia (MRF+). Almost 20% had stage cT4 (4% cT4a, 14% cT4b) of which 50% were considered "non-resectable". EMVI was seen in 33% of cT3M0 tumors and in 48% of cT4M0 tumors.

    Conclusions: In an unselected population, approximately 80% of primary rectal cancers are referred to as "locally advanced" (stage or cT3-4 or N+), meaning that they, according to many international guidelines, are recommended neo-adjuvant treatment. This study provides a detailed description of the clinical stages and presence of characteristics identifiable on MRI which are of importance when assessing the needs for RT/CRT, when using different guidelines. 

  • 129. Hammel, Pascal
    et al.
    Huguet, Florence
    Van Laethem, Jean-Luc
    Goldstein, David
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Artru, Pascal
    Borbath, Ivan
    Bouche, Olivier
    Shannon, Jenny
    Andre, Thierry
    Mineur, Laurent
    Chibaudel, Benoist
    Bonnetain, Franck
    Louvet, Christophe
    Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study2013In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 31, no 18, p. LBA4003-Article in journal (Other academic)
  • 130.
    Hammel, Pascal
    et al.
    Hop Beaujon, AP HP, Dept Digest Oncol, F-92110 Clichy, France..
    Huguet, Florence
    Tenon Hosp, AP HP, Dept Radiotherapy, Paris, France..
    van Laethem, Jean-Luc
    Erasme Univ Hosp, Dept Gastroenterol, B-1070 Brussels, Belgium..
    Goldstein, David
    Prince Wales Hosp, Dept Med Oncol, Sydney, NSW, Australia.;Australasian Gastrointestinal Trials Grp AGITG, Camperdown, NSW, Australia.;Univ New S Wales, Prince Wales Clin Sch, 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.
    Artru, Pascal
    Jean Mermoz Hosp, Dept Gastroenterol, Lyon, France..
    Borbath, Ivan
    Clin Univ St Luc, Dept Gastroenterol, B-1200 Brussels, Belgium..
    Bouche, Olivier
    Hop Robert Debre, Dept Gastroenterol, Reims, France..
    Shannon, Jenny
    Australasian Gastrointestinal Trials Grp AGITG, Camperdown, NSW, Australia.;Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia.;Nepean Hosp NSW, Dept Med Oncol, Sydney, NSW, Australia..
    Andre, Thierry
    Hop St Antoine, AP HP, Dept Med Oncol, F-75571 Paris, France..
    Mineur, Laurent
    St Catherine Inst, Dept Radiotherapy & Med Oncol, Avignon, France..
    Chibaudel, Benoist
    Franco British Hosp Inst, Dept Med Oncol, Levallois Perret, France.;Oncol Multidisciplinary Res Grp GERCOR, Paris, France..
    Bonnetain, Franck
    Hosp Minjoz, Dept Methodol & Qual Life Oncol, Besancon, France..
    Louvet, Christophe
    Inst Mutualiste Montsouris, Dept Med Oncol, Paris, France..
    Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial2016In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 315, no 17, p. 1844-1853Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE In locally advanced pancreatic cancer, the role of chemoradiotherapy is controversial and the efficacy of erlotinib is unknown.

    OBJECTIVES To assess whether chemoradiotherapy improves overall survival of patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine-based induction chemotherapy and to assess the effect of erlotinib on survival.

    DESIGN, SETTING, AND PARTICIPANTS InLAP07, an international, open-label, phase3randomized trial, 449 patientswere enrolled between 2008and 2011. Follow-up ended in February 2013.

    INTERVENTIONS In the first randomization, 223 patients received 1000mg/m(2) weekly of gemcitabine alone and 219 patients received 1000mg/m(2) of gemcitabine plus 100mg/d of erlotinib. In the second randomization involving patients with progression-free disease after 4 months, 136 patients received 2 months of the same chemotherapy and 133 underwent chemoradiotherapy (54 Gy plus capecitabine).

    MAIN OUTCOMES AND MEASURES The primary outcomewas overall survival from the date of the first randomization. Secondary outcomeswere the effect of erlotinib and quality assurance of radiotherapy on overall survival, progression-free survival of gemcitabine-erlotinib and erlotinib maintenance with gemcitabine alone at the second randomization, and toxic effects.

    RESULTS A total of 442 of the 449 patients (232 men; median age, 63.3 years) enrolled underwent the first randomization. Of these, 269 underwent the second randomization. Interim analysis was performed when 221 patients died (109 in the chemoradiotherapy group and 112 in the chemotherapy group), reaching the early stopping boundaries for futility. With a median follow-up of 36.7 months, the median overall survival from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5-18.5 months) and chemoradiotherapy at 15.2 months (95% CI, 13.9-17.3 months; hazard ratio [HR], 1.03; 95% CI, 0.79-1.34; P = .83). Median overall survival from the date of the first randomization for the 223 patients receiving gemcitabine was 13.6 months (95% CI, 12.3-15.3 months) and was 11.9 months (95% CI, 10.4-13.5 months) for the 219 patients receiving gemcitabine plus erlotinib (HR, 1.19; 95% CI, 0.97-1.45; P = .09; 188 deaths vs 191 deaths). Chemoradiotherapy was associated with decreased local progression (32% vs 46%, P = .03) and no increase in grade 3 to 4 toxicity, except for nausea.

    CONCLUSIONS AND RELEVANCE In this open-label, randomized trial involving patients with locally advanced pancreatic cancer with disease controlled after 4 months of induction chemotherapy, there was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy.

  • 131.
    Hassan, Saadia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Laryea, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Felth, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Fayad, Walid
    Linder, Stig
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Pålman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Novel activity of acriflavine against colorectal cancer tumor cells2011In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 102, no 12, p. 2206-2213Article in journal (Refereed)
    Abstract [en]

    A high-throughput screen of the cytotoxic activity of 2000 molecules from a commercial library in three human colon cancer cell lines and two normal cell types identified the acridine acriflavin to be a colorectal cancer (CRC) active drug. Acriflavine was active in cell spheroids, indicating good drug penetration and activity against hypoxic cells. In a validation step based on primary cultures of patient tumor cells, acriflavine was found to be more active against CRC than ovarian cancer and chronic lymphocytic leukemia. This contrasted to the activity pattern of the CRC active standard drugs 5-fluorouracil, irinotecan and oxaliplatin. Mechanistic studies indicated acriflavine to be a dual topoisomerase I and II inhibitor. In conclusion, the strategy used seems promising for identification of new diagnosis-specific cancer drugs.

  • 132. Hjalgrim, Henrik
    et al.
    Smedby, Karin Ekström
    Rostgaard, Klaus
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hamilton-Dutoit, Stephen
    Chang, Ellen T.
    Ralfkiaer, Elisabeth
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Melbye, Mads
    Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma2007In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, no 5, p. 2382-2388Article in journal (Refereed)
    Abstract [en]

    Infectious mononucleosis (IM) has been associated with an increased risk of Hodgkin lymphoma (HL), implicating a role for Epstein-Barr virus (EBV) in HL development. Although essential to the understanding of the association, it has remained uncertain if the relationship is restricted to the EBV-positive subset of HL. We collected information on mononucleosis history and childhood socioenvironmental characteristics in a population-based study of 586 patients with classic HL and 3,187 controls in Denmark and Sweden. Tumor EBV status was established for 499 cases by immunohistochemistry and in situ hybridization techniques. Odds ratios (OR) for the relationship between HL risk and mononucleosis and other risk factors were estimated by logistic regression for HL in younger (18-44 years) and older (45-74 years) adults, overall and by tumor EBV status. All analyses were adjusted for country-specific measures of maternal education and mononucleosis history. IM was associated with an increased risk of EBV-positive [OR, 3.23; 95% confidence interval (95% CI) 1.89-5.55] but not EBV-negative HL (OR, 1.35; 95% CI, 0.86-2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI, 2.19-7.18). IM-associated lymphomas occurred with a median of 2.9 years (1.8-4.9 years) after infection. The EBV specificity of the IM association was corroborated by a case-case comparison of IM history between younger adult EBV-positive and EBV-negative HL patients (OR(IM EBV+ HL versus EBV- HL), 2.68; 95% CI, 1.40-5.12). We found further evidence that IM is associated only with EBV-positive HL. This finding is compatible with the notion that EBV-positive and EBV-negative HL may have different etiologies.

  • 133.
    Hollander, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Rostgaard, Klaus
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark..
    Smedby, Karin E.
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Chang, Ellen T.
    Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA.;Exponent Inc, Hlth Sci, Menlo Pk, CA USA..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Brown, Peter de Nully
    Rigshosp, Dept Haematol, DK-2100 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.
    Adami, Hans-Olov
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Melbye, Mads
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hjalgrim, Henrik
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark..
    Autoimmune and Atopic Disorders and Risk of Classical Hodgkin Lymphoma2015In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 182, no 7, p. 624-632Article in journal (Refereed)
    Abstract [en]

    Results from previous investigations have shown associations between the risk of Hodgkin lymphoma (HL) and a history of autoimmune and atopic diseases, but it remains unknown whether these associations apply to all types of HL or only to specific subtypes. We investigated immune diseases and the risk of classical HL in a population-based case-control study that included 585 patients and 3,187 controls recruited from October 1999 through August 2002. We collected information on immune diseases through telephone interviews and performed serological analyses of specific immunoglobulin E reactivity. Tumor Epstein-Barr virus (EBV) status was determined for 498 patients. Odds ratios with 95% confidence intervals were calculated using logistic regression analysis. Rheumatoid arthritis was associated with a higher risk of HL (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.47, 4.70), especially EBV-positive HL (OR = 3.18; 95% CI: 1.23, 8.17), and with mixed-cellularity HL (OR = 4.25; 95% CI: 1.66, 10.90). HL risk was higher when we used proxies of severe rheumatoid arthritis, such as ever having received daily rheumatoid arthritis medication (OR = 3.98; 95% CI: 2.08, 7.62), rheumatoid arthritis duration of 6-20 years (OR = 3.80; 95% CI: 1.72, 8.41), or ever having been hospitalized for rheumatoid arthritis (OR = 7.36; 95% CI: 2.95, 18.38). Atopic diseases were not associated with the risk of HL. EBV replication induced by chronic inflammation in patients with autoimmune diseases might explain the higher risk of EBV-positive HL.

  • 134. Hoyer, Morten
    et al.
    Muren, Ludvig P.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    The evolution of radiotherapy techniques in the management of prostate cancer2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 6, p. 821-824Article in journal (Other academic)
  • 135. Huguet, F.
    et al.
    Racadot, S.
    Goldstein, D.
    Spry, N.
    Van Laethem, J.
    Van Houtte, P.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gubanski, M.
    Bonnetain, F.
    Hammel, P.
    Investigation of Relation of Radiation Therapy Quality Assurance Scores (RTQASc) With Toxicity and Survival in LAP07 Phase 3 Trial for Locally Advanced Pancreatic Carcinoma (LAPC)2013In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 87, no 2, p. S29-S30Article in journal (Other academic)
  • 136.
    Hultman, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Gunnarsson, Ulf
    Umea Univ, Dept Surg & Perioperat Sci, SE-90185 Umea, Sweden.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Prognostic factors in patients with loco-regionally advanced gastric cancer2017In: World Journal of Surgical Oncology, ISSN 1477-7819, E-ISSN 1477-7819, Vol. 15, article id 172Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this study was to investigate epidemiologic and prognostic factors relevant to the treatment of loco-regionally advanced gastric cancer (GC).

    METHODS: Two hundred and fifty-five patients with GC were identified in Uppsala County between 2000 and 2009. Patient records were analyzed for loco-regionally advanced GC defined as tumor with peritoneal involvement, excluding serosal invasion from the primary tumor only, at primary diagnosis or during follow-up. The presence or not of distant metastasis (DM), including hematogenous metastases (e.g., liver, lung, and bone) and/or distant lymph node metastases, was also analyzed. The Cox proportional hazard model was used for multivariate analysis of factors influencing survival.

    RESULTS: One hundred and twenty patients (47% of all patients with GC; median age 70.5 years) had loco-regionally advanced disease, corresponding to an incidence of 3.8 per 100,000 person-years. Forty-one percent of these also had DM. Median overall survival (mOS) from the time of the diagnosis of loco-regionally advanced disease was 4.8 months for the total patient cohort, 5.1 months for the subgroup of patients without DM, and 4.7 months for the subgroup with DM. There was no significant difference in mOS between the subgroups with synchronous versus metachronous loco-regionally advanced GC: 4.8 months (range 0.0-67.4) versus 4.7 months (range 0.0-28.3). Using multivariate Cox analysis, positive prognostic factors for survival were good performance status at diagnosis and treatment with palliative chemotherapy and/or radiotherapy. Synchronous DM was a negative prognostic factor. The mOS did not differ when comparing the time period 2000-2004 (5.1 months, range 0-67.4) with the period 2005-2009 (4.0 months, range 0.0-28.3).

    CONCLUSION: Peritoneal involvement occurred in almost half of the patients with GC in this study and was associated with short life expectancy. New treatment strategies are warranted.

  • 137.
    Hultman, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Lind, Pehr
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Haglund, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Phase II study of patients with peritoneal carcinomatosis from gastric cancer treated with preoperative systemic chemotherapy followed by peritonectomy and intraperitoneal chemotherapy2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 4, p. 824-830Article in journal (Refereed)
    Abstract [en]

    Background

    The aim was to evaluate the feasibility and the effectiveness of neoadjuvant systemic chemotherapy followed by cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC) in patients with peritoneal carcinomatosis (PC) from gastric cancer.

    Material and methods

    Eighteen patients (median age 57 years, range 38-74) were scheduled for three months' neoadjuvant systemic chemotherapy followed by CRS + HIPEC + EPIC.

    Results

    At the time of surgery, the peritoneal tumor burden was extensive with tumor growth on the entire peritoneal cavity. Only eight patients received the entire treatment and OS was 14.3 months (range 6.1-34.3, 95% CI 6.6-20.3). Six patients had macroscopically radical (CC0) surgery and for this subgroup OS was 19.1 months (range 6.1-34.3, 95% CI 6.9-27.1). Postoperative 90-day mortality was 10% (one patient) and the perioperative grades II-IV adverse events (AE) rate was 62.5%.

    Discussion

    Neoadjuvant chemotherapy followed by CRS + HIPEC + EPIC does not seem to be associated with prolonged OS in patients with extensive PC growth from gastric cancer unless macroscopically radical surgery is achieved. However, morbidity from this treatment is considerable and it cannot be recommended for routine care until a prospective randomized trial has been performed.

  • 138.
    Hultman, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Lundkvist, Jonas
    Glimelius, Bengt
    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.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Costs and clinical outcome of neoadjuvant systemic chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from gastric cancer2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, p. 112-121Article in journal (Refereed)
    Abstract [en]

    Background

    The costs for loco-regional treatment of peritoneal carcinomatosis from gastric cancer are not well investigated. The aims of this study were to evaluate the costs and clinical outcome of systemic chemotherapy followed by cytoreductive surgery and intraperitoneal chemotherapy compared to systemic chemotherapy only in patients with peritoneal carcinomatosis from gastric cancer.

    Material and methods

    Ten patients were scheduled for systemic chemotherapy followed by loco-regional treatment. A reference group of 10 matched control patients treated with systemic chemotherapy only were used and both groups were evaluated with respect to clinical outcome and cost.

    Results

    The mean overall cost in the loco-regional group was $145 700 (range $49 900-$487 800) and $59 300 (range $23 000-$94 800) for the control group. The mean overall survival for the loco-regional group was 17.4 months (range 6.0-34.3), and 11.1 months (range 0.1-24.2) for the systemic chemotherapy only group. The gain in life-years was 0.52 and in quality-adjusted life-years 0.49, leading to incremental cost per life-year and quality-adjusted life-years gained of $166 716 and $175 164, for loco-regional group compared to systemic chemotherapy.

    Discussion

    Treatment of peritoneal carcinomatosis from gastric cancer is costly irrespective of treatment modality. If the survival benefit from adding loco-regional treatment to systemic chemotherapy indicated from this comparison is true, the incremental cost is considered high.

  • 139.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gustafsson, Ann-Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Pendekanti, Prathyusha N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    The influence of AKT isoforms on radiation sensitivity and DNA repair in colon cancer cell lines2014In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 4, p. 3525-3534Article in journal (Refereed)
    Abstract [en]

    In response to ionizing radiation, several signaling cascades in the cell are activated to repair the DNA breaks, prevent apoptosis, and keep the cells proliferating. AKT is important for survival and proliferation and may also be an activating factor for DNA-PKcs and MRE11, which are essential proteins in the DNA repair process. AKT (PKB) is hyperactivated in several cancers and is associated with resistance to radiotherapy and chemotherapy. There are three AKT isoforms (AKT1, AKT2, and AKT3) with different expression patterns and functions in several cancer tumors. The role of AKT isoforms has been investigated in relation to radiation response and their effects on DNA repair proteins (DNA-PKcs and MRE11) in colon cancer cell lines. The knockout of AKT1 and/or AKT2 affected the radiation sensitivity, and a deficiency of both isoforms impaired the rejoining of radiation-induced DNA double strand breaks. Importantly, the active/phosphorylated forms of AKT and DNA-PKcs associate and exposure to ionizing radiation causes an increase in this interaction. Moreover, an increased expression of both DNA-PKcs and MRE11 was observed when AKT expression was ablated, yet only DNA-PKcs expression influenced AKT phosphorylation. Taken together, these results demonstrate a role for both AKT1 and AKT2 in radiotherapy response in colon cancer cells involving DNA repair capacity through the nonhomologous end joining pathway, thus suggesting that AKT in combination with DNA-PKcs inhibition may be used for radiotherapy sensitizing strategies in colon cancer.

  • 140.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mortensen, Anja C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Engskog, Mikael K. R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells2017In: International Journal of Oncology, ISSN 1019-6439, Vol. 50, no 1, p. 5-14Article in journal (Refereed)
    Abstract [en]

    AKT is a central protein in many cellular pathways such as cell survival, proliferation, glucose uptake, metabolism, angiogenesis, as well as radiation and drug response. The three isoforms of AKT (AKT1, AKT2 and AKT3) are proposed to have different physiological functions, properties and expression patterns in a cell type-dependent manner. As of yet, not much is known about the influence of the different AKT isoforms in the genome and their effects in the metabolism of colorectal cancer cells. In the present study, DLD-1 isogenic AKT1, AKT2 and AKT'/2 knockout colon cancer cell lines were used as a model system in conjunction with the parental cell line in order to further elucidate the differences between the AKT isoforms and how they are involved in various cellular pathways. This was done using genome wide expression analyses, metabolic profiling and cell migration assays. In conclusion, downregulation of genes in the cell adhesion, extracellular matrix and Notch-pathways and upregulation of apoptosis and metastasis inhibitory genes in the p53-pathway, confirm that the knockout of both AKT1 and AKT2 will attenuate metastasis and tumor cell growth. This was verified with a reduction in migration rate in the AKT1 KO and AKT2 KO and most explicitly in the AKT1/2 KO. Furthermore, the knockout of AKT1, AKT2 or both, resulted in a reduction in lactate and alanine, suggesting that the metabolism of carbohydrates and glutathione was impaired. This was further verified in gene expression analyses, showing downregulation of genes involved in glucose metabolism. Additionally, both AKT1 KO and AKT2 KO demonstrated an impaired fatty acid metabolism. However, genes were upregulated in the Wnt and cell proliferation pathways, which could oppose this effect. AKT inhibition should therefore be combined with other effectors to attain the best effect.

  • 141.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Nestor, Marika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells.2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e94621-Article in journal (Refereed)
    Abstract [en]

    The cell surface proteins CD133, CD24 and CD44 are putative markers for cancer stem cell populations in colon cancer, associated with aggressive cancer types and poor prognosis. It is important to understand how these markers may predict treatment outcomes, determined by factors such as radioresistance. The scope of this study was to assess the connection between EGFR, CD133, CD24, and CD44 (including isoforms) expression levels and radiation sensitivity, and furthermore analyze the influence of AKT isoforms on the expression patterns of these markers, to better understand the underlying molecular mechanisms in the cell. Three colon cancer cell-lines were used, HT-29, DLD-1, and HCT116, together with DLD-1 isogenic AKT knock-out cell-lines. All three cell-lines (HT-29, HCT116 and DLD-1) expressed varying amounts of CD133, CD24 and CD44 and the top ten percent of CD133 and CD44 expressing cells (CD133(high)/CD44(high)) were more resistant to gamma radiation than the ten percent with lowest expression (CD133(low)/CD44(low)). The AKT expression was lower in the fraction of cells with low CD133/CD44. Depletion of AKT1 or AKT2 using knock out cells showed for the first time that CD133 expression was associated with AKT1 but not AKT2, whereas the CD44 expression was influenced by the presence of either AKT1 or AKT2. There were several genes in the cell adhesion pathway which had significantly higher expression in the AKT2 KO cell-line compared to the AKT1 KO cell-line; however important genes in the epithelial to mesenchymal transition pathway (CDH1, VIM, TWIST1, SNAI1, SNAI2, ZEB1, ZEB2, FN1, FOXC2 and CDH2) did not differ. Our results demonstrate that CD133(high)/CD44(high) expressing colon cancer cells are associated with AKT and increased radiation resistance, and that different AKT isoforms have varying effects on the expression of cancer stem cell markers, which is an important consideration when targeting AKT in a clinical setting.

  • 142.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    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.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    The effect of a dimeric Affibody molecule (ZEGFR:1907)2 targeting EGFR in combination with radiation in colon cancer cell lines2012In: International Journal of Oncology, ISSN 1019-6439, Vol. 40, no 1, p. 176-184Article in journal (Refereed)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal cancer and is therefore an attractive target for treatment. (ZEGFR:1907)2 is a newly developed dimeric affibody molecule with high affinity to the extracellular part of EGFR. In this study, we evaluated the cytotoxic effects of (ZEGFR:1907)2 in combination with external radiation and the possible inhibitory effects in the EGFR signalling pathways in the colon cancer cell lines HT-29 and HCT116. The effects were compared with an EGFR antibody (cetuximab) and the tyrosine kinase inhibitors (erlotinib and sunitinib). These cell lines are genotypically different with respect to e.g. KRAS and BRAF mutational status, recently shown to be of clinical significance for therapeutic effects. Both cell lines express approximately 100,000-150,000 EGFRs per cell but differ in the radiation response (HCT116, SF2=0.28 and HT-29, SF2=0.70). Exposure to (ZEGFR:1907)2 produced a small, but significant, reduction in survival in HCT116 but did not affect HT-29 cells. Similar results were obtained after exposure to EGF and the EGFR antibody cetuximab. The EGFR tyrosine kinase targeting inhibitor erlotinib and the multi-tyrosine kinase inhibitor sunitinib reduced survival in both cell lines. However, none of the drugs had any significant radiosensitizing effects in combination with radiation. Akt and Erk are central proteins in the EGFR downstream signalling and in the cellular response to ionizing radiation. The activation of Akt (Ser 473) and Erk (Thr202/Tyr204) by radiation was both dose- and time-dependent. However the activation of EGFR was not clearly affected by radiation. Neither (ZEGFR:1907)2 nor any of the other drugs were able to completely inactivate Akt or Erk. On the contrary, erlotinib stimulated Akt phosphorylation in both cell lines and in HCT116 cells Erk was activated. Overall the results illustrate the complexity in response to radiation and drugs in cells with differential phenotypic status.

  • 143.
    Iveson, T.
    et al.
    Univ Hosp Southampton, Dept Med Oncol, Southampton, Hants, England..
    Kerr, R.
    Univ Oxford, Churchill Hosp, Oncol, Oxford, England..
    Saunders, M.
    Christie NHS Fdn Trust, Oncol, Manchester, Lancs, England..
    Hollander, N.
    Sygehus Syd Naestved, Oncology, Naestved, Denmark..
    Tabernero, J.
    VHIO, Med Oncol, Barcelona, Spain..
    Haydon, A.
    Alfred Hlth, Med Oncol, Melbourne, Vic, Australia..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Harkin, A.
    Univ Glasgow, CRUK CTU, Glasgow, Lanark, Scotland..
    Scudder, C.
    Univ Oxford, Oncol, Oxford, England..
    Boyd, K.
    Univ Glasgow, CRUK CTU, Glasgow, Lanark, Scotland..
    Waterston, A.
    Beatson West Scotland Canc Ctr, Med Oncol, Glasgow, Lanark, Scotland..
    Medley, L.
    Dr Louise Medley, Oncol, London, England..
    Wilson, C.
    Addenbrookes Hosp, Cambridge Breast Unit, Cambridge, England..
    Ellis, R.
    Royal Cornwall Hosp, Oncol, Truro, England..
    Essapen, S.
    Royal Surrey Cty Hosp, St Lukes Canc Ctr, Oncol, Guildford, Surrey, England..
    Dhadda, A.
    Castle Hill Hosp, Oncol, Cottingham, England..
    Harrison, M.
    Mt Vernon Hosp, Oncol, Northwood, Middx, England..
    Falk, S.
    Bristol Haematol & Oncol Ctr, Oncol, Bristol, Avon, England..
    Abdel-Raouf, S.
    Queens Hosp, Oncol, Romford, Essex, England..
    Paul, J.
    Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland..
    Updated results of the SCOT study: An international phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no S5, article id LBA22Article in journal (Other academic)
  • 144.
    Iveson, Timothy J.
    et al.
    Southampton Univ Hosp NHS Fdn Trust, Southampton SO16 0YD, Hants, England.
    Kerr, Rachel S.
    Univ Oxford, Dept Oncol, Oxford, England.
    Saunders, Mark P.
    Christie Hosp, Manchester, Lancs, England.
    Cassidy, Jim
    Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland.
    Henrik Hollander, Niels
    Zealand Univ Hosp, Dept Oncol & Palliat Care, Naestved, Denmark.
    Tabernero, Josep
    Vall dHebron Univ Hosp, Barcelona, Spain;Univ Autonoma Barcelona, CIBERONC, Inst Oncol, Barcelona, Spain.
    Haydon, Andrew
    Australasian Gastrointestinal Trials Grp, Melbourne, Vic, Australia.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Harkin, Andrea
    Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland.
    Allan, Karen
    Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland.
    McQueen, John
    Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland.
    Scudder, Claire
    Univ Oxford, Dept Oncol, OCTO, Oxford, England.
    Boyd, Kathleen Anne
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland.
    Briggs, Andrew
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland;Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Ctr Hlth & Policy Outcomes, New York, NY 10021 USA.
    Waterston, Ashita
    Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland.
    Medley, Louise
    Royal United Hosp, Bath, Avon, England.
    Wilson, Charles
    Addenbrookes Hosp, Cambridge, England.
    Ellis, Richard
    Royal Cornwall Hosp NHS Trust, Truro, England.
    Essapen, Sharadah
    Royal Surrey Cty Hosp NHS Fdn Trust, St Lukes Canc Ctr, Guildford, Surrey, England.
    Dhadda, Amandeep S.
    Castle Hill Hosp, Kingston Upon Hull, N Humberside, England.
    Harrison, Mark
    Mt Vernon Canc Ctr, Northwood, Middx, England.
    Falk, Stephen
    Bristol Canc Inst, Bristol, Avon, England.
    Raouf, Sherif
    Barking Havering & Redbridge Univ Hosp NHS Trust, Barking, England.
    Rees, Charlotte
    Southampton Univ Hosp NHS Fdn Trust, Southampton SO16 0YD, Hants, England.
    Olesen, Rene K.
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark.
    Propper, David
    Queen Mary Univ London, Barts Canc Inst, London, England.
    Bridgewater, John
    UCL, UCL Canc Inst, London, England.
    Azzabi, Ashraf
    Newcastle Upon Tyne Hosp NHS Fdn Trust, Newcastle, England.
    Farrugia, David
    Cheltenham Gen Hosp, Gloucestershire Oncol Ctr, Cheltenham, Glos, England.
    Webb, Andrew
    Brighton & Sussex Univ Hosp Trust, Brighton, E Sussex, England.
    Cunningham, David
    Royal Marsden Hosp, London, England.
    Hickish, Tamas
    Bournemouth Univ, Poole Hosp, Bournemouth, Dorset, England.
    Weaver, Andrew
    Oxford Univ Hosp Fdn Trust, Dept Oncol, Oxford, England.
    Gollins, Simon
    North Wales Canc Treatment Ctr, Rhyl, Wales.
    Wasan, Harpreet S.
    Imperial Coll London, Hammersmith Hosp, London, England.
    Paul, James
    Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland.
    3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial2018In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 19, no 4, p. 562-578Article in journal (Refereed)
    Abstract [en]

    Background: 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment.

    Methods: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1: 1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1.13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing.

    Findings: 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76.7% (95% CI 75.1-78.2) for the 3 month group and 77.1% (75.6-78.6) for the 6 month group, giving a hazard ratio of 1.006 (0.909-1.114, test for non-inferiority p=0.012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group).

    Interpretation: In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care.

  • 145. Iveson, Timothy
    et al.
    Kerr, Rachel
    Saunders, Mark P.
    Waterston, Ashita Marie
    Hollander, Niels Henrik
    Medley, Louise C.
    Tabernero, Josep
    Wilson, Charles
    Ellis, Richard
    Essapen, Sharadah
    Haydon, Andrew Mark
    Dhadda, Amandeep Singh
    Hughes, Robert
    Falk, Stephen
    Abdel-Raouf, Sherif
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Allan, Karen
    Barlow, Winnie
    Briggs, Andrew
    Paul, James
    Toxicity and quality of life data from SCOT: An international phase III randomized (1:1) noninferiority trial comparing 3 vs 6 months of oxaliplatin-based adjuvant chemotherapy.2015In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 33, no 15Article in journal (Other academic)
  • 146.
    Ivesono, Timothy
    et al.
    Southampton Univ Hosp NHS Fdn Trust, Southampton, Hants, England.
    Boydo, Kathleen A.
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland.
    Kerro, Rachel S.
    Univ Oxford, Dept Oncol, Oxford, England.
    Robles-Zuritao, Jose
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland.
    Saunders, Mark P.
    Christie Hosp NHS Fdn Trust, Manchester, Lancs, England.
    Briggso, Andrew H.
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland.
    Cassidyo, Jim
    Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland.
    Hollandero, Niels Henrik
    Zealand Univ Hosp, Dept Oncol & Palliat Care, Naestved, Denmark.
    Taberneroo, Josep
    Univ Autonoma Barcelona, Vall dHebron Univ Hosp, Barcelona, Spain;Univ Autonoma Barcelona, Inst Oncol, Barcelona, Spain.
    Haydon, Andrew
    Australasian Gastrointestinal Trials Grp, Camperdown, 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.
    Harkino, Andrea
    Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland.
    Allano, Karen
    Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland.
    McQueeno, John
    Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland.
    Pearsono, Sarah
    Univ Oxford, Dept Oncol, Oncol Clin Trials Off, Oxford, England.
    Waterstono, Ashita
    Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland.
    Medleyo, Louise
    Royal United Hosp, Bath, Avon, England.
    Wilsono, Charles
    Addenbrookes Hosp, Cambridge, England.
    Elliso, Richard
    Royal Cornwall Hosp NHS Trust, Truro, Cornwall, England.
    Essapen, Sharadah
    Royal Surrey Cty Hosp NHS Fdn Trust, St Lukes Canc Ctr, Guildford, Surrey, England.
    Dhaddao, Amandeep S.
    Castle Hill Hosp, Kingston Upon Hull, N Humberside, England.
    Harrison, Mark
    Mt Vernon Canc Ctr, Northwood, Middx, England.
    Falko, Stephen
    Bristol Canc Inst, Bristol, Avon, England.
    Raoufo, Sherif
    Barking Havering & Redbridge Univ Hosp NHS Trust, Barking, England.
    Rees, Charlotte
    Southampton Univ Hosp NHS Fdn Trust, Southampton, Hants, England.
    Oleseno, Rene K.
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark.
    Proppero, David
    Queen Mary Univ London, Barts Canc Inst, London, England.
    Bridgewatero, John
    UCL, Dept Oncol, London, England.
    Azzabio, Ashraf
    Newcastle Upon Tyne Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England.
    Farrugiao, David
    Cheltenham Gen Hosp, Gloucestershire Oncol Ctr, Cheltenham, Glos, England.
    Webbo, Andrew
    Brighton & Sussex Univ Hosp Trust, Brighton, E Sussex, England.
    Cunninghamo, David
    Royal Marsden NHS Fdn Trust, London, England.
    Hickish, Tamas
    Poole Hosp NHS Fdn Trust, Poole, Dorset, England.
    Weavero, Andrew
    Oxford Univ Hosp Fdn Trust, Dept Oncol, Oxford, England.
    Gollins, Simon
    North Wales Canc Treatment Ctr, Rhyl, Wales.
    Wasano, Harpreet
    Imperial Coll Healthcare NHS Trust, Hammersmith Hosp, London, England.
    Paulo, James
    Christie Hosp NHS Fdn Trust, Manchester, Lancs, England.
    3-month versus 6-month adjuvant chemotherapy for patients with high-risk stage II and III colorectal cancer: 3-year follow-up of the SCOT non-inferiority RCT2019In: Health Technology Assessment, ISSN 1366-5278, E-ISSN 2046-4924, Vol. 23, no 64, p. 1-88Article in journal (Refereed)
    Abstract [en]

    Background: Oxaliplatin and fluoropyrimidine chemotherapy administered over 6 months is the standard adjuvant regimen for patients with high-risk stage II or III colorectal cancer. However, the regimen is associated with cumulative toxicity, characterised by chronic and often irreversible neuropathy.

    Objective: To assess the efficacy of 3-month versus 6-month adjuvant chemotherapy for colorectal cancer and to compare the toxicity, health-related quality of life and cost-effectiveness of the durations.

    Design: An international, randomised, open-label, non-inferiority, Phase III, parallel-group trial.

    Setting: A total of 244 oncology clinics from six countries: UK (England, Scotland, Wales and Northern Ireland), Denmark, Spain, Sweden, Australia and New Zealand.

    Participants: Adults aged >= 18 years who had undergone curative resection for high-risk stage II or III adenocarcinoma of the colon or rectum.

    Interventions: The adjuvant treatment regimen was either oxaliplatin and 5-fluorouracil or oxaliplatin and capecitabine, randomised to be administered over 3 or 6 months.

    Main outcomes measures: The primary outcome was disease-free survival. Overall survival, adverse events, neuropathy and health-related quality of life were also assessed. The main cost categories were chemotherapy treatment and hospitalisation. Cost-effectiveness was assessed through incremental cost comparisons and quality-adjusted life-year gains between the options and was reported as net monetary benefit using a willingness-to-pay threshold of 30,000 pound per quality-adjusted life-year per patient.

    Result: Recruitment is closed. In total, 6088 patients were randomised (3044 per group) between 27 March 2008 and 29 November 2013, with 6065 included in the intention-to-treat analyses (3-month analysis, n = 3035; 6-month analysis, n = 3030). Follow-up for the primary analysis is complete. The 3-year disease-free survival rate in the 3-month treatment group was 76.7% (standard error 0.8%) and in the 6-month treatment group was 77.1% (standard error 0.8%), equating to a hazard ratio of 1.006 (95% confidence interval 0.909 to 1.114; p-value for non-inferiority = 0.012), confirming non-inferiority for 3-month adjuvant chemotherapy. Frequent adverse events (alopecia, anaemia, anorexia, diarrhoea, fatigue, hand-foot syndrome, mucositis, sensory neuropathy, neutropenia, pain, rash, altered taste, thrombocytopenia and watery eye) showed a significant increase in grade with 6-month duration; the greatest difference was for sensory neuropathy (grade >= 3 was 4% for 3-month vs.16% for 6-month duration), for which a higher rate of neuropathy was seen for the 6-month treatment group from month 4 to >= 5 years (p < 0.001). Quality-of-life scores were better in the 3-month treatment group over months 4-6. A cost-effectiveness analysis showed 3-month treatment to cost 4881 pound less over the 8-year analysis period, with an incremental net monetary benefit of 7246 pound per patient.

    Conclusions: The study achieved its primary end point, showing that 3-month oxaliplatin-containing adjuvant chemotherapy is non-inferior to 6 months of the same regimen; 3-month treatment showed a better safety profile and cost less. For future work, further follow-up will refine long-term estimates of the duration effect on disease-free survival and overall survival. The health economic analysis will be updated to include long-term extrapolation for subgroups. We expect these analyses to be available in 2019-20. The Short Course Oncology Therapy (SCOT) study translational samples may allow the identification of patients who would benefit from longer treatment based on the molecular characteristics of their disease.

  • 147.
    Jestin, P
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Heurgren, M
    Påhlman, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Glimelius, Bengt
    Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Gunnarsson, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Elective surgery for colorectal cancer in a defined Swedish population.2004In: Eur J Surg Oncol, ISSN 0748-7983, Vol. 30, no 1, p. 26-33Article in journal (Refereed)
  • 148.
    Jestin, P
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Påhlman, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Glimelius, Bengt
    Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Gunnarsson, Ulf
    Department of Medical Cell Biology.
    Cancer staging and survival in colon cancer is dependent on the quality of the pathologists' specimen examination.2005In: Eur J Cancer, ISSN 0959-8049, Vol. 41, no 14, p. 2071-8Article in journal (Other scientific)
  • 149.
    Jestin, Pia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nilsson, J.
    Heurgren, M.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gunnarsson, U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Emergency surgery for colonic cancer in a defined population2005In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 92, no 1, p. 94-100Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this study was to identify risk factors in emergency surgery for colonic cancer in a large population and to investigate the economic impact of such surgery. METHODS: Data from the colonic cancer registry (1997-2001) of the Uppsala/Orebro Regional Oncological Centre were analysed and classified by hospital category. Some 3259 patients were included; 806 had an emergency and 2453 an elective procedure. Data for calculating effects on health economy were derived from a national case-costing register. RESULTS: Patients who had emergency surgery had more advanced tumours and a lower survival rate than those who had an elective procedure (5-year survival rate 29.8 versus 52.4 per cent; P < 0.001). There was a stage-specific difference in survival, with poorer survival both for patients with stage I and II tumours and for those with stage III tumours after emergency compared with elective surgery (P < 0.001). Emergency surgery was associated with a longer hospital stay (mean 18.0 versus 10.0 days; P < 0.001) and higher costs (relative cost 1.5 (95 per cent confidence interval 1.4 to 1.6)) compared with elective surgery. The duration of hospital stay was the strongest determinant of cost (r(2) = 0.52, P < 0.001). CONCLUSION: Emergency surgery for colonic cancer is associated with a stage-specific increase in mortality rate.

  • 150.
    Johansson, Birgitta
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Holmberg, Lars
    Department of Surgical Sciences.
    Berglund, Gunilla
    Department of Public Health and Caring Sciences.
    Sjöden, P-O
    Department of Public Health and Caring Sciences.
    Glimelius, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Determinants of cancer patients' utilization of hospital care within two years after diagnosis.2004In: Acta Oncol, ISSN 0284-186X, Vol. 43, no 6, p. 536-44Article in journal (Refereed)
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