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  • 1. Aapro, Matti S.
    et al.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bokemeyer, Carsten
    Cornes, Paul
    Foubert, Jan
    Gascon, Pere
    Glaspy, John
    Hellström-Lindberg, Eva
    Link, Hartmut
    Ludwig, Heinz
    Österborg, Anders
    Repetto, Lazzaro
    Soubeyran, Pierre
    Erythropoietins should be used according to guidelines2008In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 9, no 5, p. 412-3Article in journal (Refereed)
  • 2. Beets, Geerard L.
    et al.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Adjuvant chemotherapy for rectal cancer still controversial2014In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 15, no 2, p. 130-131Article in journal (Other academic)
  • 3. Bujko, Krzysztof
    et al.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Adjuvant chemotherapy for rectal cancer2014In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 15, no 6, p. E194-E195Article in journal (Refereed)
  • 4. Buunen, Mark
    et al.
    Veldkamp, Ruben
    Hop, Wim C. J.
    Kuhry, Esther
    Jeekel, Johannes
    Haglind, Eva
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Cuesta, Miguel A.
    Msika, Simon
    Morino, Mario
    Lacy, Antonio
    Bonjer, Hendrik J.
    Survival after laparoscopic surgery versus open surgery for colon cancer: long-term outcome of a randomised clinical trial2009In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 10, no 1, p. 44-52Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Laparoscopic surgery for colon cancer has been proven safe, but debate continues over whether the available long-term survival data justify implementation of laparoscopic techniques in surgery for colon cancer. The aim of the COlon cancer Laparoscopic or Open Resection (COLOR) trial was to compare 3-year disease-free survival and overall survival after laparoscopic and open resection of solitary colon cancer. METHODS: Between March 7, 1997, and March 6, 2003, patients recruited from 29 European hospitals with a solitary cancer of the right or left colon and a body-mass index up to 30 kg/m(2) were randomly assigned to either laparoscopic or open surgery as curative treatment in this non-inferiority randomised trial. Disease-free survival at 3 years after surgery was the primary outcome, with a prespecified non-inferiority boundary at 7% difference between groups. Secondary outcomes were short-term morbidity and mortality, number of positive resection margins, local recurrence, port-site or wound-site recurrence, and blood loss during surgery. Neither patients nor health-care providers were blinded to patient groupings. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00387842. FINDINGS: During the recruitment period, 1248 patients were randomly assigned to either open surgery (n=621) or laparoscopic surgery (n=627). 172 were excluded after randomisation, mainly because of the presence of distant metastases or benign disease, leaving 1076 patients eligible for analysis (542 assigned open surgery and 534 assigned laparoscopic surgery). Median follow-up was 53 months (range 0.03-60). Positive resection margins, number of lymph nodes removed, and morbidity and mortality were similar in both groups. The combined 3-year disease-free survival for all stages was 74.2% (95% CI 70.4-78.0) in the laparoscopic group and 76.2% (72.6-79.8) in the open-surgery group (p=0.70 by log-rank test); the difference in disease-free survival after 3 years was 2.0% (95% CI -3.2 to 7.2). The hazard ratio (HR) for disease-free survival (open vs laparoscopic surgery) was 0.92 (95% CI 0.74-1.15). The combined 3-year overall survival for all stages was 81.8% (78.4-85.1) in the laparoscopic group and 84.2% (81.1-87.3) in the open-surgery group (p=0.45 by log-rank test); the difference in overall survival after 3 years was 2.4% (95% CI -2.1 to 7.0; HR 0.95 [0.74-1.22]). INTERPRETATION: Our trial could not rule out a difference in disease-free survival at 3 years in favour of open colectomy because the upper limit of the 95% CI for the difference just exceeded the predetermined non-inferiority boundary of 7%. However, the difference in disease-free survival between groups was small and, we believe, clinically acceptable, justifying the implementation of laparoscopic surgery into daily practice. Further studies should address whether laparoscopic surgery is superior to open surgery in this setting.

  • 5.
    Charalampoudis, Petros
    et al.
    Guys & St Thomas NHS Fdn Trust, Breast Unit, London, England; Kings Coll London, Div Canc Studies, London, England.
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Neoadjuvant chemotherapy for early breast cancer2018In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 19, no 3, p. E128-E128Article in journal (Other academic)
  • 6. Cuzick, Jack
    et al.
    Thorat, Mangesh A
    Andriole, Gerald
    Brawley, Otis W
    Brown, Powel H
    Culig, Zoran
    Eeles, Rosalind A
    Ford, Leslie G
    Hamdy, Freddie C
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ilic, Dragan
    Key, Timothy J
    La Vecchia, Carlo
    Lilja, Hans
    Marberger, Michael
    Meyskens, Frank L
    Minasian, Lori M
    Parker, Chris
    Parnes, Howard L
    Perner, Sven
    Rittenhouse, Harry
    Schalken, Jack
    Schmid, Hans-Peter
    Schmitz-Dräger, Bernd J
    Schröder, Fritz H
    Stenzl, Arnulf
    Tombal, Bertrand
    Wilt, Timothy J
    Wolk, Alicja
    Prevention and early detection of prostate cancer.2014In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 15, no 11, p. e484-92Article in journal (Refereed)
    Abstract [en]

    Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.

  • 7.
    Duffau, Hugues
    et al.
    Montpellier Med Univ Ctr, Hop Guide Chauliac, Dept Neurosurg, Montpellier, France.;Inst Neurosci, INSERM U1051, Montpellier, France.;Univ Montpellier, Montpellier, France..
    Mandonnet, Emmanuel
    Lariboisiere Hosp, AP HP, Dept Neurosurg, Paris, France.;Univ Paris 07, Paris, France.;IMNC, UMR 8165, Orsay, France..
    Pallud, Johan
    St Anna Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Sorbonne Paris Cite, Paris, France.;INSERM, U894, Ctr Psychiat & Neurosci, Paris, France..
    Krieg, Sandro
    Tech Univ Munich, Klinikum Rechts Isar, Dept Neurosurg, Munich, Germany..
    Gil Robles, Santiago
    Hosp Univ Quiron, Madrid, Spain.;Bio Cruces Res, Bilbao, Spain..
    Hamer, Philip de Witt
    Vrije Univ Amsterdam Med Ctr, Neurosurg Ctr Amsterdam, Amsterdam, Netherlands..
    Schucht, Philippe
    Univ Hosp Bern, Dept Neurosurg, Bern, Switzerland..
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Santarius, Thomas
    Univ Cambridge, Addenbrookes Hosp, Dept Neurosurg, Cambridge, England..
    Colle, Henry
    AZ St Luca, Funct Neurosurg, Ghent, Belgium..
    Ryan, Mathew
    Leeds Gen Infirm, Dept Neurosurg, Leeds, W Yorkshire, England..
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci, Inst Neurosci & Physiol, Gothenburg, Sweden..
    von Campe, Gord
    Med Univ Graz, Dept Neurosurg, Graz, Austria..
    Bello, Lorenzo
    Univ Milan, Dept Oncol & Hematooncol, Neurosurg Oncol Unit, Milan, Italy.;IRCCS, Humanitas Res Hosp, Milan, Italy..
    Forster, Marie-Therese
    Goethe Univ, Dept Neurosurg, Frankfurt, Germany..
    Sarubbo, Silvio
    Santa Chiara Hosp, Struct & Funct Connectiv Lab, Trento, Italy..
    Spena, Giannantonio
    Spedali Civil Brescia, Clin Neurochirurg, Brescia, Italy..
    Baron, Marie-Helene
    CHRU Jean Minjoz, Dept Oncol Radiotherapie, Besancon, France..
    Yordanova, Yordanka
    Percy Army Training Hosp, Neurosurg Dept, Clamart, France..
    Darlix, Amelie
    Inst Regional Canc Montpellier ICM, Dept Med Oncol, Montpellier, France..
    Viegas, Catarina
    Hosp Garcia Orta, Dept Neurosurg, Almada, Portugal..
    Almairac, Fabien
    Univ Hosp Nice, Dept Neurosurg, Nice, France..
    Martino, Juan
    Hosp Univ Marques Valdecilla, Fdn Inst Invest Marques Valdecilla IDIVAL, Dept Neurol Surg, Avda Valdecilla S-N, Santander, Spain.;Inst Salud Carlos III, Avda Valdecilla S-N, Santander, Spain..
    Goodden, John
    Dept Neurosurg, Leeds, W Yorkshire, England..
    Chumas, Paul
    Dept Neurosurg, Leeds, W Yorkshire, England..
    Freyschlag, Christian
    Med Univ Innsbruck, Dept Neurosurg, Innsbruck, Austria..
    Robe, Pierre
    Univ Med Ctr Utrecht, Dept Neurosurg, Utrecht, Netherlands..
    Wager, Michel
    Univ Poitiers Hosp, INSERM U1084, Neurosurg Dept, Poitiers, France..
    Polivka, Marc
    Lariboisiere Hosp, AP HP, Dept Neuropathol, Paris, France..
    Giakoumettis, Dimitris
    Neurosurg Evangelismos Hosp, Athens, Greece..
    Robert, Erik
    AZ SintLucas & AZ Maria Middelares, Dept of Aphasiol, Ghent, Belgium..
    Guillevin, Remy
    Univ Poitiers Hosp, Neuroradiol Dept, Poitiers, France..
    Grivas, Athanasios
    Univ Glasgow, Queen Elizabeth Univ Hosp, Inst Neurol Sci, Dept Neurosurg, Glasgow, Lanark, Scotland..
    Fontaine, Denys
    Univ Hosp Nice, Dept Neurosurg, Nice, France..
    van Geemen, Kim
    Brain Res Ctr Amsterdam, Amsterdam, Netherlands..
    Lubrano, Vincent
    Univ Toulouse, CHU Toulouse, Toulouse NeuroImaging Ctr, INSERM UMR 1214,ToNIC, Toulouse, France..
    Rutten, Geert-Jan
    St Elisabeth Tweesteden Hosp, Dept Neurosurg, Tilburg, Netherlands..
    Barone, Fabio
    Cannizzaro Gen Hosp, Dept Neurosurg & Gamma Knife, Catania, Italy..
    Rofes, Adria
    Trinity Coll Dublin, Global Brain Hlth Inst, Dublin, Ireland..
    Rech, Fabien
    CHRU Nancy, Serv Neurochirurg, Nancy, France..
    Rigau, Valerie
    Gui Chauliac Hosp, Dept Pathol, Montpellier, France..
    Wagemakers, Michiel
    Univ Med Ctr, Neurosurg Dept, Groningen, Belgium..
    Papagno, Costanza
    Univ Trento, CeRiN & CIMeC, Rovereto, Italy..
    Aerts, Annelies
    AZ Sint Lucas, Ghent, Belgium.;Artevelde Univ Coll, Ghent, Belgium..
    Visch-Brink, Evy
    Erasmus MC, Dept Neurol, Rotterdam, Netherlands.;Erasmus MC, Dept Neurosurg, Rotterdam, Netherlands..
    Tate, Matthew
    Northwester Med Group, Dept Neurosurg, Chicago, IL USA..
    Garg, Neha
    Univ Delhi, Delhi, India..
    Klein, Martin
    Vrije Univ Amsterdam Med Ctr, Clin Neuropsychol Dept, Amsterdam, Netherlands..
    Satoer, Djaina
    Erasmus MC, Dept Neurol, Rotterdam, Netherlands.;Erasmus MC, Dept Neurosurg, Rotterdam, Netherlands..
    de Witte, Elke
    Vrije Univ Brussel, Neurolinguist Dept, Brussels, Belgium..
    Van Brussel, Lore
    Onze Lieve Vrouw Hosp, Neurosurg Dept, Moorselbaan, Aalst, Belgium..
    Reyes, Andres
    Univ Groningen, Dept Clin Linguist, Groningen, Netherlands.;EMCL Univ Potsdam, Potsdam, Germany.;El Bosque Univ, Expt Psychol Lab, Fac Psychol, Bogota, Colombia.;Inst Neurosci, Bogota, Colombia..
    van Ierschot, Fleur
    Univ Trent, Ctr Mind Brain Sci, Trento, Italy.;Univ Groningen, Fac Arts, Groningen, Belgium.;Macquarie Univ, Dept Cognit Sci, Sydney, NSW, Australia..
    Veenstra, Wencke
    Univ Groningen, Dept Linguist, Groninge, Belgium..
    Snijders, Tom
    Univ Med Ctr Utrecht, Dept Neurol & Neurosurg Hosp, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Taillandier, Luc
    CHU Nancy, Neurol Dept, Nancy, France..
    Blonski, Marie
    CHU Nancy, Neurol Dept, Nancy, France..
    Evidenced-based medicine in glioma: molecular biology is only part of the story2017In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 18, no 8, p. E429-E429Article in journal (Refereed)
  • 8.
    Erlandsson, Johan
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden..
    Holm, Torbjörn
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden..
    Pettersson, David
    Karolinska Inst, Dept Mol Med & Surg, Norrtalje, Sweden.;Norrtalje Hosp, Dept Surg, Norrtalje, Sweden..
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Cedermark, Björn
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden..
    Radu, Calin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Johansson, Hemming
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Machado, Mikael
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.;Karolinska Inst, Ersta Hosp, Stockholm, Sweden..
    Hjern, Fredrik
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.;Karolinska Inst, Ersta Hosp, Stockholm, Sweden..
    Hallböök, Olof
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Syk, Ingvar
    Lund Univ, Dept Surg, Malmo, Sweden..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Martling, Anna
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden..
    Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial2017In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 18, no 3, p. 336-346Article in journal (Refereed)
    Abstract [en]

    Background: Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery.

    Methods: In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 x 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4-8 weeks (short-course radiotherapy with delay) or 25 x 2 Gy radiation dose with surgery after 4-8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1.7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813.

    Findings: Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33.4 months (range 18.2-62.2) in the short-course radiotherapy group and 19.3 months (8.5-39.5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33.3 months (range 17.8-114.3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1.44 [95% CI 0.41-5.11]; long-course radiotherapy with delay 2.24 [0.71-7.10]; p=0.48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (<1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 [50%] of 129 patients in the short-course radiotherapy group; 48 [38%] of 128 patients in the short-course radiotherapy with delay group; 50 [39%] of 128 patients in the long-course radiotherapy with delay group; odds ratio [OR] vs short-course radiotherapy: short-course radiotherapy with delay 0.59 [95% CI 0.36-0.97], long-course radiotherapy with delay 0.63 [0.38-1.04], p=0.075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 [53%] of 355 vs 188 [41%] of 357; OR 0.61 [95% CI 0.45-0.83] p=0.001).

    Interpretation: Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery.

  • 9.
    Ferolla, Piero
    et al.
    Umbria Reg Canc Network, Multidisciplinary NET Grp, Dept Med Oncol, I-06126 Perugia, Italy.;Univ Perugia, Perugia, Italy..
    Brizzi, Maria Pia
    San Luigi Hosp, Dept Oncol, Orbassano, Italy..
    Meyer, Tim
    Royal Free Hosp, Dept Med Oncol, London, England.;UCL, London, England..
    Mansoor, Wasat
    Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England..
    Mazieres, Julien
    Univ Paul Sabatier, CHU Toulouse, Pneumol, Toulouse, France..
    Do Cao, Christine
    CHRU Lille, Med Oncol, Lille, France..
    Lena, Herve
    Ctr Hosp Univ, Pneumol, Rennes, France..
    Berruti, Alfredo
    Univ Brescia, Med Oncol, Brescia, Italy..
    Damiano, Vincenzo
    Univ Naples Federico II, Mol Canc Therapy, Naples, Italy..
    Buikhuisen, Wieneke
    Netherlands Canc Inst, Dept Thorac Oncol, Amsterdam, Netherlands..
    Gronbaek, Henning
    Aarhus Univ Hosp, Dept Hepatol & Gastroenterol, Aarhus, Denmark..
    Lombard-Bohas, Catherine
    Hosp Civils Lyon, Dept Med Oncol, Lyon, France..
    Grohe, Christian
    Evangel Lungenklin Berlin, Thorac Oncol, Berlin, Germany..
    Minotti, Vincenzo
    Osped S Maria Misericordia, Dept Med Oncol, Perugia, Italy..
    Tiseo, Marcello
    Univ Hosp Parma, Med Oncol, Parma, Italy..
    De Castro, Javier
    Hosp La Paz Madrid, Oncol, Madrid, Spain..
    Reed, Nicholas
    Gartnavel Royal Hosp, Clin Oncol, Glasgow, Lanark, Scotland..
    Gislimberti, Gabriella
    Novartis Farma SpA, Origgio, Italy..
    Singh, Neha
    Cognizant Technol Solut, Bombay, Maharashtra, India..
    Stankovic, Miona
    Novartis Pharma Serv Inc, Belgrade, Serbia..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Baudin, Eric
    Inst Gustave Roussy, Endocrine Oncol & Nucl Med, Villejuif, France..
    Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial2017In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 18, no 12, p. 1652-1664Article in journal (Refereed)
    Abstract [en]

    Background

    There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus.

    Methods

    LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0–2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing.

    Findings

    Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2–55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6–49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1–73·7) in the combination group. The most common grade 1–2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3–4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related.

    Interpretation

    The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids.

  • 10. Gimsing, Peter
    et al.
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Turesson, Ingemar
    Fayers, Peter
    Waage, Anders
    Vangsted, Annette
    Mylin, Anne
    Gluud, Christian
    Juliusson, Gunnar
    Gregersen, Henrik
    Hjorth-Hansen, Henrik
    Nesthus, Ingerid
    Dahl, Inger Marie S.
    Westin, Jan
    Nielsen, Johan Lanng
    Knudsen, Lene Meldgaard
    Ahlberg, Lucia
    Hjorth, Martin
    Abildgaard, Niels
    Andersen, Niels Frost
    Linder, Olle
    Wisloeff, Finn
    Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial2010In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 11, no 10, p. 973-982Article in journal (Refereed)
    Abstract [en]

    Background Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. Methods This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials. gov, number NCT00376883. Findings From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62.9-70.0) in the 90 mg group and 68 points (64.6-71.4) in the 30 mg group (95% CI of difference -6.6 to 3.3; p=0.52). Median time to first skeletal-related event in patients who had such an event was 9.2 months (8.1-10.7) in the 90 mg group and 10-2 months (7.3-14.0) in the 30 mg group (p=0.63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. Interpretation Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma.

  • 11.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Is the benefit of oxaliplatin in rectal cancer clinically relevant?2015In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 16, no 8, p. 883-885Article in journal (Other academic)
  • 12.
    Gyllensten, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lindell, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Gustafsson, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    HPV test shows low sensitivity of Pap screen in older women2010In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 11, no 6, p. 509-510Article in journal (Refereed)
  • 13.
    Hansson, Mats G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    van Ommen, Gert Jan
    Chadwick, Ruth
    Dillner, Joakim
    Patients would benefit from simplified ethical review and consent procedure2013In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 14, no 6, p. 451-453Article in journal (Refereed)
  • 14. Hess, Viviane
    et al.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Grawe, Philipp
    Dietrich, Daniel
    Bodoky, György
    Ruhstaller, Thomas
    Bajetta, Emilio
    Saletti, Piercarlo
    Figer, Arie
    Scheithauer, Werner
    Herrmann, Richard
    CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial2008In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 9, no 2, p. 132-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Several studies in patients undergoing chemotherapy for advanced pancreatic carcinoma have linked a decrease in the concentration of the tumour marker carbohydrate antigen (CA) 19-9 to lengthened survival. The aim of this study was to test the hypotheses that an early decrease in baseline serum CA 19-9 concentration (on day 42, after two cycles of chemotherapy) by at least 50% is associated with lengthened survival, and that a decrease in CA 19-9 concentration of at least 50% from the baseline concentration to the lowest value measured at any time during treatment (nadir) is of prognostic significance, enabling its use as a surrogate endpoint for survival. METHODS: CA 19-9 serum concentration was measured at baseline and every 3 weeks thereafter in patients with histologically proven advanced pancreatic carcinoma enrolled in a randomised trial of gemcitabine versus gemcitabine plus capecitabine. Patients were excluded if baseline serum CA 19-9 concentration was below the upper limit of normal (ULN) in the laboratory or if this measurement was missing. Comparisons of survival between patients with and without a CA 19-9 response were corrected for the guarantee-time bias by the landmark method. The trial on which this study is based is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00030732. FINDINGS: 247 of 319 randomised patients were assessable for analysis of baseline serum CA 19-9 concentration, and, of these, 175 patients were assessable for tumour-marker response to treatment. Median overall survival for patients with a baseline CA 19-9 concentration equal to or above the median value (ie, 59xULN) was 5.8 months (95% CI 5.1-7.0), which was significantly shorter than that for patients with baseline concentrations below the median value (10.3 months [95% CI 8.6-12.8], p<0.0001). An early decrease in CA 19-9 concentration of at least 50% after two cycles of chemotherapy was not associated with a longer overall survival compared with patients who did not have a decrease of at least 50% (median 10.1 months [9.2-12.7] vs 8.6 months [6.9-11.2], p=0.53; hazard ratio for death 1.11 [0.81-1.52]). Furthermore, a decrease in CA 19-9 concentration of at least 50% reached at the CA 19-9 nadir concentration was not associated with a longer overall survival compared with those patients who did not have a decrease of at least 50% (median 7.8 months [6.5.10.1] vs 6.7 months [5.5-9.8], p=0.74; 0.95 [0.69-1.31]) after adjusting for the guarantee-time bias. INTERPRETATION: Pretreatment serum CA 19-9 concentration is an independent prognostic factor for survival, but a decrease in concentration during chemotherapy is not significantly associated with lengthened survival compared with those who did not have a corresponding decrease. Our data suggest that CA 19-9 response during chemotherapy is not a valid surrogate endpoint for survival in clinical trials.

  • 15.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    The role of the primary-care physician in oncology care. Primary healthcare and specialist cancer services.2005In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 6, no 2, p. 121-2Article in journal (Refereed)
  • 16.
    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.

  • 17. Joensuu, Heikki
    et al.
    Kellokumpu-Lehtinen, Pirkko-Liisa
    Huovinen, Rukka
    Jukkola-Vuorinen, Arja
    Tanner, Minna
    Asola, Raija
    Kokko, Riitta
    Ahlgren, Johan
    Auvinen, Paivi
    Hemminki, Akseli
    Paija, Outi
    Helle, Leena
    Nuortio, Lauri
    Villman, Kenneth
    Nilsson, Greger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lahtela, Sirpa-Liisa
    Lehtiö, Kaisa
    Pajunen, Marjo
    Poikonen, Paula
    Nyandoto, Paul
    Kataja, Vesa
    Bono, Petri
    Leinonen, Mika
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial2009In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 10, no 12, p. 1145-1151Article in journal (Refereed)
    Abstract [en]

    Background Standard adjuvant chemotherapy regimens for patients with moderate-to-high-risk early breast cancer typically contain a taxane, an anthracycline, and cyclophosphamide. We aimed to investigate whether integration of capecitabine into such a regimen enhances outcome. Methods In this open-label trial, we randomly assigned (centrally by computer; stratified by node status, HER2 status, and centre) 1500 women with axillary node-positive or high-risk node-negative breast cancer to either three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (capecitabine group, n=753), or to three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (control group, n=747). The primary endpoint was recurrence-free survival. A planned interim analysis was done after 3 years' median follow-tip. Efficacy analyses were by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT00114816. Findings Two patients in each group were excluded from efficacy analyses because of wthdrawal of consent or distant metastases. After a median follow-up of 35 months (IQR 25.5-43-6), recurrence-free survival at 3 years was better with the capecitabine regimen than with control (93% vs 89%; hazard ratio 0.66, 95% CI 0.47-0-94; p=0.020). The capecitabine regimen was associated with more cases of grade 3 or 4 diarrhoea (46/740 [6%] vs 25/741 [3%]) and hand-foot syndrome (83/741 [11%] vs 2/741 [<1%]) and the control regimen with more occurrences of grade 3 or 4 neutropenia (368/375 198%] vs 325/378 186%]) and febrile neutropenia (65/741[9%] vs 33/742 [4%]). More patients discontinued planned treatment in the capecitabine group than in the control group (178/744 [24%] vs 23/741 [3%]). Four patients in the capecitabine group and two in the control group died from potentially treatment-related causes. Interpretation The capecitabine-containing chemotherapy regimen reduced breast cancer recurrence compared with a control schedule of standard agents. Capecitabine administration was frequently discontinued because of adverse effects. Funding Roche, Sanofi-Aventis, AstraZeneca, Cancer Society of Finland.

  • 18.
    Johansson, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Steineck, Gunnar
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Johansson, Jan-Erik
    Nyberg, Tommy
    Ruutu, Mirja
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Long-term quality-of-life outcomes after radical prostatectomy or watchful waiting: the Scandinavian Prostate Cancer Group-4 randomised trial.2011In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 12, no 9, p. 891-899Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: For men with localised prostate cancer, surgery provides a survival benefit compared with watchful waiting. Treatments are associated with morbidity. Results for functional outcome and quality of life are rarely reported beyond 10 years and are lacking from randomised settings. We report results for quality of life for men in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) after a median follow-up of more than 12 years. METHODS: All living Swedish and Finnish men (400 of 695) randomly assigned to radical prostatectomy or watchful waiting in SPCG-4 from 1989 to 1999 were included in our analysis. An additional 281 men were included in a population-based control group matched for region and age. Physical symptoms, symptom-induced stress, and self-assessed quality of life were evaluated with a study-specific questionnaire. Longitudinal data were available for 166 Swedish men who had answered quality-of-life questionnaires at an earlier timepoint. FINDINGS: 182 (88%) of 208 men in the radical prostatectomy group, 167 (87%) of 192 men in the watchful-waiting group, and 214 (76%) of 281 men in the population-based control group answered the questionnaire. Men in SPCG-4 had a median follow-up of 12·2 years (range 7-17) and a median age of 77·0 years (range 61-88). High self-assessed quality of life was reported by 62 (35%) of 179 men allocated radical prostatectomy, 55 (34%) of 160 men assigned to watchful waiting, and 93 (45%) of 208 men in the control group. Anxiety was higher in the SPCG-4 groups (77 [43%] of 178 and 69 [43%] of 161 men) than in the control group (68 [33%] of 208 men; relative risk 1·42, 95% CI 1·07-1·88). Prevalence of erectile dysfunction was 84% (146 of 173 men) in the radical prostatectomy group, 80% (122 of 153) in the watchful-waiting group, and 46% (95 of 208) in the control group and prevalence of urinary leakage was 41% (71 of 173), 11% (18 of 164), and 3% (six of 209), respectively. Distress caused by these symptoms was reported significantly more often by men allocated radical prostatectomy than by men assigned to watchful waiting. In a longitudinal analysis of men in SPCG-4 who provided information at two follow-up points 9 years apart, 38 (45%) of 85 men allocated radical prostatectomy and 48 (60%) of 80 men allocated watchful waiting reported an increase in number of physical symptoms; 50 (61%) of 82 and 47 (64%) of 74 men, respectively, reported a reduction in quality of life. INTERPRETATION: For men in SPCG-4, negative side-effects were common and added more stress than was reported in the control population. In the radical prostatectomy group, erectile dysfunction and urinary leakage were often consequences of surgery. In the watchful-waiting group, side-effects can be caused by tumour progression. The number and severity of side-effects changes over time at a higher rate than is caused by normal ageing and a loss of sexual ability is a persistent psychological problem for both interventions. An understanding of the patterns of side-effects and time dimension of their occurrence for each treatment is important for full patient information. FUNDING: US National Institutes of Health; Swedish Cancer Society; Foundation in Memory of Johanna Hagstrand and Sigfrid Linnér.

  • 19. Klug, Stefanie J
    et al.
    Ressing, Meike
    Koenig, Jochem
    Abba, Martin C
    Agorastos, Theodoros
    Brenna, Sylvia M F
    Ciotti, Marco
    Das, B R
    Del Mistro, Annarosa
    Dybikowska, Aleksandra
    Giuliano, Anna R
    Gudleviciene, Zivile
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Haws, Andrea L F
    Helland, Aslaug
    Herrington, C Simon
    Hildesheim, Alan
    Humbey, Olivier
    Jee, Sun H
    Kim, Jae Weon
    Madeleine, Margaret M
    Menczer, Joseph
    Ngan, Hextan Y S
    Nishikawa, Akira
    Niwa, Yoshimitsu
    Pegoraro, Rosemary
    Pillai, M R
    Ranzani, Gulielmina
    Rezza, Giovanni
    Rosenthal, Adam N
    Roychoudhury, Susanta
    Saranath, Dhananjaya
    Schmitt, Virginia M
    Sengupta, Sharmila
    Settheetham-Ishida, Wannapa
    Shirasawa, Hiroshi
    Snijders, Peter J F
    Stoler, Mark H
    Suárez-Rincón, Angel E
    Szarka, Krisztina
    Tachezy, Ruth
    Ueda, Masatsugu
    van der Zee, Ate G J
    von Knebel Doeberitz, Magnus
    Wu, Ming-Tsang
    Yamashita, Tsuyoshi
    Zehbe, Ingeborg
    Blettner, Maria
    TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies2009In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 10, no 8, p. 772-784Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. METHODS: Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. FINDINGS: The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). INTERPRETATION: Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies.

  • 20. Modlin, Irvin M.
    et al.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Chung, Daniel C.
    Jensen, Robert T.
    de Herder, Wouter W.
    Thakker, Rajesh V.
    Caplin, Martyn
    Delle Fave, Gianfranco
    Kaltsas, Greg A.
    Krenning, Eric P.
    Moss, Steven F.
    Nilsson, Ola
    Rindi, Guido
    Salazar, Ramon
    Ruszniewski, Philippe
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Gastroenteropancreatic neuroendocrine tumours2008In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 9, no 1, p. 61-72Article, review/survey (Refereed)
    Abstract [en]

    Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.

  • 21. Nordlinger, Bernard
    et al.
    Sorbye, Halfdan
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Poston, Graeme J.
    Schlag, Peter M.
    Rougier, Philippe
    Bechstein, Wolf O.
    Primrose, John N.
    Walpole, Euan T.
    Finch-Jones, Meg
    Jaeck, Daniel
    Mirza, Darius
    Parks, Rowan W.
    Mauer, Murielle
    Tanis, Erik
    Van Cutsem, Eric
    Scheithauer, Werner
    Gruenberger, Thomas
    Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial2013In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 14, no 12, p. 1208-1215Article in journal (Refereed)
    Abstract [en]

    Background Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. Methods This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m2 (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. This trial is registered with ClinicalTrials.gov, number NCT00006479. Findings Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8.5 years (IQR 7.6-9.5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0.88, 95% CI 0.68-1.14; p=0.34). In all randomly assigned patients, median overall survival was 61.3 months (95% CI 51.0-83.4) in the perioperative chemotherapy group and 54.3 months (41.9-79.4) in the surgery alone group. 5-year overall survival was 51.2% (95% CI 43.6-58.3) in the perioperative chemotherapy group versus 47.8% (40.3-55.0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. Interpretation We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients.

  • 22. Reijneveld, Jaap C
    et al.
    Taphoorn, Martin J B
    Coens, Corneel
    Bromberg, Jacoline E C
    Mason, Warren P
    Hoang-Xuan, Khê
    Ryan, Gail
    Hassel, Mohamed Ben
    Enting, Roelien H
    Brandes, Alba A
    Wick, Antje
    Chinot, Olivier
    Reni, Michele
    Kantor, Guy
    Thiessen, Brian
    Klein, Martin
    Verger, Eugenie
    Borchers, Christian
    Hau, Peter
    Back, Michael
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Golfinopoulos, Vassilis
    Gorlia, Thierry
    Bottomley, Andrew
    Stupp, Roger
    Baumert, Brigitta G
    Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.2016In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 17, no 11, p. 1533-1542Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy.

    METHODS: We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0-1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m(2) daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer's [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819.

    FINDINGS: Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months' follow-up (mean between group difference [averaged over all timepoints] 0·06, 95% CI -4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up.

    INTERPRETATION: The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma.

    FUNDING: Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

  • 23.
    Saussele, Susanne
    et al.
    Heidelberg Univ, Dept Haematol & Oncol, Univ Hosp Mannheim, Mannheim, Germany.
    Richter, Johan
    Skane Univ Hosp, Dept Haematol Oncol & Radiat Phys, Lund, Sweden.
    Guilhot, Joelle
    Ctr Hosp Univ CHU Poitiers, Ctr Invest Clin 1402, INSERM, Poitiers, France.
    Gruber, Franz X.
    Univ Hosp North Norway, Dept Haematol, Tromso, Norway.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Haematol, Trondheim, Norway.
    Almeida, Antonio
    Inst Portugues Oncol Francisco Gentil, Lisbon, Portugal.
    Janssen, Jeroen J. W. M.
    Vrije Univ Amsterdam Med Ctr, Dept Haematol, Amsterdam, Netherlands.
    Mayer, Jiri
    Masaryk Univ, Dept Internal Med Haematol & Oncol, Brno, Czech Republic;Univ Hosp Brno, Brno, Czech Republic.
    Koskenvesa, Perttu
    Univ Helsinki, Haematol Res Unit Helsinki, Helsinki, Finland;Helsinki Univ Hosp, Ctr Comprehens Canc, Helsinki, Finland.
    Panayiotidis, Panayiotis
    Univ Athens, Dept Internal Med 1, Laikon Gen Hosp, Athens, Greece.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Martinez-Lopez, Joaquin
    Univ Complutense Madrid, Hosp Univ Octubre 12, Ctr Nacl Invest Oncol, Ctr Invest Biomed Red Canc, Madrid, Spain.
    Rousselot, Philippe
    Univ Paris Saclay, Dept Haematol & Oncol, Univ Versailles St Quentin En Yvelines, Ctr Hosp Versailles,Inserm,Unite Mixte Rech 1173, Le Chesnay, France.
    Vestergaard, Hanne
    Odense Univ Hosp, Dept Haematol, Odense, Denmark.
    Ehrencrona, Hans
    Off Med Serv, Dept Clin Genet & Pathol, Lab Med, Lund, Sweden;Lund Univ, Div Clin Genet, Lund, Sweden.
    Kairisto, Veli
    Turku Univ, Cent Hosp, Dept Clin Chem, Turku, Finland;Turku Univ, Cent Hosp, Dept Genet, Turku, Finland.
    Polakova, Katerina Machova
    Inst Hematol & Blood Transfus, Prague, Czech Republic.
    Mueller, Martin C.
    Inst Hematol & Oncol, Mannheim, Germany.
    Mustjoki, Satu
    Univ Helsinki, Haematol Res Unit Helsinki, Helsinki, Finland;Univ Helsinki, Dept Clin Chem & Haematol, Helsinki, Finland;Helsinki Univ Hosp, Ctr Comprehens Canc, Helsinki, Finland.
    Berger, Marc G.
    CHU Estaing, Hematol Biol & Equipe Accueil Hemopaties Chron He, Clermont Ferrand, France;Univ Clermont Auvergne, Clermont Ferrand, France.
    Fabarius, Alice
    Heidelberg Univ, Dept Haematol & Oncol, Univ Hosp Mannheim, Mannheim, Germany.
    Hofmann, Wolf-Karsten
    Heidelberg Univ, Dept Haematol & Oncol, Univ Hosp Mannheim, Mannheim, Germany.
    Hochhaus, Andreas
    Univ Klinikum Jena, Klin Innere Med 2, Jena, Germany.
    Pfirrmann, Markus
    Ludwig Maximilians Univ Munchen, Inst Med Informat Verarbeitung Biometrie & Epidem, Munich, Germany.
    Mahon, Francois-Xavier
    Univ Bordeaux, Bergonie Canc Inst, INSERM, Unit 916, Bordeaux, France.
    Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial2018In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 19, no 6, p. 747-757Article in journal (Refereed)
    Abstract [en]

    Background Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. Methods In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0.1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. Findings Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1.14 [95% CI 1.05-1.23]; p=0.0010) and longer deep molecular response durations (1.13 [1.04-1.23]; p=0.0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1.13 [0.98-1.29]; p=0.08). TKI discontinuation was associated with substantial cost savings (an estimated (sic)22 million). No serious adverse events were reported. Interpretation Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure. Copyright (c) 2018 Elsevier Ltd. All rights reserved.

  • 24.
    ter Veer, Emil
    et al.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands.
    van Rijssen, L. Bengt
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Surg, Amsterdam, Netherlands..
    Besselink, Marc G.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Surg, Amsterdam, Netherlands..
    Mali, Rosa M. A.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands..
    Berlin, Jordan D.
    Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Nashville, TN USA..
    Boeck, Stefan
    Ludwig Maximilians Univ Munchen, Klinikum Grosshadern, Ctr Comprehens Canc, Dept Internal Med 3, Munich, Germany..
    Bonnetain, Franck
    Univ Hosp Besancon, Methodol & Qual Life Oncol Unit, Besancon, France..
    Chau, Ian
    Royal Marsden NHS Fdn Trust, London, England.;Royal Marsden NHS Fdn Trust, Brompton, Surrey, England..
    Conroy, Thierry
    Inst Cancerol Lorraine, Dept Med Oncol, Vandoeuvre Less Nancy, France.;Lorraine Univ, Vandoeuvre Less Nancy, France..
    Van Cutsem, Eric
    Univ Hosp Gasthuisberg Leuven, Dept Gastroenterol & Digest Oncol, Leuven, Belgium.;Katholieke Univ Leuven, Leuven, Belgium..
    Deplanque, Gael
    Hop Riviera Chablais, Dept Oncol, Vevey, Switzerland..
    Friess, Helmut
    Tech Univ Munich, Klinikum Rechts Isar, Dept Surg, Munich, Germany..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Goldstein, David
    Univ New South Wales, Prince Wales Clin Sch, Prince Wales Hosp, Nelune Canc Ctr, Randwick, NSW, Australia..
    Herrmann, Richard
    Univ Hosp Basel, Dept Med Oncol, Basel, Switzerland..
    Labianca, Roberto
    ASST Papa Giovanni XXIII, Ctr Canc, Bergamo, Italy..
    Van Laethem, Jean-Luc
    Univ Libre Bruxelles, Erasme Univ Hosp, Gastrointestinal Canc Unit, Dept Gastroenterol, Brussels, Belgium..
    Macarulla, Teresa
    Vall dHebron Inst Oncol VHIO, Vall dHebron Univ Hosp, Barcelona, Spain..
    van der Meer, Jonathan H. M.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Surg, Amsterdam, Netherlands..
    Neoptolemos, John P.
    Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England..
    Okusaka, Takuji
    Natl Canc Ctr, Dept Hepatobiliary & Pancreat Oncol, Tokyo, Japan..
    O'Reilly, Eileen M.
    Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, Dept Med, Gastrointestinal Oncol Serv,Div Solid Tumor Oncol, New York, NY USA..
    Pelzer, Uwe
    Charite Univ Med Berlin, Dept Hematol Oncol & Tumor Immunol, Berlin, Germany.;Humboldt Univ, Freie Univ Berlin, Berlin, Germany.;Berlin Inst Hlth, Berlin, Germany..
    Philip, Philip A.
    Wayne State Univ, Dept Oncol, Karmanos Canc Ctr, Detroit, MI USA..
    van der Poel, Marcel J.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Surg, Amsterdam, Netherlands..
    Reni, Michele
    IRCCS San Raffaele Sci Inst, Dept Med Oncol, Milan, Italy..
    Scheithauer, Werner
    Med Univ Vienna, Dept Internal Med 1, Vienna, Austria..
    Siveke, Jens T.
    Univ Hosp Essen, West German Canc Canc, Div Solid Tumor, Translat Oncol, Essen, Germany.;German Canc Consortium DKTK, Partner Site Essen, Heidelberg, Germany.;DKFZ, German Canc Res Ctr, Heidelberg, Germany..
    Verslype, Chris
    Univ Hosp Leuven, Dept Digest Oncol, Leuven, Belgium..
    Busch, Olivier R.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Surg, Amsterdam, Netherlands..
    Wilmink, Johanna W.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands..
    van Oijen, Martijn G. H.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands..
    van Laarhoven, Hanneke W. M.
    Acad Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands..
    Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease2018In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 19, no 3, p. E151-E160Article, review/survey (Refereed)
    Abstract [en]

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

  • 25.
    Tolmachev, Vladimir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Stone-Elander, Sharon
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Radiolabelled receptor-tyrosine-kinase targeting drugs for patient stratification and monitoring of therapy response: prospects and pitfalls2010In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 11, no 10, p. 992-1000Article, review/survey (Refereed)
    Abstract [en]

    Transmembrane receptor tyrosine kinases (RTKs) are overexpressed in many malignancies. RTK signalling triggers cell proliferation, suppression of apoptosis, increased motility, and recruitment of neovasculature. Overexpressed RTKs are the molecular targets for an increasing number of anticancer drugs. Monoclonal antibodies block the ligands or their binding sites and prevent receptor dimerisation, thereby hindering RTK signalling. The antibody-dependent cellular cytotoxicity can boost the therapeutic effect. Small-molecule tyrosine kinase inhibitors (TKIs) hamper downstream RTK signalling by targeting the intracellular kinase domain. These drugs have significantly increased survival in several patient groups. Improved patient stratification and therapy monitoring might further enhance the efficacy of anti-RTK therapy. Radionuclide-based molecular imaging can provide methods for localising and estimating the expression of RTKs. It can potentially identify patients who have tumours that overexpress RTK and would, therefore, most likely benefit from a targeted treatment. Monitoring changes in RTK expression during therapy could help avoid overtreatment and undertreatment. Radionuclide-based methods are less invasive and less sensitive to expression heterogeneity than more conventional sampling methods. The biochemical information is also obtained in an anatomical context. The development of radiolabelled anti-RTK drugs and their analogues is the subject of intensive preclinical and translational research. In this review, we present current approaches to developing imaging probes for in-vivo RTK visualisation and discuss their advantages and disadvantages.

  • 26. Torchia, Jonathon
    et al.
    Picard, Daniel
    Lafay-Cousin, Lucie
    Hawkins, Cynthia E.
    Kim, Seung-Ki
    Letourneau, Louis
    Ra, Young-Shin
    Ho, King Ching
    Chan, Tiffany Sin Yu
    Sin-Chan, Patrick
    Dunham, Christopher P.
    Yip, Stephen
    Ng, Ho-Keung
    Lu, Jian-Qiang
    Albrecht, Steffen
    Pimentel, Jose
    Chan, Jennifer A.
    Somers, Gino R.
    Zielenska, Maria
    Faria, Claudia C.
    Roque, Lucia
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Birks, Diane
    Foreman, Nick
    Strother, Douglas
    Klekner, Almos
    Garami, Miklos
    Hauser, Peter
    Hortobagyi, Tibor
    Bognar, Laszlo
    Wilson, Beverly
    Hukin, Juliette
    Carret, Anne-Sophie
    Van Meter, Timothy E.
    Nakamura, Hideo
    Toledano, Helen
    Fried, Iris
    Fults, Daniel
    Wataya, Takafumi
    Fryer, Chris
    Eisenstat, David D.
    Scheineman, Katrin
    Johnston, Donna
    Michaud, Jean
    Zelcer, Shayna
    Hammond, Robert
    Ramsay, David A.
    Fleming, Adam J.
    Lulla, Rishi R.
    Fangusaro, Jason R.
    Sirachainan, Nongnuch
    Larbcharoensub, Noppadol
    Hongeng, Suradej
    Barakzai, Muhammad Abrar
    Montpetit, Alexandre
    Stephens, Derek
    Grundy, Richard G.
    Schueller, Ulrich
    Nicolaides, Theodore
    Tihan, Tarik
    Phillips, Joanna
    Taylor, Michael D.
    Rutka, James T.
    Dirks, Peter
    Bader, Gary D.
    Warmuth-Metz, Monika
    Rutkowski, Stefan
    Pietsch, Torsten
    Judkins, Alexander R.
    Jabado, Nada
    Bouffet, Eric
    Huang, Annie
    Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis2015In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 16, no 5, p. 569-582Article in journal (Refereed)
    Abstract [en]

    Background Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. Methods We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Findings Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0.004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0.033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0.001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2.02 (95% CI 1.04-3.85; p=0.038) and 3.98 (1.71-9.26; p=0.001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. Interpretation An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours.

  • 27. van Gijn, Willem
    et al.
    Marijnen, Carrie A. M.
    Nagtegaal, Iris D.
    Kranenbarg, Elma Meershoek-Klein
    Putter, Hein
    Wiggers, Theo
    Rutten, Harm J. T.
    Påhlman, 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.
    van de Velde, Cornelis J. H.
    Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial2011In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 12, no 6, p. 575-582Article in journal (Refereed)
    Abstract [en]
    Background The TME trial investigated the value of preoperative short-term radiotherapy in combination with total mesorectal excision (TME). Long-term results are reported after a median follow-up of 12 years. Methods Between Jan 12, 1996, and Dec 31, 1999, 1861 patients with resectable rectal cancer without evidence of distant disease were randomly assigned to TME preceded by 5 x 5 Gy radiotherapy or TME alone (ratio 1:1). Randomisation was based on permuted blocks of six with stratification according to centre and expected type of surgery. The primary endpoint was local recurrence, analysed for all eligible patients who underwent a macroscopically complete local resection. Findings 10-year cumulative incidence of local recurrence was 5% in the group assigned to radiotherapy and surgery and 11% in the surgery-alone group (p<0.0001). The effect of radiotherapy became stronger as the distance from the anal verge increased. However, when patients with a positive circumferential resection margin were excluded, the relation between distance from the anal verge and the effect of radiotherapy disappeared. Patients assigned to radiotherapy had a lower overall recurrence and when operated with a negative circumferential resection margin, cancer-specific survival was higher. Overall survival did not differ between groups. For patients with TNM stage III cancer with a negative circumferential resection margin, 10-year survival was 50% in the preoperative radiotherapy group versus 40% in the surgery-alone group (p=0.032). Interpretation For all eligible patients, preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone without an overall survival benefit. For patients with a negative resection margin, the effect of radiotherapy was irrespective of the distance from the anal verge and led to an improved cancer-specific survival, which was nullified by an increase in other causes of death, resulting in an equal overall survival. Nevertheless, preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and Trim stage III. Future staging techniques should offer possibilities to select patient groups for which the balance between benefits and side-effects will result in sufficiently large gains.
  • 28. Van Hemelrijck, Mieke
    et al.
    Adolfsson, Jan
    Garmo, Hans
    Regional Oncologic Centre, Uppsala University, Uppsala.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Bratt, Ola
    Ingelsson, Erik
    Lambe, Mats
    Regional Oncologic Centre, Uppsala University, Uppsala.
    Stattin, Pär
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Risk of thromboembolic diseases in men with prostate cancer: results from the population-based PCBaSe Sweden2010In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 11, no 5, p. 450-458Article in journal (Refereed)
    Abstract [en]

    Background Cancer is associated with an increased risk of thromboembolic diseases, but data on the association between prostate cancer and thromboembolic diseases are scarce. We investigated the risk of thromboembolic disease in men with prostate cancer who were receiving endocrine treatment, curative treatment, or surveillance. Methods We analysed data from PCBaSe Sweden, a database based on the National Prostate Cancer Register, which covers over 96% of prostate cancer cases in Sweden. Standardised incidence ratios (SIR) of deep-venous thrombosis (DVT), pulmonary embolism, and arterial embolism were calculated by comparing observed and expected (using the total Swedish male population) occurrences of thromboembolic disease, taking into account age, calendar-time, number of thromboembolic diseases, and time since previous thromboembolic disease. Findings Between Jan 1, 1997, and Dec 31, 2007, 30 642 men received primary endocrine therapy, 26 432 curative treatment, and 19 526 surveillance. 1881 developed a thromboembolic disease. For men on endocrine therapy, risks for DVT (SIR 2.48, 95% CI 2.25-2.73) and pulmonary embolism (1.95, 1.81-2.15) were increased, although this was not the case for arterial embolism (1.00, 0.82-1.20). Similar patterns were seen for men who received curative treatment (DVT: 1.73, 1.47-2.01; pulmonary embolism: 2.03, 1.79-2.30; arterial embolism: 0.95, 0.69-1.27) and men who were on surveillance (DVT: 1.27, 1.08-1.47; pulmonary embolism: 1.57, 1.38-1.78; arterial embolism: 1.08, 0.87-133). Increased risks for thromboembolic disease were maintained when patients were stratified by age and tumour stage. Interpretation All men with prostate cancer were at higher risk of thromboembolic diseases, with the highest risk for those on endocrine therapy. Our results indicate that prostate cancer itself, prostate cancer treatments, and selection mechanisms all contribute to increased risk of thromboembolic disease. Thromboembolic disease should be a concern when managing patients with prostate cancer.

  • 29.
    Öberg, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Modlin, Irvin M.
    Yale Univ, Sch Med, New Haven, CT 06510 USA..
    De Herder, Wouter
    Erasmus MC, Endocrinol Sect, Dept Internal Med, Rotterdam, Netherlands..
    Pavel, Marianne
    Charite, D-13353 Berlin, Germany..
    Klimstra, David
    Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA..
    Frilling, Andrea
    Univ London Imperial Coll Sci Technol & Med, London, England..
    Metz, David C.
    Univ Penn Hlth Syst, Div Gastroenterol, Philadelphia, PA USA..
    Heaney, Anthony
    Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA..
    Kwekkeboom, Dik
    Erasmus MC, Dept Nucl Med, Rotterdam, Netherlands..
    Strosberg, Jonathan
    H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA..
    Meyer, Timothy
    UCL, Inst Canc, London, England..
    Moss, Steven F.
    Brown Univ, Liver Res Ctr, Providence, RI 02912 USA..
    Washington, Kay
    Vanderbilt Univ, Dept Pathol, Med Ctr, Nashville, TN 37235 USA..
    Wolin, Edward
    Univ Kentucky, Markey Canc Ctr, Lexington, KY USA..
    Liu, Eric
    Vanderbilt Univ, Dept Surg, Med Ctr, Nashville, TN 37235 USA..
    Goldenring, James
    Vanderbilt Univ, Dept Cell & Dev Biol, Med Ctr, Nashville, TN 37235 USA..
    Consensus on biomarkers for neuroendocrine tumour disease2015In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 16, no 9, p. E435-E446Article, review/survey (Refereed)
    Abstract [en]

    Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at > 75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specifi city necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours.

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