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1. Abstracts from the 8th Annual Meeting of the Scientific Association of Swiss Radiation Oncology (SASRO)

Author

Ph Morel, H. P. Do, W. Van den Bogaert, M. F. Fey, P. Hueber, H. Schefer, G. Goitein, S. Bressan, C. Verdan, W. Jeanneret Sozzi, L. Escudé, J. Heuberger, J. C. Horiot, O. Stadelmann, S. Balmer Majno, D. Schneiter, G. Lutters, A. Schott, Damien C. Weber, R. Mini, Peter Thum, Gábor J. Székely, G. Höpfl, B. Lippold, A. Coray, A. Azria, J. B. Davis, M. Betz, A. Hügli, Y. Zimmer, S. Berthou, Ch. Landmann, T. Boehringer, M. I. Saunders, S. Gourgou, L. Bortoluzzi, G. Ries, M. Allaoua, E. J. Born, A. Gallino, Christos Kolotas, G. Ueltschi, S. Bouville, Alessandra Bolsi, A. Richetti, K. T. Beer, S. Presilla, A. D. Roth, B. Streit, Richard H. Greiner, A. J. Lomax, F. Corminboeuf, J. Verwey, R. D. Gelber, J. Lindtner, O. Özsoy, R. Stupp, B. Thürlimann, R. H. Greiner, B. Hofstetter, I. F. Ciernik, M.-A. Bründler, C. von Briel, M. Honer, A. Merçay, E. Tschanz, M. Pruschy, L. Kemmerling, K. Rufibach, A. Franzetti, F. Luthi, A. Goldhirsch, J. Krayenbühl, St. Bodis, P. Martineau, Karl T. Beer, A. Pèlegrin, Peter D. Juelke, S. Cunat, J. Curschmann, M. Huser, A. Carbone, H. Rutz, Anthony Lomax, S. M. Bentzen, David Azria, W. Weder, N. Mach, H. Kranzbuehler, F. Mahler, L. Cozzi, P. Jichlinski, K. N. Price, M. Jörger, A. S. Coates, Christine Bouchardy, Frank Behrensmeier, Oscar Matzinger, Urs M. Lütolf, C. Taverna, H. Vees, D. Szczerba, R. Miralbell, D. Stalder, P. Pasche, C. Oehler, Eros Pedroni, M. Notter, P. Pujol, S. Bulling, W. Krek, D. Zingg, C. Larbouret, B. Pajic, G. Gruber, Oliver Riesterer, Beate Timmermann, L. Guillou, D. Weber, P. Dulguerov, P. Tebeu, F. Ludicke, P. Gervaz, Dagmar Laluhová, F. Munier, Abderrahim Zouhair, S. Lin, R. Gol-ouh, Ch. Taverna, M. Motta, R. Bigler, J. C. Luthi, S. Bieri, Malgorzata Roos, Paul Erne, S. Ganapathipillai, S. Ametamey, A. Tenzer, C. Burger, C. Bonny, B. J. Cummings, Stefanie Ohlerth, J. Bernier, M. Castiglione-Gertsch, M. Mollà, G. Pasche, J. F. Valley, G. Romieu, A. S. Allal, N. Stanek, U. Ulmer, Hans-Peter Hafner, S. Bodis, D. B. Evans, E. Pedroni, C.-M. Rudenstam, A. A. Khalil, G. Curti, D. M. Aebersold, C. Girardet, M. Jerman, A. Pica, G. Pache, E. Simoncini, R. Moeckli, T. Collen, A. Balmer, P. Mhawech, Peiman Jamshidi, Hans Peter Rutz, George N. Thalmann, Bernhard Isaak, E. E. Friedrich, M. Suleiman, M. Becker, D. Taussky, S. B. Holmberg, V. Vuong, Philippe Coucke, M. Abdou, Max Gassmann, G. Pesce, D. Crivellari, M. Weitzel, C. Rohrer Bley, H. Verkooijen, E. Schoenmaker, R. Stahel, R.O. Mirimanoff, C. Ares, M. Rouzaud, M. Bonetti, J. Collins, Barbara Kaser-Hotz, M. Bargetzi, P. Gertsch, H. P. Hafner, Y. Popowski, G. Nicolini, Natalie Inteeworn, Melanie Wergin, K. Allemann, P. Nouet, P. Kestenholz, H. Zenklusen, Brigitta G. Baumert, M. Usel, D. Lardinois, Therese Josephine Resink, S. Dische, H. Wang, H. Kranzbühler, T. Kebdani, D. Vetterli, H. J. Vees, W. Jochum, I. A. Norton, J. B. Dubois, C. Jargy, D. O. Slosman, A. Kramar, A. Fogliata, G. Studer, M. L. Nasi, Mahmut Ozsahin, G. Dipasquale, and P. Huguenin

Subjects
Radiation therapy, medicine.medical_specialty, Oncology, business.industry, medicine.medical_treatment, Radiation oncology, MEDLINE, medicine, Radiology, Nuclear Medicine and imaging, Medical physics, business
Published
2016

2. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial

Author

S M, Bentzen, R K, Agrawal, E G A, Aird, J M, Barrett, P J, Barrett-Lee, J M, Bliss, J, Brown, J A, Dewar, H J, Dobbs, J S, Haviland, P J, Hoskin, P, Hopwood, P A, Lawton, B J, Magee, J, Mills, D A L, Morgan, J R, Owen, S, Simmons, G, Sumo, M A, Sydenham, K, Venables, and U, Wells

Subjects
Time Factors, medicine.medical_treatment, Pilot Projects, Kaplan-Meier Estimate, Mastectomy, Segmental, 030218 nuclear medicine & medical imaging, Radiotherapy, High-Energy, 0302 clinical medicine, Reference Values, Aged, 80 and over, Standard treatment, Age Factors, Radiotherapy Dosage, General Medicine, Middle Aged, 3. Good health, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Female, Adult, Breast Neoplasms, Risk Assessment, 03 medical and health sciences, Sex Factors, Breast cancer, Median follow-up, Confidence Intervals, Fast track — Articles, medicine, Humans, Neoplasm Staging, Aged, Proportional Hazards Models, Intention-to-treat analysis, business.industry, Dose fractionation, Dose-Response Relationship, Radiation, medicine.disease, Survival Analysis, United Kingdom, Radiation therapy, Regimen, Dose Hypofractionation, Quality of Life, Radiotherapy, Adjuvant, Dose Fractionation, Radiation, Neoplasm Recurrence, Local, Nuclear medicine, business, Follow-Up Studies
Abstract

Background The international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size. Methods Between 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy versus 41.6 Gy or 39 Gy in 13 fractions of 3.2 Gy or 3.0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. Findings 749 women were assigned to the 50 Gy group, 750 to the 41.6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5.1 years (IQR 4.4-6.0) the rate of local-regional tumour relapse at 5 years was 3.6% (95% CI 2.2-5.1) after 50 Gy, 3.5% (95% CI 2.1-4.3) after 41.6 Gy, and 5.2% (95% CI 3.5-6.9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0.2% (95% CI -1.3% to 2.6%) after 41.6 Gy and 0.9% (95% CI -0.8% to 3.7%) after 39 Gy. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0.69 (95% CI 0.52-0.91, p=0.01). From a planned meta-analysis with the pilot trial, the adjusted estimates of alpha/beta value for tumour control was 4.6 Gy (95% CI 1.1-8.1) and for late change in breast appearance (photographic) was 3.4 Gy (95% CI 2.3-4.5). Interpretation The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41.6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions.

Published
2008
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3. Relationship between DNA double-strand breaks, cell killing, and fibrosis studied in confluent skin fibroblasts derived from breast cancer patients

Author

S. M. Bentzen, Jens Overgaard, Ekkehard Dikomey, J. Johansen, and Ingo Brammer

Subjects
Cancer Research, Programmed cell death, Pathology, medicine.medical_specialty, DNA Repair, Cell Survival, Somatic cell, medicine.medical_treatment, Breast Neoplasms, Radiation Dosage, Radiation Tolerance, Cell Line, Breast cancer, Fibrosis, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Radiosensitivity, Fibroblast, Skin, Radiation, business.industry, Radiobiology, DNA, Neoplasm, Fibroblasts, medicine.disease, Radiation therapy, Cell killing, medicine.anatomical_structure, Oncology, Cancer research, Female, business, DNA Damage
Abstract

Purpose: To investigate the relationship between DNA double-strand breaks (dsbs), cell killing, and fibrosis using skin fibroblasts derived from breast cancer patients who received postmastectomy radiotherapy. Methods and Materials: Experiments were performed with 12 lines of normal skin fibroblasts derived from recurrence-free breast cancer patients. Cells were irradiated in confluence and cell survival was determined either after immediate or delayed (14 h) plating using a colony-forming assay. Dsbs were measured by constant-field gel electrophoresis. The "excess risk of fibrosis" was previously scored by Johansen et al. ( IJRB 1994;66:407–412). Results: The 12 cell lines showed a typical spectrum of radiosensitivity. The mean value of surviving fraction after 3.5 Gy (SF3.5) was 0.063 for immediate and 0.174 for delayed plating with a coefficient of variation (CV) of 44 and 39%, respectively. There was also a broad variation in the extent of recovery from potentially lethal damage (RPLD), which was not correlated with the immediate sensitivity. The number of initial dsbs as well as the half-times of dsb repair showed little variation, whereas there were considerable differences in the number of residual dsbs (CV = 29%). The number of residual dsbs after 100 Gy was correlated significantly only with SF3.5 after delayed ( r 2 = 0.59; p = 0.006) but not after immediate plating ( r 2 = 0.21, p = 0.16). There was also no significant relationship between residual dsbs and the "excess risk of fibrosis" determined for the respective patients. Conclusion: It is shown that the number of residual dsbs measured in confluent human fibroblast lines can be used to predict the cellular radiosensitivity after delayed but not after immediate plating and also not to predict the excess risk of fibrosis of the respective breast cancer patients.

Published
2000
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4. Time factor for tonsillar carcinoma

Author

S. M. Bentzen and Howard D. Thames

Subjects
Cancer Research, medicine.medical_specialty, Radiation, business.industry, medicine.medical_treatment, Dose fractionation, Radiation therapy, Time factor, Oncology, Hockey stick, Total dose, medicine, Radiotherapy dose, Radiology, Nuclear Medicine and imaging, Radiology, External beam radiotherapy, business, Accelerated repopulation
Abstract

The overall treatment time is of such great interest in radiotherapy because it modifies the biological meaning of a radiation dose, no matter how precisely that dose has been determined physically. This has been recognized almost from the beginnings of radiation treatments 100 years ago, and many different experimental and theoretical models have been set up in attempts to describe the influence of protraction ( 13). An important step forward in the 1970s was Rod Withers’ breakdown of the biological basis for the time factor into the four Rs. Of these, two (repair and repopulation) have been particularly prominent in recent years, with lesser roles for redistribution and reoxygenation. Repopulation in particular has come under close scrutiny as a possible reason for local failure when the overall time is unduly protracted. This possibility, demonstrated experimentally in the 1980s by Trott and Kummermehr (14) and many others, was put on front stage clinically by the seminal multiinstitutional analysis of head and neck data by Withers and colleagues (16) in 1988. The main conclusions from this analysis were that the estimated tumor control dose remained relatively constant up until about 4 weeks after beginning a fractionated treatment, that after this it increased with increasing treatment time at a rate of 0.6 Gy/day (leading to a graph prescribed dose vs. time with the appearance of a “dog leg” or hockey stick), and finally that this increase was the result of accelerated repopulation of tumor clonogens. This paper has unleashed a veritable flood of articles in which an effect of time, in one form or another, has been recognized [see ref. (7) for examples]. At the same time clinical trials of accelerated fractionation, a strategy designed to shorten the overall time and thereby to lessen the deleterious effects of repopulation, have been started and their results will be known soon. We published a contrarian view (4), namely that the increase in radiotherapy dose with treatment time may have had other sources, for example, differences in dose prescription between the centers, and furthermore, that patient selection bias may have played a role. The doseprescription argument goes somewhat like this: in view of the shallow dose-response [an apparent D,, of 29 Gy (8)], differences in total dose from a low of 50 to a high of 70 Gy would not be recognizable. Therefore, it was at least possible that the data said nothing about repopulation, but rather a lot about differences in dose prescription (put another way: if straight lines are drawn through the data in Fig. 3, (15) a slope of about 0.5 Gy/day results, similar to the estimate in Table 5; this could have been because therapists precisely offset the effect of tumor clonogen regeneration when they prolonged treatment, but other explanations are possible, that is, that higher total doses are given when treatments with similar doses per fraction are prolonged). A further point was that the semblance of a hockey stick was lost when the data were replotted to allow for the very shallow dose-response. Along the same lines, Dubben (6) pointed out that the upward trend in given dose with overall time was independent of treatment outcome (cure or failure) and therefore would have the same appearance, whatever was happening with repopulation. It was therefore with great interest that we read the new contribution of Withers and colleagues ( 15) in this issue. The authors’ purpose was to investigate, for tonsil tumors, the importance to treatment outcome of dose per fraction, overall time, and total dose, and to this end they undertook a collaborative retrospective study of 676 eligible cases in nine centers that used widely different dose fractionation patterns for external beam radiotherapy. These patterns fall into three main “schools,” that is, Manchester (50-55 Gy/ 1516 fractions/3 weeks), Edinburgh (50-55 Gy/20 fractions/4 weeks), and Paris (66-72 Gy/32-40 fractions/6.5-8 weeks). The advantages of this approach are twofold, namely that a wide variation in fractionation patterns should enable more precise estimation of biological parameters, and that the in

Published
1995
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5. Fourth meeting of the European Neurological Society 25–29 June 1994 Barcelona, Spain

Author

H. Hattig, C. Delli Pizzi, M. C. Addonizio, Michelle Davis, A. R. Giovagnoli, L. Florensa, M. Roth, J. de Kruijk, Francisco Lacruz, Ph. Dewailly, A. Toygar, C. Avendano, P.P. De Deyn, J. F. Hurtevent, F. Lomeila, T. W. Wong, Gordon T. Plant, M. Bud, H. J. Willison, DH Miller, D. W. Langdon, R. Cioni, J. Servan, A. Kaygisiz, E. Racadot, D. B. Schens, E. Picciola, L. Falip, C. Bouchard, J. Jotova, A. Jorge-Santamaria, P. Misra, A. Dufour, C. P. Panagopoulos, A. Venneri, B. Sredni, B. Angelard, M. Janelidze, M. Carreno, J. Obenberger, J. Pouget, H. W. Moser, R. Kaufmann, J. A. Molina, D. Linden, A. Martin Urda, E. Uvestad, A. Krone, J. P. Cochin, J. Mallecourt, A. Cambon-Thomsen, K. Violleau, P. Osschmann, A. M. Durocher, E. Bussaglia, D. M. Danielle, H. Efendi, C. Van Broeckhoven, K. G. Jordan, W. Rautenberg, C. Iniguez, J. M. Delgado, Graham Watson, M. Lawden, Gareth J. Barker, K. Stiasny, James T. Becker, G. Campanella, E. Peghi, A. Poli, A. Haddad, T. Yamawaki, Giacomo P. Comi, S. Sotgiu, B. Ersmark, A. Pomes, M. Ziegler, P. Ferrante, P. Ruppi, H. KuÇukoglu, R. Bouton, U. K. Rinne, P. Vieregge, M. Dary, P. Giunti, Peter J. Goadsby, S. Jung, E. Secor, A. Steinberg, N. Vila, M. A. Hernandez, M. Cursi, A. Enqelhardt, A. Engelhardt, J. Veitch, F. Di Silverio, F. Arnaud, B. Neundörfer, R. Brucher, Dominique Caparros-Lefebvre, B. Meyer, Marianne Dieterich, M. H. Snidaro, R. Gomez, R. Cerbo, M. Ragno, J. M. Vance, S. Nemni, A. Caliskan, F. Barros, I. Velcheva, D. Ceballos-Baumann, V. Barak, A. Avila, N. Antonova, F. Resche, S. Pappata, L. Varela, S. R. Silveira Santos, A. Cammarota, L. Naccache, Y. Nara, E. Tournier-Lasserves, R. Mobner, T. Chase, A. Ensenyat, J. Ulrich, G. Giegerich, M. Rother, M. Revilla, N. Nitschke, K. Honczarenko, E. Basart Tarrats, J. Blin, B. Jacob, J. Santamaria, S. Knezevic, J. L. Castillo, M. Antem, J. Colomer, O. Busse, Didier Hannequin, S. Carrier, J. B. Ruidavets, C. Rozman, J. Bogoussslavsky, J. Pascual Calvet, E. Monros, J. M. Polo, M. Zucconl, Javier Muruzabal, R. R. Allen, R. Rivolta, K. Haugaard, A. Nespolo, K. Hoang-Xuang, G. Bussone, T. Avramidis, E. Corsini, Christiana Franke, T. Vinogradova, H. Boot, K. Vestergaard, G. H. Jansen, N. Argentino, M. Raltzig, W. Linssen, Mark B. Pepys, P. Roblot, L. Lauritzen, E. Fainardi, D. Morin, T. X. Arbizu Urdiain, J. Wollenhaupt, S. Bostantjopoulou, G. Pavesi, A. D. Forman, Giovanni Fabbrini, D. Jean, J. J. Archelos, M. I. Blanchs, M. Del Gobbo, Anna Carla Turconi, Ch. Derouesné, Elio Scarpini, A. Visbeck, P. Castejon, J. P. Renou, F. Mounier-Vehier, G. Potagas, Ch. Duyckaerts, A. Filla, R. Schneider, G. Ronen, K. Nagata, J. P. Vedel, A. Henneberg, G. van Melle, C. Baratti, H. Knott, M. C. Prevett, A. Bes, B. Metin, Jos V. Reempts, L. Martorell, Mefkure Eraksoy, H. O. Handwerker, D. S. Younger, O. Oktem, D. Frongillo, C. Soriano-Soriano, L. Niehaus, F. Zipp, A. Tartaro, S Newman, R. H. Browne, P. Davous, R. Sanchez, M. Muros, M. E. Kornhuber, A. Lavarone, M. Mohr, M. R. Garcia, S. Russell, H. Kellar-Wood, M. R. Tola, B. Ostermeyer, Ch. Tzekov, K. Sartor, E. B. Ringelstein, P. P. Gazzaniga, Paul Krack, H. Fidaner, H. Rico, T. Dbaiss, F. Alameda, E. Torchiana, L. Rumbach, I. Charques, J. M. Bogaard, C. D. Frith, L. J. Rappelle, R. Brenner, A. Joutel, K. Fuxe, G. HÄcker, M. J. Blaser, J. Valls-SolÇ, G. Ulm, M. Alberdi, A. Bock, F. W. Bertelsmann, U. Wieshmann, J. Visa, J. R. Lupski, D. D'Amico, L. M. P. Ramos, A. A. Vanderbark, R. Horn, M. Warmuth, Dietmar Kühne, Mark S. Palmer, C. Ehrenheim, E. Canga, S. Viola, O. Scarpino, P. Naldi, R. Almeida, A. A. Raymond, J. Gamez, Stephan Arnold, A. DiGiovanni, J. Dalmau, C. C. Chari, H. F. Beer, J. C. Koetsier, J. Iriarte, E. Yunis, J. Casadevall, E. Le Guern, E. Stenager, S. R. Benbadis, J. M. Warter, F. Burklin, I. Theodorou, L. Johannesen, G. A. Graveland, X. Leclerc, I. Vecchio, L. Ozelius, G. Nicoletti, R. K. Gherardi, E. Esperet, M. L. Delodovici, F. Cattin, F. Paiau, Giorgio Sacilotto, C. A. J. Broere, D. Chavdarov, J. P. Willmer, C. H. Hawkes, Th. Naegele, E. Ellie, E. Dartigues, M. J. Guardiola, S. Hesse, Z. Levic, Marco Rovaris, P. Saugeir-Veber, B. A. Yaqub, H. F. Durwen, R. Larumbe, J. Ballabrina, M. Sendtner, J. Röther, M. Horstink, C. Kluglein, M.P. Montesi, H. Apaydin, J. Montoya, E. Waubant, Ch. Verellen-Dunoulin, A. Nicolai, J. Lopez-Delval, R. Lemon, G. Cantinho, E. Granieri, A. Zeviani, Wolfgang H. Oertel, U. Ficola, V. Di Piero, V. Fragola, K. Sabev, M. V. Guitera, I. Turki, F. Bolgert, P. Ingrand, J. M. Gobernado, L. M. E. Grimaldi, S. Baybas, B. Eymard, Y. Rolland, Y. Robitaille, Ta. Pampols, P. J. Koehler, A. Carroacedo, J. Vilchez, S. Di Vittorio, I. R. Rise, T. Nagy, M. Kuffner, E. Palazzini, A. Ott, J. Pruim, T. X. Arbizu, E. Manetti, C. Cervera, S. Felber, G. Gursoy, J. Scholz, G. A. Buscaino, M. S. Chen, A. Pascual, J. Hazan, J. U. Gajda, J. G. Cea, G. Bottini, G. Damalik, F. Le Doze, G. Bonaldi, J. M. Hew, C. Messina, A. M. Kennedy, J. M. Carney, N. M. F. Murray, M. Parent, M. Koepp, V. Dimova, D. De Leo, K. Jellinger, G. Salemi, S. Mientus, M. L. Hansen, F. Mazzucchelli, J. Vieth, M. Mauri, E. Bartels, L. Johannsen, C. Humphreys, J. Emile, D. N. Landon, E. Kansu, R. Sanchez-Pernaute, Rsj Frackowiak, M. Gonzalez Torres, L. Oller, C. Machedo, J. Kother, M. Billiard, H. Durak, T. Schindler, A. Frank, A. Uncini, A. Sbriccoli, C. Farinas, D. W. Paty, N. Fast, A. T. Zangaladze, A. Kerkhofs, J. M. Pino Garcia, I. De la Fuente, B. Marini, L. Gomez, I. Rubio, Alessandra Bardoni, C. Brodie, P. Acin, U. Sliwka, S. A. Hawkins, S. Tardieu, F. Vitullo, J. M. Pereira Monteino, R. Gagliardi, T. Jezewski, A. Cano, T. Lempert, F. Abad Alegria, G. Rotondo, D. Ince, C. Martinez Parra, Y. Huang, H. Luders, Y. Steinvil, F. G. A. Van Der Meche, R. Bianchi, A. Sanchez, T. Sevilla, J. M. Ketelslegers, A. Domzal-Stryga, M. Pandolfo, M. O. Josse, K. W. Neff, I. Blanco, G. W. Bruyn, O. W. Witte, J. L. Thibault, G. Andersen, J. Pariset, A. Marcone, R. J. M. Lane, A. Hofman, M. Verin, T. Matilla, P. Bedoucha, J. Roche, M. Lai, M. Collard, A. Ugarte, F. Gallecho, D. Silbersweig, C. Kennard, J. P. Azulay, T. W. Ho, P. L. I. Dellemijn, R. Girardello, F. Baas, B. Voss, F. Rozenberg, E. M. Brocker, V. Stanev, A. A. J. Soeterboek, A. Marra, A. Rey, E. Ertem, M. Sawradewicz-Rybak, J. De Keyser, P. Cavallari, F. Proust, Y. Chevalier, H. C. Hansen, D. Leys, C. A. Davie, K. Hoang-Xuan, C. Bairati, H. van Crevel, Thomas T. Warner, B. Bompais, A. Dobbeleir, T Campbell, C. Macko, C. J. M. Klijn, M. Dussallant, T. P. Berlit, W. Rozenbaum, M. J. van den Bent, W. A. Rocca, M. Muller, H. Hundemer, U. Zifko, M. Campera, F. Drislane, D. Ranoux, T. M. Kloss, Anil Kumar, I. Ruolt, C. Bargnani, B. Marescau, N. A. Losseff, S. Notermans, B. Kint, E. T. Burke, C. Aykut, J. Matias Guiu, P. Maquet, T. Drogendijk, M. Leone, K. von Ammon, M. Pepeliarska, C. Prados, L. DiGiamberardino, T. Logtenberg, G. Lenoir, I. Castaldo, Damhaut, M. Radionova, G. Sirabian, R. Navon, Giovanni Antonini, K. Al Moutaery, E. Chamas, R. Schönhuber, M. Giannini, B. Debilly, I. Labatut, H. Henon, J. A. Egido, M. Baudrimont, J. N. Lorenzo, J. E. C. Bromberg, R. Antonacci, J. J. Vilchez, T. Moulin, B. Rautenstrauss, Giovanni Meola, J. Noth, S Mammi, P. Laforet, F. Lopez, C. Gehring, S. Bort, G. Rancurel, D. Decamps, S. Kostadinova, Y. Shapira, B. Neundoerfer, D. Chavrot, M. Solimena, J. P. Salier, W. Deberdt, R. Hoff-Jörgensen, A. Messina, S. Meairs, G. Rosoklija, E. Nelis, I. Bertran, C. Ertekin, J. Lohmeyer, Mitermayer Galvao dos Reis, L. Calo, E. Maccagnano, A. P. Hays, J. Verlooy, M. G. Forno, T. Blanco, L. Bail, Gabriella Silvestri, J. Montero, F. Bertrand, R. T. Ghnassia, C. Besses, T. Sereghy, F. Shalit, G. Bogliun, S. Braghi, St. Baykouchev, C. Franke, A. Lasa, L. C. Archard, J. Kriebel, S. Shaunak, M. Nocito, Alexander Tsiskaridze, E. Manfredini, T. Seigal, David G. Gadian, M. Barlas, J. D. Degos, C. Seeber, J. Caemert, J. L. Mas, R. B. Pepinsky, M. G. 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Meinardi, F. Carrara, J. Kuehnen, C. Peiro, H. Lassmann, K. Skovgaard Olsen, A. McDonald, L. Sciulli, A. Cobo, A. Monticelli, B. Conrad, J. Bagunya, J. Benitez, V. Desnizza, B. Dupont, O. Delrieu, D. Moraes, J. J. Heimans, F. Garcia Rio, M. Matsumto, A. Fernandez, R. Nermni, R. Chalmers, M. J. Marchau, F. Aguado, P. Velupillai, P. J. Martin, P. Tassan, V. Demarin, A. Engelien, T. Gerriets, Comar, J. L. Carrasco, J. P. Pruvo, A. Lopez de Munain, D. Pavitt, J. Alarcon, Chris H. Polman, B. Guldin, N. Yeni, Hartmut Brückmann, N. Wilczak, H. Szwed, R. Causaran, G. Kyriazis, M. E. Westarp, M. Gasparini, N. Pecora, J. M. Roda, E. Lang, V. Scaioli, David R. Fish, D. Caputo, O. Gratzl, R. Mercelis, A. Perretti, G. Steimetz, I. Link, C. Rigoletto, A. Catafau, G. Lucotte, M. Buti, G. Fagiolari, A. Piqueras, C. Godinot, J. C. Meurice, Erodriguez J. Dominigo, F. Lionnet, H. Grzelec, David J. Brooks, P. M. G. Munro, F. X. Weilbach, M. Maiwald, W. Split, B. Widjaja-Cramer, V. Ozturk, J. Colas, E. Brizioli, J. Calleja, L. Publio, M. Desi, R. Soffietti, P. Cortinovis-Tourniaire, E. F. Gonano, G. Cavaletti, S. Uselli, K. Westerlind, H. Betuel, C. O. Dhiver, H. Guggenheim, M. Hamon, R. Fazio, P. Lehikoinen, A. Esser, B. Sadzot, G. Fink, Angelo Antonini, D. Bendahan, V. Di Carlo, G. Galardi, A. F. Boller, M. Aksenova, Del Fiore, V. de la Sayette, H. Chabriat, A. Nicoletti, A. Dilouya, M. L. Harpin, E. Rouillet, J. Stam, A. Wolters, M. R. Delgado, Eduardo Tolosa, G. Said, A. J. Lees, L. Rinaldi, A. Schulze-Bonhage, MA Ron, C. Lefebvre, E. W. Radü, R. Alvarez, M. L. Bots, P. Reganati, S. Palazzi, A. Poggi, N. J. Scolding, V. Sazdovitch, T. Moreau, E. Maes, M. A. Estelies, P. Petkova, Jose-Felix Marti-Masso, G De La Meilleure, N. Mullatti, M. Rodegher, N. C. Notermans, T. A. T. Warner, S. Aktan, J. P. Louboutin, L. Volpe, C. Scheidt, W. Aust, C. M. Wiles, U. Schneider, S. K. Braekken, W. R. Willems, K. Usuku, Peter M. Rothwell, C. Talamon, M. L. Sacchetti, A. Codina, M. H. Marion, A. Santoro, J. Roda, A. Bordoni, D. J. Taylor, S. Ertas, H. H. Emmen, J. Vichez, V. BesanÇon, R. E. Passingham, M. L. Malosio, A. Vérier, M. Bamberg, A. W. Hansen, E. Mostacero, G. Gaudriault, Marie Vidailhet, B. Birebent, K. Strijckmans, F. Giannini, T. Kammer, I. Araujo, J. Nowicki, E. Nikolov, A. Hutzelmann, R. Gherardi, J. Verroust, L. Austoni, A. Scheller, A. Vazquez, S. Matheron, H. Holthausen, J. M. Gerard, M. Bataillard, S. Dethy, V. H. Patterson, V. Ivanez, N. P. Hirsch, F. Ozer, M. Sutter, C. Jacomet, M. Mora, Bruno Colombo, A. Sarropoulos, T. H. Papapetropoulos, M. Schwarz, D. S. Dinner, N. Acarin, B. Iandolo, J. O. Riis, P. R. J. Barnes, F. Taroni, J. Kazenwadel, L. Torre, A. Lugaresi, I. L. Henriques, S. Pauli, S. Alfonso, Pedro Quesada, A. S. T. Planting, J. M. Castilla, Thomas Gasser, M. Van der Linden, A. Alfaro, E. Nobile-Orazio, G. Popova, W. Vaalburg, F. G. A. van der Mech, L. Williams, F. Medina, J. P. Vernant, J. Yaouanq, B. Storch-Hagenlocher, A. Potemkowski, R. Riva, M. H. Mahagne, M. Ozturk, Ve. Drory, N. Konic, C. Jungreis, A. Pou Serradell, J. L. Gauvrit, G. J. Chelune, S. Hermandez, T. Dingus, L. Hewer, Ch. Koch, M. N. Metz-Lutz, G. Parlato, M. Sinaki, Charles Pierrot-Deseilligny, H. C. Diener, J. Broeckx, J. Weill-Fulazza, M. L. Villar, M. Rizzo, O. Ganslandt, C. Duran, N. A. Fletcher, G. Di Giovacchino, Susan T. Iannaccone, C. Kolig, N. Fabre, H. A. Crockard, Rita Bella, M. Tazir, E. Papagiannuli, K. Overgaard, Emma Ciafaloni, I. Lorenzetti, F. Viader, P. A. H. Millac, I. Montiel, L. H. Visser, M. Palomar, P. L. Murgia, H. Pedersen, Rafael Blesa, S. Seddigh, W. O. Renier, I. Lemahieu, H. M. L. Jansen, L. Rosin, J. Galofre, K. Mattos, M. Pondal, G. M. Hadjigeorgiou, D. Francis, L. Cantin, D. Stegeman, M. Rango, A. B. M. F. Karim, S. Schraff, B. Castellotti, I. Iriarte, E. Laborde, T. J. Tjan, R. Mutani, D. Toni, B. Bergaasco, J. G. Young, C. Klotzsch, A. Zincone, X. Ducrocq, M. Uchuya, O. J. Kolar, A. Quattrone, T. Bauermann, Nereo Bresolin, J. Vallée, B. C. Jacobs, A. Campos, Werner Poewe, J. A. Villanueva, A. W. Kornhuber, A. Malafosse, E. Diez-Tejedor, G. Jungreia, M. J. A. Puchner, A. Komiyama, O. Saribas, V. Volpini, L. Geremia, S. Bressi, A. Nibbio, Timothy E. Bates, T. z. Tzonev, E. Ideman, G. A. Damlacik, G. Martino, G. Crepaldi, T. Martino, Kjell Någren, E. Idiman, D. Samuel, J. M. Perez Trullen, Y. van der Graaf, J. O. Thorell, M. J. M. Dupuis, E. Sieber, R. D'Alessandro, C. Cazzaniga, J. Faiss, A. Tanguy, A. Schick, I. Hoksergen, A. Cardozo, R. Shakarishvili, G. K. Wennlng, J. L. Marti-Vilalta, J. Weissenbach, I. L. Simone, Amalia C. Bruni, Darius J. Adams, C. Weiller, A. Pietrangeli, F. Croria, C. Vigo-Pelfrey, Patricia Limousin, A. Ducros, G. Conti, O. Lindvall, E. Richter, M. Zuffi, A. Nappo, T. Riise, J. Wijdenes, M. J. Fernandez, J. Rosell, P. Vermersh, S. Servidei, M. S. C. Verdugo, F. Gouttiere, W. Solbach, M. Malbezin, I. S. Watanabe, A. Tumac, W. I. McDonald, D. A. Butterfield, P. P. Costa, F. deRino, F. Bamonti, J. M. Cesar, C. H. Lahoz, I. Mosely, M. Starck, M. H. Lemaitre, K. M. Stephan, S. Tex, R. Bokonjic, I. Mollee, L. Pastena, M. Gutierrez, F. Boiler, M. C. Martinez-Para, M. Velicogna, O. Obuz, A. Grinspan, M. Guarino, L. M. Cartier, E. Ruiz, D. Gambi, S. Messina, M. Villa, Michael G. Hanna, J. Valk, Leone Pascual, M. Clanet, Z. Argov, B. Ryniewicz, E. Magni, B. Berlanga, K. S. Wong, C. Gellera, C. Prevost, F. Gonzalez-Huix, R. Petraroli, J. E. G. Benedikz, I. Kojder, C. Bommelaer, L. Perusse, M. R. Bangioanni, Guy M. McKhann, A. Molina, C. Fresquet, E. Sindern, Florence Pasquier, M. J. Rosas, M. Altieri, O. Simoncini, M. Koutroumanidis, C. A. F. Tulleken, M. Dary-Auriol, S. Oueslati, H. Kruyer, I. Nishisho, C. R. Horning, A. Vital, G. V. Czettritz, J. Ph. Neau, B. Mihout, A. Ameri, M. Francis, S. Quasthoff, D. Taussig, S. Blunt, P. Valentin, C. Y. Gao, O. Heinzlef, H. d'Allens, C. Coudero, M. Erfas, G. Borghero, P. J. Modrego Pardo, M. C. Patrosso, N. L. Gershfeld, P. A. J. M. Boon, O. Sabouraud, M. Lara, J. Svennevig, G. L. Lenzi, A. Barrio, H. Villaroya, JosÇ M. Manubens, O. Boespflug-Tanguy, M. Carreras, D. A. Costiga, J. P. Breux, S. Lynn, C. Oliveras Ley, A. G. Herbaut, J. Nos, C. Tornali, Y. A. Hekster, J. L. Chopard, J. M. Manubens, P. Chemouilli, A. Jovicic, F. Dworzak, S. Smirne, S. E. Soudain, B. Gallano, D. Lubach, G. Masullo, G. Izquierdo, A. Pascual Leone Pascual, A. Sessa, V. Freitas, O. Crambes, L. Ouss, G. W. Van Dijk, P. Marchettini, P. Confalonieri, M. Donaghy, A. Munnich, M. Corbo, and M. E. L. van der Burg

Subjects
Neurology, business.industry, Media studies, Library science, Medicine, Neurology (clinical), business
Published
1994
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7. Altered fractionation and combined radio-chemotherapy approaches: pioneering new opportunities in head and neck oncology

Author

J, Bernier and S M, Bentzen

Subjects
Clinical Trials, Phase III as Topic, Head and Neck Neoplasms, Carcinoma, Squamous Cell, Humans, Antineoplastic Agents, Dose Fractionation, Radiation, Combined Modality Therapy, Randomized Controlled Trials as Topic
Abstract

Squamous cell carcinoma of the head and neck (HNSCC) are increasingly treated by multimodality approaches combining surgery, radiotherapy and chemotherapy. Randomised controlled trials have demonstrated major improvements in loco-regional tumour control from altered fractionation radiotherapy, accelerated fractionation and hyperfractionation, as compared with conventional fractionation. This experience is summarised, and the limit as to how far these modifications can be taken is discussed. It is emphasised that radiation fractionation will need to be optimised separately in multimodality strategies. Combined chemotherapy and radiotherapy has also been shown in phase III trials to produce an improved survival and an improved disease control. Chemotherapy may be given as neoadjuvant, concurrent or adjuvant treatment and the biological rationales for each of these, and the data supporting them, are reviewed. Although, large meta-analyses have shown concurrent chemoradiation to be the most effective, there is still a strong rationale for trying to develop neoadjuvant and adjuvant schedules. New, more active drugs may be important in this context. As therapy is becoming more intense, a careful recording and reporting of treatment-related morbidity is a crucial element in estimating the therapeutic gain from competing therapeutic management strategies. Development of non-cytostatic drugs and individualization of therapy using molecular prognostic markers are exciting areas of research with a great potential for improving therapy in the next decade and these are briefly discussed. Finally, a number of avenues for further research are identified.

Published
2003

9. Use of tumour markers in monitoring the course of ovarian cancer

Author

G J, Rustin, A E, Nelstrop, S M, Bentzen, M J, Piccart, and K, Bertelsen

Subjects
Ovarian Neoplasms, CA-125 Antigen, Antineoplastic Combined Chemotherapy Protocols, Decision Making, Disease Progression, Humans, Female, Neoplasm Recurrence, Local
Abstract

There is a need to delineate how the best available serum marker for ovarian cancer, CA 125 should be used in monitoring the treatment of individual patients, and in clinical trials.The situations where measurement of CA 125 could alter the management of individual patients during therapy and at relapse were critically analysed. Precise definitions for response according to CA 125 were first developed and tested on 989 patients receiving first line therapy and have since been tested on over 2000 patients in phase 2 trials. Precise definitions for progression were developed from 71 patients during and on 255 patients both during and after initial chemotherapy.In individual patient management, progression on initial chemotherapy can be demonstrated by serial rise in CA 125 suggesting the need for a change in therapy. A confirmed doubling of CA 125 from the upper limit of normal during follow up accurately predicts relapse. This endpoint needs prospective testing for use in clinical trials. Precise definitions of response based on a 50% or 75% fall in CA 125 levels accurately predicts whether a cytotoxic agent is active against ovarian cancer.Precise definitions of response based on CA 125 should be used in phase 2 trials of new cytotoxic drugs.

Published
1999

10. Proliferative activity (MIB-1 index) is an independent prognostic parameter in patients with high-grade soft tissue sarcomas of subtypes other than malignant fibrous histiocytomas: a retrospective immunohistological study including 216 soft tissue sarcomas

Author

V, Jensen, F B, Sørensen, S M, Bentzen, M, Ladekarl, O S, Nielsen, J, Keller, and O M, Jensen

Subjects
Adult, Aged, 80 and over, Adolescent, Infant, Nuclear Proteins, Antigens, Nuclear, Sarcoma, Soft Tissue Neoplasms, Middle Aged, Prognosis, Immunohistochemistry, Survival Rate, Ki-67 Antigen, Proto-Oncogene Proteins c-bcl-2, Child, Preschool, Humans, Tumor Suppressor Protein p53, Child, Cell Division, Aged, Follow-Up Studies, Retrospective Studies
Abstract

To evaluate the prognostic value of tumour proliferative activity, p53 accumulation and bcl-2 expression in a retrospective series of 216 patients with soft tissue sarcomas (STS).The immunohistochemical analyses were performed on formalin-fixed, paraffin-embedded tissue. The proliferative activity was assessed by use of the monoclonal antibody MIB-1 and evaluated in multiple, random systematic sampled fields of vision. The percentage of proliferating cells (the MIB-1 index) ranged between 1% and 85% (median 12%). A significant increase in mean MIB-1 index was seen with increasing histological malignancy grade. Variation in the incidence of p53 accumulation and bcl-2 positivity among different histological subtypes was observed. p53 accumulation was frequent in synovial sarcomas and leiomyo- and rhabdomyosarcomas, whereas bcl-2 preferentially was expressed in synovial sarcomas. Univariate analysis identified patient age, tumour size, histological grade of malignancy, MIB-1 index and p53 accumulation as significant prognostic parameters. Multivariate Cox analysis, including tests for interaction terms between histological subtypes and MIB-1 index, showed independent prognostic effect of MIB-1 index and tumour size in patients with high-grade tumours of other subtypes than malignant fibrous histiocytoma (MFH).Histopathological malignancy grading is the most important single prognostic factor for overall survival in STS, but estimation of MIB-1 index is useful for identifying the least favourable subgroup of high grade STS of other subtypes than MFH, for whom adjuvant therapy may be indicated.

Published
1998

12. Serum markers of bone metabolism in multiple myeloma: prognostic value of the carboxy-terminal telopeptide of type I collagen (ICTP). Nordic Myeloma Study Group (NMSG)

Author

N, Abildgaard, S M, Bentzen, J L, Nielsen, and L, Heickendorff

Subjects
Adult, Male, Osteocalcin, Middle Aged, Alkaline Phosphatase, Bone and Bones, Peptide Fragments, Humans, Female, Collagen, Multiple Myeloma, Peptides, beta 2-Microglobulin, Biomarkers, Procollagen, Aged
Abstract

This study was performed to evaluate the prognostic significance of serum markers of bone and collagen metabolism in multiple myeloma. Serum C-terminal telopeptide of type I collagen (ICTP) reflects degradation of bone, whereas serum osteocalcin, together with serum C-terminal propeptide of procollagen type I (PICP) and serum bone-specific alkaline phosphatase (bAP) reflect synthesis of bone matrix. The N-terminal propeptide of procollagen type III (PIIINP) in serum reflects synthesis of type III collagen. We analysed frozen sera from 109 patients with newly diagnosed multiple myeloma. Serum ICTP was elevated (5.0 micrograms/l) in most patients (median 6.6 micrograms/l range 1.4-29.4 micrograms/l). Serum PIIINP was elevated (4.2 micrograms/l) in 46% (median 4.0 micrograms/l, range 1.4-20.1 micrograms/l). Serum PICP was generally within the reference limits, whereas serum osteocalcin and serum bAP were elevated in 19% and 37%, respectively. Serum ICTP correlated with serum PIIINP, serum beta 2-microglobulin (beta 2m), serum calcium, performance status, and stage. In univariate analysis, the test variables serum ICTP (P = 0.026) and serum osteocalcin (P = 0.036) were found to be of prognostic value, but PIIINP, PICP, or bAP in serum were not. Serum ICTP and serum beta 2m had a similar prognostic value. In multivariate analysis, serum calcium showed the highest prognostic significance, and serum beta 2m was the only other variable of independent prognostic value. However, in normocalcaemic patients, serum ICTP showed the highest prognostic significance, followed by serum osteocalcin. Thus, the serum levels of ICTP and osteocalcin seem related to bone turnover and calcium metabolism, and provide further information about myeloma activity, particularly in normocalcaemic patients.

Published
1997

13. Histopathologic, stereologic, epidemiologic, and clinical parameters in the prognostic evaluation of squamous cell carcinoma of the oral cavity

Author

T, Bundgaard, S M, Bentzen, J, Wildt, F B, Sørensen, H, Søgaard, and J E, Nielsen

Subjects
Cell Nucleus, Male, Survival Rate, Alcohol Drinking, Multivariate Analysis, Smoking, Carcinoma, Squamous Cell, Mitotic Index, Humans, Female, Mouth Neoplasms, Prognosis, Follow-Up Studies
Abstract

Prognostic indicators that could assist in a more precise selection of patients with oral cancer for differentiated therapy would be clinically valuable.A consecutive series of 161 cases of intraoral squamous cell carcinoma (SCC) occurring during a 5-year period in a population of 1.4 million inhabitants, was evaluated by histopathologic (the modified classification of Jakobsson et al.), stereologic, clinical, and epidemiologic parameters and the serum markers hemoglobin and rhesus blood group.Univariate analysis established a significant prognostic value in terms of cause-specific survival for T stage (P.0001), stage (P.0001), maximum tumor diameter (P.0001), N stage (N+/NO) (P.0001), alcohol consumption (P = .03), stereologic estimates of nuclear volume (P = .04), and the histomorphologic parameters mode of invasion (P = .001), pattern (P = .01), vascular invasion (P = .02), depth (P = .006), and mean histologic score. Tobacco consumption was borderline significant (P = .055). A multivariate analysis using the Cox proportional hazard analysis showed that both clinical (stage, P.0001; size, P = .0027), epidemiologic (tobacco consumption, P = .0054), morphohistopathologic (mode of invasion P.0001), and stereologic (nuclear volume, P = .0010) parameters had an independent significant effect on survival. Inversely, the mean histologic score had no prognostic value. From the final regression model prognostic forecasts were calculated. Twelve patients (25%) with stage I disease had unfavorable histologic and stereologic parameters. The observed survival (+/- 1 standard error of the estimate) for these patients was 33% +/- 18%. The observed survival for stage I patients with more favorable histologic and stereologic characteristics (n = 36) was 76% +/- 8%.The use of a combination of clinical, histologic, epidemiologic, and stereologic parameters will assist the design of treatment strategies for intraoral SCC.

Published
1996

14. Proliferative response of mouse spermatogonial stem cells after irradiation: a quantitative model analysis of experimental data

Author

L, Judas, S M, Bentzen, P V, Hansen, and J, Overgaard

Subjects
Male, Mice, Stem Cells, Cell Cycle, Testis, Animals, Regeneration, Models, Theoretical, Flow Cytometry, Cell Division, Spermatogonia
Abstract

The testes of CDF1 mice were irradiated with single doses of X-rays ranging from 2-16 Gy. The number of haploid cells in the testis at different times after irradiation (42-350 days) was determined by one-parameter flow cytometry both for irradiated animals and for age-matched controls. Based on literature data on the kinetics of the spermatogenesis in mice, a mathematical model of the (hierarchical) germ tissue was developed. Using this model, the processes of radiation-induced cell loss and subsequent recovery were simulated and free parameters of the model were estimated by fitting the model prediction to the experimental data. One of the aims of the study was to investigate the kinetic behaviour of spermatogonial stem cells and the corresponding control mechanisms. In order to fit the data, the model has to include the following features: (i) A preferential self-repopulation of spermatogonial stem cells following tissue injury. The model-estimated probability of a self-renewing division rises from 50% (the steady-state value) to 95% if the stem-cell population is reduced to 10% of its normal size. (ii) A relatively low, almost constant turnover rate of the stem-cell compartment. It is suggested by the analysis that less than 10% of the spermatogonial stem cells present in the testis divide per day, regardless of the degree of cellular depletion. (iii) A mechanism responsible for incomplete recovery. The observed incomplete recovery of spermatogenesis after single doses exceeding 10 Gy can be described quantitatively assuming that the stem cells are organized into discrete proliferative structures, the number of cells per structure being about 60.

Published
1996

15. Is there a radiobiologic basis for improving the treatment of advanced stage cervical cancer?

Author

J C, Lindegaard, J, Overgaard, S M, Bentzen, and D, Pedersen

Subjects
Brachytherapy, Carcinoma, Squamous Cell, Humans, Uterine Cervical Neoplasms, Dose-Response Relationship, Radiation, Female, Radiotherapy Dosage, Radiation Tolerance, Neoplasm Staging
Abstract

The success of radiotherapy in eradicating the primary tumor in patients with locally advanced cervical cancer is limited by normal tissue tolerance. Systematic recording of morbidity and treatment parameters is therefore very important for radiobiologic treatment optimization and clinical decision making. There is substantial evidence that fractionation schedules employing large doses per fraction lead to a loss of therapeutic ratio. A similar argument could be used for high-dose-rate (HDR) brachytherapy that should also be administered in small dose fractions. However, HDR brachytherapy might convey some advantage to physical dose distribution that should be weighed against the radiobiologic advantages of low-dose-rate (LDR) continuous irradiation. Increasing overall treatment time reduces local control probability, whereas a shorter overall treatment time by accelerated fractionation may improve the therapeutic ratio, at least in fast-growing tumors. Hypoxia and reduced oxygen delivery are associated with poor radiation response. Anemia should be compensated, if necessary. The role of hypoxic modification needs to be further explored. In the future, the therapeutic ratio may also be improved by the use of chemical and biologic response modifiers. Tumors are heterogeneous with respect to intrinsic radiosensitivity, proliferation parameters, and extent of hypoxia. Until a detailed prognostic profile can be obtained for each patient, optimal curative radiotherapy must aim for a sufficient dose, short overall treatment time, hypoxic modification, and LDR or low dose per fraction.

Published
1996

16. [Consumption of tobacco and alcohol as prognostic factors in oral cancer]

Author

T, Bundgaard, S M, Bentzen, and J W, Wildt

Subjects
Adult, Male, Alcohol Drinking, Smoking, Carcinoma, Squamous Cell, Humans, Female, Mouth Neoplasms, Prospective Studies, Middle Aged, Prognosis, Aged, Follow-Up Studies
Abstract

The aim of the study was to assess the potential prognostic value of tobacco and alcohol consumption. 161 consecutive patients with intra-oral squamous cell carcinoma were included in a prospective follow-up study and valid data on tobacco and alcohol consumption were obtained. Univariate analysis showed that alcohol consumption had a significant influence and tobacco consumption had a borderline significant influence on the prognosis. Tobacco and alcohol consumption were strong correlated and each of these correlated to sex. Clinical staging (TNM), tumor size and sex all had a significant prognostic impact. A multivariate analysis showed that clinical stage, tumor size and tobacco consumption, but not alcohol consumption had significant influence on the prognosis. Thus tobacco smoking is an important clinical parameter both from a prophylactic and a therapeutic point of view.

Published
1995

17. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology

Author

J, Overgaard, D, Gonzalez Gonzalez, M C, Hulshof, G, Arcangeli, O, Dahl, O, Mella, and S M, Bentzen

Subjects
Adult, Aged, 80 and over, Male, Skin Neoplasms, Hyperthermia, Induced, Middle Aged, Prognosis, Combined Modality Therapy, Survival Rate, Treatment Outcome, Lymphatic Metastasis, Humans, Regression Analysis, Female, Neoplasm Recurrence, Local, Melanoma, Aged
Abstract

The value of hyperthermia as an adjuvant to radiotherapy in patients with malignant melanoma was studied in a European multicentre trial. 134 metastatic or recurrent lesions of malignant melanoma in 70 patients were randomly assigned to receive radiotherapy (three fractions of 8 Gy or 9 Gy in 8 days) alone or followed by hyperthermia (43 degrees C for 60 min). Overall, the 2-year actuarial local tumour control was 37 (SE 5)%. Univariate analysis showed a beneficial effect of hyperthermia (radiation alone 28% vs combined treatment 46%, p = 0.008) and radiation dose (24 Gy 25% vs 27 Gy 56%, p = 0.02), but no effect of tumour size (or = 4 cm 42% vs4 cm 29%, p = 0.21). Cox multivariate regression analysis showed the most important prognostic variables to be hyperthermia (odds ratio for 2-year local control 1.73 [95% CI 1.07-2.78], p = 0.023), tumour size (0.91 [0.85-0.99], p = 0.05), and radiation dose (1.17 [1.01-1.36], p = 0.05). Addition of heat did not significantly increase acute or late radiation reactions. Heating was well tolerated, but because of difficulties with equipment only 14% of treatments achieved the protocol objective. The overall 5-year survival rate was 19%, but 38% of the patients for whom all known disease was controlled survived 5 years. Adjuvant hyperthermia significantly improved local tumour control when applied in association with radiation in treatment of malignant melanoma. Successful local treatment of patients with a single or a few metastatic malignant melanoma lesions has significant curative potential.

Published
1995

19. DNA flow cytometry in uterine endometrial carcinoma

Author

M, Jacobsen, M, Høyer, S M, Bentzen, and K, Nielsen

Subjects
Ploidies, Receptors, Estrogen, Carcinoma, Uterine Neoplasms, Humans, Cell Differentiation, Female, DNA, Neoplasm, Flow Cytometry, Receptors, Progesterone
Abstract

The DNA content was investigated by means of flow cytometry in frozen tumor specimens from 33 patients with uterine endometrial carcinoma. The association was tested between ploidy and S-phase fraction on one hand and clinico-pathological parameters on the other. Aneuploidy appeared in 15 (45%) of the patients, and the average S-phase fraction was 0.18 (0.04-0.34). There was a highly significant correlation between DNA-Index (DI) and histologic differentiation (p = 0.01) and a less significant correlation between DI and estrogen receptor content (p = 0.04). DNA ploidy measured by flow cytometry is a highly reproducible parameter that in addition to routine histopathological examination may provide useful information. Further studies are needed to establish the prognostic importance of the flow cytometric parameters.

Published
1991

20. Does variation in the in vitro cellular radiosensitivity explain the shallow clinical dose-control curve for malignant melanoma?

Author

S. M. Bentzen, Howard D. Thames, and Jens Overgaard

Subjects
Cellular radiosensitivity, Control curve, Pathology, medicine.medical_specialty, Radiological and Ultrasound Technology, In Vitro Techniques, Cell Survival, Melanoma, In vitro toxicology, Dose-Response Relationship, Radiation, Biology, medicine.disease, Prognosis, Models, Biological, Radiation Tolerance, In vitro, Cancer research, medicine, Fractionation sensitivity, Humans, Radiology, Nuclear Medicine and imaging, Radiosensitivity
Abstract

In radiotherapy, clinical dose-control curves are generally more shallow than what should be expected from in vitro dose-survival curves for human cells of the same histology. One possible explanation is that a considerable inter-tumor heterogeneity in radiosensitivity flattens out the presumably steep individual dose-control curves. This paper compares dose-control curves for malignant melanomas derived from clinical data with curves derived from in vitro cell-survival experiments. Although inter-tumour variability in the in vitro dose and fractionation sensitivity may explain parts of the discrepancy between the steepness of clinical and in vitro dose-control curves, the present calculation indicates that a considerable additional variability, undetected by current in vitro assays, must be assumed to exist in order to resolve the discrepancy.

Published
1990

21. Phase III trial of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) versus cisplatin, etoposide, bleomycin and prednisone (CisEBP) for the treatment of advanced non-Hodgkin's lymphoma of high grade malignancy. The Danish Lymphoma Study Group

Author

J, Andersen, K, Thorling, S M, Bentzen, H, Brincker, B E, Christensen, and M, Pedersen

Subjects
Adult, Male, Lymphoma, Non-Hodgkin, Middle Aged, Bleomycin, Random Allocation, Doxorubicin, Vincristine, Antineoplastic Combined Chemotherapy Protocols, Drug Evaluation, Humans, Prednisone, Female, Cisplatin, Cyclophosphamide, Aged, Etoposide
Abstract

The trial included 85 previously untreated patients (median age 61 years) with stage III or IV non-Hodgkin's lymphoma (NHL) of the subtypes centrocytic lymphoma, diffuse centroblastic lymphoma, immunocytoma, immunoblastic lymphoma, or unclassified lymphoma of high grade malignancy. The patients were randomized to 9 monthly treatment cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CisEBP (cisplatin, bleomycin, etoposide, prednisone). Patients who had failed to achieve even a partial response (PR) after the completion of 2 cycles were switched to the alternative regimen. Complete response (CR) on primary treatment was obtained in 70% (55-83%) of CHOP-treated patients and in 25% (13-41%) of CisEBP-treated patients (p = 0.0004). Secondary CHOP treatment produced CR in 7 (30%) of 24 patients and secondary CisEBP treatment led to CR in 2 (15%) of 14 patients. The median survival was 3.4 years in the CHOP arm and 2.6 years in the CisEBP arm (p = 0.78). Hematologic toxicity was mainly leukocytopenia and anemia in both treatment arms. Non-hematological toxicity was slight, and late toxicity was insignificant. Three treatment-related deaths were noted. We conclude that CHOP induces more remissions than CisEBP in advanced lymphomas of high grade malignancy.

Published
1990

25. Corrigendum

Author

S M. Bentzen and H. D. Thames

Subjects
Radiology, Nuclear Medicine and imaging, General Medicine
Published
1990
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27. Evaluation of the spatial resolution of a CT scanner by direct analysis of the edge response function

Author

S M, Bentzen

Subjects
Evaluation Studies as Topic, Tomography, X-Ray Computed
Abstract

A new approach to the measurement of the spatial resolution of a computed tomography (CT) scanner system is presented. The method is based on a direct least-squares fit of an analytical expression to a set of data obtained from a CT image of the interface between two materials. The implementation of the method in connection with the G.E.RTPLAN computer configuration is described. The method has been applied in determining the resolution of an EMI-7070 scanner and it is shown that the assumption of uniformity of the system resolution across the CT image is fulfilled within the accuracy of the present method. The reproducibility of the method has been estimated from a series of spatial resolution determinations performed on ten images taken with identical scan parameters. The standard deviation of this series was 3.2%.

Published
1983

28. Prognostic factors in osteosarcomas. A regression analysis

Author

S M, Bentzen, H S, Poulsen, S, Kaae, O M, Jensen, H, Johansen, H T, Mouridsen, S, Daugaard, and C, Arnoldi

Subjects
Adult, Male, Osteosarcoma, Time Factors, Adolescent, Age Factors, Prognosis, Radiography, Sex Factors, Child, Preschool, Humans, Regression Analysis, Female, Child, Retrospective Studies
Abstract

A multivariate regression analysis of survival data, using the Cox proportional hazards model (PHM), was performed on the retrospective material of 184 osteosarcoma patients treated at the Aarhus and Copenhagen oncology centers, Denmark, from 1963 to 1984. All patients were previously untreated. Radical surgery, in general ablative when possible, was the primary treatment goal throughout this period. A number of clinical and pathologic variables were tested in the model to elucidate their prognostic importance. Tumors localized to the trunk, pelvis, or femur, and symptom duration of less than 6 months were poor prognostic signs. Tumors dominated by fibroblastic cells and a patient age of approximately 25 to 30 years were associated with an especially good prognosis. The prognosis worsened with advancing age. Children, adolescents, and adults ages 5 to 25 years had significantly poorer prognosis than young adults 25 to 30 years of age. Sex, radiologic appearance, and year of referral had no significant prognostic value in this series. Based on the regression model, a prognostic index is derived and survival is calculated for a good and a poor prognostic case. The overall 10-year survival with one standard deviation was 28.6 +/- 3.5%. Cancer deaths continue to occur 10 years after initial treatment, and the estimated hazard rate is still four times greater than that of a sex- and age-matched group of healthy individuals.

Published
1988

29. Cytotoxic effect of misonidazole and cyclophosphamide on aerobic and hypoxic cells in a C3H mammary carcinoma in vivo

Author

Cai Grau, Jens Overgaard, and S. M. Bentzen

Subjects
Male, Cancer Research, Misonidazole, Cyclophosphamide, Cell Survival, Ratón, Pharmacology, Biology, Mice, chemistry.chemical_compound, In vivo, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, medicine, Animals, Cytotoxic T cell, Cytotoxicity, Mammary Neoplasms, Experimental, Hypoxia (medical), medicine.disease, Oxygen, Oncology, chemistry, Immunology, medicine.symptom, Research Article, medicine.drug
Abstract

The chemosensitising effect of the nitroaromatic radiosensitiser misonidazole (MISO) on the alkylating agent cyclophosphamide (CTX) has been investigated in a C3H mammary carcinoma in CDF1 mice. The selective cytotoxicity against aerobic and hypoxic cells was measured indirectly, using a local tumour control (TCD50) assay. The hypoxic fraction was calculated from the dose difference between the TCD50S for tumours irradiated either in air or under clamped conditions. The relative survival of tumour cells after drug therapy was expressed as a surviving fraction (SF). CTX (100 mg kg-1) was found to be considerably more toxic towards hypoxic than aerobic cells (SF 4% versus 52%). MISO (1000 mg kg-1) was almost exclusively toxic to hypoxic cells (SF 22%). When MISO and CTX were administered simultaneously a decrease in the surviving fraction was observed. The effect on aerated cells was found to be 10-fold more than expected from addition of toxicities, suggesting a chemosensitising effect on these cells by MISO when used in combination with CTX. No synergistic effect was found on radiobiologically hypoxic cells. The exact role of hypoxia for the development of chemosensitisation seems to be complex and requires additional research in the future.

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