Annual Report 1992 THENETHERLANDSCANCERINSTITUTE CANCER RESEARCH LABORATORY AND CANCER HOSPITAL

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2 Annual Report 1992 THENETHERLANDSCANCERINSTITUTE CANCER RESEARCH LABORATORY AND CANCER HOSPITAL

3 Annual Report 1992 Illustrations and unpublished data in these reports should not be used without permission of the author. Copyright : The Netherlands Cancer Institute Antoni van Leeuwenhoek Huis PIesmanlaan CX Amsterdam The Netherlands Phone Fax ISSN

4 CONTENTS Board Members 6 Research and Hospital Divisions 8 Introduction 11 Clinical W orking Parties 17 1 Cell Biology 23 II Molecular Carcinogenesis 31 III Cellular Biochemistry 39 IV Immunology 51 V Molecular Biology 63 VI Tumor Biology 73 VII Molecular Genetics 81 VIII Experimental Therapy 91 IX Radiotherapy 103 X Medical Oncology 113 XI Surgical Oncology 127 XII Psychosocial Research and Epidemiology 139 Biometrics Department 149 Laboratory Animal Department 177 Biophysics Department 181 Education in Oncology 185 Cancer Hospital 197 Projects 203 Publications 213 Author index 245 Personnel-project index 257

5 6 BOARD MEMBERS International Scientific Advisory Board Jon J van Rood, Professor ofimmuno-hematology, Leiden, president Joseph R Bertino, American Cancer Society Professor of Medicine and Pharmacology, New Haven, USA George Klein, Professor of Tumor Biology, Stockholm, Sweden Hilary Koprowski, Professor Director of the Wistar Institute, Philadelphia, USA Susumu Tonegawa, Professor of Biology, MIT, Center of Cancer Research, Cambridge, Mass, USA I Bernard Weinstein, Professor of Medicine and Environmental Sciences, New York, USA Charles Weissmann, Professor of Molecular Biology, Zürich, Switzerland National Scientific Advisory Board D Bootsma, Professor of Cell Biology and Genetics, Rotterdam AJ van der Eb, Professor of Fundamental Tumor Virology, Leiden CAM Haanen, Professor of Internal Medicine, Nijmegen WGJ Hol, Professor of Molecular Biology, Groningen SWJ Lamberts, Professor of Internal Medicine, Rotterdam HL Langevoort, Professor of Histology and Embryology, Amsterdam CJLM Meijer, Professor of Pathological Anatomy, Amsterdam J Oldhoff, Professor of General Surgery, Groningen JJ van Rood, Professor of Immuno-Hematology, Leiden E van der Schueren, Professor of Oncology, Leuven GNJ Tytgat, Professor of Gastro-enterology, Amsterdam o Vos, Professor of Cell Biology, Histology and Microscopical Anatomy, Rotterdam

6 7 Board of Directors P Borst, chairman and director of research SGTh Hulst, clinical director (tiu ) DHJ van Buren, clinical director a.i. (from ) A Roest, tinancial director HM Pinedo, director of clinical research Laboratory Research Coordinator ERoos Board of Governors JD Hooglandt, president ML Frohn-de Winter, vice-president P den Tex, secretary o Hattink, treasurer AC van den Blink JEG de Boer HPM van der Drift R Hazelhoff PH H ugenholtz J van der Meer P Siderius (ti ) JHMTemmink GNJ Tytgat Ladies Committee MC Sickinge-van Eeghen, president YJ Engelsman-Prins, secretary D Jurgens-Kupsch, treasurer

7 8 RESEARCH AND HOSPIT AL DIVISIONS Research Divisions I Cell biology E Roos, head J Cal afat JG Collard CA Feitkamp A Sonnenberg n Molecular carcinogenesis R Bernards, head L den Engelse, head (till ) E Kriek (honorary staff member) E Scherer JG Westra ni Cellular biochemistry WH Mooienaar, head WJ van Blitterswijk HL Ploegh (till ) A Tulp LN Vernie IV Immunology AM Kruisbeek, head WS Bont (honorary staff member) J Borst CG Figdor A Hekman EM Rankin Ph Rümke (honorary staff member) CJM Vennegoor (stationed at the Free University) FA Vyth-Dreese V Molecular biology RHA Plasterk, head P Borst APMJongsma HV Westerhoff VI Tumor biology WJ Mooi, head JH Daams AA van der Gugten PhC Hageman J Hilkens D Ivanyi RJAM Michalides M Sluyser AA Verstraeten vn Molecular genetics AJM Berns, head P Demant LCJM Oomen (till ) M Snoek MA van der Valk M Zijlstra (deceased ) VIn Experimental therapy AC Begg, head H Bartelink WJ Nooijen HM Pinedo S Rodenhuis LA Smets FA Stewart IX Radiotherapy JV Lebesque, head G Baris H Bartelink RW de Boer JH Borger IAD Bruinvis BNFM van Bunningen JMV Burgers LGH Dewit AAM Hart RB Keus BJ Mijnheer H Meertens LMF Moonen SH Muller CCE Schaake-Koning FW Wittkämper X Medical oncology PF Bruning, head WW ten Bokkei Huinink JMG Bonfrèr H Boot CC Delprat CA Hoefnagel SP Israëls WJ Nooijen HM Pinedo EM Rankin DJ Richel S Rodenhuis JH Schornagel R Somers

8 9 BGTaal RA Valdés Olmos N van Zandwijk XI Surgical oncology FAN Zoetrnulder, he ad EJ Aartsen AJM Balm F van Coevorden J A van Dongen E Gortzak RT Gregor FJM Hilgers ThJM Helrnerhorst S HorenbIas BBR Kroon EJTh Rutgers XII Psychosocial research and epidemiology NK Aaronson, head FSAM van Dam FE van Leeuwen Laboratory animal department RGM ten Berg, head Biophysics department GJF Blornmestijn, head LCJM Oomen ELL Sonnhammer (till ) HJ Stoffers Hospita! Divisions Anesthesia M Hellendoorn-Smit, head C Blackburn MKaag HVis Biometrics department OB Dalesio, head HStoffers (till ) H van Tinteren Clinical chemistry and hematology WJ Nooijen, head JMG Bonfrèr Clinical research manager SEM Kloezen (till ) Dental surgery S Gonggrijp APTimmers ENT head and neck surgery FJM Hilgers, head AJM Balm RT Gregor Gastroenterology H Boot BGTaal Gynecology ThJM Helrnerhorst, head EJ Aartsen P Kenemans Hospital pastors LCM Blomjous-Maillete de Buy Wenniger PG Kousemaker AH Tönis Internal medici ne R Somers, head WW ten BokkeI Huinink PF Bruning SP Israëls HM Pinedo EM Rankin DJ Richel S Rodenhuis J Schornagel N uclear medicine CA Hoefnagel, head SH Muller RA Valdés Olmos Nursing HIM Camerik, head Pathology WJ Mooi, he ad MPWGallee P van Heerde BM Loftus-Coll JL Peterse K Weijer Patient counsellor M Keessen-van Luyken Psychiatry LM Gualthérie van Wee zei Psychosocial service EH Klein Poelhuis Pulmonology P Baas N van Zandwijk Radiotherapy H Bartelink, head G Baris RW de Boer JH Borger IAD Bruinvis BNFM van Bunningen JMV Burgers LGH Dewit

9 10 AAM Hart RB Keus JV Lebesque EAH Masselink H Meertens LMF Moonen BJ Mijnheer CCE Schaake-Koning FW Wittkämper Diagnostic radiology R Steinmetz, head P Cohen R Kröger F de Leeuw Surgery J A van Dongen, head F van Coevorden E Gortzak BBR Kroon OE Nieweg EJTh Rutgers FAN Zoetmulder Urology S HorenbIas Consultant Staff Bacteriology WPauw Dermatology H Neering General practitioner CC Delprat Neurology W Boogerd 11 van der Sande Plastic surgery JB de Boer KBos Rehabilitation ELD Angenot Heads of General Services Audiovisual service JM Lomecky Central cancer library MBA de Gouw Custodian research laboratory CA FeItkamp Financial administration JK Koppenol Housekeeping services RMD Schellens Medical administration JH Helversteyn MAC Galesloot, acting head (till ) Out-patient clinic MAC Galesloot, manager Personnel department JR de Bruyn Safety, health and welfare P de Lange Technical service TCM Wilmering N eurosurgery ZD Goedhart B Matricali Ophthalmology L Koornneeff Orthopedie surgery JW van der Eijken MW Fidler Pediatrics PA Voûte Pharmacy JH Beijnen ACA Paalman

10 11 INTRODUCTION The year 1992 was a turbulent one for the Netherlands Cancer Institute/ Antoni van Leeuwenhoek Huis (NKI/ A vl). We presented our long-term plans for a new NKI/ AvL to the government for support. We are aiming for a completely new building next to one of the two academic hospitals in Amsterdam. As the realization of these ambitious plans will take years, we also completed plans for a sober but substantial renovation and expansion of our present overcrowded hospital facilities. With the help of experts, we devised a new organizational structure for the hospital (including clinical research) of the NKI / A v L, that win be implemented in Despite these administrative distractions the science flourished and the scientific reputation of the institute received an additional boost in 1992 by the award of prestigious prizes to some of its members, with concomitant publicity in the lay press. R esearch highlights E Roos and associates (Division I) found that a cen surface protein, the integrin cx6fj4, is involved in the adhesion of carcinoma cens to liver cens. The expression of cx6 fj4 is often high in carcinomas and this integrin may therefore be involved in metastasis formation, at least in the liver. The new group of R Bernards (Division 11) found that a segment of several viral and cenular transcription factors th at bind to the general transcription factor TFIID also bind to the retinoblastoma gene product. This suggests that the retinoblastoma protein inhibits cen proliferation, at least in part, by preventing the interaction of certain key transcription factors with the general transcription machinery. WH Mooienaar and associates (Division 111) continued their work on the phospholipid derivative lysophosphatidic acid (LP A), a novel signal transduction molecule discovered by Mooienaar. In 1992 they found a novel signal transduction pathway triggered by LP A and the protease thrombin, in which a heterotrimeric G protein regulates activation of the proto-oncogene product p21 ras. Furthermore, they showed th at LP A is released from activated platelets, thus assigning a normal physiological role to LPA in wound healing processes. It is anticipated that LPA, like other platelet-derived mitogens, is also secreted by certain tumor cens, thereby creating an element of positive feedback in the unregulated growth of these cens. RL van der Bend and WJ van Blitterswijk (Division 111) found the putative LP A receptor to be present in brain stem and spinal cord but not other parts of the brain. This intriguing finding expands on their previous work on the biochemical identification of the LPA receptor in neuroblastoma and carcinoma cens and supports the view that LPA and its receptor have multiple functions. CG Figdor and associates (Division IV) cloned a novel gene encoding the gp 1 00 protein expressed in melanoma cens throughout tumor development. Further molecular characterization of this tumorassociated antigen should make it possible to generate cytotoxic T cens th at can recognize segments of this protein. These could then be investigated for anti-tumor activity. AM Kruisbeek and co-workers (Division IV) are developing procedures to break the non-responsiveness of the immune system to some foreign antigens. Manipulation of antigen presenting function of tumor ceus is explored as an intervention aimed at yielding more effective anti-tumor responses, with a focus on improving CD28-B7 co-stimulatory interactions. Kruisbeek found that CD28-B7 interactions are clearly required for induction oft-cen activation by superantigens. In contrast, clonal deletion induced by superantigens is not affected by a blockade in CD28-B7 interactions, suggesting that T cens utilize different signauing pathways for clonal activation and deletion. P Borst and his associates (Division V) celebrated the birth of mice rendered fully defective in the synthesis of one of the three mouse P glycoproteins. Mice homozygous for disruption of the mdr2 gene as weu as the mdrla gene we re obtained. P glycoproteins are known to be involved in some forms of multi-drug resistance but their physiological functions are still unknown. The 'knock-out' mice defective in the synthesis of one of these proteins, should help to define these functions. RHA Plasterk and his associates (Division V) succeeded in dissecting the functional domains of the integrase encoded by the Human Immunodeficiency Virus, which causes AIDS. They showed that a single active site of this versatile enzyme catalyses both the cutting of viral DNA and the integration of this DNA in host DNA, but that another part of the enzyme takes care of the DNA binding required for these activities. The Plasterk group also developed an ingenious method to disrupt any known gene of the nematode C elegans. This organism is used as a simple eukaryotic model system to study the function of genes that control the communication between ceus and the multiplication and differentiation of cells; processes of central importance in cancer.

11 12 Introduction J Hilkens and associates (Division VI) found that aberrant expression of the transmembrane glycoprotein episialin exerted a marked negative effect on cell-cell and cell-matrix adhesion. Such an aberrant expression occurs in many common malignant tumors; this finding is therefore of immediate relevance to a large number of tumors treated in the clinic. E Schuuring, working in the group of RJAM Michalides (Division VI), found a significant correlation of 11ql3 amplification and Iymph node metastasis in breast cancel This finding capitalizes on his previous work, in which he identified two genes on 11 q 13 that are overexpressed as a result of llq 13 amplification, namely, cyclin Dl and EMS-I. H te Riele, AJM Berns and associates (Division VII) succeeded in generating several novel mouse mutants via homologous recombination in embryonic stem (ES) cells. Mice lacking a functional retinoblastoma tumor susceptibility gene we re embryonic Jethal, showing defects in fetal erythropoiesis and neural development. As this phenotype precluded studying tumor predisposition, chimeric mice we re generated from normal ES cells and ES cells in which both alleles of the Rb gene had been inactivated. In these mice the cells lacking functional Rb protein contributed to most, if not all tissues in the adult animal, thereby showing that most mouse cells can function without any Rb protein. Mutant mice lacking the functional proto-oncogene pim-l exhibited a subtle but intriguing hematopoietic phenotype; complete loss of function of the bmi-l protooncogene led to a progressive depletion of lymphoid cells in mice. It is clear th at such mutant mice will be invaluable for understanding the complex multi-step process of oncogenesis (and the complex multi-step process of generation of mammals in generai). N van Zandwijk, FA Stewart and associates (Division VIII) found that the combination of photodynamic therapy (oxygen dependent) with the bioreductive drug Mitomycin C (hypoxic dependent) gave synergistic effects in mouse tumors. The magnitude of the effects were unexpectedly large compared with other, theoretically more potent, bioreductive agents. The promise of this combination has led to the design of a clinical protocol. The combined efforts of radiotherapists (Division IX) and surgeons (Division XI) were highlighted by the results of a large retrospective study which showed excellent local con trol rates (2% recurrence at five years) of patients treated with breast conserving therapy in our institute. The large number of patients in this study allo wed the identification of high risks groups for this kind of treatment. DJ Richel and S Rodenhuis (Division X) recently published their first results with our high-dose chemotherapy regimen for autologous bone marrow or stem cell transplantation for patients with solid tumors. The chemotherapy consists of high dose carboplatin, cyclophosphamide and thiothepa. It appears to be weil tolerated and is being studied as part of salvage treatment in advanced germ cell cancer and as adjuvant treatment in high risk breast cancer patients. Introduction of peripheral stem cell reinfusion cuts down considerably on the period of pancytopenia after this high-dose chemotherapy. NK Aaronson and his colleagues within the EORTC completed international field testing of the QLQ-C30, a cancer-specific quality of life questionnaire designed specifically for use in international clinical trials in oncology. The questionnaire has proven to be a valid, reliable and responsive measure of patients' quality of life. It has now been adopted as the standard quality of life measure by the EOR TC and is being employed by diverse clinical trial groups in the United States, Canada, and Western Europe. This brief list of research highlights represents our personal choice and is necessarily incomplete and somewhat arbitrary. The pages that follow present a more complete overview of our accomplishments (and set-backs) in Honors P Borst received the Dr HP Heineken Prize for biochemistry and biophysics of the Royal Netherlands Academy of Sciences in Amsterdam, for his fundamental contributions to biochemistry. The prize was presented to P Borst by His Royal Highness Prince Claus of the Netherlands in a ceremony in the New Church in Amsterdam (see photograph). P Borst also received the Gold Medal of the Robert Koch Foundation in Cologne, Germany. HM Pinedo presented the Hamilton Fairley Lecture at the ESMO meeting in Lyon, and was awarded the Geflux Alexandre Olivia 1992 Award for his twenty years research work in the field of Medical Oncology. HM Pinedo also received the Bristol-Myers Squibb Foundation Cancer Grant Award for his work in Pharmacology and Development ofnew Anticancer Agents. On December 19, 1992 HM Pinedo was awarded the 'Bronze Bull Award'. These awards are intended for people from the West-Indies for their exceptional achievements in the field of commerce, sciences, welfare, culture and sports. The award was granted to HM Pinedo in the World Trade Center by P Jonker, Alderman of Economic Affairs in Amsterdam. H te RieJe was the recipient of the Antoni van Leeuwenhoek Prize 1991 for his fundamental contributions to the study of oncogenes in mice. He was the first to inactivate both alleles of a gene, the pim-l proto-oncogene, in embryonic stem cells by means of gene targeting. He discovered th at the efficiency of homologous recombination in stem cells is critically dependent on a complete homology between donor and acceptor DNA. The AvL prize is awarded every year to the young investigator(s), student or post doc, who make(s) the most important contribution to cancer research in the NKI. The funds for this Prize are generously provided by Boehringer Mannheim Ltd. Other honors include: - E de Waard, our staff physician, received the 'HJ Doctor-Award' upon completion of her studies. - A Working Group of the Department of Radiotherapy on portal imaging received the ESTRO Calergo Award for the project 'The introduction of a new quality assurance technique in the clinic: the QUIRT project'.

12 Introduction 13 His Royal Higness Prince Claus of the Netherlands presents to P Borst the work of art that goes with the Dr HP Heineken Prize. ( Photograph: Capital Press & Photo Productions bv). H M Pinedo recipient of the Gejlux Alexandre Olivia Award, Bristol-Myers Squibb Award and the Bronze Bull Award., ) \ I I~ - H te Riele recipient of the Antoni van Leeuwenhoek Prize. I, \. ~ /' &... E de Waard recipient ofthe Doctor Award. Some members ofthe Working Party which received the ESTRO Calergo Award.

13 14 Introduction Research quality Table I presents two parameters used as international measures for research quality. The trend is pleasing, confirming other indications that the NKV AvL is on the right track. The quality of our research is also reflected in our ability to obtain competitive grants, as shown in Table 11; project grants rose to f 15.4 million in 1992, which represents more that one third of our total budget. As there is no overhead component in Dutch research grants and as most of the equipment also has to be paid from core grants, the present level of competitive grants is near the maximum that our infrastructure can bear. Table I Short term citations and impact of scientific articles pu blished by the NKI research staff : Publication year Citations* Impact** * In the two years after publication, corrected for self citations and articles on work not done in the NKI. ** The impact factor is the average number of citations of an article in a given journal. The total impact is the sum of the impacts of all articles published that year. The N KJ Graduate School and some new NKJ professors Although the NKII AvL has no formal teaching obligations (and receives hardly any money for teaching) various forms of teaching are intertwined with our research activities, as detailed elsewhere in the Report. The number of graduate students doing research towards a PhD has increased over the years and was nearly 90 in Since 1989 the in-house teaching of these students has been formalized in the NKI Graduate School, the first fully operational graduate school in the Netherlands. As the government decided that the NKI Graduate School could only receive formal recognition as part of a collaborative school with one of the universities, we joined forces with our oncological colleagues in the University of Amsterdam and the Free University (also located in Amsterdam) to start the Oncology Graduate School Amsterdam in The NKI/ AvL cannot award degrees and we therefore have to rely for this on the local universities. Fortunately, we collaborate with many university groups interested in oncology and these collaborations are increasingly being formalized by the institution of special part-time chairs for NKII AvL staffmembers, who acquired the ius promovendi (the right to act as promoter for their own students) in this way. The year 1992 saw the appointment of four of these professors, who usually spent about 10% of their time on their university tasks: AlM Berns (Division VII) was appointed part-time professor of Molecular Genetics at the University of Amsterdam. CG Figdor (Division IV) was appointed part-time professor of Cell Biophysics at the University of Twente. He will contribute to the research in the Technical Physics department. AM Kruisbeek (Division IV) was appointed part-time professor of Molecular Aspects in the Development of the Immune System at the Free University of Amsterdam. Wl Mooi, head of Division VI and head of the Department of Pathology, was appointed part-time professor of Tumor Pathology at the Free U niversity of Amsterdam. Site visit A site visit was organized on December 3 rd and 4 th 1992 to examine a substantial part of the clinical research program. The site visit team consisted of lr Bertino (Memorial Sloan-Kettering Cancer Center, New York), E van der Schueren (Academic Hospital Table TI NKI research budgets, * Budgets (x 10 6 HFL) 1. Annual program grants a. Department of health: - structural incidental 1.0 b. Dutch Cancer Society KWF - structural incidental Large equipment and special facilities l Project grants Yield bond issue 0.9 l l Deficit l *Estimate

14 Introduction 15 St. Rafael, Leuven), JF Smyth (Western General Hospital, Edinburgh), and HD Suit (Massachusetts General Hospital, Boston). The site visit was a special one because it was selected by the Royal Academy to test out a scheme of site vi sits of medical research to be implemented in the Netherlands in the coming years. As the NKV AvL is the only institute with broad experience with scientific site visits, we were happy to act as a guinea pig. The site visit was a most stimulating experience for the oncologists and radiotherapists involved in our clinical research program and led to several specific suggestions to strengthen this program. The European Cancer Center The European Cancer Center (EEC) was inaugurated by her Royal Highness Princess Margriet on March 16, A symposium was organized with presentations by groups of the Netherlands Cancer Institute, the Free University Hospital and the Academic Medical Center of the University of Amsterdam. Changes in personnel In the beginning of 1992 we were shocked by the sudden death of Dr M Zijlstra, who had joined Division VII half a year earl ier as an AvL fellow and who was just establishing his own research group. In him we have lost a dedicated scientist and a wonderful colleague. He will be remembered for his seminal contributions to the field of molecular immunology. In 1992 we said goodbye to HL Ploegh, head of the Division of Cellular Biochemistry. After 8 years in the NKV A vl, Ploegh accepted a position as tenured full professor at the Massachusetts Institute of Technology in Cam bridge, USA. Although it is an honor for our institute that one of its younger staff members was selected for such a lofty chair, the departure of HL Ploegh is a severe loss to the institute. Ploegh was the first new staff member hired after P Borst took over the directorship of the institute in 1983 and to many people he has personified the new research policy of the institute. His manifold contributions to cellular biochemistry, notably the routing of class land class II MHC molecules in the cell and the nature of the antigenic peptides presented by these surface molecules, have contributed greatly to the reputation of the institute. A charismatic speaker and an avid traveiler, he was an excellent ambassador for the institute. He contributed many new developments to the institute, both scientific and organizational. He was the driving force behind the NKI Graduate School, and its first dean, and he conceived the AvL fellowships. We honored this charismatic, brilliant and charming colleague at his departure with a highly successful oneday symposium highlighting some of the recent developments in cell biology. In January 1992 we welcomed a new staff member, R Bernards, who left the Massachusetts General Cancer Center in Boston, USA, to join the Molecular Carcinogenesis Division of the NKV AvL. As Bernards is a molecular biologist working on nuclear oncogenes, he provides essential expertise for introducing molecular biological elements in some of the chemical carcinogenesis programs of the division, in accordance with the recomrnendation of a site visit carried out in In 1992 A Sonnenberg, a former student of the institute, returned as a new staff member of the Cell Biology Division. Sonnenberg made important con tribu tions to the discovery of two in tegrins, the cx6f31 (VLA-6) and the cx6f34 integrins, and he showed that cx6f31 is the cellular receptor for laminin. His return further strengthens the NKI/ AvL research on cell-cell and cellmatrix interactions, already a major research focus in several divisions. The ENT department welcomed R T Gregor as a new staff member. SEM Kloezen departed as the clinical research manager. She was the first person to occupy this new function and has made it an indispensable one. Finally, SG Hulst resigned as clinical director in the beginning of We are indebted to him for his efforts to improve the facilities for advanced patient care; facilities that are also indispensable for clinical research. For 6 months one of our medical oncologists, JH Schornagel, acted as an effective stand-in clinical director and we are most grateful for his willingness to take on this rat her thankless job and help the other directors to run the institute. In September 1992 DHJ van Buren took over as interim clinical director to allow more time to work out a long-term solution for the management of the hospita!. National and international activities Besides their research and clinical activities, staff members of the Netherlands Cancer Institute participated in a large number of important functions in international organizations such as AACR, CIBA, EACR, EBCTCG, EMBO, EORTC, ESSO, ICRU, MRC, OECI, WHO. Staff members also served on boards of organizations such as the EOR TC cooperative groups, International Association for Breast Cancer Research, Nederlandse Commissie voor Stralingsdosimetrie, Nederlandse Werkgroep Hoofd Halstumoren, Oog en Orbita Commissie, American Association for Psychological Oncology, European Community Committee on Palliative Cancer Care, Comprehensive Cancer Center Amsterdam, European Society for Therapeutic Oncology, the WHO Quality of Life Group, the International Academy of Pathology, the Gezondheidsraad, the NWO Gebiedsbestuur der Medische Wetenschappen, National Advisory Board on AIDS, Netherlands Health Council Committee on Home care for Cancer Patients, Scientific Council on Social Oncology (WRSO) of the Dutch Cancer Society, etc. Others served as editors of scientific books or served on editorial boards of 38 prestigious journais. Staff members were also active in organizing national and international oncology meetings, workshops and congresses, and participated in teaching for the European School of Oncology and the ESTRO teaching Course on Quality Assurance of Equipment for External Beam Therapy and the ESTRO teaching course on Basic Clinical Radiobiology. Clinical specialists from the hospital also gave oncological advice to colleagues in 23 hospitals in the Amsterdam area and other parts of Holland.

15 16 Introduction HM Pinedo was president ofthe 7th NCI-EORTC Symposium on new drugs in cancer therapy, which took place in Amsterdam, March 17-20, The future ofthe NKlI AvL In the past three years we have had intensive discussions about the future of the NKI/ AvL. Our present space and facilities are stretched to the limit and the hospital is hopelessly outdated and unsuitable for the practice of state-of-the-art oncology. Our initial plans aimed for a dras tic renovation and expansion of our present building. As the in-house discussions continued we gradually realized the disadvantages of such an in situ rejuvenation. We would be in for years of building and renovation activities on a site where patient care and research would have to go on between the drilling, the hammering, the dust and the continuing hassle of relocating activities. Moreover, even if the end result would be satisfactory, the location of the renovated NKI/ AvL would still be less than optima!. The increasing need for close collaboration with an academic hospital, to provide optimal care in the non-onco10gical medical specialties, would render a location for the NKI/ AvL directly adjacent to an academic hospital highly preferabie. With this in mind we drew up plans for a new state-of-the-art cancer center next to one of the academic hospitals in Amsterdam. We are fortunate that both hospitals are keen on having us as neighbours and that the new plans have been received with considerable enthusiasm by the municipal government and the Ministry of Health. A small problem remains, the f 300 million required to build the center, but we are working on that. In 1992 we again had the support ofmany people in our efforts to keep the NKI/ AvL at the cutting edge of cancer research and care. Our governing board spent long hours helping us to draw up plans for the future and to restructure the organization of the hospital; our scientific advisory boards gave sound advice and tempered our enthusiasm for unrealistic growth; the governing board and staff of the Dutch Cancer Society gave us strong support when we had to fight another cut in our government core grant; the mayor of Amsterdam, E van Thijn, joined the Health Secretary during his visit to the institute in June 1992 and strongly supported the plans for a new NKI/ AvL in Amsterdam; and many others are hel ping us in various ways. We are grateful to each of them and we hope th at they wiu continue their indispensable support in Piet Borst, Director of Research Bob Pinedo, Director of Clinical Research

16 17 CLINICAL WORKING PARTIES The multidisciplinary character of the Netherlands Cancer Institute and the collaboration between basic research and patient care is expressed by the way the tumor oriented working parties perform their research activities. The following list provides an overview of their activities in Some of the research projects listed here are described in detail in the mentioned division. A NTIEME TICS Chairman: BG Taal BIOANALYSIS AND EARLY CLINICAL TRIALS GROUP (BECTG) Chairmen: ww ten Bokkei Hu in inkl J H Beijnen Phase land 11 studies with Taxol in ovarian and breast cancer. Phase land pharmacokinetic study with intopoline. Phase land pharmacokinetic study with topotecan given in a 24 hour infusion every 3 weeks. Phase 1/ 11 studies in gastrointestinal cancer with 5FU, leucovorin and TCNU and/ or etoposide. Bioanalysis of investigational vinca-alkaloids: (Navelbine, N(deacetyl-O-l-vinblastoyl-23-)Lethyl isoleucinate. Bioanalysis of folates: (d-and lleucovorin, 5, 10 dideazatetrahydrofolate( ddthf)). Bioanalysis of investigational anti cancer drugs (Topotecan, Camptothecin, EOG, intopoline, taxol, carzelesin). BREAST CANCER Chairman: JA van Dongen: til! August , EJTh Rutgersfrom September Cel1ular proliferation parameters during initial breast cancer treatment as predictors of clinical response. A case con trol study of risk factors for breast cancer. Breast conserving therapy. Optimizing boost dose and boost technique in breast conserving therapies. Intensive chemotherapy with peripheral stem cell support in breast cancer. Visualization of regional metastatic path~ays in breast cancer, using lymphoscintigraphy. Treatment choice and survival in elderly breast cancer patients. Quality control studies (radiotherapy aspects in breast conserving therapy: axillary clearance). Feasability study of immediate iridium implant technique in breast conserving therapy. Angiosarcoma af ter breast conserving therapy. Participation in trials designed for primary breast cancer patients. Bilateral breast cancer. Division X Division X Division X Division X Division X Division X Division X Division VI Division XII Division IX, XI Division IX DivisionX Division XI Division XII Division IX, XI Division IX, XI Division XI Division X, XI Division XII

17 18 Clinical Working Parties Breast conserving therapy in T3 breast cancer. Treatment results in clinically operabie apex node biopsie positive breast cancer. Prevalance and screening of psychiatric disorder and psychological distress among primary breast cancer patients. Characterization of DCIS. Risk factor for local recurrence after breast conserving therapy. Profyt study: a Dutch study of chemoprevention of breast cancer in woman at risk; tamoxifen versus placebo. Life-style and metabolic- endocrine risk factors in breast cancer. Mechanism of hormonal treatment of advanced breast cancer with aromatase inhibitor and / or hydrocortisone. Prevention of accelerated bone loss after premature menopause due to adjuvant chemotherapy. Division XI, IX Division IX, XI Division XII Division XI Division IX, XI Division X, XI Division X Division X Division X GASTROINTESTINAL TUMORS Chairman: FAN Zoetmulder HD rate intraluminal radiotherapy in esophageal cancer. Survival af ter resection of liver metastasis. Unlabeled MIBG in the treatment of carcinoid syndrome. Adjuvant 5FU Ilevamisole in completely resected colorectal carcinoma. Chemotherapy in gastric and colorectal cancer. SehCA T tests in patients with small bowel damage due to irradiation. Tumor markers in gastric cancer. Surgical intervention for radiation damage of the small bowel. Sphincter saving surgery for locally recurrent anal carcinoma af ter radiotherapy. GYNECOLOGICAL TUMORS Chairman: ThlM Helmerhorst HPV in follow up of patients with abnormal cervical smears. Female lower genital intraepithelial neoplasia: - Clinical significance of ECC as part of colposcopic evaluation. - Comparing two methods of cervical smear sampling. - Quantification of colposcopy. Hormones in epithelial ovarian cancer. Radioimmunotargeting in ovarian carcinoma. Chemotherapy in ovarian cancer. Prognostic factors in cervical carcinoma FIGO stage IB and HA. Intraperitoneal photodynamic therapy. HEAD AND NECK TUMORS Chairman: AlM Balm Voice rehabilitation af ter totallaryngectomy with the Provox voice prosthesis. The influence of the heat and moisture exchanger on lung complaints in laryngectomy patients. Division IX Division XI Division X Division XI Division X Division X Division X Division XI Division XI Division XI Division XI Division XI Division X, XI Division XI Division X, XI Division XI Division VIII, XI Division XI Division XII

18 Clinical Working Parties 19 The development of new reconstructive techniques in head and neck surgery. Radionuclide serial monitoring of salivary gland function after radiotherapy in head and neck cancer. Ploidy measurements in squamous cell carcinomas of the he ad and neck. Tumor detection with MoAbs l75f4/ Fll in patients with head and neck squamous cell carcinomas. Cytokeratin expression in tissues of the head and neck. N-Acetylcysteine, DNA damage and micronuclei in smokers. A retrospective analysis of treatment resuits in oropharyngeal carcinoma. Identification and cloning oftwo new chromosome llq13 proto-oncogenes, involved in human breast cancer and squamous cell carcinomas of the head and neck. Division XI Division X Division XI Division VI Division VI Division II Division XI Division VI IMMUNOTHERAPY Chairman: EM Rankin The use of monoclonal antibodies for tumor localization using gamma camera imaging or immunoguided surgery. Recombinant interleukin 2 (ril-2) as a continuous long-term infusion in melanoma and renal cell cancel Monoclonal anti body therapy in combination with recombinant IL-2. Techniques to enhance presentation of melanoma antigens to T -cell system. A phase I study of recombinant interleukin-l beta in patients with solid tumors. A randomized phase II study of the tumor necrosis factor, melphalan, hyperthermia + interferon gamma in isolated limb perfusion in patients with melanoma. Division XI Division X Division X, VI Division IV Division X Division XI, X LUNG CANCER GROUP Chairman: N van Zandwijk Photodynamic therapy in the lab and clinic. Prognostic factors - oncogenes - in lung cancel Intrabronchial brachytherapy. In vivo/ vitro application of monoclonal antibodies in (N)SCLC. Euroscan, a European study on chemoprevention with vitamin A and N-acetylcysteïne. Radiotherapy + Cisplatinum as a radiosensitizer in locoregional NSCLC. Radioprotection with N-acetylcysteïne in lung and mammary carcinoma and Hodgkin's disease. MALIGNANT LYMPHOMA Chairman: EM Rankin Extensive retrospective and prospective research into the development of second tumors. New techniques for the prediction of radiation damage to normal tissues. Immunotherapy in non-hodgkin lymphoma: anti-cd19 and recombinant IL2. Ph ase I-II study of the Campath-1H monoclonal antibody in patients with non-hodgkin lymphoma. Intensive chemotherapy with autologous bone marrow transplantation in intermediate and high grade lymphoma. The significance of circulating bcl-2 positive cells in non-hodgkin lymphoma. Division VIII, X Division VIII, X Division X Division VI, X Division X Division IX Division X Division XII Division X Division X, IV DivisionX Division X Division X, VI

19 20 Clinical Working Parties MELANOMA Chairman: BBR Kroon EORTC / WHO 15: A randomized trial on prophylactic isolation perfusion for stage I high risk ( > 1.5 mm thickness), malignant melanoma of the limbs. Isolation perfusion with TNFa, Melphalan + gamma IFN in irresectable metastatic melanoma of the limbs. WHO 16: Evaluation of efficacy of adjuvant rifna-2a treatment in cutaneous melanoma patients with regionallymph node metastases after radical surgery. EORTC A randomized trial on elective lymph node dissection in stage I melanoma (Breslow thickness 1,5-4mm) of the head and neck. Analysis of 499 regional isolation perfusions performed from in the Dr Daniel den Hoed Cancer Center (Rotterdam) and the Netherlands Cancer Institute. Sequential combination of hyperthermia and Melphalan in regional isolation perfusion. The application of whole blood in regional isolation perfusion; monitoring tissue perfusion by per-operative transcutaneous oxygen tension measurement. Tumor-imaging and gamma-detection with the help of probe assisted surgery of in vivo labeled melanoma tissue with the monocjonal anti body S (Teknemab, Sorin). Stage IV melanoma: Phase I study of recombinant interleukin 2 (ril-2). High dose Tamoxifen + DTIC, BCNU and Cisplatin in stage IV melanoma patients. The application of DNCB in patients with skin metastases. IBZM-((S)-2hydroxy-3iodo-6methoxy-N-[1-ethyl-2-pyrrolidinyl-methyl]-benzamide)-imaging in disseminated patients. Division XI Division XI Division X, XI Division XI Division XI Division XI Division XI Division XI Division X Division X Division X Division X NEURO-ONCOLOGY Chairman: W Boogerd Thallium and HMPAO Speet scanning in brain tumors. Treatment of meningeal carcinomatosis in breast cancer. Prospective comparative studies on the efficacy of systemic chemotherapy (CMF) versus R Tin brain metastases form breast cancer. Radiotherapy in brain metastasis. Division X Division X Division X, XI Division X, XI SOFT TISSUE TUMORS AND ORTHOPEDIC ONCOLOGY Chairman: F van Coevorden The combined surgical and radiotherapeutic management of soft tissue usarcomas. Neoadjuvant chemotherapy in soft tissue sarcomas. Chemotherapy in advanced soft tissue sarcomas. Chemotherapy in bone sarcomas. UROLOGICAL TUMORS Chairman: S HorenbIas Treatment results of squamous cell carcinoma of the penis, a retrospective study. Treatment results of interstitial radiation therapy localized prostatie carcinoma ( implantation), a prospective study. Treatment results of interstitial radiation therapy of small solitary bladder carcinoma, a prospective study. Division XI Division X Division X Division X Division XI Division XI Division XI

20 Clinical Working Parties 21 IUDR study of kinetics in bladder carcinoma. Wait and see in non-seminoma testicular carcinoma stage I, a prospective study. The role of surgery after chemotherapy in disseminated non-seminoma testicular cancer, a retrospective and prospective study. The results of treatment with Suramine in hormonal escaped prostatie carcinoma, a phase II study. The role of InterIeukin-2 in disseminated renal cell carcinoma, a phase II study. The role of HPV in penile carcinoma. Urinary reconstruction af ter cystectomy. Division IX Division XI Division XI Division X Division X Division XI Division XI