Annals of Oncology: Official Journal of the European Society for Medical Oncology

218 Pages·1991·10.643 MB·English

by  Brian L. Samuels, John E. Ultmann (auth.), John E. Ultmann, Brian L. Samuels (eds.)

Direct sequence analysis of 14q+ and 18q. chromosome junctions at the MBA and MCR revealing clustering within the MBA
in follicular lymphoma
F. E. Cotter, C. Price, J. Meerabux, E. Zucca & B. D. Young 93
The significance of B-clonal excess in peripheral blood in patients with non-Hodgkin's lymphoma in remission
A. Johnson, E. Caval/in-Stahl & M. Akerman 99
Expression of myelomonocytic antigens is associated with unfavourable clinicoprognostic factors in B-cell chronic lymphocytic
leukaemia
A. Pinto, L. Del Vecchio, A. Carbone, M. Roncadin, R. Volpe, D. Serraino, S. Monfardini, A. Colombatti & V. Zagonel 107
Follicular lymphoma: A model of lymphoid tumor progression in man
A. D. Zelenetz, M. J. Campbell, D. W. Bahler, S. Takahashi, R. Oren, L. Esserman, D. T. Umetsu, L. W. Kwak, D. G. Maloney,
S. Brown, T. T. Chen, M. L. Andria, S. Levy, R. A. Miller & R. Levy 115
Follicular lymphomas: Assessment of prognostic factors in 127 patients followed for 1 0 years
Y. Bastion, F. Berger, P.-A. Bryon, P. Felman, M. Ffrench & B. Coiffier 123
The management of follicular lymphoma
T. A. Lister 131
Stage I-ll low-grade lymphomas: A prospective trial of combination chemotherapy and radiotherapy
P. McLaughlin, L. Fuller, J. Redman, F. Hagemeister, E. Durr, P. Allen, L. Holmes, W. Velasquez, F. Swan & F. Cabanillas 137
lnterferon-a2b in the treatment of follicular lymphoma: Preliminary results of a trial in progress
C. G. A. Price, A. Z. S. Rohatiner, W. Steward, D. Deakin, N. Bailey, A. Norton, G. Blackledge, D. Crowther & T. A. Lister 141
Myeloablative therapy with autologous bone marrow transplantation as consolidation of remission in patients with follicular
lymphoma
A. Z. S. Rohatiner, C. G. A. Price, S. Arnott, A. Norton, M. L. Evans, F. Cotter, E. Dorey, C. L. Davis, P. Clark, J. Sterlini, J. Lim,
M. Horton & T. A. Lister 147
Expression of growth-related genes and drug-resistance genes in HTLV-1-positive and HTLV-1-negative post-thymic T-cell
malignancies
1.-J. Su, I.-C. Chang & A.-L. Cheng 151
Peripheral T-celllymphoma in Japan: Recent progress
M. Shimoyama 157
Peripheral T-celllymphomas
H. Stein, D. Dienemann, F. Dal/enbach & M. Kruschwitz 163
The present status of therapy for patients with aggressive non-Hodgkin's lymphoma
J. M. Vose & J. 0. Armitage 171
Prospective multicenter trial for the response-adapted treatment of high-grade malignant non-Hodgkin's lymphomas:
Updated results of the COP-BLAMIIMVP-16 protocol with randomized adjuvant radiotherapy
M. Engelhard, P. Meusers, G. Brittinger, N. Brack, W. Dornoff, W. Enne, W. Gassmann, H. Gerhartz, M. Hallek, J. Heise,
W. Hettchen, D. Huhn, K. Kabelitz, R. Kuse, E. Lengfelder, F. Ludwig, I. Meuthen, H. Radtke, C. Schadeck, C. SchOber,
E. Schumacher, W. Siegert, H.-J. Staiger, E. Terhardt, E. Thiel, M. Thomas, T. Wagner, M. G. Willems, W. Wilmanns, T.
Zwingers, H. Stein, M. Tiemann & K. Lennert 177
Autologous bone marrow transplantation for advanced stage adult lymphoblastic lymphoma in first complete remission
G. Santini, P. Coser, T. Chisesi, A. Porcellini, R. Sertoli, A. Contu, 0. Vinante, A. M. Congiu, A. M. Carella, T. D'Amico,
D. Pierluigi, E. Rossi, D. Scarpati & V. Rizzoli 181
Radioimmunotherapy of B-celllymphoma
J. F. Eary 187
The occurrence of opportunistic non-Hodgkin's lymphomas in the setting of infection with the human immunodeficiency virus
J. M. Pluda, R. Yarchoan & S. Broder 191
Hodgkin's disease in 63 intravenous drug users infected with human immunodeficiency virus
S. Monfardini, U. Tirel/i, E. Vaccher, R. Foa & F. Gavosto 201
Workshop on growth factors
D. Crowther, M. B. Sporn, A. B. Roberts & B. G. M. Durie 207
Report of the first workshop on prognostic factors in large-cell lymphomas
B. Coiffier, M. A. Shipp, F. Cabanillas, D. Crowther, J. 0. Armitage & G. P. Cane/los 213
Workshop on pediatric lymphomas: Current results and prospects
S. B. Murphy & I. T. Magrath 219
Conference program 225
Subject index 229
Editor-in-Chief: F. Cavalli (Bellinzona)
Associate Editor: H. M. Pinedo (Amsterdam)
Editorial Office: Annals of Oncology. Vi:;t Soldino 22, CH-6903 Lugano, Switzerland
Editorial Board G. Klein. Stockholm. Sweden M. F. Rajewsky. Essen, Germany
G. Bonadonna, Milan, Italy B. Leyland-Jones. Montreal, Canada S. Seeber, Essen, Germany
J. C. Cerottini, Epalinges, Switzerland J. G. McVie. London. UK K. Sikora. London, UK
H. Cortes-Funes. Madrid, Spain R. Mertelsmann, Freiburg, Germany J. F. Smyth, Edinburgh, UK
D. Crowther. Manchester, UK S. Monfardini, Aviano, Italy S. Tanneberger, Bologna, Italy
H. H. Hansen, Copenhagen, Denmark F. M. Muggia. Los Angeles, USA E. van der Schueren; Leuven, Belgium
C. Jasmin, Villejuif. France M. Ogawa, Tokyo, Japan R. Zittoun, Paris, France
Editorial Staff' and Consultants R. Gelber, Boston, USA U. Metzger, Zurich, Switzerland
(Editorial Committee) C. Hurny. Bern, Switzerland A. Pedrazzini. Bellinzona, Switzerland
A. Goldhirsch. Lugano, Switzerland R. Joss, Luzern. Switzerland A. Santoro, Milan. Italy
(Coordinator) S. Leyvraz, Lausanne. Switzerland C. Sessa, Bellinzona, Switzerland
J. Bernier. Bellinzona, Switzerland R. Malinverni. Bern. Switzerland P. Yalagussa. Milan, Italy
M. D'lncalci, Milan, Italy A. Mantovani, Milan. Italy
Annals of Oncology is covered in Current Colltents!Ciinical Medicine®, Science Citation Index®, Index Medicus!MEDLINE!MEDLARS, E.rcerpta Medica (Emhase)
Fourth International Conference on Malignant Lymphoma
June 6-9, 1990 - Lugano, Switzerland
Selected Papers
Guest editors:
John E. Ultmann & Brian L. Samuels
Section ofH ematology/Oncology, Department ofM edicine,
The University of Chicago Cancer Research Center, Chicago, Illinois, USA
Organizing Committee:
F. Cavalli, Bellinzona
G. Bonadonna, Milan
T.A. Lister, London
M. Rozencweig, Wallingford
J.E. Ultmann, Chicago
R. Zittoun, Paris
Advisory Board:
C.W. Berard, Memphis
S.B. Murphy, Chicago
H. Rappaport, Duarte
S.A. Rosenberg, Stanford
R.C. Young, Philadelphia
Technical Editor:
Joan A. David
This Supplement was published with the financial contribution of
the Organizing Committee, Mr E. Camponovo (Chiasso, Switzerland) and
an educational grant provided by the Govemment of Canton Ticino (Switzerland).
ISBN 978-1-4899-7294-1 ISBN 978-1-4899-7305-4 (eBook)
DOI 10.1007/978-1-4899-7305-4
Editor-in-Chief: F. Cavalli (Bellinzona)
Associate Editor: H.M. Pinedo (Amsterdam)
Editorial Oftice: Annals ofOncology, Via Soldino 22, CH 6903 Lugano, Switzerland
Editorial Board
G. Bonadonna, Milan, Italy B. Leyland-Jones, Montreal, Canada S. Seeber, Leverkusen, Germany
J.C. Cerottini, Epalinges, Switzerland J.G. McVie, London, UK K. Sikora, London, UK
H. Cortes-Funes, Madrid, Spain R. Mertelsmann, Freiburg, Germany J.F. Smyth, Edinburgh, UK
D. Crowther, Manchester, UK S. Monfardini, A viano, Italy S. Tanneberger, Bologna, Italy
H.H. Hansen, Copenhagen, Denmark F.M. Muggia, Los Angeles, USA E. Van der Schueren, Leuven, Belgiu
C. Jasmin, ViIIejuif, France M. Ogawa, Tokyo, Japan R. Zittoun, Paris, France m
G. Klein, Stockholm, Sweden M.F. Rajewsky, Essen, Germany
Editorial StaJf and COlIsultants
(Editorial Co mmittee)
A. Goldhirsch, Lugano, Switzerland C. Hlimy, Bem, Switzerland U. Metzger, Zlirich, Switzerland
(Coordinator) R. Joss, Luzern, Switzerland A. Pedrazzini, Bellinzona, Switzerland
J. Bemier, Bellinzona, Switzerland S. Leyvraz, Lausanne, Switzerland A. Santoro, Milan, Italy
M. D'Incalci, Milan, ltaly R. Malinverni, Bem, Switzerland C. Sessa, Bellinzona, Switzerland
R. Gelber, Boston, USA A. Mantovani, Milan, Italy P. Valagussa, Milan,ltaly
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Originally published by Kluwer Academic Publishers in 1991
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Allllais of Ollcology is covered in Curmlt ContentslClinical Medicille®, Science Citation Index®, Index MedicuslMEDLlNEIMEDLARS and
Excerpta Medica (Embase).
Contents
List of contributors v
An overview
B. L. Samuels & J. E. Ultmann 1
Original articles
Molecular biology of lymphoid malignancies
J. Kagan & C. M. Croce 9
An epidemiologist's view of the new molecular biology findings in Hodgkin's disease
N. Mueller 23
The continuing challenge of Hodgkin's disease
S. A. Rosenberg 29
The nature of Hodgkin and Reed-Sternberg cells, their association with EBV, and their relationship to anaplastic
large-cell lymphoma
H. Stein, H. Herbst, I. Anagnostopoulos, G. Niedobitek, F. Dallenbach & H.-C. Kratzsch 33
Quantitative magnetic resonance studies of lumbar vertebral marrow in patients with refractory or relapsed
Hodgkin's disease
S. R. Smith, C. E. Williams, R. H. T. Edwards & J. M. Davies 39
Low serum interleukin-2 receptor levels correlate with a good prognosis in patients with Hodgkin's lymphoma
A. Gause, V. Roschansky, A. Tschiersch, K. Smith, D. Hasenclever, R. Schmits, V. Diehl & M. Pfreundschuh 43
A randomised study of adjuvant MVPP chemotherapy after mantle radiotherapy in pathologically staged IA-IIB
Hodgkin's disease: 10 -year follow-up
H. Anderson, D. Crowther, D.P. Deakin, W. D. J. Ryder & J. A. Radford 49
Alternating versus hybrid MOPP-ABVD in Hodgkin's disease: The Milan experience
S. Viviani, G. Bonadonna, A. Santoro, M. Zanini, R. Zucali, E. Negretti & P. Valagussa 55
Management of relapse and survival in advanced stage Hodgkin's disease: The EORTC experience
J. M. V. Burgers, R. Somers, M. Henry-Amar, M. Tarayre, P. Carde, J. Thomas, A. Hagenbeek, M. Monconduit,
B. E. dePauw, W. P.M. Breed, L. Verdonck, M. Hayat & R. Zittoun 63
Autologous bone marrow transplantation for refractory or relapsed Hodgkin's disease: The Memorial Sloan
Kettering Cancer Center experience using high-dose chemotherapy with or without hyperfractionated accelerated
total lymphoid irradiation
J. Yahalom & S. Gulati 67
Cardiopulmonary toxicity after three courses of ABVD and mediastinal irradiation in favorable Hodgkin's disease
P. Brice, J. Tredaniel, J. J. Monsuez, J. P. Marolleau, C. Ferme, C. Hennequin, J. Frija, C. Gisselbrecht
& M. Boiron 73
Long-term toxicity of early stages of Hodgkin's disease therapy: The EORTC experience
J. M. Cosset, M. Henry-Amar & J. H. Meerwaldt 77
Non-Hodgkin's lymphoma arising in patients treated for Hodgkin's disease in the BNLI: A 20-year experience
M. H. Bennett, K. A. MacLennan, G. Vaughan Hudson & B. Vaughan Hudson 83
Direct sequence analysis of 14q+ and 18q-chromosome junctions at the MBR and MCR revealing clustering within
the MBR in follicular lymphoma
F. E. Cotter, C. Price, J. Meerabux, E. Zucca & B. D. Young 93
The significance of B-clonal excess in peripheral blood in patients with non-Hodgkin's lymphoma in remission
A. Johnson, E. Caval/in-Stahl & M. Akerman 99
Expression of myelomonocytic antigens is associated with unfavourable clinicoprognostic factors in B-cell chronic
lymphocytic leukaemia
A. Pinto, L. Del Vecchio, A. Carbone, M. Roncadin, R. Volpe, D. Serraino, S. Monfardini, A. Colombatti
& V.Zagonel 107
Follicular lymphoma: A model of lymphoid tumor progression in man
A. D. Zelenetz, M. J. Campbell, D. W. Bahler, S. Takahashi, R. Oren, L. Esserman, D. T. Umetsu, L. W. Kwak,
D. G. Maloney, S. Brown, T. T. Chen, M. L. Andria, S. Levy, R. A. Miller & R. Levy 115
Follicular lymphomas: Assessment of prognostic factors in 127 patients followed for I 0 years
Y. Bastion, F. Berger, P.-A. Bryon, P. Felman, M. Ffrench & B. Coiffier 123
Continued overleaf
Annals of Oncology, Supplement 2 to Volume 2: 1-7, 1991.
© 1991 K/uwer Academic Publishers.
An overview
The fourth international conference on malignant lymphoma
Brian L. Samuels & John E. Ultmann
Department of Medicine and Cancer Research Center, University of Chicago, Chicago, Illinois, USA
Introduction The nature of the Reed-Sternberg cell
The Fourth International Conference on Malignant The etiology of Hodgkin's disease and the nature of the
Lymphoma was held in Lugano, Switzerland, from Reed-Sternberg cell continue to fascinate investigators.
June 6th to June 9th, 1990.11 was attended by over 1100 Hodgkin's disease was virtually the first neoplasm to be
delegates from around the world. As at previous Con curable with combination chemotherapy, even in ad
ferences, a large number of invited papers, brief pre vanced cases. Paradoxically, a quarter century later, we
sentations, and posters were presented on a wide vari understand far less about the biology of Hodgkin's dis
ety of topics in the field of lymphoma research. A great ease than about many solid tumors, for which no effec
deal of excitement was generated by the advances pre tive therapy yet exists.
sented in the basic science sessions. Although steady Most evidence favors a lymphoid origin for Hodg
progress is being made in the therapy of lymphomas, kin's disease. Previously, immunologic and molecular
few major advances were reported in the clinical arena. evidence for both T and B cell lineage has been pub
In contrast, the application of the techniques of im lished, as well as data suggesting a macrophage origin
munology and molecular genetics has resulted in fas and an association with interdigitating reticulum cells.
cinating discoveries that are increasing our understand Data were presented at the Conference to indicate
ing of the fundamental nature of lymphoproliferative that the Epstein-Barr virus may be causally involved in
disorders. These discoveries may lead to innovative Hodgkin's disease. Although the association of
therapeutic strategies unlike any currently in use. Epstein-Barr virus and Hodgkin's disease has long
This introductory overview clearly cannot include been established, many have felt that Epstein-Barr
all of the work presented at the Conference. This virus infection was a consequence of the immune
volume is a collection of selected clinical papers with defect seen in patients with Hodgkin's disease. Stein
summaries of some of the workshops held during the presented data to demonstrate that Epstein-Barr virus
Conference. A few basic science papers have been in genome is incorporated into host DNA in 57% of
cluded with the relevant clinical material, rather than in Hodgkin's disease patients. In cases in which the loca
a separate basic science section. We will therefore at tion was determined, the Epstein-Barr virus DNA was
tempt to give an idea of the breadth of presentations, in the Reed-Sternberg cells, rather than the reactive
with emphasis on the basic science papers that have not lymphocytes. Moreover, the Epstein-Barr virus
been included. genome was clonal, suggesting that incorporation oc
At the Third International Conference in 1987, it curred before rather than after malignant transforma
was evident from the work presented that the field of tion.
lymphoma research was beginning to be caught up in Evidence was presented by Uccini to show that
the biological revolution. It became clear during the Epstein-Barr virus genome was present in 20% of the
Fourth Conference that major strides have now been malignant cells in AIDS-associated Hodgkin's disease.
made in understanding the biology of lymphoma. Much It is possible that an immune defect, leading to Epstein
of this work has been possible as a result of the ad Barr virus infection, might be involved in the initial
vances in technology that are an integral part of that in stages of neoplastic transformation in this situation.
tellectual revolution.
New information regarding the biology of lym
phoma was presented, mainly in the areas of etiology Relationship of Hodgkin's disease and non-Hodgkin's
and pathobiology. In addition, it was evident that more lymphoma
insight has been gained into the prognostic factors that
are of true importance in lymphomas. A striking finding was recently reported by Cossman
and colleagues and was discussed by Rosenberg at the
4
tact (the so-called 'juxtacrine' effect). Dexter also dis have been sufficient for practical prognostication; for
cussed the intriguing possibility of using growth inhibi non-Hodgkin's lymphoma there has been a plethora of
tors at the time of chemotherapy to protect marrow prognostic factors described over the years, possibly
stem cells by taking them temporarily out of cycle. because none are adequate. Most have been derived
There might even be a protective effect for other rapid from retrospective analysis of patients treated with a
ly cycling tissues, such as the oral and intestinal mu specific regimen. In this sense, they are statistical phe
cosa. nomena only, and possibly of relevance only to that
Sporn discussed the role of negative regulation of particular patient group. A truly relevant prognostic
growth by factors such as transforming growth factor-B factor should be relatively independent of the exact
(TGF-B). TGF-B controls the growth and differentia regimen used, otherwise it will be of little use to the
tion of immune effector cells and the growth and proli practicing clinician. With increasingly detailed knowl
feration of target cells. It functions as a suppressor of edge of the biology of lymphoma, it is to be expected
proliferation, particularly in lymphocytes and epithelial that more fundamental and important prognostic indi
cells. Almost all normal cells have TGF-B receptors. cators will thereby be identified.
Transformed lymphocytes have been shown to have A workshop on prognostic factors in large cell lym
lost their TGF-B receptors and thus are released from phoma was held prior to the Conference and was
the negative control of this factor. This may lead to un reported by Canellos. It was agreed that a new staging
controlled proliferation of these cells. Use of differen system is required, since the Ann Arbor system is unsa
tiating agents such as retinoids or phorbol esters which tisfactory for non-Hodgkin's lymphoma. In essence,
up-regulate expression of TGF-B receptors, may have a stage, measured tumor bulk, lactate dehydrogenase
role in treating a large variety of neoplasms, including level, and possibly B-2 microglobulin, were the critical
lymphoproliferative disorders. High concentrations of determinants identified. All are clearly indirect evalua
such agents may even stimulate transformed cells to tions of total tumor burden. It is clear that a single, ac
secrete TGF-B itself, thus restoring an autocrine feed curate marker of tumor burden is required. A start has
back. been made towards determining the utility of prognos
The characterization of the hematopoietic growth tic factors generated by analysis of one lymphoma
factors and the cloning of their genes represent a major database in predicting outcome of patients in a dif
theoretical and clinical advance. A number of clinical ferent database. It was agreed that this should be con
studies using various growth factors in an attempt to tinued and that in particular, the databases of the
ameliorate myelosuppression from chemotherapy were French GELA group Study Group for Aggressive Lym
presented at the Conference. Molecular genetic anal phomas, the Dana Farber Cancer Institute, and the
yses show that many growth factor genes and growth M.D. Anderson Hospital should be evaluated in this
factor receptor genes are found at loci that are signifi fashion. Data presented by Crowther and by Felman
cant for translocations and deletions. suggested that measurement of the proliferative activity
The pace of discovery is accelerating. New factors of the tumor did not offer additional prognostic infor
continue to be described almost monthly. The increas mation. However, during the Conference, Armitage re
ing number of available factors and their myriad inter ported a study in which proliferative activity was highly
actions on each other, on hematopoiesis, and on many correlated with survival. The relevance of proliferative
nonhematopoietic organs and physiologic functions are activity clearly will require further study. It was felt that
a potential morass. There is a danger of squandering the prognostic importance of patient age may currently
time and resources in trying every permutation of be underestimated because many aggressive chemo
growth factor and chemotherapeutic agent. Intensive therapy protocols have routinely excluded elderly pa
research is now under way to try to determine the most tients. The importance of adequate statistical analysis,
effective way to take advantage of the promise offered including multivariate analysis was stressed. It was
by these proteins. agreed that there are not yet sufficient data to allow for
It will be important that thoughtful and well de mulation of a new staging system. However, with inter
signed studies are carried out in order to do this. For group and interinstitutional cooperation, it is hoped
example, the use of specific factors in the appropriate that such data will become available in the future.
sequence may greatly enhance the resulting effect on
hematopoiesis. If this careful design phase is carried
out, it is likely that growth factor therapy will revolu Prognostic factors in Hodgkin's disease
tionize the way chemotherapy will be administered in
the 1990s. Patients with Hodgkin's disease have higher serum
levels of circulating interleukin-2 receptor (CD25) than
normal subjects. From data presented by Pfreund
Relevance of prognostic factors schuh, the degree of elevation appears to correlate with
clinical stage, outcome of initial therapy, and prognosis
Whereas for Hodgkin's disease, four clinical stages for relapse. In addition, soluble CD30 antigen in the
(each with two substages) and four histologic subtypes, serum of Hodgkin's patients appears to indicate a lower
5
complete response rate and a higher relapse rate. It is therapeutic regimen. As DeVita discussed, this aspect
not yet clear whether such immunologic prognostic of the theory has not been proven in an adequate, pros
parameters are regimen independent and whether they pective fashion. Unfortunately, such tests may be very
provide independent prognostic information. hard to carry out. DeVita also discussed the concept of
dose intensity as contrasted with total dose adminis
tered. In curable malignancies such as lymphoma, out
Prognostic factors in non-Hodgkin's lymphoma come analysis suggests that total dose may influence
median survival, but the cure rate is more dependent
Markers that may be of biological significance for prog on dose intensity. There are many potential mechan
nosis in non-Hodgkin's lymphoma were discussed by isms for clinical resistance to chemotherapy. Strategies
several investigators. They included immunological to overcome this resistance must be developed. Several
markers, molecular genetic markers, and cytogenetic were discussed by DeVita, including attention to dose
markers. intensity and scheduling and pharmacologic modula
The list of nonrandom cytogenetic abnormalities as tion of multidrug resistance. Future chemotherapy regi
sociated with non-Hodgkin's lymphoma continues to mens must be designed with these mechanisms and
grow. This list is considerably longer than the one that kinetics in mind.
was available at the time of the Third Conference in
1987. Schouten discussed the relevance of specific, re
current cytogenetic abnormalities as indicators of prog Clinical aspects of Hodgkin's disease
nosis. In addition, the concept of cytogenetic progres
sion (or its equivalent molecular genetic change) as a Rosenberg gave his perspective as to where staging and
predictor of later histologic progression was discussed. therapy for Hodgkin's disease are heading. He stressed
the importance of patient age as a prognostic variable
as well as the continuing role of lymphangiography and
Clonal excess as a prognostic factor the evolving role of MRI in staging. In a disorder in
which 83% of all patients survive 16 years or more,
Some reputed prognostic factors may not stand the test toxicity of therapy is becoming an increasingly impor
of time. The clonal excess technique attempting to pre tant parameter. Short-term toxicity may be addressed
dict relapse was reported at the last conference. At by modifying treatment programs commensurately
least one report at the meeting suggested that there may with risk level. In this regard, Ann Arbor stage and
be no prospective predictive ability for this test. Future histologic subtype seem to be less important than pa
studies may resolve the question, using increasingly tient age and tumor bulk. The reduction of therapy for
sensitive detection techniques. good-risk cases and the early application of intensive
therapy for poor-risk patients would be the goals of
such an approach. The concept of tailoring treatment to
Biology of lymphomas - Summary the patient's status would be enhanced by a better
understanding of the biology and genetics of Hodgkin's
Progress has been exciting in basic science research in disease. If this could be achieved, distinct subsets de
the lymphoma field. This bodes well for the future of fined by immunologic or molecular genetic techniques
clinical as well as basic science. At present, there are could be singled out for specific therapeutic ap
not many significant clinical advances being reported in proaches.
either Hodgkin's disease or non-Hodgkin's lymphoma, One of the problems that continue to plague clini
but this situation is likely to change as new understand cians dealing with a curable neoplasm in largely young
ing of biology suggests new and possibly radically dif patients is that of the long-term toxicities of therapy.
ferent approaches to therapy. These are now well known, as confirmed by Cosset in
reporting the overall EORTC (European Organization
for Treatment and Research of Cancer) experience in
Influence of drug resistance on protocol design over 1650 patients. Late gastrointestinal, pulmonary,
and cardiac complications and secondary malignancies
DeV ita delivered a thoughtful discussion of the ways in are among the prominent toxicities described. One
which protocol design should be manipulated to take response to this problem is to attempt to minimize
account of knowledge of drug resistance mechanisms. therapy in good prognostic subgroups. This may be
In the Henry Kaplan Memorial Lecture, he explored achieved by using reduced amounts of both chemo
what is known about drug resistance and the kinetics of therapy and radiation. For example, regimens were
resistance development. In particular, the Goldie described by Anderson and by Brice that utilized short
Coldman hypothesis predicts a relationship between courses of chemotherapy in addition to radiation for
tumor size and likelihood of resistance developing by early stage Hodgkin's disease. A cautionary note was
somatic mutation. The prediction from this would be sounded in the Pediatric Lymphoma session however.
that all effective drugs should be used in the initial The omission of procarbazine from a regimen resulted
6
in a major decrease in efficacy in a German Coopera high grade lymphomas. The controversy over whether
tive study. more is better rages on. The data reviewed by Armitage
The question of the optimal initial therapy continues suggest that dose intensity and schedule are important,
to cause debate. The CALGB (Cancer and Leukemia rather than number of drugs in a regimen. This implies
Group B) data from a large randomized trial reported that CHOP administered in full dose, on time, may be
the superiority of ABVD over MOPP in a North as good as a third generation regimen.
American population, but failed to show an additional The matter is far from settled, however. The EORTC
advantage to alternating MOPP with ABVD. However, data presented here suggested that, all other factors
both the alternating regimen and the combination being equal, a more aggressive regimen gives better
MOPP-ABV 'hybrid' regimen gave more striking results. The SWOG (South West Oncology Group)
results in Milan, approaching a 90% complete response data suggest that there may be no difference in out
rate in advanced disease. come between the various third generation regimens.
Analysis of dose intensity will be essential in any future
attempts to compare the efficacy of treatment regi
Relapsed/refractory Hodgkin's disease mens.
The problem of relapsed disease continues to be a
vexing one, given the generally poor prognosis when Autologous bone marrow reinfusion
this occurs. One approach is to improve the results of
initial therapy so as to reduce the number of relapses. Philip discussed the therapy of relapsed lymphoma,
In the EORTC experience reported here, as well as the stressing that aggressive therapy may be necessary.
experience of many other groups, many relapses occur However, he noted that at this time the interim data
at the site of original disease. It was suggested that from the PARMA randomized trial show no difference
adding involved field radiation to chemotherapy might in outcome between aggressive conventional chemo
reduce the relapse rate. The role of salvage radiation in therapy and high dose therapy with autologous bone
relapsed disease of limited extent was also discussed. marrow rescue.
The duration of remission before relapse continues to For patients with relapsed lymphoma, the situation
have prognostic importance. Canellos reported that the is relatively straightforward, in that action is imme
EVA (etoposide, vinblastine, Adriamycin) regimen was diately required. Should high risk patients have aggres
equivalent to the ABVD regimen in salvaging patients sive consolidation therapy in first remission, without
who had failed MOPP therapy. Several reports were waiting for relapse to occur? An example would be the
also given relating to developments in the field of high use of high dose chemotherapy for patients with lym
dose chemotherapy with autologous bone marrow res phoblastic lymphoma in remission, as reported by
cue for relapsed Hodgkin's disease. This approach is Santini.
becoming safer and more appropriately utilized among High-risk B-cell malignancies may also benefit from
specific subgroups of patients most likely to benefit. the approach of transplantation in the first remission,
as was discussed by Freedman.
The place of autologous bone marrow rescue in the
Hodgkin's disease - Challenges for the 1990s therapy of follicular lymphomas continues to be con
troversial, as was discussed by Lister and by Rohatiner.
We have seen that the biology of Hodgkin's disease re Evidence is now emerging to suggest that patients with
mains mysterious. If enough effort is directed towards follicular lymphoma who relapse after therapy have a
elucidating the pathologic processes which cause relatively poor prognosis. In this situation, the role of
Hodgkin's disease, further improvements in therapy high-dose chemotherapy with or without bone marrow
will follow almost automatically. This should also allow rescue, is probably to consolidate gains made with
more definitive description of biologically significant more conventional therapy and attempt to secure more
prognostic factors. With this, allocation to therapy durable subsequent remissions. Again, it was suggested
groups should be more precise, enabling many young that transplantation in first remission may be advan
people to escape the potential complications of chemo tageous, if a reliable way to determine risk of second
therapy. relapse could be determined, so that unnecessary treat
ment could be avoided.
Therapy of aggressive lymphomas
Growth factors
Armitage defined four subgroups of patients with ag
gressive lymphomas which should be the subjects of The preclinical promise of growth factor therapy as a
particular research interest in the near future. These are means of reducing myelosuppression is starting to be
patients with localized disease, elderly patients, come reality. Phase I and II trials with four growth fac
patients with HIV-related lymphoma, and patients with tors: granulocyte colony stimulating factor (G-CSF),
7
granulocyte-macrophage colony stimulating factor Speculations
(GM-CSF), multi-colony stimulating factor (M-CSF),
and interleukin-3, have been carried out. Three other What topics will be discussed at the Fifth International
agents - interleukin-1, interleukin-4, and interleukin-6 Conference in 1993? There are several possibilities for
- are still in initial trials. Good randomized studies translating the recent basic science advances into clini
have not as yet been done. The conclusion reached cal strategies:
from these early trials is that there appears to be some As knowledge of lymphoma biology increases, it
benefit in terms of the rate of recovery from neutro should become possible to tailor therapy more to
penia and depth of the nadir count when growth factors specific prognostic groups. Thus excessive toxicity may
are used after conventional chemotherapy drugs. In be avoided in patients likely to be cured anyway and
some series, the time to first appearance of myeloid high risk patients may be given more intensive therapy
cells was not changed, suggesting that the agent was not from the start.
acting on the very earliest precursors, but on later, With increasing evidence of viral involvement in the
more committed progenitor cells. etiology of some lymphomas, the use of antiviral thera
py and of molecular strategies to reverse the viral lesion
may become feasible. Reversing the malignant pheno
Non-Hodgkin's lymphoma- Challenges for the 1990s type in such a fashion is now within sight, using, for
example, antisense oligonucleotides to tum off over
Identification of biologically significant prognostic sub expressed oncogenes.
groups is a major challenge, as was recognized at this Alternatively, where tumor suppressor genes are de
conference. With new understanding of the biology of leted, it may become possible to replace the missing
follicular lymphoma, new approaches to therapy are gene product, much as insulin is replaced today. If such
now possible. The matter of CHOP versus the new suppressor genes are demonstrated to be implicated in
comers may take years to resolve, as the data from the pathogenesis of lymphoma, the therapy of lym
randomized studies mature. In the interim, a logical ap phoma may change radically within a very few years.
proach, based on the available data, may be indicated.
Similarly, a great deal of thought and planning now will Correspondence to:
save many blind alleys and false negative results when Brian L. Samuels
Department of Medicine and Cancer Research Center
clinical results of trials involving chemotherapy and
University of Chicago
growth factors are analyzed.
Chicago, Illinois, USA