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G.MATHE Institut de Cancerologie et d'Immunogenetique (INSERM et
Association Claude-Bernad), H6pital Paul-Brousse and Institute
Gustave-Roussy, Villejuif 20 years ago, the main, if not only
object of the cancer therapist was to effect complete surgical
exeresis or radiotherapeutic destruction of a local tumor, or to
obtain, by means of chemotherapy, an "apparently complete
regression" of a local or disseminated neoplasia. Today it is
realized that (a) at the time of the operation or radiotherapy, two
patients in every three carrying an apparently localized tumor have
a few cancer cells outside the area where the tumor seems
localized; (b) when "apparently complete regression" or even an
"apparently complete remission" is induced by chemotherapy, not all
the neoplastic cells have been eradicated. In both cases an
imperceptible residual neoplasm persists, the growth of which will
in due course make it perceptible again, giving rise to metastasis
or to a systemic or localized relapse. There is thus an urgent need
for a new technique capable of killing the last cell or cells. Our
experiments in mice on the effectiveness of active immunotherapy,
which involves the manipulation of the immune machinery, have shown
that this treatment is able to kill all the cells, down to the very
last cell of a given leukemia, provided that the total number of
cells does not exceed a few thousand [1, 2].
A prospective randomized clinical trial of treatment with
vincristine, cyclophosphamide, methotrexate and 5-fluorouracil
after conventional curative treatment for stage II breast cancer is
described. The results at 2 years are recorded together with
details of toxicity. Future plans are discussed briefly.
Acknowledgement We wish to acknowledge the participation of all the
collaborators in this study, the co-ordinator Dr. ERICA MANSBACHER
and the support of Action Cancer in Belfast. References 1. Ahmann,
D. L. , O'Connell, M. J. , Hahn, R. G. , Bisel, H. F. , Lee, R. A.
, Edmonson, J. H. : An evaluation of early or delayed adjuvant
chemotherapy in premenopause1 patients with advanced breast cancer
undergoing oophorectomy. New Engl. J. Med. 297, 356-360 (1977) 2.
Ahmann, D. L. , Scanlon, P. W. , Bisel, H. F. , Edmonson, J. H. ,
Frytak, S. , Payne, W. S. , O'Fallon, J. R. , Hahn, R. J. , Ingle,
J. N. , O'Connell, M. J. , Rubin, J. : Repeated adjuvant
chemotherapy with Phenyl-alanine mustard, or 5-Fluorouracil,
Cyclophosphamide and Prednisone with or without radiation after
mastectomy for breast cancer. Lancet 1978//, 893-896 3. Bonadonna,
G. , Rossi, A. , Valagussa, P. , Banfi, A. , Veronesi, U. : The CMF
program for operable breast cancer with positive axillary nodes.
Cancer 39, 2904-2915 (1977) 4. Edelstyn, G. A. , Bates, T. S. ,
Brinkley, D. , Macrae, K. D. , Spittle, M. , Wheeler, T. :
Comparison of 5-day, I-day and 2-day cyclical combination
chemotherapy in advanced breast cancer.
Local treatment cures about 30 to 40% of cancers, this proportion
depending on the follow-up required to establish it. This means
that 60 to 70% of the malignant neoplasias are disseminated either
perceptibly (leukemias, visible metas- tases) or imperceptibly,
forming a 'minimal imperceptible disease', which local treatment
leaves, whether it consists of surgery, radiotherapy, or surgery
plus radiotherapy. When the neoplastic tissue is voluminous enough
to be per- ceptible, cures can be obtained with chemotherapy or
chemo- immunotherapy. When the neoplastic disease is imperceptible,
made up of micrometastases, it apparently can be cured by systemic
postsurgical chemotherapy, immunotherapy, or chemoimmunotherapy.
Hence there is the need for intensive development of these medical
therapies which are applied by the medical oncol- ogist and, at
present, consist of chemotherapy, immuno- therapy, or
chemoimmunotherapy. These medical thera- peutics can only grow with
scientific development, the main weapon of which is experimental
and clinical pharmacology. These volumes report the communications
presented at the 1979 EORTC Annual Plenary Session on Cancer Chemo-
and Immunopharmacology.
G. MATHE and R. K. OLDHAM' Institut de Cancerologie et d'Immunogem
tique, Hopital Paul Brousse, Villejuif Since the last war, cancer
chemotherapy has been the object of very intensive and expensive
research. Nevertheless, its development has been very slow, and its
ultimate potential is today somewhat in doubt. In doubt because it
does not cure any cancer patients except a) females carrying
placental choriocarcinoma, a semi-allogenic tumor, in which case,
cure may be in fluenced by immune rejection, and b) children
suffering from Burkitt's tumor, where the probable reason for the
cure is that all the neoplastic cells are in the cycle, which is a
unique condition among all the human tumor varieties. Whether the
long term survivors in acute leukemia, lymphomas, certain sarcomas
and certain testicular tumors are "cures" will require longer
follow-up. The idea that chemotherapy does not cure most cancer
patients because all their neoplastic cells are not in cycle has
led to the use of drug combinations. Whatever they are, "cocktail
combinations" which are made up of drugs given according to any
timing, or scientific combinations, based on pharmacodynamics,
pharmaco kinetics or cell kinetics data, are more toxic than single
drugs, and are all the more toxic as the number of drugs in the
combination is increased."
Scientific and Ethical Discipline in Clinical Trials on Acute
Leukemia G. MATHE Institut de Cancerologie ct d'Immunogenetique "',
Hi'ipital Paul-Brousse "."", Villejuif/France Clinical research is
still in an evolutionary stage. Although scientific technology was
readily accepted and applied, scientific methodology has been
accepted much more slowly and is very rarely properly applied.
There are three reasons why this is so. First, medical ethics
frequently limits the applicability of clinical research, for
doctors have to be more than scientists. They must also remain
moral philosophers, as they were before medicine became a science.
Second, the heterogeneity of the material on which clinical
researchers work in studying human diseases makes the application
of scientific methodology difficult. Third, researchers must
publish. This means that they must obtain publishable results, and
too often this means results in accordance with established
concepts, easily accepted by the editors of established journals,
which are read by the establishment. It is the privilege of too
many people to be able to accept "truth" and recipes from other
people and confirm their truth and results. It is the mission of a
very few others to accept nothing as "truth" and to consider no
recipe ideal, either in concept or detail.
The impressive advances in all branches of medical science during
the first half of this century with the discovery of many
chemotherapeutic or immunogenic agents gave rise to brilliant
achievements in the struggle against some infectious diseases and
aroused in many scientists the wishful thought that drugs for
cancer therapy would, soon lead to additional great success.
Notwithstanding ever-increasing worldwide endeavors, the major
problems in prevention or treatment of neoplastic diseases are
still unsolved. The approach to the resolution of these problems
follows many different pathways. Basic research tries to cast light
on the genetic and biochemical processes underly ing cell division
and differentiation as well as the interactions occurring between
the cell and the oncogenic stimulus, or between the neoplastic
cells and the different body systems endowed with immunological
reactivity. Another line of approach, coherent with the classic
basis of chemotherapy, relies upon the search for new compounds
selectively blocking the multiplication of the neoplastic cells.
The remarkable progress made in treating human cancer, as a result
of these efforts, has been until now ascribable chiefly to the
accomplishment of the chemo therapeutic approach. Studies on the
cytostatic activity of the anthracycline antibiotics carried out
over many years eventually led the investigators of Farmitalia
(Milan, Italy) to discover and characterize some new compounds
endowed with interesting chemotherapeutic properties against
malignant neoplastic diseases."
CNRS International Colloquium, Held in Paris on June 22-24, 1977
P. Denoix and G. Mathe Approximately 70% of cancer patients relapse
after surgery before the 5th year and, in most cases, for example
in breast carcinoma, they relapse still later up to the 20th year.
For some considerable time, the strategy of cancer treatment has
been limited to the sophistication of surgery-radiotherapy
combinations that maximally decreased the incidence of local and
regional relapses in sites that were within their reach. Today, the
practice of clinical oncology is unthinkable without the active
participation of the medical oncologist. He is the "third man" of
the clinical oncology team, and he has recently focused attention
on the fact that most relapses arise from distant metastases due to
the proliferation of cells seeded there after having left the
primary tumor site at the time of operation and, hence, are
inaccessible to any form oflocal and/or regional treatment. On this
evidence, medical oncologists have proposed the application of
medical treatments for disseminated minimal residual disease (MRD).
They have two available means: chemother apy and immunotherapy.
Medical oncologists in general can be divided into three groups:
chemotherapists, immunotherapists, and chemoimmunotherapists. The
pure chemotherapists, who had already cured some malignant
neoplasias such as Hodgkin's disease, acute lymphoid leukemia,
placental choriocarcinoma, and Wilms' tumor, thought they might
have the means of attacking the residual disease of common
cancers."
We have studied 24 cases of secondarily leukemic (stage V)
lymphosarcoma (LS), 31 cases of "d'emblee" leukemic LS, and ten
cases of lymphoid leukemic neoplasias transitional between
"d'emblee" leukemic LS and chronic lymphocytic leukemia (eLL).
These cases only concern the common types ofthe WHO classification
ofLS, i.e., the prolymphocytic, the lymphoblastic, and the
immunoblastic. Some cases have also been classified by cell surface
markers. The secondarily leukemic conversion occurred in 40% of the
lymphoblastic types, in 14% of the prolymphocytic types, and in 17%
of the immunoblastic types. It never occurred at stage I but could
occur after any other stage. The mediastinal involvement was
observed in three types, but most often in the lymphoblastic type.
The prognosis after an acute lymphoid leukemia (ALL) treatment
comprising active immunotherapy following chemo(radio)therapy is
better for the leukemic prolymphocytic and lymphoblastic LS than
for the immunoblastic type. Two patients (one of the lymphoblastic
type) are in complete remission after 8 and 5 years, respectively.
We have described ten cases of "d'emblee" leukemic LS with either
large lymphoid or extra lymphoid masses, bone marrow leukemic cell
involvement, and LS aspects of neoplastic cells. Mediastinal,
abdominal, or other tumor masses are frequent."
Fresh living Bacillus Calmette-Guerin (BeG), injected i.v. into
(C57BI/ 6xDBA/2)FI mice, activated peritoneal macrophages rendering
them highly cytotoxic for tumor cells in vitro. This cytotoxic
activity w s already maximal 14 days after injection of 1 mg of BCG
and remained stable when 3 or 5 mg of BCG were given. At the same
time spleen cells of the BCG-treat d mice showed strongly depressed
responses to the T-cell mitogens, PHA and Con A, irrespective of
the dose of BCG injected. The inhibitory effect was shown to be
mediated by suppressor cells which had characteristics of
macrophages since they could be removed by carbonyl iron and magnet
treatment and were adherent to plastic. In contrast to it was
observed after injec tion of 1 mg of BCG, these suppressor cells
alone did not account for the depression of T-cell re.sponses
induced by higher doses of BCG. Nylon-nonadherent cell populations
obtained from spleen cells treated with 3 or 5 mg BCG partially
retained the inhibitory activity suggesting that suppressor T cells
were also induced after injection of high doses of BCG. In
contrast, the responses to the B-cell mitogen LPS of unfractionated
and macrophage-depleted spleen cells were not affected or
significantly enhanced depending on the dose of BCG injected."
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